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CURRENT THERAPY IN NEUROLOGIC DISEASE Copyright 2006, Mosby Inc.

ISBN 13: 978-0-323-03432-6 ISBN 10: 0-323-03432-2

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ISBN-13: 978-0-323-03432-6 ISBN-10: 0-323-03432-2

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Contributors
Neha P. Amin, B.S., B.A.S.
Medical Student, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Optic Neuritis

Anish Bhardwaj, M.D., F.A.H.A., F.C.C.M.


Associate Professor of Neurology, Neurological Surgery, and Anesthesiology Critical Care Medicine; Director, Neuroscience Critical Care Fellowship Program; Vice Chairman, Department of Neurology, Johns Hopkins University School of Medicine; Co-Director, Neurosciences Critical Care Division; Attending Physician, Johns Hopkins Hospital and Bayview Medical Center, Baltimore, Maryland
The Unconscious Patient

Charles E. Argoff, Ph.D.


Assistant Professor of Neurology, New York University School of Medicine; Director, Cohn Pain Management Center, North Shore University Hospital, Bethpage, New York
Chronic Pain Management: General Principles

Kevin M. Biglan, M.D., M.P.H. Allen J. Askamit, Jr., M.D.


Associate Professor of Neurology, Mayo College of Medicine; Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota
Acute Bacterial Meningitis

Assistant Professor of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York
Huntingtons Disease

Tom J. Blanchard, M.R.C.P., DTM&H, Ph.D.


Senior Lecturer in Tropical Medicine, Clinical Research Group, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
Cerebral Malaria

Alon Y. Avidan, M.D., M.P.H.


Assistant Professor of Neurology, University of Michigan Medical School; Director, Sleep Disorders Clinic, University of Michigan Health System, Ann Arbor, Michigan
Parasomnias

John B. Bodensteiner, M.D.


Professor of Clinical Pediatrics and Neurology, Department of Pediatrics, University of Arizona College of Medicine; Chief, Pediatric Neurology, St. Josephs Hospital and Childrens Health Center, and Barrow Neurological Institute, Phoenix, Arizona
Tuberous Sclerosis Complex

Laura J. Balcer, M.D., M.S.C.E.


Associate Professor of Neurology and Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Optic Neuritis

Tallie Z. Baram, M.D., Ph.D.


Professor of Pediatrics, Anatomy/Neurobiology, and Neurology and Danette Shepard Professor of Neurological Sciences, Department of Pediatrics, University of California, Irvine, School of Medicine, Irvine, California
Neonatal Seizures and Infantile Spasms

Devin L. Brown, M.D.


Assistant Professor of Neurology, University of Michigan Medical School; Staff Neurologist, Stroke Program, University of Michigan Health System, Ann Arbor, Michigan
Emboli of Cardiac Origin

Allan J. Belzberg, M.D.


Associate Professor of Neurosurgery, Johns Hopkins University School of Medicine; Attending Neurosurgeon, Johns Hopkins Hospital, Baltimore, Maryland
Peripheral Nerve Injury

John C. M. Brust, M.D.


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

Sara E. Benjamin, M.D.


Chief Resident, Department of Neurology, George Washington University School of Medicine and Health Sciences, Washington, DC
Wernicke Disease and Korsakoff Psychosis

Arthur L. Burnett, M.D.


Professor of Urology, Johns Hopkins University School of Medicine; Active Staff, Johns Hopkins Hospital, Baltimore, Maryland
Urinary and Sexual Dysfunction in Multiple Sclerosis and Myelitis

Anthony S. Burns, M.D.


Assistant Professor of Rehabilitation Medicine, Jefferson Medical College of Thomas Jefferson University; Assistant Director, Regional Spinal Cord Injury Center of the Delaware Valley, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
Acute Spinal Cord Injury

iii

iv

Contributors

Peter Calabresi, M.D.


Associate Professor of Neurology, Johns Hopkins University School of Medicine; Director, Multiple Sclerosis Center, Johns Hopkins Hospital, Baltimore, Maryland
Multiple Sclerosis

Ricardo Cruciani, M.D., Ph.D.


Assistant Professor, Department of Neurology and Anesthesiology, Albert Einstein College of Medicine of Yeshiva University, Bronx; Director, Research Division, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, New York
Herpes Zoster and Postherpetic Neuralgia

Grant L. Campbell, M.D., Ph.D.


Chief, Arboviral Diseases Branch, Epidemiology Section, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado
Arthropod-Borne Virus Infections

Marinos C. Dalakas, M.D.


Chief, Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
Immune-Mediated Inflammatory Myopathies

Vinay Chaudhry, M.D., F.R.C.P.


Professor of Neurology, Johns Hopkins University School of Medicine; Vice Chair, Clinical Affairs, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
Intravenous Immunoglobulin and Plasmapheresis in the Treatment of Neurologic Disease

Josep Dalmau, M.D., Ph.D.


Associate Professor of Neurology, University of Pennsylvania School of Medicine; Attending Neurologist, Section of Neuro-oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Remote Effects of Cancer: Treatment of Paraneoplastic Neurologic Syndromes

William P. Cheshire, Jr., M.D., M.A.


Associate Professor of Neurology, Mayo Clinic College of Medicine, Jacksonville, Florida
Trigeminal and Glossopharyngal Neuralgia

Stephanie K. Daniels, Ph.D.


Adjunct Assistant Professor, Department of Psychiatry and Neurology, Tulane University School of Medicine; Research Speech Pathologist, Research Service, VA Medical Center, New Orleans, Louisiana
Dysphagia: Diagnosis and Treatment

Kenneth Cohen, M.D., M.B.A.


Associate Professor of Oncology and Pediatrics, Johns Hopkins University School of Medicine; Director, Pediatric Neuro-oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
Childhood Brain Tumors

Larry E. Davis, M.D., F.A.A.N., F.A.C.P.


Professor of Neurology, University of New Mexico School of Medicine; Chief, Neurology Service, New Mexico VA Health Care System, Albuquerque, New Mexico
Fungal Infections

Andrew J. Cole, M.D., F.R.C.P.C.


Associate Professor of Neurology, Harvard Medical School; Director, MGH Epilepsy Service, Neurology Service, Massachusetts General Hospital, Boston, Massachusetts
First Generalized Seizure

David W. Dodick, M.D.


Professor of Neurology, Mayo Clinic College of Medicine, Scottsdale, Arizona
Chronic Daily Headache

Anne Comi, M.D.


Assistant Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Director, Johns HopkinsKennedy Krieger Sturge-Weber Syndrome Center, Baltimore, Maryland
Sturge-Weber Syndrome

Heinrich Elinzano, M.D.


Postdoctoral Fellow in Neuro-oncology, Medical Oncology Department, Johns Hopkins University School of Medicine, Baltimore; Clinical Fellow in Neuro-oncology, Neuro-oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Epidural Spinal Cord Compression and Leptomeningeal Metastasis

James J. Corbett, M.D.


McCarly Professor and Chair, Department of Neurology, and Professor of Ophthalmology, University of Mississippi School of Medicine, Jackson, Mississippi; Lecturer in Ophthalmology, Harvard Medical School/Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
Idiopathic Intracranial Hypertension

Robert D. Fealey, M.D.


Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota
Neurogenic Orthostatic Hypotension

Andrea M. Corse, M.D.


Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Attending Neurologist and Director, Neuromuscular Pathology Laboratory, Johns Hopkins Hospital, Baltimore, Maryland
Myasthenia Gravis

Anne L. Foundas, M.D.


Professor of Neurology, Department of Psychiatry and Neurology, Tulane University School of Medicine; Research Clinician, Neurology Service, VA Medical Center, New Orleans, Louisiana
Dysphasia: Diagnosis and Treatment

Nathan E. Crone, M.D.


Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Absence Seizures

Jacqueline A. French, M.D.


Professor of Neurology, University of Pennsylvania School of Medicine; Co-Director, Penn Epilepsy Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Treatment of Newly Diagnosed Complex Partial Seizures

Contributors

Linda P. Fried, M.D., M.P.H.


Professor of Medicine, Epidemiology, Health Policy, and Nursing, Johns Hopkins University School of Medicine; Director, Division of Geriatric Medicine and Gerontology; Director, Center on Aging and Health, Johns Hopkins Medical Institutions, Baltimore, Maryland
Frailty in Older Adults

Benjamin M. Greenberg, M.D., M.H.S.


Instructor, Johns Hopkins University School of Medicine; Fellow, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland
Intravenous Immunoglobulin and Plasmapheresis in the Treatment of Neurologic Disease

Adam L. Hartman, M.D. Scott Fromherz, M.D.


Fellow, Sleep Disorders Clinic, Stanford University Hospital and Clinics, Stanford, California
Narcolepsy

Fellow, Department of Pediatric Neurology, Johns Hopkins Hospital, Baltimore, Maryland


Febrile Seizures

Susan T. Herman, M.D. Bhuwan P. Garg, M.B., B.S.


Professor of Neurology, Section of Child Neurology, Indiana University School of Medicine; Pediatric Neurologist, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana
Neurofibromatosis

Assistant Professor of Neurology, University of Pennsylvania School of Medicine; Director, Epilepsy Monitoring Unit, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Treatment of Newly Diagnosed Complex Partial Seizures

Donald L. Gilbert, M.D., M.S.


Associate Professor of Pediatrics and Neurology, Division of Neurology, University of Cincinnati School of Medicine; Director, Movement Disorders Clinics, Cincinnati Childrens Hospital Medical Center, Cincinnati, Ohio
Tourettes Syndrome

Argye E. Hillis, M.D., M.A.


Associate Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Acute Ischemic Stroke

Michio Hirano, M.D.


Associate Professor of Neurology, Columbia University College of Physicians and Surgeons; Associate Attending, Department of Neurology, New YorkPresbyterian Hospital, Columbia University Medical Center, New York, New York
Mitochondrial Encephalomyopathies

Mark R. Gilbert, M.D.


Associate Professor and Deputy Chairman, Department of Neuro-oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Glioma

David Irani, M.D. Donald H. Gilden, M.D.


Louise Baum Professor and Chairman, Department of Neurology, University of Colorado Health Sciences Center School of Medicine; Staff Physician, University of Colorado Hospital, Denver, Colorado
Bells Palsy

Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Attending Neurologist, Johns Hopkins Hospital, Baltimore, Maryland
Transverse Myelitis

Sallu Jabati, M.D.


Attending, Spine Institute, Department of Surgery, Cleveland Clinic Foundation, Cleveland, Ohio
Herpes Zoster and Postherpetic Neuralgia

Frank G. Gilliam, M.D., M.P.H.


Professor of Neurology, Columbia University College of Physicians and Surgeons; Director, Columbia Comprehensive Epilepsy Center; Staff Neurologist, New YorkPresbyterian Hospital, New York, New York
Recurrent Generalized and Partial Seizures

Alan C. Jackson, M.D., F.R.C.P.C.


Professor, Departments of Medicine (Neurology) and Microbiology and Immunology, Queens University Faculty of Medicine; Attending Neurologist, Kingston General Hospital, Kingston, Ontario, Canada
Rabies Virus Infection

Jonathan P. Gladstone, B.Sc., M.D.


Division of Neurology, University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada
Chronic Daily Headache

Jee-Hyang Jeong, M.D.


Fellow, Department of Neurology, University of California, San Francisco, School of Medicine, San Francisco, California
Frontotemporal Degeneration

Jonathan D. Glass, M.D.


Professor of Neurology and Pathology, Emory University School of Medicine, Atlanta, Georgia
Toxic Neuropathy

H. A. Jinnah, M.D., Ph.D.


Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
The Dystonias

David S. Goldstein, M.D., Ph.D.


Chief, Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
Complex Regional Pain Syndromes

S. Claiborne Johnston, M.D., Ph.D.


Associate Professor, Departments of Neurology and Epidemiology, University of California, San Francisco, School of Medicine; Director, Stroke Service, UCSF Medical Center, San Francisco, California
Management of Intracranial Aneurysms and Other Vascular Malformations

Joao A. Gomes, M.D.


Neurocritical Care Fellow, Departments of Neurology, Anesthesia, and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Management of Subarachnoid Hemorrhage

vi

Contributors

Burk Jubelt, M.D.


Professor of Neurology, Department of Microbiology/Immunology; Director, Neuroscience Program, State University of New York Upstate Medical University College of Medicine; Attending Neurologist, University Hospital, Syracuse, New York
Enterovirus Infections

Robert Laureno, M.D.


Professor of Neurology, George Washington University School of Medicine and Health Sciences; Chairman, Department of Neurology, Washington Hospital Center, Washington, DC
Wernicke Disease and Korsakoff Psychosis

Rafael H. Llins, M.D., F.A.H.A. Douglas Kerr, M.D., Ph.D.


Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Johns Hopkins Hospital, Baltimore, Maryland
Cervical Spondylosis

Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Director, Cerebrovascular Disease Section, Department of Neurology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland
Transient Ischemic Attacks

Richard M. Kimball, M.S.


Research Nurse, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
Amyotrophic Lateral Sclerosis

Elan D. Louis, M.D., M.S.


Associate Professor of Neurology, Columbia University College of Physicians and Surgeons; Associate Attending Neurologist, G.H. Serievsky Center, Columbia University Medical Center, New York, New York
Essential Tremor

Kleopas A. Kleopa, M.D.


Senior Consultant Neurologist, Division of Clinical Neurosciences, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
Familial Neuropathies

Yukari Manabe, M.D.


Assistant Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Tuberculous Meningitis

Carol Lee Koski, M.D.


Professor of Neurology, University of Maryland School of Medicine; Director, Neuromuscular Division, University of Maryland Medical Systems, Baltimore, Maryland
Chronic Inflammatory Demyelinating Polyneuritis

Nicholas J. Maragakis, M.D.


Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Amyotrophic Lateral Sclerosis

Morri E. Markowitz, M.D. Eric H. Kossoff, M.D.


Assistant Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Staff, John M. Freeman Pediatric Epilepsy Center, Baltimore, Maryland
Headaches in Children

Professor of Pediatrics, Albert Einstein College of Medicine of Yeshiva University; Director, Pediatric Environmental Science Clinic, Childrens Hospital at Montefiore, Bronx, New York
Management of Lead Poisoning in Children

Allan Krumholz, M.D.


Professor of Neurology, University of Maryland School of Medicine; Director, Epilepsy Center, University of Maryland Medical Center, Baltimore, Maryland
Psychogenic Nonepileptic Seizures

Christina M. Marra, M.D.


Professor of Neurology, University of Washington School of Medicine; Attending, Harborview Medical Center, Seattle, Washington
Neurosyphilis

Roger W. Kula, M.D.


Associate Professor of Clinical Neurology, State University of New York Downstate Medical Center College of Medicine, Brooklyn; Medical Director, The Chiari Institute, North Shore University Hospital, Manhasset; Director, Neuromuscular Clinic, Long Island Jewish Medical Center, New Hyde Park; Co-Director, Neuromuscular Clinic, Pediatric Neurology, Schneider Childrens Hospital, New Hyde Park, New York
Chiari Malformations and Syringomyelia

Laura Marsh, M.D.


Associate Professor of Psychiatry and Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Depression in Neurological Disorders

James A. Mastrianni, M.D., Ph.D.


Assistant Professor of Neurology, The University of Chicago Pritzker School of Medicine; Co-Director, Center for Comprehensive Care and Research on Memory Disorders, The University of Chicago Hospitals, Chicago, Illinois
The Prion Diseases

Ralph W. Kuncl, M.D., Ph.D.


Adjunct Professor of Neurology, University of Pennsylvania School of Medicine; Staff, Hospital of the University of Pennsylvania, Philadelphia; Professor of Biology and Provost, Bryn Mawr College, Bryn Mawr, Pennsylvania
Use and Misuse of Corticosteroids

Justin C. McArthur, M.B.B.S., M.P.H.


Professor of Neurology, Pathology, and Epidemiology and Acting Chair, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Giant Cell Arteritis and CNS Vasculitis

John Laterra, M.D., Ph.D.


Professor, Departments of Neurology, Oncology, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
Epidural Spinal Cord Compression and Leptomeningeal Metastasis

Una D. McCann, M.D.


Associate Professor of Psychiatry, Johns Hopkins University School of Medicine; Attending, Johns Hopkins Bayview Medical Center, Baltimore, Maryland
Overdose and Withdrawal in Drug Abuse

Contributors

vii

Micheline McCarthy, M.D., Ph.D.


Associate Professor of Neurology, University of Miami Leonard M. Miller School of Medicine; Associate Chief, Neurology Service, Miami Veterans Affairs Medical Center, Miami, Florida
Herpesvirus Infections

Avindra Nath, M.D.


Professor of Neurology, Johns Hopkins University School of Medicine; Director, Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Baltimore, Maryland
Human Immunodeficiency Virus Infections

Emmanuel Mignot, M.D., Ph.D.


Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford; Director, Stanford Center for Narcolepsy; Investigator, Howard Hughes Medical Institute, Palo Alto, California
Narcolepsy

Elizabeth OHearn, M.D.


Assistant Professor, Department of Neurology and Neurosciences, Johns Hopkins University School of Medicine; Staff Neurologist, Johns Hopkins Hospital, Baltimore, Maryland
Inherited Cerebellar Ataxia

Bruce Miller, M.D.


A.W. Margaret Clausen Distinguished Professor, Department of Neurology, University of California, San Francisco, School of Medicine, San Francisco, California
Frontotemporal Degeneration

Richard K. Olney, M.D.


Professor of Neurology, University of California, San Francisco, School of Medicine, San Francisco, California
Guillain-Barr Syndrome

Steven P. Miller, M.D., C.M., F.R.C.P.C.


Assistant Adjunct Professor, Departments of Neurology and Pediatrics, University of California, San Francisco, School of Medicine, San Francisco, California; Assistant Professor, Department of Pediatrics, University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada
Neonatal Encephalopathy

Andrew R. Pachner, M.D.


Professor of Neurology, UMDNJNew Jersey Medical School, Newark, New Jersey
Lyme Disease

Carlos A. Pardo-Villamizar, M.D.


Assistant Professor of Neurology and Pathology, Johns Hopkins University School of Medicine; Staff Neurologist, Johns Hopkins Hospital, Baltimore, Maryland
Neurosarcoidosis

Lewis B. Morgenstern, M.D.


Associate Professor of Neurology, Emergency Medicine, Neurosurgery, and Epidemiology, University of Michigan Medical School and School of Public Health; Director, Stroke Program, University of Michigan Health System, Ann Arbor, Michigan
Emboli of Cardiac Origin

Roy A. Patchell, M.D.


Chief, Neuro-oncology Division, Department of Neurosurgery, University of Kentucky Chandler Medical Center, Lexington, Kentucky
Brain Metastases

Richard T. Moxley III, M.D.


Professor of Neurology and Pediatrics, Department of Neurology, University of Rochester School of Medicine and Dentistry; Attending Physician, Strong Memorial Hospital; Director, Neuromuscular Disease Center, Department of Neurology, University of Rochester Medical Center, Rochester, New York
Muscular Dystrophies

Michael Polydefkis, M.D.


Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Johns Hopkins Hospital, Baltimore, Maryland
Diabetic Neuropathies

Beth S. Porter, M.D., Ph.D.


Assistant Professor, Department of Medicine, Division of Infectious Diseases, University of New Mexico School of Medicine; Staff Physician, Spinal Cord Injury Center and Department of Infectious Diseases, New Mexico VA Health Care System, Albuquerque, New Mexico
Fungal Infections

Beth Murinson, M.S., M.D., Ph.D.


Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
Painful Neuropathy

Neal J. Naff, M.D.


Assistant Professor of Neurosurgery, Johns Hopkins University School of Medicine; Chief of Neurosurgery, Sinai Hospital of Baltimore, Baltimore, Maryland
Failed Back Syndrome

Michael Pourfar, M.D.


Staff Physician, Center for Parkinsons Disease and Other Movement Disorders, Columbia University Medical Center, New York, New York
Essential Tremor

Vinodh Narayanan, M.D.


Associate Professor of Clinical Pediatrics and Neurology, Department of Pediatrics, University of Arizona College of Medicine; Pediatric Neurologist, St. Josephs Hospital and Childrens Health Center and Barrow Neurological Institute, Phoenix; Adjunct Professor, School of Life Sciences, Arizona State University, Tempe, Arizona
Tuberous Sclerosis Complex

Tyler Reimschisel, M.D.


Assistant Professor of Neurology, Washington University, St. Louis, Missouri
The Dystonias

George A. Ricaurte, M.D., Ph.D.


Associate Professor of Neurology, Johns Hopkins University School of Medicine; Attending, Johns Hopkins Bayview Medical Center, Baltimore, Maryland
Overdose and Withdrawal in Drug Abuse

viii

Contributors

Daniele Rigamonti, M.D.


Professor of Neurosurgery, Johns Hopkins University School of Medicine; Director, Division of Stereotatic Radiosurgery; Co-Director, Adult Hydrocephalus Program, Johns Hopkins Hospital, Baltimore, Maryland
Normal Pressure Hydrocephalus

Jehuda Sepkuty, M.D.


Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Director, Intraoperative Neuromonitoring; Attending Neurologist, Epilepsy Monitoring Unit, Johns Hopkins Hospital, Baltimore, Maryland
Status Epilepticus

Stacie L. Ropka, Ph.D., M.B.A.


Research Assistant Professor, Department of Neurology, State University of New York Upstate Medical University College of Medicine, Syracuse, New York
Enterovirus Infections

Barbara E. Shapiro, M.D., Ph.D.


Associate Professor of Neurology, Case School of Medicine; Director, Neuromuscular Research, University Hospitals of Cleveland, Cleveland, Ohio
The Periodic ParalysesCurrent Therapy

Paul Rosenberg, M.D.


Assistant Professor of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore; Director of Neuropsychiatry, The Copper Ridge Institute, Sykesville, Maryland
Depression in Neurological Disorders

Rachelle Smith Doody, M.D., Ph.D.


Effie Marie Cain Chair in Alzheimers Disease Research, Department of Neurology, Baylor College of Medicine; Active Staff, Department of Neurology, The Methodist Hospital, Houston, Texas
Alzheimers Disease

Robert L. Ruff, M.D., Ph.D.


Professor of Neurology, Case School of Medicine; Director, Spinal Cord Injury Unit, Cleveland VA Medical Center, Cleveland, Ohio
The Periodic Paralyses

Yuen T. So, M.D., Ph.D.


Professor of Neurology, Department of Neurology and Neurological Sciences, Stanford University School of Medicine; Director, Neurology Clinic, Stanford Hospital and Clinics, Stanford, California
Entrapment Neuropathies

David B. Rye, M.D., Ph.D.


Associate Professor of Neurology, Emory University School of Medicine; Director, Emory Healthcare Program in Sleep Medicine, Atlanta, Georgia
Restless Legs Syndrome

Tom Solomon, M.D., Ph.D.


Senior Lecturer in Neurology, Department of Neurological Science; Senior Lecturer in Medical Microbiology and Genitourinary Medicine, University of Liverpool; Honorary Consultant Neurologist, Walton Centre for Neurology and Neurosurgery and Royal Liverpool University Hospital, Liverpool, United Kingdom
Cerebral Malaria

Steven S. Scherer, M.D., Ph.D.


William N. Kelley Professor, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Familial Neuropathies

Elijah W. Stommel, M.D., Ph.D.


Associate Professor of Medicine, Section of Neurology, Dartmouth Medical School, Hanover; Attending Neurologist, Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
Marine Toxins and Assorted Biological Toxins

Jacob P. Schwarz, M.D.


Instructor in Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
Failed Back Syndrome

Erick Scott, M.D.


Fellow, Department of Psychiatry and Behavioral Sciences, Stanford Center for Narcolepsy, Stanford, California
Cervical Spondylosis

Gene Sung, M.D., M.P.H.


Director, Neurocritical Care and Stroke Section, Department of Neurology, Keck School of Medicine of USC, Los Angeles, California
Intracerebral Hemorrhage

James J. Sejvar, M.D.


Neuroepidemiologist, Division of Vector-Borne Infectious Diseases and Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
Arthropod-Borne Virus Infections

Tricia Ting, M.D.


Assistant Professor of Neurology, University of Maryland School of Medicine; Director, Ambulatory Services, Maryland Epilepsy Center, University of Maryland Medical Center, Baltimore, Maryland
Psychogenic Nonepileptic Seizures

Michael E. Selzer, M.D., Ph.D.


Professor of Neurology, Departments of Neurology and Physical Medicine and Rehabilitation, University of Pennsylvania School of Medicine; Attending Physician, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Acute Spinal Cord Injury

B. Todd Troost, M.D.


Professor of Neurology Emeritus, Wake Forest University School of Medicine; Chief Emeritus, Department of Neurology, North Carolina Baptist Hospital, Winston-Salem, North Carolina
Migraine and Cluster Headache

Contributors

ix

Eileen P. G. Vining, M.D.


Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Associate Director, Pediatrics Epilepsy Clinic, Johns Hopkins Hospital, Baltimore, Maryland
Febrile Seizures

Michael A. Williams, M.D.


Associate Professor of Neurology, Johns Hopkins University School of Medicine; Director, Adult Hydrocephalus Program, Johns Hopkins Hospital, Baltimore, Maryland
Normal Pressure Hydrocephalus

Max Wiznitzer, M.D. Jerrold L. Vitek, M.D., Ph.D.


Co-Chairman, Center for Neurological Restoration, Cleveland Clinic Foundation, Cleveland, Ohio
Parkinsons Disease

Associate Professor of Pediatrics, Neurology, and International Health, Case School of Medicine; Pediatric Neurologist, Rainbow Babies and Childrens Hospital, Cleveland, Ohio
Attention Deficit Hyperactivity Disorders and Learning Disabilities

Kathryn R. Wagner, M.D., Ph.D.


Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Muscular Dystrophies

Wendy L. Wright, M.D.


Professor of Neurology, Emory University School of Medicine; Active Staff, Neuroscience Critical Care Division, Emory University Hospital, Atlanta, Georgia
Brain Abscess and Parameningeal Infection

Mark F. Walker, M.D.


Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
Vertigo and Disequilibrium

Kaleb Yohay, M.D.


Instructor, Department of Neurology, Division of Child Neurology, Johns Hopkins University, Baltimore, Maryland
Childhood Brain Tumors

Laurence Walsh, M.D.


Assistant Professor of Clinical Neurology and Medical and Molecular Genetics; Director, Child Neurology Section, Department of Neurology, Indiana University School of Medicine; Director, Pediatric Neurology, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana
Neurofibromatosis

Phyllis C. Zee, M.D., Ph.D.


Professor of Neurology, Northwestern University Feinberg School of Medicine; Director, Sleep Disorders Center, Department of Neurology, Northwestern Memorial Hospital, Chicago, Illinois
Parasomnias

Benjamin L. Walter, M.D.


Associate Staff, Center for Neurological Restoration, Cleveland Clinic Foundation, Cleveland, Ohio
Parkinsons Disease

Wendy C. Ziai, M.D.


Assistant Professor, Departments of Neurology and Anesthesia/Critical Care Medicine, Johns Hopkins University School of Medicine; Attending Physician, Neurocritical Care, Johns Hopkins Hospital and Bayview Medical Center, Baltimore, Maryland
Management of Subarachnoid Hemorrhage

Michael R. Watters, M.D., F.A.A.N.


Professor of Medicine, Division of Neurology, University of Hawaii JAB School of Medicine; Core Neurologist, Office of Neurology and Aging Research, Specialized Neuroscience Research Program in NeuroAIDS; Associate Director of Medical Education, Queens Neuroscience Institute, Honolulu, Hawaii
Marine Toxins and Assorted Biological Toxins

Andrew W. Zimmerman, M.D.


Associate Professor of Neurology, Psychiatry, and Pediatrics, Johns Hopkins University School of Medicine; Pediatric Neurologist, Kennedy Krieger Institute and Johns Hopkins Hospital, Baltimore, Maryland
Autism

Preface
Current Therapy in Neurologic Disease 7 marks the 20th anniversary of this series. Technically, this is not the seventh edition, since each of the seven volumes has been a fresh collection of statements on management and therapy by a new group of specialists. This series was launched to fill a perceived shortcoming in the neurology literature. Many fine textbooks and monographs cover the etiology, pathogenesis, clinical symptoms and signs, imaging, and pathology of neurology diseases. Instruction on management, specific therapy, and patient education, however, tends to be presented in generalizations replete with conflicting views. The practical issues of when and how to initiate drugs and at what doses, the management of complications of the disease and the drugs, and advice on when to call for aid of colleagues in other fields are left to the informal education of corridor or curbstone consultation. Since its introduction, this series has presented a specific stepby-step approach to patient management given by a seasoned clinician. It has provided an informal practical consultation for the neurologist, neurosurgeon, internist, pediatrician, or family practitioner. Because authors, and therefore options, are changed with each volume, you, like the editors, may wish to save volumes 5 and 6 for a second opinion that you may favor over an opinion in this volume. The advice of the contributors is not necessarily the approach of the editors or a consensus of the neurologic community; they are the management techniques of an experienced clinician. Today, neurologic practice should be driven by evidencebased neurology, and obviously class I evidence from randomized clinical trials plays a major role in the choice of therapy. Usually, however, this evidence is not adequate to provide advice regarding specifics of management of the patient. This book provides not only evidence-based approaches but experience-based approaches from expert authors. As before, some new topics have been added and others droppedat least for this edition. New additions include daily headache, autism, Sturge-Weber syndrome, Bells palsy, Creutzfeldt-Jakob disease, and new general topics of the fragile elderly, plasmapheresis and intravenous immunoglobulin G, and the use and abuse of corticosteroids in neurologic practice. Each author has been given the same charge: to describe his or her approach to treatment and management of patients. Drug dosages have been checked, but the reader should always scrutinize product information sheets or online sources for dosage, interactions, and contraindications. The editors thank Sofia Rodriguez for editorial assistance. Richard T. Johnson, M.D., F.R.C.P. John W. Griffin, M.D. Justin C. McArthur, M.B.B.S., M.P.H.

xi

SECTION 1

Disorders of Consciousness
The Unconscious Patient
Anish Bhardwaj, M.D.
vasopressors to keep mean arterial blood pressure above 70 mm Hg Hypertension can result from brain injury (intracranial hypertension, drug intoxication with cocaine or amphetamines)administer labetalol 10 to 20 mg intravenously (IV) every 10 minutes (up to a maximum of 300 mg) Hypothermia can result from neuroendocrine disorders (hypopituitarism, hypothyroidism), drug ingestion (barbiturates, alcohol, general anesthetics), Wernickes encephalopathy, diencephalic injury Hyperthermia can result from thyrotoxicosis, sepsis, hypothalamic injury, malignant hyperthermia, heat stroke Tachycardia can result from hypo`volemia, infection/ sepsis, pain and discomfort, pulmonary embolism Bradycardia can result from intracranial hypertension, drug overdose (e.g., tricyclic antidepressants) Malignant cardiac arrhythmias can result from ventricular fibrillation, ventricular tachycardia (e.g., amphetamine overdose)
INITIATE FLUID MANAGEMENT

States of Altered Consciousness


Consciousness is a state of awareness of self and environment and is dependent on two essential elements that have an anatomic basis: arousal, which is related to the integrity of the ascending reticular activating system, and awareness, which is related to the integrity of the cerebral cortex. Derangement in the level of consciousness comprises a spectrum of disorders ranging from acute confusional states to coma (Table 1). Disturbances in its content range from global cognitive impairment to more focal brain dysfunction, including deficits in language, memory, sensation and perception, motivation, and executive function.

Initial Diagnostic Work-up and Emergent Management of an Unconscious Patient


The classification and major causes of altered consciousness are presented in Table 2. The diagnosis and management of an unconscious patient are presented here in algorithmic fashion as follows:
ESTABLISH AND MAINTAIN THE AIRWAY, BREATHING, AND CIRCULATION (ABCs)

Establish IV access and commence IV infusion of isotonic fluids (1 to 1.5 mL/kg/hr of 0.9% saline)
ASSESS NEUROLOGIC FUNCTION

Place oropharyngeal airway and provide bag-mask ventilation, intubation (fiberoptic if spinal cord injury is suspected) Monitor oxygenation with pulse oximetry and maintain SaO2 higher than 90% with supplemental O2
MONITOR VITAL SIGNS

Assess level of consciousness Cranial nervesObserve eye movements, pupillary and corneal responses, oculocephalic/vestibulo-ocular reflex, cough and gag reflexes Motor examinationObserve resting posture, spontaneous motor activity, response to stimulation
ORDER LABORATORY SCREENING

Hypotension can result from hypovolemia, myocardial infarction, pulmonary embolism, sepsis, acidosis provide fluid resuscitation with isotonic fluids and
Johnson: Current Therapy in Neurologic Disease (7/E)

Obtain blood samples for Glucosehypoglycemia, hyperglycemia (nonketotic) Arterial blood gaseshypoxemia, hypercarbia, acidosis (drug ingestion, ketoacidosis, lactic acidosis) Electrolyteshyponatremia/hypernatremia, hypocalcemia/hypercalcemia, hypomagnesemia/hypermagnesemia, azotemia 1

The Unconscious Patient

TABLE 1 States of Altered Consciousness


Type of State Acute confusional state Delirium Akinetic mutism Manifestations Impaired attention, memory, and thinking Incoherent conversation with easy distraction Acute confusional state accompanied by autonomic dysfunction (fever, hypertension, sweating, and tachycardia) Little or no awareness of surroundings Absence of spontaneous motor activity Minimal motor response to noxious stimuli Intact sleep-wake cycles Consciousness preserved Selective deafferentation of all extremities and lower cranial nerves resulting in quadriplegia and inability to vocalize Sparing of vertical eye movements, blinking, hearing, and respiratory function Usually results from an acute pontine lesion Complete unawareness of self and surroundings Spontaneous eye opening may occur with some response to verbal stimuli that is not meaningful Inability to follow commands or localize to noxious stimulus Intact sleep-wake cycles and circulatory, respiratory, and brainstem reflexes Identified as such if state persists for >1 mo for nontraumatic etiology and >1 yr following traumatic brain injury Mental dullness or blunting with increased sleeping time Can be aroused to follow commands but with slowed responses and little interest in surroundings Reduced mental and physical activity Can be aroused with repeated and vigorous stimuli Restlessness; stereotypic motor responses Sleeplike state of unresponsiveness with absence of awareness of self and environment; does not respond to stimuli Motor impairment variable No spontaneous eye opening or reaction to stimulus Absent sleep-wake cycles

Locked-in syndrome

Persistent vegetative state

Obtundation Stupor Coma

Thyroid function testshypothyroidism, myxedema Liver function testshyperammonemia White blood cell countleukocytosis (infection/ sepsis) Obtain urine specimen for urinalysis and urine toxicology screenurosepsis, drug intoxication Check serum glucose level at bedside
INITIATE SPECIFIC TREATMENT

PERFORM ADDITIONAL DIAGNOSTIC TESTS

Administer thiamine, 100 mg IV, followed by 25 gm of glucose (50 mL of 50% solution) Naloxone (0.4 to 2 mg IV every 3 minutes or continuous IV infusion 0.8 mg/kg/hr) if narcotic overdose is suspectedmay precipitate rapid and florid withdrawal syndrome Flumazenil, 0.2 mg/min, maximum dose 1 mg IV, only if benzodiazepine overdose is suspectedmay precipitate cardiac arrhythmias and lower seizure threshold Lavage with activated charcoal (60 to 100 gm) and normal saline for suspected drug ingestion
OBTAIN DETAILED HISTORY AND PERFORM SYSTEMATIC EXAMINATION

Obtain the following diagnostic tests as needed: Nonenhanced computed tomographic (CT) scan of the brain, particularly in patients with focal neurologic findings Lumbar puncture for suspected infection (meningitis, encephalitis), subarachnoid hemorrhage Cerebral angiography for suspected vertebrobasilar insufficiency Electroencephalography for suspected nonconvulsive seizures Magnetic resonance imaging with venography for suspected basilar artery thrombosis and sinus venous thrombosis

Neurologic Evaluation of Altered Consciousness


Neurologic examination of an unconscious patient is focused on four major components: level of consciousness, cranial nerve and motor examinations, and respiratory pattern.
Johnson: Current Therapy in Neurologic Disease (7/E)

The Unconscious Patient

3
Disorders of Consciousness

TABLE 2 Classification and Major Causes of Alterations in Consciousness


Structural Brain Injury Hemisphere Unilateral (with midline shifts/displacement) Intracerebral and subarachnoid hemorrhage Large hemispheric ischemic stroke with accompanying edema Hemorrhagic contusion Cerebral abscess Brain tumor Bilateral Penetrating traumatic brain injury, traumatic brain contusions, diffuse axonal injury Multiple cerebral cortical infarcts (vasculitis, coagulopathy, cardiac embolism) Bilateral thalamic infarcts Malignancy (lymphoma, gliomatosis, multiple brain metastasis) Encephalitis (viral, paraneoplastic) Acute disseminated encephalomyelitis Anoxic-ischemic encephalopathy Cerebral edema Acute hydrocephalus Leukoencephalopathy (chemotherapy or radiation) Brainstem Pontine hemorrhage Basilar artery occlusion Central pontine myelinolysis Brainstem hemorrhagic contusion Brainstem tumor Cerebellum (with displacement causing brainstem compression) Cerebellar infarct Cerebellar hematoma Cerebellar abscess Cerebellar glioma or metastatic tumor Acute Metabolic-Endocrine Derangement Disturbances in serum glucose (hypoglycemia, hyperglycemia) Disturbances in serum sodium (hyponatremia, hypernatremia) Addisons disease Hypercalcemia Acute panhypopituitarism Hypothyroidism (myxedema coma) Acute azotemia/uremia Hypoxia, hypercapnia Diffuse Physiologic Brain Dysfunction Drug overdose and poisoning Generalized tonic-clonic seizures or nonepileptic seizures Hypothermia Gas inhalation (carbon monoxide) Basilar migraine Psychogenic Unresponsiveness Acute (lethal) catatonia, malignant neuroleptic syndrome Hysterical coma Malingering
Adapted from Wijdicks EFM: Neurologic complications of critical illness, ed 2, New York, 2002, Oxford University Press; and Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press.

LEVEL OF CONSCIOUSNESS Level of unresponsiveness should be established. Special attention should be paid to body position, spontaneous motor activity, and eye movements. The Glasgow Coma Scale (GCS), originally designed for patients with traumatic brain injury, is used widely in patients with neurologic impairments as an objective scoring system because of its easy interexaminer reliability and reproducibility. GCS comprises eye opening and motor and verbal responses; however, it does not incorporate focal sensory-motor deficits and is limited in patients with craniofacial trauma resulting in orbital swelling. CRANIAL NERVE EXAMINATION Pupillary Responses Pupillary dilation indicates ipsilateral uncal herniation secondary to a lesion (e.g., tumor, abscess, intraparenchymal hematoma, cerebral edema) impinging on the pupillary dilator fibers encasing the oculomotor nerve. Unilateral miosis is suggestive of Horners syndrome due to sympathetic denervation. Bilateral fixed, dilated pupils are indicative of massive drug overdose (e.g., tricyclic antidepressants, amphetamines, carbamazepine), extensive brainstem injury, or central herniation leading to brain death. Bilateral miotic pupils are indicative of narcotic overdose, pontine injury, organophosphate ingestion, or local instillation of miotic eye drops. Other Changes Spontaneous eye opening does not necessarily reflect awareness, in that patients in coma (e.g., persistent vegetative state) may have spontaneous eye opening. Nystagmus at primary gaze is indicative of seizure activity or of diffuse brain injury. A variety of other gaze abnormalities and spontaneous eye movements (skew deviation, ocular bobbing, ping-pong gaze, tonic upward or downward gaze deviation, roving eye movements, convergence nystagmus) that are of localizing value have been well described. Impaired oculocephalic and vestibulo-oculocephalic reflexes are indicative of brainstem dysfunction. The corneal response tests the integrity of the trigeminal (afferent) and facial (efferent) nerves. Facial asymmetry may be indicative of central or peripheral facial nerve palsy. The glossopharyngeal and vagus nerves are tested with the cough and gag reflexes by stimulation of the posterior pharynx. MOTOR EXAMINATION Special attention should be paid to resting posture and spontaneous movements or those in response to stimulation. Motor responses that are commonly observed include (1) involuntary movements that may suggest focal or generalized seizures, myoclonic activity, or enhanced tremor frequently associated with toxicmetabolic etiologies; and (2) those to stimuli that may be absent, reflexic, or purposeful and may be of localizing value.

Johnson: Current Therapy in Neurologic Disease (7/E)

Vertigo and Disequilibrium

Flexor (decorticate) posturing characterized by flexion and abduction of the arms and wrists and extension of the lower extremities is indicative of loss of inhibitory influences from the higher centers and suggests damage to the cerebral hemispheres and the thalamus with structures below the diencephalons remaining intact. Extensor (decerebrate) posturing characterized by adduction, extension, and pronation of the arms and wrists and extension of the lower extremities is indicative of injury to deep bilateral cerebral hemispheres, midbrain and pons, above the vestibular nuclei, and may accompany severe toxicmetabolic brain injury. Triple flexion in the lower extremities is a spinal reflex of no localizing value. Flaccidity accompanied by no response to painful stimuli is indicative of injury to the lower medulla or severe injury to the central and peripheral nervous systems. RESPIRATORY PATTERN Altered states of consciousness are frequently accompanied by changes in respiratory patterns that may reflect injury to brainstem respiratory centers. Hypotonia of the upper airway due to bulbar dysfunction (oropharynx, tongue) manifests itself as hypoxia and hypercapnia, whereas lower airway dysfunction, secondary to weakness of intercostal muscles or diaphragmatic paralysis, leads to reduced vital capacity and hypercarbia. Localizing value of respiratory patterns is frequently obscured by a combination of toxic-metabolic and neurogenic etiologies. Cheyne-Stokes breathing (tachypnea alternating with apnea) is usually indicative of severe bilateral hemispheric dysfunction. Biots breathing (irregular Cheyne-Stokes) suggests a localization in the lower brainstem. Central neurogenic hyperventilation typically accompanies damage to the rostral brainstem tegmentum and the paramedian pontine reticular formation. Apneustic breathing (brief end-inspiratory pauses alternating with end-expiratory pauses) is indicative of injury to the respiratory centers in midcaudal pons. Ataxic breathing is commonly seen with injury to the reticular formation of the dorsomedial medulla extending to the obex and occurs with acute medullary compression.

hyperventilation to maintain a PaCO2 level of 25 to 30 mm Hg, osmotherapy (mannitol 1 gm/kg IV) and diuretics (furosemide 10 to 20 mg IV), and neurosurgical consultation for external drainage of cerebrospinal fluid or emergent surgical procedures for decompression. Admission and emergent transfer of such a patient to a critical care unit setting are necessary for appropriate further management.

SUMMARY
Although the causes of coma are numerous, the principles of management of an unconscious patient center on early recognition and timely evaluation of possible reversible or treatable causes. These principles include (1) providing cardiopulmonary support to maintain oxygenation and cerebral perfusion to limit propagation of secondary brain injury; (2) close and frequent neurologic follow-up examinations to detect early deterioration; and (3) emergent measures for brain resuscitation in patients with severe brain injury. Following emergent critical care, the clinician has the luxury of time to embark on a more thorough evaluation of history of illness and further diagnostic tests to arrive at an etiologic diagnosis. Adherence to these principles can frequently lead to good outcomes in patients with treatable causes of coma from brain injury. SUGGESTED READING
Bhardwaj A: Cerebral edema and intracranial hypertension. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press. Plum F, Posner JB: The pathologic physiology of signs and symptoms of coma. In The diagnosis of stupor and coma, ed 3, New York, 1982, Oxford University Press, 1-86. Wijdicks EFM: Coma and other states of altered awareness. In Neurologic complications of critical illness, ed 2, New York, 2000, Oxford University Press, 3-27. Ziai WC: Coma and altered consciousness. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press.

Brain Resuscitation
Alterations in the level of consciousness from catastrophic brain injuries including trauma and subdural, subarachnoid, and intraparenchymal hemorrhage are encountered commonly in clinical practice. Early recognition of herniation syndromes or clinical evidence of intracranial hypertension warrants an emergent response to confirm clinical diagnosis with a noncontrast CT scan of brain and institution of therapies for brain resuscitation. General measures include avoidance of agitation and fever, maintenance of a euvolemic state and systemic blood pressure, facilitating venous outflow by elevating the head to 30 degrees, and maintaining the neck in a midline position. Specific therapies include emergent endotracheal intubation for controlled

Vertigo and Disequilibrium


Mark F. Walker, M.D.

Dizziness is a common complaint because it encompasses a wide variety of symptoms, and terms such as dizziness, light-headedness, and even disequilibrium may have many different meanings. Thus, an important first step in the treatment of patients with dizziness is to make the correct diagnosis. Too often, patients are simply labeled as having vertigo and given a vestibular suppressant medication without an adequate attempt to characterize the actual symptom or its underlying cause.
Johnson: Current Therapy in Neurologic Disease (7/E)

Vertigo and Disequilibrium

Flexor (decorticate) posturing characterized by flexion and abduction of the arms and wrists and extension of the lower extremities is indicative of loss of inhibitory influences from the higher centers and suggests damage to the cerebral hemispheres and the thalamus with structures below the diencephalons remaining intact. Extensor (decerebrate) posturing characterized by adduction, extension, and pronation of the arms and wrists and extension of the lower extremities is indicative of injury to deep bilateral cerebral hemispheres, midbrain and pons, above the vestibular nuclei, and may accompany severe toxicmetabolic brain injury. Triple flexion in the lower extremities is a spinal reflex of no localizing value. Flaccidity accompanied by no response to painful stimuli is indicative of injury to the lower medulla or severe injury to the central and peripheral nervous systems. RESPIRATORY PATTERN Altered states of consciousness are frequently accompanied by changes in respiratory patterns that may reflect injury to brainstem respiratory centers. Hypotonia of the upper airway due to bulbar dysfunction (oropharynx, tongue) manifests itself as hypoxia and hypercapnia, whereas lower airway dysfunction, secondary to weakness of intercostal muscles or diaphragmatic paralysis, leads to reduced vital capacity and hypercarbia. Localizing value of respiratory patterns is frequently obscured by a combination of toxic-metabolic and neurogenic etiologies. Cheyne-Stokes breathing (tachypnea alternating with apnea) is usually indicative of severe bilateral hemispheric dysfunction. Biots breathing (irregular Cheyne-Stokes) suggests a localization in the lower brainstem. Central neurogenic hyperventilation typically accompanies damage to the rostral brainstem tegmentum and the paramedian pontine reticular formation. Apneustic breathing (brief end-inspiratory pauses alternating with end-expiratory pauses) is indicative of injury to the respiratory centers in midcaudal pons. Ataxic breathing is commonly seen with injury to the reticular formation of the dorsomedial medulla extending to the obex and occurs with acute medullary compression.

hyperventilation to maintain a PaCO2 level of 25 to 30 mm Hg, osmotherapy (mannitol 1 gm/kg IV) and diuretics (furosemide 10 to 20 mg IV), and neurosurgical consultation for external drainage of cerebrospinal fluid or emergent surgical procedures for decompression. Admission and emergent transfer of such a patient to a critical care unit setting are necessary for appropriate further management.

SUMMARY
Although the causes of coma are numerous, the principles of management of an unconscious patient center on early recognition and timely evaluation of possible reversible or treatable causes. These principles include (1) providing cardiopulmonary support to maintain oxygenation and cerebral perfusion to limit propagation of secondary brain injury; (2) close and frequent neurologic follow-up examinations to detect early deterioration; and (3) emergent measures for brain resuscitation in patients with severe brain injury. Following emergent critical care, the clinician has the luxury of time to embark on a more thorough evaluation of history of illness and further diagnostic tests to arrive at an etiologic diagnosis. Adherence to these principles can frequently lead to good outcomes in patients with treatable causes of coma from brain injury. SUGGESTED READING
Bhardwaj A: Cerebral edema and intracranial hypertension. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press. Plum F, Posner JB: The pathologic physiology of signs and symptoms of coma. In The diagnosis of stupor and coma, ed 3, New York, 1982, Oxford University Press, 1-86. Wijdicks EFM: Coma and other states of altered awareness. In Neurologic complications of critical illness, ed 2, New York, 2000, Oxford University Press, 3-27. Ziai WC: Coma and altered consciousness. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press.

Brain Resuscitation
Alterations in the level of consciousness from catastrophic brain injuries including trauma and subdural, subarachnoid, and intraparenchymal hemorrhage are encountered commonly in clinical practice. Early recognition of herniation syndromes or clinical evidence of intracranial hypertension warrants an emergent response to confirm clinical diagnosis with a noncontrast CT scan of brain and institution of therapies for brain resuscitation. General measures include avoidance of agitation and fever, maintenance of a euvolemic state and systemic blood pressure, facilitating venous outflow by elevating the head to 30 degrees, and maintaining the neck in a midline position. Specific therapies include emergent endotracheal intubation for controlled

Vertigo and Disequilibrium


Mark F. Walker, M.D.

Dizziness is a common complaint because it encompasses a wide variety of symptoms, and terms such as dizziness, light-headedness, and even disequilibrium may have many different meanings. Thus, an important first step in the treatment of patients with dizziness is to make the correct diagnosis. Too often, patients are simply labeled as having vertigo and given a vestibular suppressant medication without an adequate attempt to characterize the actual symptom or its underlying cause.
Johnson: Current Therapy in Neurologic Disease (7/E)

Vertigo and Disequilibrium

5
Disorders of Consciousness

Vertigo is an illusory sense of motion, such as spinning, rocking, or tilting, that is caused by an imbalance in the labyrinthine inputs or their central connections. It is important to ask patients with vertigo whether it has happened just once or if there have been multiple attacks, the duration of the episodes (e.g., minutes, hours, days), whether there are any provoking factors (e.g., head movement), and what, if any, are the associated symptoms (e.g., hearing loss, ear pain/pressure, posterior circulation symptoms). A basic differential diagnosis of common causes is given in Table 1. Disequilibrium is a less precisely defined symptom. I use this term to describe feelings of imbalance or unsteadiness, most prominent when standing and generally minimal when at rest. Other symptoms that may be labeled dizziness but should be distinguished from true vertigo include motion sickness, whether evoked by true motion or by motion of the visual scene (e.g., when watching television), presyncopal sensations, and anxiety. Obviously, this is important, because faintness due to intermittent hypotension requires a cardiovascular evaluation, and an anxiety disorder may need psychiatric treatment. In addition to the history, a careful examination is essential. Patients with dizziness should be evaluated for any evidence of reduced vestibular function in one or both ears. The most useful bedside test of peripheral vestibular function is the head impulse or head thrust test. This is a rapid small-amplitude manual rotation performed while the subject fixates the examiners nose. If vestibular function is reduced on the side to which the head is rotated, the eyes will move with the head, and after the head stops, a catch-up saccade will be seen as the eyes return to the original target. Hearing should also be tested, including audiometry, particularly to look for a unilateral hearing loss that would support a peripheral problem. The other cranial
TABLE 1 Causes of Vertigo and Disequilibrium
Cause Acute Prolonged Vertigo, Single Episode Vestibular neuritis/labyrinthitis Labyrinthine infarction Cerebellar or brainstem infarction or hemorrhage Recurrent Vertigo Benign paroxysmal positional vertigo Transient ischemic attacks Menieres disease (endolymphatic hydrops) Migraine Autoimmune (systemic or labyrinthine only) Anxiety

nerves should also be tested, keeping in mind the need to rule out a cerebellar or brainstem lesion. Finally, patients with recurrent vertigo should be subjected to positional testing (i.e., the Dix-Hallpike maneuver) to look for evidence of positional vertigo and nystagmus. Laboratory testing of vestibular function includes caloric testing, which is best for identifying a unilateral vestibular deficit, and rotatory chair testing, which is best for identifying bilateral vestibular hypofunction.

Treatment of Vertigo
The treatment of vertigo depends on the underlying cause. We consider the most common entities here. ACUTE PROLONGED VERTIGO Acute prolonged vertigo refers to a single episode (nonrecurrent) of spontaneous vertigo, usually accompanied by nausea, vomiting, and imbalance, that lasts for hours to days. It is important to make sure that the vertigo is continuous rather than occurring in multiple frequent but brief episodes (e.g., positional vertigo). Causes of acute prolonged vertigo include vestibular neuritis (labyrinthitis) and labyrinthine ischemia. In patients who are older or otherwise at risk for vascular disease, an ischemic cause should be ruled out by magnetic resonance (MR) imaging and MR angiography of the posterior circulation, including visualization of the neck vessels from the vertebral origins. Patients in whom there is any suspicion of a central lesion should be imaged emergently to look for a brainstem or cerebellar infarct or hemorrhage. Vestibular neuritis generally improves over several days, with subsidence of vertigo and nystagmus, although there is often a lingering imbalance and

Comments

Vertigo, nausea, and vomiting lasting hours to days; slow recovery over weeks to months Similar to vestibular neuritis but caused by ischemia

Attacks provoked by changes in head position relative to gravity, lasting for seconds; positive Dix-Hallpike maneuver Episodes generally last minutes, often accompanied by other posterior circulation symptoms Severe vertigo, nausea, and vomiting, lasting hours; accompanied by transient low-frequency hearing loss, low-pitched tinnitus, ear pain and/or fullness in the affected ear Wide range of symptoms from brief attacks of vertigo to prolonged disequilibrium; may be similar to Menieres disease, but without hearing loss; vestibular symptoms often occur without headache Fluctuating vertigo and hearing loss; may progress to bilateral deafness if not treated Panic attacks and chronic anxiety may include vertiginous sensations and disequilibrium

Johnson: Current Therapy in Neurologic Disease (7/E)

Vertigo and Disequilibrium

motion sensitivity that may last for months. It has been proposed to treat acute vestibular neuritis with steroids and/or antiviral agents, based on the hypothesis that an inflammatory process, perhaps related to a herpesvirus, is responsible. A recent randomized study found that patients begun on a methylprednisolone taper within 3 days of symptom onset had less caloric asymmetry 12 months later (implying greater recovery in the affected ear). Valacyclovir had no effect. Thus, it is reasonable to treat patients with steroids in the acute stage if there are no contraindications, keeping in mind that it is not yet known whether there is a difference in functional outcome. If acute hearing loss is present, high-dose steroids (e.g., a prednisone taper beginning at 60 to 100 mg/day) should be given, and the patient should be referred to a neuro-otologist; autoimmune inner ear disease can cause severe bilateral hearing loss, if not treated promptly. Patients with vestibular neuritis usually benefit from a vestibular suppressant and/or an antiemetic (see later), which should only be given for several days, while symptoms are most severe. Long-term vestibular suppression should be avoided because it may interfere with central compensatory mechanisms that promote functional recovery. To facilitate compensation, it is important that normal activity be resumed as quickly is possible. Patients should be referred for vestibular therapy, if it is available. MENIERES DISEASE Menieres disease, also called endolymphatic hydrops, is thought to be due to an excess of endolymph fluid in the inner ear. Clinically, it produces recurrent episodes characterized by pain, pressure, and fullness in the affected ear; a low-pitched, roaring tinnitus; low-frequency hearing loss; and acute vertigo with nausea and vomiting. Episodes typically last for hours. Although hearing generally recovers between attacks, over time, after repeated episodes, there may be a permanent loss. The hearing loss associated with Menieres disease is most severe at low frequencies; this helps to distinguish it from other causes of sensorineural hearing loss, which typically affect the high frequencies. Diagnosis of Menieres disease is made on clinical grounds. Audiometry is important, and transtympanic electrocochleography may help, by demonstrating abnormal evoked electrical potentials that occur with hydrops. Patients who have recurrent vertigo without hearing loss or other aural symptoms are more likely to have another cause, such as vestibular migraine. Patients in whom Menieres disease is suspected should be tested for inflammatory and infectious causes with an erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, rheumatoid factor, thyroidstimulating hormone, and rapid plasma reagin/fluorescent treponemal antibody (autoimmune disease and otosyphilis can mimic Menieres disease). Initial treatment of Menieres disease includes sodium restriction (1 gm of Na+ per day) and diuretic therapy. Options include acetazolamide hydrochlorothiazide and hydrochlorothiazide/triamterene. If attacks persist, the patient should be referred to a

neuro-otologist for consideration of ablative therapy. Intratympanic gentamicin is the current treatment of choice. If this is done properly, enough hair cell damage can be effected to alleviate attacks without causing severe vestibular hypofunction or significant hearing loss. Since the advent of gentamicin therapy, surgical ablation (labyrinthectomy or vestibular nerve section) is seldom needed. When attacks are prolonged and cannot be fully controlled, a vestibular suppressant (see later) may be prescribed to be taken at the onset of an attack. VESTIBULAR MIGRAINE Migraine is one of the most common causes of episodic vestibular symptoms. Migraine-related dizziness may have many forms, including attacks of vertigo that last from minutes to hours, as well as disequilibrium and motion sensitivity that may last for days to weeks or longer. Sensitivity to visual motion (e.g., watching movies or television) is common. Occasionally, vertigo occurs as an aura followed by headache, but most often dizzy spells and headaches occur independently. There is also a vestibular form of migraine in children (benign paroxysmal vertigo of childhood). Vestibular migraine is treated similarly to other forms of migraine (see Chapter 18). In general, vestibular symptoms are reduced or prevented by the usual migraine prophylactic agents. The choice of a particular drug often is based on comorbidities (e.g., anxiety, depression, hypertension). It is important to be aware that depression and anxiety are common in these patients, particularly those with more severe chronic symptoms. In those cases, assessment by a psychiatrist may be helpful. If a prophylactic medication is given, the dose must be titrated up to a therapeutic level, and sufficient time (weeks to several months) must be given to determine its full effect. I most commonly begin treatment with an antidepressant (e.g., nortriptyline or venlafaxine). I begin with nortriptyline 10 to 25 mg at bedtime and titrate the daily dose by 10 to 25 mg once a week, up to a total dose of 75 to 100 mg if needed and tolerated. Venlafaxine XR is started at 37.5 mg per day, usually best taken in the morning, and titrated by 37.5 mg per day once a week. Most patients need doses of 150 to 300 mg per day for adequate prophylaxis. Other options include beta blockers (if the blood pressure will tolerate them), calcium channel blockers (e.g., verapamil), and anticonvulsants (e.g., gabapentin, topiramate, valproate). BENIGN PAROXYSMAL POSITIONAL VERTIGO Benign paroxysmal positional vertigo (BPPV) is caused by otoconial debris that dislodges from the otolith membrane and becomes free-floating in the endolymph. If it falls into one of the semicircular canals (usually the posterior), it can cause excitation of the canal when the head moves relative to gravity. The typical scenario is brief (<1 minute) vertigo provoked by lying back, rolling over in bed, or putting the head back to look up. Attacks do not occur spontaneously without head movement. BPPV is diagnosed by
Johnson: Current Therapy in Neurologic Disease (7/E)

Vertigo and Disequilibrium

7
Disorders of Consciousness

the Dix-Hallpike maneuver, which for posterior canal BPPV should produce a transient upbeating and torsional nystagmus when the affected ear is down. The aim of BPPV treatment is to facilitate movement of the otoconia out of the posterior canal and back into the vestibule, where they will hopefully dissolve and be reabsorbed. There are several repositioning maneuvers that are quite effective. I usually use the Epley maneuver. As shown in Figure 1, the treatment begins by putting the patient in the Dix-Hallpike position with the affected ear down. The head is then turned to the other side (without lifting it). Next the patient is asked to roll over on his or her side, with the head positioned such that the nose is pointing to the floor. Finally, the patient sits up on the side of the bed. If successful, there will be no more vertigo or nystagmus when the maneuver is repeated. The patient can be taught to perform this maneuver at home, using pillows under

the shoulders so that the head can hang back but still rest on the bed.* Vestibular suppressant medications are not generally helpful for BPPV, because the attacks are too short; by the time the medication has taken effect, the vertigo has subsided. TRANSIENT ISCHEMIC ATTACKS Recurrent vertigo may be caused by ischemia; it usually is accompanied by other posterior circulation symptoms but occasionally occurs in isolation. Patients suspected of having ischemic vertigo should be given antiplatelet
*Illustrations of this technique and an alternative treatment, the Semont maneuver, can be found at http://www.dizzinessand-balance.com/disorders/bppv/bppv.html#treatment and http:// www.neurology.org/cgi/content/full/63/1/150/DC1.

Posterior canal

Particles Vantage point

Gravity

A
Superior canal

Superior canal Utriculus Posteriorcanal ampulla

D
Posterior canal Superior canal Utriculus Particles

Gravity Particles

Vantage point

B
Superior canal Posterior canal

Posterior-canal ampulla

Vantage point

Gravity

Particles

FIGURE 1. Epley maneuver for treatment of right posterior canal BPPV. Gravity is used to move the otoconia out of the posterior canal. The position of the particles in the labyrinth at the end of each step is shown in red. Each position should be held for 30 seconds. A, The head is turned 45 to the affected side, and the patient is brought to the head-hanging supine position (this step is the same as the Dix-Hallpike maneuver). B, The head is turned 90 (away from the affected ear) without lifting it. C, The patient is brought into the seated position with the head tilted slightly down. (Reprinted from Furman JM, Cass SP: Benign paroxysmal positional vertigo. N Engl J Med 341:1590-1596, with permission.) Johnson: Current Therapy in Neurologic Disease (7/E)

Neurogenic Orthostatic Hypotension

agents and should have the appropriate cerebrovascular evaluation.

Treatment of Disequilibrium
Disequilibrium (see earlier) may have many different causes. In general, there are two groups of patients in this category: (1) those who have an objective balance deficit due to a specific central or peripheral neurologic disorder, including bilateral vestibular hypofunction; and (2) those who have the perception of imbalance, but whose neurologic and vestibular examinations are unremarkable. Treatment of neurologic causes of imbalance is focused on the underlying disorder. Common causes of disequilibrium without neurologic or vestibular deficits include migraine and anxiety disorders. These patients often respond to treatment with an antidepressant medication or another migraine prophylactic agent. BILATERAL VESTIBULAR HYPOFUNCTION Bilateral vestibular hypofunction causes imbalance, worse in the dark, and oscillopsia and visual blurring with head movement (due to the loss of the vestibulo-ocular reflex). This diagnosis may be missed, and thus, vestibular function should be explicitly tested in any patient who complains of disequilibrium or imbalance. The head impulse test described earlier is the best bedside test; in the laboratory, rotational testing is the most sensitive. The most common identified cause of bilateral vestibular hypofunction is ototoxicity, particularly from aminoglycosides. Other causes include hereditary degenerations, autoimmune disorders, bilateral internal auditory canal tumors (MR imaging should be done), bilateral vestibular neuritis, and bilateral Menieres disease. In the case of ototoxicity, an important part of treatment is to detect this early and stop the medication. Once damage has occurred, it is generally irreversible. In that case, the goal becomes to maximize the central compensatory process. To this end, vestibular rehabilitation therapy is helpful. Future use of potentially ototoxic drugs should be avoided. Vestibular suppressants are not helpful for bilateral vestibular hypofunction or other neurologic causes of disequilibrium; in fact, they may make balance worse.

preventive measures; and for occasional use for the prevention of motion sickness. In general, vestibular suppressants should not be used chronically, and they should not be given to patients with imbalance and nonvestibular dizziness. A limiting side effect is often sedation. Meclizine (12.5 to 25 mg up to three times a day) can be used for mild attacks of vertigo and for motion sickness. Promethazine (25 mg two to four times a day) is useful for more severe vertigo accompanied by nausea and vomiting. Benzodiazepines (e.g., diazepam, lorazepam, clonazepam) are also effective vestibular suppressants for short-term use. SUGGESTED READING
Baloh RW: Dizziness, hearing loss, and tinnitus, Los Angeles, 1998, FA Davis. Furman JM, Cass SP: Benign paroxysmal positional vertigo, N Engl J Med 341:1590-1596, 1999. Neuhauser H, Lempert T: Vertigo and dizziness related to migraine: a diagnostic challenge, Cephalalgia 24:83-91, 2004. Radtke A, von Brevern M, Tiel-Wilck K, et al: Self-treatment of benign paroxysmal positional vertigo: Semont maneuver versus Epley procedure, Neurology 63:150-152, 2004. Strupp M, Zingler VC, Arbusow V, et al: Methylprednisolone, valacyclovir, or the combination for vestibular neuritis, N Engl J Med 351:354-361, 2004.

PATIENT RESOURCES
Videos demonstrating the Semont maneuver and the Epley procedure: http://www.neurology.org/cgi/content/full/63/1/150/DC1 Information on vestibular disorders: http://www.dizziness-and-balance.com/disorders/ Patient support groups: http://www.vestibular.org/ http://www.menieres.org/

Neurogenic Orthostatic Hypotension


Robert D. Fealey, M.D.
Orthostatic hypotension has been defined as a reduction in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg, within 3 minutes of standing up. Orthostatic hypotension most often produces intermittent symptoms. Lightheadedness, weakness or tiredness, impaired concentration, and visual blurring or dimming are common symptoms. Typically these occur on standing in the morning, after heavy meals, during times of elevated core or environmental temperature, and with prolonged standing and exertion in the upright position. The symptoms are caused by cerebral hypoperfusion, their intermittent nature due to transient worsening by vasodilating stressors (alcohol, heat, meal-induced neurohumoral changes, medication effects) and variable degrees of dehydration, anemia, and postural deconditioning.
Johnson: Current Therapy in Neurologic Disease (7/E)

Vestibular Suppressant Medications


In general, the treatment of vestibular disorders should focus on the underlying cause. However, vestibular suppressants and antiemetics may be useful in some cases for the symptomatic management of vertigo. Their most appropriate use is in the acute phase of a unilateral vestibular syndrome (e.g., vestibular neuritis), when vertigo, nausea, and vomiting are most severe; for occasional symptomatic treatment of recurrent vertigo in patients with disorders such as Menieres disease and migraine, when attacks cannot be fully controlled by

Neurogenic Orthostatic Hypotension

agents and should have the appropriate cerebrovascular evaluation.

Treatment of Disequilibrium
Disequilibrium (see earlier) may have many different causes. In general, there are two groups of patients in this category: (1) those who have an objective balance deficit due to a specific central or peripheral neurologic disorder, including bilateral vestibular hypofunction; and (2) those who have the perception of imbalance, but whose neurologic and vestibular examinations are unremarkable. Treatment of neurologic causes of imbalance is focused on the underlying disorder. Common causes of disequilibrium without neurologic or vestibular deficits include migraine and anxiety disorders. These patients often respond to treatment with an antidepressant medication or another migraine prophylactic agent. BILATERAL VESTIBULAR HYPOFUNCTION Bilateral vestibular hypofunction causes imbalance, worse in the dark, and oscillopsia and visual blurring with head movement (due to the loss of the vestibulo-ocular reflex). This diagnosis may be missed, and thus, vestibular function should be explicitly tested in any patient who complains of disequilibrium or imbalance. The head impulse test described earlier is the best bedside test; in the laboratory, rotational testing is the most sensitive. The most common identified cause of bilateral vestibular hypofunction is ototoxicity, particularly from aminoglycosides. Other causes include hereditary degenerations, autoimmune disorders, bilateral internal auditory canal tumors (MR imaging should be done), bilateral vestibular neuritis, and bilateral Menieres disease. In the case of ototoxicity, an important part of treatment is to detect this early and stop the medication. Once damage has occurred, it is generally irreversible. In that case, the goal becomes to maximize the central compensatory process. To this end, vestibular rehabilitation therapy is helpful. Future use of potentially ototoxic drugs should be avoided. Vestibular suppressants are not helpful for bilateral vestibular hypofunction or other neurologic causes of disequilibrium; in fact, they may make balance worse.

preventive measures; and for occasional use for the prevention of motion sickness. In general, vestibular suppressants should not be used chronically, and they should not be given to patients with imbalance and nonvestibular dizziness. A limiting side effect is often sedation. Meclizine (12.5 to 25 mg up to three times a day) can be used for mild attacks of vertigo and for motion sickness. Promethazine (25 mg two to four times a day) is useful for more severe vertigo accompanied by nausea and vomiting. Benzodiazepines (e.g., diazepam, lorazepam, clonazepam) are also effective vestibular suppressants for short-term use. SUGGESTED READING
Baloh RW: Dizziness, hearing loss, and tinnitus, Los Angeles, 1998, FA Davis. Furman JM, Cass SP: Benign paroxysmal positional vertigo, N Engl J Med 341:1590-1596, 1999. Neuhauser H, Lempert T: Vertigo and dizziness related to migraine: a diagnostic challenge, Cephalalgia 24:83-91, 2004. Radtke A, von Brevern M, Tiel-Wilck K, et al: Self-treatment of benign paroxysmal positional vertigo: Semont maneuver versus Epley procedure, Neurology 63:150-152, 2004. Strupp M, Zingler VC, Arbusow V, et al: Methylprednisolone, valacyclovir, or the combination for vestibular neuritis, N Engl J Med 351:354-361, 2004.

PATIENT RESOURCES
Videos demonstrating the Semont maneuver and the Epley procedure: http://www.neurology.org/cgi/content/full/63/1/150/DC1 Information on vestibular disorders: http://www.dizziness-and-balance.com/disorders/ Patient support groups: http://www.vestibular.org/ http://www.menieres.org/

Neurogenic Orthostatic Hypotension


Robert D. Fealey, M.D.
Orthostatic hypotension has been defined as a reduction in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg, within 3 minutes of standing up. Orthostatic hypotension most often produces intermittent symptoms. Lightheadedness, weakness or tiredness, impaired concentration, and visual blurring or dimming are common symptoms. Typically these occur on standing in the morning, after heavy meals, during times of elevated core or environmental temperature, and with prolonged standing and exertion in the upright position. The symptoms are caused by cerebral hypoperfusion, their intermittent nature due to transient worsening by vasodilating stressors (alcohol, heat, meal-induced neurohumoral changes, medication effects) and variable degrees of dehydration, anemia, and postural deconditioning.
Johnson: Current Therapy in Neurologic Disease (7/E)

Vestibular Suppressant Medications


In general, the treatment of vestibular disorders should focus on the underlying cause. However, vestibular suppressants and antiemetics may be useful in some cases for the symptomatic management of vertigo. Their most appropriate use is in the acute phase of a unilateral vestibular syndrome (e.g., vestibular neuritis), when vertigo, nausea, and vomiting are most severe; for occasional symptomatic treatment of recurrent vertigo in patients with disorders such as Menieres disease and migraine, when attacks cannot be fully controlled by

Neurogenic Orthostatic Hypotension

9
Disorders of Consciousness

Although normal individuals can have orthostatic hypotension, this chapter concentrates on patients with disorders of the central or peripheral autonomic nervous system that disrupt the autonomous regulation of blood pressure. These patients are said to have neurogenic orthostatic hypotension. Some of the neurologic disorders that commonly cause neurogenic orthostatic hypotension include pure autonomic failure, multiple system atrophy, autonomic neuropathy (diabetic, amyloidosis, immune mediated), and high thoracic and cervical myelopathy. Many pathophysiologic factors are involved in neurogenic orthostatic hypotension; those having therapeutic implications are briefly discussed next. Reduction in effective blood volume can result from denervation of blood vessels. Resistance vessels fail to constrict on standing, and blood volume pools in the legs and abdomen in venous capacitance circuits having reduced vascular tone. Decreased red blood cell mass or a normochromic-normocytic anemia can develop from denervation of the kidney and relative decreased erythropoietin production. Denervation of arterial and lowpressure cardiopulmonary baroreceptors and mesenteric capacitance bed results in both upright hypotension and supine hypertension. Loss of afferent input to the brain also can cause excessive renal loss of water and sodium during recumbency, producing nocturnal polyuria. Neurogenic constipation and upper intestinal hypomotility with decreased appetite and food/fluid intake can result in dehydration, reduced blood volume, and muscle protein loss, further aggravating neurogenic orthostatic hypotension. Neurogenic diarrhea can occur, producing rapid dehydration and electrolyte abnormalities. Mindful of these pathophysiologic mechanisms and confounding medical conditions (bladder infections, anemia, dehydration and preexisting hypertension, secondary anxiety/depression) that often coexist in these patients, I next discuss the principles and specifics of treatment.

The steps of neurogenic orthostatic hypotension treatment include patient education; dietary changes and adjustments to the home environment and timing of activities; physical measures such as countermaneuvers; support garments; exercises; and, finally, drug therapy. PATIENT EDUCATION Patient education is most important, and both patient and caregiver need to hear the instructions. Patients learn the symptoms of low blood pressure (lightheadedness; slowed, confused thinking; visual blackening or blurring; loss of postural tone with falls or jerky movements) and when they are most likely to occur (when first arising in the morning, after a meal, in hot environments, when febrile). I provide a prescription for an automated digital sphygmomanometer for brachial blood pressure measurements and have patients log their readings several times a day, 3 days a week. One-minute supine and 1-minute standing blood pressure and heart rate are taken on first arising; just before and 1 to 2 hours after taking pressor medications; just before and 30 minutes after a meal; and at bedtime. The log is a self-education tool for patients who learn specific symptoms that correlate with low blood pressure and what their orthostatic stressors are. The log provides physicians with documentation of response to treatment and a way of recognizing supine hypertension that may require therapy. DIETARY MEASURES Increase salt and fluid intake, so that 6 to 8 gm of sodium (15 to 20 gm of salt) and 2.0 to 2.5 L of fluid is ingested daily. Foods rich in salt include canned soups, chili, ham, bacon, sausage, soy sauce, commercially processed canned products, fast food, and salty snacks; salt can be added during preparation and at the table. Patients taking the potassium-depleting mineralocorticoid fludrocortisone acetate (Florinef) should eat highpotassium foods such as fruits, vegetables, No-salt, poultry, fish, beef, and pork. Juices and sports drinks can make up some of the fluid intake. Sports drinks with less carbohydrate and more sodium and some potassium are preferred (e.g., per 8 oz: 2.5% to 6% carbohydrate and 110 to 244 mg sodium content.* One or two 8-oz (237-mL) bottles can be given with each meal. Tap water taken orally in amounts of 500 mL in 5 minutes with meals and 200 to 300 mL between major meals also can be an effective pressor agent. Salt tablets can be used for a portion of the extra salt intake. I use Thermotabs, which have 450 mg of sodium chloride and 30 mg of potassium chloride per tablet. Two or three tablets can be given two or three times a day. A 24-hour urinary sodium excretion of 170 mg or more suggests a high salt intake is being accomplished.

Specific Goals and Steps of Neurogenic Orthostatic Hypotension Treatment


One of the first steps in treating neurogenic orthostatic hypotension is to review the patients medications for drugs contributing to hypotension. Stopping or substituting for such a drug (Table 1) may provide dramatic improvement. Severe anemia, dehydration, or elevated core temperature should be corrected, if present. Further treatment is guided by four goals: (1) to eliminate or reduce symptoms of upright hypotension; (2) to minimize supine hypertension; (3) to measurably increase standing time and the patients ability to do upright activities of daily living; and (4) to provide practical advice on diet, lifestyle changes, nonpharmacologic measures, and monitoring of blood pressure so patients are actively involved in their treatment. The specific steps to accomplish these goals are given in the next section.
Johnson: Current Therapy in Neurologic Disease (7/E)

*I use Pedialyte, which has 2.5% carbohydrate and 244 mg sodium per 8 oz.

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Neurogenic Orthostatic Hypotension

TABLE 1 Medications that Worsen Orthostatic Hypotension: Alternative Treatment


Specific Agent or Class Antihypertensive Drugs Sympatholytic drugs (methyldopa, reserpine, guanethidine) Alpha-adrenergic blockers Beta-adrenergic blockers Diuretics Calcium channel blockers Peripheral vasodilators (hydralazine) Angiotensin-converting enzyme inhibitors and angiotensin blockers Coronary Vasodilators Nitroglycerin, isosorbide dinitrate, nitrate patches Urologic (Sphincter Inhibitor) Drugs Alpha-adrenergic inhibitors (prazosin, terazosin) Psychiatric Drugs Tricyclic antidepressants Neuroleptics Antiparkinson Agents Carbidopa-levodopa, dopamine D2 agonists Suggested Remedial Steps

Consider carefully stopping these drugs under physician observation Consider stopping under physician supervision Consider switch to a beta blocker with intrinsic sympathomimetic activity (e.g., pindolol) Reduce or stop agent under physician supervision Use ionotropics instead of diuretics for treating congestive heart failure Consider using only at bedtime (e.g., nifedipine 10 mg hs) to treat supine hypertension Use at bedtime to counteract disease- and treatment-related recumbent hypertension Often can be continued at lower dose, especially in diabetic autonomic neuropathyassociated neurogenic orthostatic hypotension Consider alternative treatment of coronary ischemia (e.g., angioplasty/stent) Nitrate patch can be used at bedtime for supine hypertension Consider switch to tamsulosin Consider stopping and performing a TURP if urodynamics and cystoscopy show significant obstructive component Consider switch to SSRI agents Consider switch to atypical antipsychotics (quetiapine) Add fludrocortisone and midodrine if dopa responsive Consider stopping if disorder is dopa unresponsive Switch to amantadine or cholinergic antagonist (e.g., benztropine, trihexyphenidyl)

SSRI, Selective serotonin reuptake inhibitor; TURP, transurethral resection of prostate.

A high-fiber diet (1 cup of bran daily, 1 tsp of methylcellulose up to three times a day) with increased protein and reduced carbohydrate and smaller, more frequent meals is important to avoid constipation and postprandial exacerbation of orthostatic hypotension. If supine hypertension is a problem, a carbohydrate-rich snack just before bedtime can reduce blood pressure for 1 to 2 hours. Vasodilators such as alcohol exacerbate orthostatic hypotension and should be avoided. Two cups of strong, caffeinated coffee (about 250 mg of caffeine) in the morning followed by 250 to 500 mL of liquid with pressor medications and 30 minutes of sitting in bed before getting up for the day is suggested for early-morning neurogenic orthostatic hypotension. Patients can be expected to gain from 2 to 4 kg (4 to 8 lb) above their ideal body weight when these dietary measures are coupled with volume-expanding pharmacologic treatment. PHYSICAL MEASURES Head-up tilt can be accomplished with 4-inch blocks under the bed legs, or a foam wedge can be used under the mattress; an electric hospital bed is essential in

severe cases, and some patients require a recliner chair. Head-up tilt helps to reduce supine blood pressure and provides a stimulus to recondition postural reflexes. Physical countermaneuvers are simple methods that patients can learn to combat orthostatic dizziness. Crossing legs above the knees and squeezing the thigh muscles together, bending forward as if to tie a shoe, raising a flexed leg up on a chair, or squatting when ableall act to increase thoracic blood volume, left ventricular filling pressure, cerebral perfusion, and upright blood pressure. While sitting, patients can cross their legs or sit in knee-chest position to produce the same effects. Such maneuvers can be applied instantly to prevent syncope or increase standing time (the amount of time after standing before orthostatic symptoms develop); the latter may increase by 1 to 2 minutes, allowing many activities done standing still to be accomplished. Exercise can consist of graded walks or timed treadmill sessions. A rolling walker with a seat may allow even severely affected patients to participate. I recommend compression tights (pantyhose style, compression 30 to 40 mm Hg) in patients who are able to get them on and tolerate them. In some patients,
Johnson: Current Therapy in Neurologic Disease (7/E)

Neurogenic Orthostatic Hypotension

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Disorders of Consciousness

a well-fitting abdominal binder with a thigh-high stocking is better tolerated. Many companies make compression garments, which the patient needs to have fitted carefully and put on while still recumbent in the morning. I prescribe two pairs at onset so one can be washed while the other is worn. Elevating legs slightly during the night reduces pedal edema and permits continued use with volume expansion treatment. These dietary and physical measures constitute initial, basic, or standard steps of therapy. These are critical to have in place before initiating pharmacologic agents that cause blood volume expansion, adrenergic receptor stimulation, or vasodilation blocking.

Pharmacologic Therapy
Drug therapy is added to the initial steps for patients still symptomatic with neurogenic orthostatic hypotension. The principal medications I use for neurogenic orthostatic hypotension are shown in Table 2. Brief comments regarding each agent are given in the following sections. VOLUME-EXPANDING AGENTS Fludrocortisone acetate is a potent mineralocorticoid that remains a mainstay of therapy for neurogenic

orthostatic hypotension. Fludrocortisone has a half-life of 3 hours and is given twice a day. Its full effect requires 1 to 2 weeks and is accompanied by a 3- to 6-lb weight gain. Its renal cellular effects cause retained sodium and enhanced potassium excretion, resulting in hypokalemia commonly and hypomagnesemia rarely. The starting dose is usually 0.1 mg orally twice a day. Increments of 0.1 mg per dose per week are used until an effect on weight and blood pressure is realized. Doses higher than 0.4 mg per day are infrequently needed, and higher doses produce severe supine hypertension, glucocorticoid effect, headache, and congestive heart failure. Weekly potassium determinations for a month and then monthly should help determine the level of supplementation required. Supine blood pressure is checked daily, and patients are instructed not to lie flat. Supine hypertension (180/100 mm Hg) is treated by dose reduction or as specified in Table 2. Other drugs used for transient sodium retention and volume expansion include indomethacin (50 to 75 mg orally three times a day), ibuprofen (400 mg orally three times a day), and rofecoxib (Vioxx) 50 mg twice a day. SYMPATHOMIMETICS Midodrine is an alpha1-adrenergic receptor agonist acting peripherally and constricting both arterioles

TABLE 2 Pharmacologic Treatment of Neurogenic Orthostatic Hypotension


Drug Fludrocortisone (Florinef) Dose Purpose, Mechanism of Action, When to Start Volume expansion; start after high salt (6-8 gm sodium or 10-15 gm salt) and fluid (2-2.5 L/day) intake has been established Vasoconstrictor: alpha1- agonist; increases peripheral resistance and blood pressure, reduces venous capacitance; initiate alone in mild NOH, with fludrocortisone in severe NOH. Enhances sympathetic ganglionic transmission, GI tract smooth muscle contraction; for NOH with neurogenic constipation or supine hypertension Expand blood volume; correct anemia of autonomic failure; use when other treatments not working Renal V2 vasopressin receptor agonist, antidiuretic; advanced disease with nocturnal polyuria Used in patients with severe postprandial hypotension; combine with midodrine, 5-10 mg (30 min before meal), for best effect Side Effects and Precautions Expect 3-6 lb weight gain with mild pedal edema; supine hypertension, hypokalemia are common; hypomagnesemia, CHF rare; headache in young Piloerection, scalp itching, urinary urgency/hesitancy; supine hypertension; do not give after 5:00-6:00 PM Abdominal cramping and diarrhea, salivation, tearing, muscle twitches; may need to combine with low-dose midodrine; rule out GI mechanical obstruction before starting Must supplement iron, potassium before and during use; headache, supine hypertension, high cost, venous thrombosis Start in hospital setting in patients with severe nocturnal polyuria; check serum Na+, intake and output; avoid hyponatremia Given by SC injection; warm solution, give small volume to minimize pain; may alter insulin requirements; nausea, diarrhea, gallstones, cramps

Midodrine (ProAmatine)

Pyridostigmine (Mestinon)

Initial: 0.1 mg qAM; increase by 0.1 mg weekly to 0.1-0.2 mg bid, second dose at noon 2.5 mg PO, 30-45 min before breakfast and lunch; increase each dose by 2.5 mg/wk up to 10 mg PO qid if needed 30 mg PO bid (morning and noon); increase by 30 mg/day weekly up to 60 mg tid
25-50 U/kg daily SC for 2-3 wk, then maintenance 25-50 U/kg three times weekly for 3 mo 5-10 g intranasal (0.2 mg PO) qhs to start maintenance: 10-40 g intranasal (0.2-0.6 mg PO) Initial: 0.2 g/kg tid with meals; up to 1 g/kg given with breakfast

Erythropoietin (Epogen) Desmopressin (DDAVP) Octreotide (Sandostatin)

CHF, Congestive heart failure; GI, gastrointestinal; NOH, neurogenic orthostatic hypotension.

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Neurogenic Orthostatic Hypotension

and veins. It is currently the drug of choice. The drug is well absorbed and does not cause tachycardia or central stimulation. A pressor effect lasts 2 to 4 hours for a 10-mg dose. The starting dose is usually 2.5 to 5 mg two or three times a day given about 45 minutes before meals. Piloerection, scalp itching, supine hypertension, headache, urinary urgency and retention, and nocturnal natriuresis are the main side effects. The drug is used with fludrocortisone and dietary and physical measures for greatest benefit; use without fludrocortisone if supine hypertension is present. Do not give a dose after 6 PM. Do not lie down for 4 hours after a midodrine dose. Uncommonly midodrine is not tolerated and another sympathomimetic is used. Phenylpropanolamine (12.5 to 50 mg) and similar drugs (ephedrine, 12.5 to 50 mg, and pseudoephedrine, 30 to 60 mg) are indirect alpha1adrenergic agonists. The dose is given three times a day. Yohimbine is an alpha2-adrenergic antagonist that acts at central and peripheral presynaptic receptors to increase sympathetic output. The dose is 5.4 mg three times a day. Central nervous system stimulation and supine hypertension are common with these agents. They are hard to obtain as a result of a U.S. Food and Drug Administration decision to urge pharmaceutical companies to withdraw these agents from their formularies. There is evidence that 3,4-DL-threodihydroxyphenylserine (DL-DOPS) has promise as a novel agent that can increase endogenous norepinephrine and blood pressure in neurogenic orthostatic hypotension. It acts peripherally, and the decarboxylase inhibitor carbidopa lessens the pressor effect. However, DL-DOPS is still under investigation and is not generally available. ACETYLCHOLINESTERASE INHIBITORS Recently Singer and Schondorf and colleagues (see Suggested Readings) have described the use of acetylcholinesterase inhibition to treat neurogenic orthostatic hypotension. Pyridostigmine (Mestinon), 60 mg three times a day, reduced standing blood pressure fall and symptoms without raising supine blood pressure. Pyridostigmine may be combined with midodrine and allow a dose reduction in patients with supine hypertension or midodrine side effects. Pyridostigmine is useful in patients with neurogenic orthostatic hypotension and constipation. Diarrhea, nausea, cramping, muscle twitching, and bradycardia, are side effects.

hypotension. The treatment includes smaller, more frequent low-carbohydrate/high-protein meals and avoidance of alcohol; sitting with legs crossed at the thigh or in knee-chest position; water ingestion, 500 mL over 5 to 10 minutes, 15 minutes before each meal; and caffeine, 200 mg in the morning only. If additional treatment is needed, use indomethacin, 25 to 75 mg three times a day; midodrine, 5 to 10 mg 30 minutes before the meal; and, in severe cases, octreotide injections, 0.2 g/kg up to 1 g/kg subcutaneously just before meals. SUPINE HYPERTENSION Frequently, profound standing hypotension is complicated by worrisome supine hypertension that is both disease and treatment related. Sustained blood pressures higher than 200/120 mm Hg develop at night with recumbency, a characteristic of neurogenic orthostatic hypotension. Rarely a cerebral hemorrhage occurs; left ventricular strain and hypertrophy may develop. Increased renal perfusion produces nocturnal polyuria and subsequent sleep disruption. Helpful measures include increasing head-up tilt of the bed, a carbohydrate snack and exercise at bedtime, and the use of short-acting antihypertensive drugs such as hydralazine, 25 to 75 mg twice daily, during the night. Transdermal nitroglycerin, 0.025 to 0.1 mg/hr at bedtime, and nifedipine, 10 mg orally at bedtime, are alternatives. Measure supine blood pressure 1 to 2 hours after dosing to verify effect. Check antinuclear antibody titers periodically with hydralazine, and give supplemental pyridoxine, 50 mg daily. CHRONIC ANEMIA OF AUTONOMIC FAILURE Chronic anemia of autonomic failure may occur with neurogenic orthostatic hypotension. Serum erythropoietin levels are usually normal but relatively reduced. When anemia is moderate (hemoglobin between 8 and 10 gm/dL) and the patient is symptomatic on conventional orthostatic hypotension treatment, I will give erythropoietin. The caregiver and the patient are taught to give subcutaneous injections. Check iron stores and administer iron (ferrous sulfate, 200 mg orally two or three times a day). The dose is 25 to 50 U/kg, three times a week for 8 weeks, or until hematocrit normalizes. Supine hypertension, headache, and thrombotic events are potential adverse effects. SUGGESTED READING
Fealey RD, Robertson D: Management of orthostatic hypotension. In Low PA, editor: Clinical autonomic disorders, ed 2, Philadelphia, 1997, Lippincott-Raven, 763-775. Low PA: Neurogenic orthostatic hypotension. In Noseworthy JH, editor: Neurological therapeutics: principles and practice, New York, 2003, Martin Dunitz, 2267-2274. Robertson D: Primer on the autonomic nervous system, ed 2, San Diego, 2004, Elsevier, 403-421. Schondorf R: Acetylcholinesterase inhibition in the treatment of hypotension, J Neurol Neurosurg Psychiatry 74:1187, 2003. Johnson: Current Therapy in Neurologic Disease (7/E)

Treatment of Common Diseaseand Therapy-Related Problems of Neurogenic Orthostatic Hypotension


POSTPRANDIAL EXACERBATION OF ORTHOSTATIC HYPOTENSION Ingestion of food can cause severe supine and upright hypotension in patients with neurogenic orthostatic hypotension for up to 2 hours postprandially. Large, high-carbohydrate meals are most likely to produce

Parasomnias Singer W, Opfer-Gehrking TL, McPhee BR, et al: Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension, J Neurol Neurosurg Psychiatry 74:1294-1298, 2003.

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(obstructive sleep apnea, periodic leg movement), stress, or environmental factors. CONFUSIONAL AROUSALS Confusional arousals are characterized by mental or behavioral confusion associated with arousals from sleep, typically from slow-wave sleep in the first part of the night. Episodes typically last several minutes, and patients are usually disoriented and amnesic when awoken. The underlying pathophysiology is thought to be an incomplete awakening from slow-wave sleep, leading to intensification and prolongation of the normal period for transition from sleep to wakefulness. Confusional arousals represent an admixture of wakefulness into non-REM sleep. Patients awaken partially, exhibiting marked confusion, slow mentation, disorientation, perceptual impairment, and errors of logic. Behaviors can be simple to complex and may be inappropriate and even violent. Talking, shouting, and bruxism may also be seen. Attempts to console the child or awaken an individual may further increase agitation. Predisposing factors for confusional arousals include other conditions that disrupt sleep architecture such as circadian rhythm sleep disorders (shift work), sleep apnea, narcolepsy, and encephalopathies. Furthermore, sleep deprivation, fever, alcohol, stimulants, drug abuse, and exposure to other agents that deepen sleep and impair alertness can be precipitating factors. Confusional arousals may be experimentally induced by attempts at forced arousal from slow-wave sleep. Differential diagnosis for confusional arousals include sleepwalking, sleep terrors, RBD, and, less frequently, nocturnal epileptic seizures of the complex partial type. Preventive measures include maintaining a regular sleep-wake schedule and avoidance of predisposing factors such as sleep deprivation, shift work, or central nervous system (CNS) depressants, which reduce slowwave sleep. During a confusional arousal, efforts to curtail the behavior should be avoided because they may lead to aggression and prolongation of the spell. The episode should simply be allowed to run itself out,
TABLE 1 Classification of Parasomnia
Disorders of arousal (from non-REM sleep) Confusional arousals Sleepwalking Sleep terrors Parasomnias usually associated with REM sleep REM sleep behavior disorder Recurrent isolated sleep paralysis Nightmare disorder Other parasomnias Sleep related dissociative disorder Nocturnal enuresis Sleep related groaning (Catathrenia) Exploding head syndrome Sleep-related eating disorder
REM, Rapid eye movement. Based on: The International Classification of Sleep Disorders. 2005, Westchester, IL: American Academy of Sleep Medicine.

PATIENT RESOURCES
American Autonomic Society: http://www.americanautonomicsociety.org/ Shy-Drager/Multiple System Atrophy online support group: http://health.groups.yahoo.com/group/shydrager/

Parasomnias
Alon Y. Avidan, M.D., M.P.H., and Phyllis C. Zee, M.D., Ph.D.
Parasomnias are undesirable, nondeliberate physical or emotional events that accompany sleep. They most often occur during entry into sleep or during arousals from sleep and may be augmented by the sleep state. Parasomnias may be extremely undesirable to some but may be of no concern to others. They may include abnormal movements, behaviors, emotions, perceptions, dream mentation, and autonomic activity. In addition, basic drives, such as hunger, sex, and aggression, may manifest as sleep-related eating, sleep-related sexual behaviors, and sleep-related violence. Parasomnias have a bizarre nature but are readily explainable, diagnosable, and treatable. They are related to a change in brain organization across states and are particularly apt to occur during the transition from one sleep stage to another. One hypothesis to help explain parasomnias is that sleep and wakefulness are not mutually exclusive states. Intrusion of wakefulness into non-rapid eye movement (REM) sleep produces arousal disorders, and intrusion of wakefulness into REM sleep produces REM sleep parasomnias, most notably REM sleep behavior disorder (RBD). The International Classification of Sleep Disorders lists 15 categories of parasomnias. In this chapter, we limit the discussion to some of the more common parasomnias encountered in the practice of neurology. These include disorders of arousal from non-REM sleep (confusional arousals, sleepwalking, sleep terrors) and REM sleep (RBD, nightmare disorder) (Table 1).

Disorders of Arousal
Disorders of arousal (confusional arousals, sleepwalking, and sleep terrors) share the common feature of arousals from non-REM sleep, typically slow-wave (delta) sleep, accompanied by abnormal behavior and impaired judgment. Arousal disorders are most common in children and young adults. These events usually begin within the first 1 to 2 hours after sleep onset and may be triggered by underlying primary sleep disorders
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Parasomnias Singer W, Opfer-Gehrking TL, McPhee BR, et al: Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension, J Neurol Neurosurg Psychiatry 74:1294-1298, 2003.

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Disorders of Consciousness

(obstructive sleep apnea, periodic leg movement), stress, or environmental factors. CONFUSIONAL AROUSALS Confusional arousals are characterized by mental or behavioral confusion associated with arousals from sleep, typically from slow-wave sleep in the first part of the night. Episodes typically last several minutes, and patients are usually disoriented and amnesic when awoken. The underlying pathophysiology is thought to be an incomplete awakening from slow-wave sleep, leading to intensification and prolongation of the normal period for transition from sleep to wakefulness. Confusional arousals represent an admixture of wakefulness into non-REM sleep. Patients awaken partially, exhibiting marked confusion, slow mentation, disorientation, perceptual impairment, and errors of logic. Behaviors can be simple to complex and may be inappropriate and even violent. Talking, shouting, and bruxism may also be seen. Attempts to console the child or awaken an individual may further increase agitation. Predisposing factors for confusional arousals include other conditions that disrupt sleep architecture such as circadian rhythm sleep disorders (shift work), sleep apnea, narcolepsy, and encephalopathies. Furthermore, sleep deprivation, fever, alcohol, stimulants, drug abuse, and exposure to other agents that deepen sleep and impair alertness can be precipitating factors. Confusional arousals may be experimentally induced by attempts at forced arousal from slow-wave sleep. Differential diagnosis for confusional arousals include sleepwalking, sleep terrors, RBD, and, less frequently, nocturnal epileptic seizures of the complex partial type. Preventive measures include maintaining a regular sleep-wake schedule and avoidance of predisposing factors such as sleep deprivation, shift work, or central nervous system (CNS) depressants, which reduce slowwave sleep. During a confusional arousal, efforts to curtail the behavior should be avoided because they may lead to aggression and prolongation of the spell. The episode should simply be allowed to run itself out,
TABLE 1 Classification of Parasomnia
Disorders of arousal (from non-REM sleep) Confusional arousals Sleepwalking Sleep terrors Parasomnias usually associated with REM sleep REM sleep behavior disorder Recurrent isolated sleep paralysis Nightmare disorder Other parasomnias Sleep related dissociative disorder Nocturnal enuresis Sleep related groaning (Catathrenia) Exploding head syndrome Sleep-related eating disorder
REM, Rapid eye movement. Based on: The International Classification of Sleep Disorders. 2005, Westchester, IL: American Academy of Sleep Medicine.

PATIENT RESOURCES
American Autonomic Society: http://www.americanautonomicsociety.org/ Shy-Drager/Multiple System Atrophy online support group: http://health.groups.yahoo.com/group/shydrager/

Parasomnias
Alon Y. Avidan, M.D., M.P.H., and Phyllis C. Zee, M.D., Ph.D.
Parasomnias are undesirable, nondeliberate physical or emotional events that accompany sleep. They most often occur during entry into sleep or during arousals from sleep and may be augmented by the sleep state. Parasomnias may be extremely undesirable to some but may be of no concern to others. They may include abnormal movements, behaviors, emotions, perceptions, dream mentation, and autonomic activity. In addition, basic drives, such as hunger, sex, and aggression, may manifest as sleep-related eating, sleep-related sexual behaviors, and sleep-related violence. Parasomnias have a bizarre nature but are readily explainable, diagnosable, and treatable. They are related to a change in brain organization across states and are particularly apt to occur during the transition from one sleep stage to another. One hypothesis to help explain parasomnias is that sleep and wakefulness are not mutually exclusive states. Intrusion of wakefulness into non-rapid eye movement (REM) sleep produces arousal disorders, and intrusion of wakefulness into REM sleep produces REM sleep parasomnias, most notably REM sleep behavior disorder (RBD). The International Classification of Sleep Disorders lists 15 categories of parasomnias. In this chapter, we limit the discussion to some of the more common parasomnias encountered in the practice of neurology. These include disorders of arousal from non-REM sleep (confusional arousals, sleepwalking, sleep terrors) and REM sleep (RBD, nightmare disorder) (Table 1).

Disorders of Arousal
Disorders of arousal (confusional arousals, sleepwalking, and sleep terrors) share the common feature of arousals from non-REM sleep, typically slow-wave (delta) sleep, accompanied by abnormal behavior and impaired judgment. Arousal disorders are most common in children and young adults. These events usually begin within the first 1 to 2 hours after sleep onset and may be triggered by underlying primary sleep disorders
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unless there is an attempt to leave the bed or to leave the premises. Pharmacologic treatment is rarely necessary because most episodes in children remit with age. Some patients are helped by tricyclic antidepressants such as clomipramine. Avoidance of the facilitating factors (e.g., sleep deprivation, stimulants) and treatment of underlying sleep disorders such as sleep apnea are key in the management of confusional arousals. Table 2 summarizes the key feature of this parasomnias with regard to treatment, semiology, and sleep stage propensity. SLEEPWALKING Sleepwalking (somnambulism) consists of complex behaviors that are initiated during slow-wave sleep and result in walking during sleep. In addition to routine behaviors such as walking and talking, sleepwalking is often accompanied by inappropriate behaviors, such as urinating in a trash can, moving furniture, or driving a car. The individual is usually extremely difficult to awaken and may become increasingly agitated and violent with vigorous attempts to awaken the subject. These episodes generally last from 1 to 5 minutes. The peak incidence is usually between 4 and 8 years of age with spontaneous remission thereafter. However, sleepwalking can persist beyond adolescence and rarely begins in adulthood. In children, calm sleepwalking may be considered part of the normal developmental process, but in adults, sleepwalking can often cause sleep disruption and injury. The male-to-female ratio is 1:1, and familial patterns are common. The differential diagnosis consists of RBD, confusional arousals, and, rarely, sleep-related partial complex seizures with ambulatory automatisms. Sleep-related respiratory events including obstructive sleep apnea are recognized triggers for sleepwalking in children. Other predisposing factors include sleep deprivation, unfamiliar sleep environment, fever, stress, alcohol, and medications such as chlorohydrate, lithium, perphenazine, and desipramine. Stimuli such as a distended bladder or disruption of the sleep environment by noise, light, and changes in temperature may also trigger episodes. The main concern with this parasomnia is the risk of injury. Patients may engage in activities that may produce cuts and bruises from bumping into objects or falling. Treatment is focused on avoiding the precipitating factors and providing patients with a safe sleeping environment: removing sharp objects from bedroom, locking doors, and arranging for a ground floor bedroom. The primary prevention of nocturnal events is based on reducing stress, improving sleep hygiene, and avoiding substances that may cause sleep deprivation and cognitive impairment. Patients with underlying sleep disorders (e.g., sleep apnea and circadian rhythm disturbances) and periodic limb movements should have these disorders appropriately treated to decrease the potential for sleep disruption. When sleepwalking spells are severe and refractory, the use of medications such as tricyclic antidepressants or benzodiazepines has been advocated. Table 2 summarizes key features of this parasomnia.

SLEEP TERRORS (PAVOR NOCTURNUS) Sleep terrors consist of a sudden arousal from slow-wave sleep manifested by a piercing scream accompanied by significant autonomic arousal and behavioral manifestations of intense fear. This is the most dramatic of the arousal disorders. On the sleep study, the episodes are associated with sympathetic activity manifested by tachycardia, tachypnea, reduced skin resistance that reflects diaphoresis, flushing of the skin, mydriasis, and increased muscle tone. Sleep terrors reflect a state of cerebral hyper-responsiveness consisting of incoherent vocalizations, extreme agitation, escape behavior, and marked confusion. The duration of sleep terrors is usually between 30 seconds to 3 minutes. Spells may be experimentally induced by forced arousals from slow-wave sleep. The prevalence of recurrent sleep terrors is 1% to 6% in prepubertal children, decreasing to less than 1% in adults, with no gender differences in either age group. Predisposing and precipitating factors are similar to those described for sleepwalking. Psychopathology is rare in affected children but may play a role in adult patients. There is evidence for comorbid mood and anxiety disorder in adults with sleep terrors. Differential diagnosis includes REM nightmares, nocturnal anxiety attack related to obstructive sleep apnea, nocturnal cardiac ischemia, and sleep-related epileptic seizures. Nightmares are distinguishable from sleep terrors in that they are often associated with a vivid recall of the dream event during which they occurred, they are less dramatic, and they do not have the typical autonomic hyperarousal that characterizes the latter. Treatment is often unnecessary when episodes are rare (see Table 2). As in the previous two parasomnias, the attacks should be left to terminate spontaneously. Facilitating and precipitating factors, such as poor sleep hygiene, sleep deprivation, stress, and ingestion of CNS-depressant substance should be identified and avoided. When episodes are frequent, intense, and disruptive to the patients sleep, a benzodiazepine such as diazepam or clonazepam may be used at low doses during the night. An example may include diazepam, 5 mg, at bedtime. Benzodiazepines may act by increasing arousal threshold, reducing slow-wave sleep, and suppressing the autonomic excitability that accompanies this behavior. Other treatment options include tricyclic antidepressants. Adult sufferers in the setting of a history of a psychiatric disorder may benefit from psychotherapy and stress reduction as well as reassurance.

Parasomnias Associated with REM Sleep


These parasomnias are exquisitely associated with REM sleep. The two most important ones to consider clinically include RBD and nightmare disorder. REM SLEEP BEHAVIOR DISORDER RBD is one of the most dramatic and potentially injurious parasomnias to consider. Spells consist of dream
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TABLE 2 Features of Parasomnias


Somnambulism Stage REM sleep, typically in the last third of the night Sleep Terrors REM Sleep Behavior Disorder Nightmares

Feature

Confusional Arousals

Stage of sleep

Spell symptoms

Stage REM sleep, sometimes, stage II sleep typically in the second half of the night Sudden awakening with anxiety and dream recall

Duration Recall of the dream

Disorders of Consciousness

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Postspell symptoms EEG pattern during spell Transition from slow-wave sleep to stage I or diffuse and slow alpha; highamplitude burst of delta waves Arousal from non-REM (typically slow-wave sleep) associated with marked tachycardia, tachypnea, reduced skin resistance

Stage slow-wave sleep, typically in the first third of the night Sudden arousal, confusion, disorientation, inappropriate behavior Secondsseveral minutes Amnesia, confusion Limb twitching, yelling, talking, kicking, punching, singing correlating with reported dream mentation 1-10 min

Stage slow-wave sleep, typically in the first third of the night Complex ambulatory automatisms, getting out of bed, walking 1-5 min; 30-60 min in rare episodes Amnesia, confusion

Stage slow-wave sleep, typically in the first third of the night Sudden arousal, piercing scream, confusion, inconsolability, disorientation, extreme autonomic discharge, agitation Secondsseveral minutes Amnesia, confusion

Slow-wave activity, interspersed with alpha, poorly reactive alpha

Secondsseveral minutes Vivid recall of a frightening dream Increased eye movements during REM sleep

Pathophysiology

Disorders of partial arousal reflecting incomplete arousal from deep non-REM sleep Predisposing factors include any that deepen sleep and those that impair arousal from sleep such as CNS-acting drugs, previous sleep deprivation

Increased sympathetic arousal Precipitated by daytime stress, drugs (especially beta blockers, neuroleptics, cholinergic agents) and withdrawal from REMsuppressing agent No No No Avoid injury, protect patient, avoid precipitating factors Clonazepam at bedtime Other options include melatonin, L-dopacarbidopa, imipramine, carbamazepine Reassurance, reduction of stresses, improvement in sleep hygiene, psychotherapy, REM-suppressing agent (e.g., tricyclic antidepressants)

No

Augmentation of chin and limb EMG muscle activity during REM sleep Loss of EMG atonia, which typically occurs during REM sleep or during REM sleep-to-wake transition Nonidiopathic/nontoxic, metabolic form is related to dysfunction of the brainstem mechanism responsible for REM-associated muscle atonia Pathophysiology for idiopathic form is unknown Common

Identifiable neuropathology Genetic predisposition Treatments Avoid injury, protect patient, avoid precipitating factors, psychotherapy Benzodiazepines or tricyclic antidepressants

Yes Avoid precipitating factors such as poor sleep hygiene and sleep deprivation Benzodiazepines at bedtime, tricyclic antidepressants

Avoidance of precipitating factors Tricyclic antidepressants may be useful

Parasomnias

EEG, Electroencephalogram; EMG, electromyogram; REM, rapid eye movement; CNS, central nervous system.

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enactment associated with loss of muscle atonia during REM sleep. RBD was originally predicted by experiments in the cat model. This was a fascinating experiment of nature where bilateral lesions adjacent to the locus ceruleus of the pontine region induced absence of the atonia that is typically associated with the REM sleep. RBD was eventually confirmed to also occur in humans and became an officially recognized parasomnia in 1987. The characteristic polysomnogram (sleep study) demonstrates intermittent loss of REM sleep-associated muscle atonia (reflected by the polysomnogram) associated with the patient manifesting an elaborate motor activity associated with dream-mentation. During these spells, which rarely last more than a few minutes, patients are observed to be talking, yelling, punching, kicking, running, and screaming. RBD is often referred to as the Jekyll and Hyde syndrome because patients tend to have a peaceful demeanor during the day but become very combative during the night. The potential for self-injury and bed partner injury is high, especially during severe episodes. Most cases occur with advancing age; approximately 60% are idiopathic, whereas the remaining 40% may have an underlying neuropathology. RBD typically manifests itself in the 6th or 7th decade. This parasomnia has a particular predilection to occur in a number of synucleinopathies and other neurodegenerative disorders such as dementia of the diffuse Lewy body type, Parkinsons disease, olivopontocerebellar degeneration, Shy-Drager syndrome and multiple system atrophy (MSA). Patients with MSA are commonly affected with RBD. Investigators have studied polysomnographic records of patients with MSA of whom nearly two thirds reported nocturnal paroxysmal episodes related to dreams suggesting the clinical diagnosis of RBD. The data show that RBD represents the most common clinical sleep manifestation and polysomnographic findings in patients with MSA. RBD can frequently herald the appearance of other MSA symptoms by years; therefore, expanded polysom- nographic montage including REM sleep behavior montage and video monitoring is recommended in patients with MSA. Secondary causes include disorders that disrupt brainstem centers involved in REM sleepgenerated muscle atonia such as multiple sclerosis, cerebral vascular accidents, and brainstem neoplasm. The acute onset of RBD is typically related to medications such as tricyclic antidepressants, monamine oxidase inhibitors, and selective serotonin reuptake inhibitors. Other acute cases are related to acute alcohol and barbiturate withdrawal. Caffeine use has also been recently implicated in causing RBD. In many cases, the diagnosis is suspected clinically by confirming the presence of recurrent and frequent dream-enacting behaviors with the help of the bed partner. Diagnosis of RBD is made if there is a clear history of nocturnal behavioral spells along with polysomnographic evidence of increased electromyographic (EMG) bursts of chin EMG or limb electrodes seen during REM sleep on polysomnography. The sleep study may also capture the actual spells during which the abnormal spell is demonstrated (limb jerk on

complex, vigorous-violent behaviors). If there is evidence of an abnormal neurologic examination, a full neurologic work-up, including brain magnetic resonance imaging, may be needed. The differential diagnosis of RBD is extensive and includes sleepwalking, nocturnal seizures, post-traumatic stress disorder (PTSD), psychogenic dissociative state, sleep terrors, nocturnal panic disorders, delirium, sleep-related gastroesophageal reflux, periodic limb movement disorder of sleep, and confusional arousals with sleep apnea. Distinguishing RBD from nocturnal seizures may be difficult. However, unlike nocturnal seizures, the typical RBD spell is usually not stereotypical and is often variable. Additional laboratory studies may be needed especially if the clinical history remains vague or ambiguous. When the possibility of nocturnal seizures cannot be reliably excluded, additional sleep testing may be warranted. Sleep studies on multiple nights may be needed for confirmation. For example, polysomnography with video monitoring using four-limb EMG electrodes done during the first night followed by polysomnography with expanded EEG montage performed on the subsequent night generally may be fruitful. Environmental safety is prudent in every patient with suspected RBD. Pharmacotherapy for RBD (summarized in Table 2) may be in the form of clonazepam, 0.252 mg orally at bedtime, which is effective in 90% of cases. There is little evidence of tolerance or abuse with this form of treatment. Treatment with this drug has little or no effect on the characteristic elevated limb EMG tone during the night, but it acts to prevent the arousals associated with the REM disassociation. Clonazepams safety for use during pregnancy has not been established. Caution should be exercised when using it in patients with chronic respiratory diseases or impaired renal function, and it is contraindicated in patients with documented hypersensitivity, severe liver disease, or acute narrow-angle glaucoma. Abrupt discontinuation of clonazepam can precipitate withdrawal symptoms. Other agents that may be helpful include imipramine, 25 mg orally at bedtime; carbamazepine, 100 mg orally three times a day; and levodopa in cases where RBD is associated with Parkinsons disease. Recent studies have also demonstrated improvement with the use of melatonin, which is believed to exert its therapeutic effect by restoring REM sleep atonia. One study reported that melatonin was effective in 87% of patients taking 3 to 9 mg at bedtime, whereas a later study reported resolution in those taking 6 to 12 mg of melatonin at bedtime. The reader is reminded that melatonin, a food supplement, is not approved by the U.S. Food and Drug Administration and is not strictly regulated for uniformity of pharmacologic preparation. Especially in elderly patients, it should be used only with great care because it is vasoactive in laboratory animals and side effects have not been widely studied. NIGHTMARE DISORDER Nightmares are almost always long, complicated dreams that become increasingly frightening during the end of
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the dream event. Although quite common in children, predisposing factors among adult sufferers include anxiety disorders. Daytime stress may also play a major role. A sizable portionabout 20% to 40%of these patients have a history of schizotypal personality, borderline and schizoid personality disorder, or schizophrenia. A common cause of nightmares may be REM rebound. These spells may be more common especially during nights of recuperation after REM sleep deprivation. Certain medications, including L-dopa, monamine oxidase inhibitors, and beta-adrenergic blockers, or withdrawal of REM suppressants can induce or increase the incidence of nightmares. Ten percent to 50% of children 3 to 5 years of age have enough nightmares to disrupt the sleep of their parents. The sex ratio demonstrates an equal sex ratio in children, whereas in adults there is a ratio of 2:1 or 4:1, favoring women. A familial pattern has not been clearly documented. Treatment is often in the form of reassurance, reduction of stresses that have precipitated the nightmare, improvement in sleep hygiene, and occasional psychotherapy may be of help. Some have advocated the use of systematic desensitization and relaxation techniques to countercondition a relaxation response to anxiety-provoking nightmare contents, whereas others have also recommended the use of imagery rehearsal to reduce nightmare distress, and frequency. When the episodes are severe and refractory to nonpharmacologic therapy, the use of an REM-suppressing agent (tricyclic antidepressant or selective serotonin reuptake inhibitor) (see Table 2) for a short period may be helpful.

studies are usually not required. On the other hand, further evaluation, including a polysomnogram, is warranted if the parasomnias and associated behaviors are violent, cause injury, are frequent and disruptive to the sleep of the patient and/or household members, and result in excessive daytime sleepiness. The use of polysomnogram is also indicated to evaluate for the presence of coexisting obstructive sleep apnea, periodic limb movements disorders, as well as other parasomnias. The use of video and electroencephalographic (EEG) monitoring or polysomnogram with expanded EEG channels is indicated for the evaluation of nocturnal seizures when the episodes are repetitive and stereotypical and the distinction from other parasomnias by history is difficult.

Treatment of Parasomnias
Successful amelioration of disturbing parasomnias depends on accurate diagnosis. Reassurance, addressing safety issues, and education are important in the management of parasomnias. The patient and the family need to maintain a safe bedroom environment, to relocate the sleeping area to the ground floor of the house and if possible, to lock all windows, and to cover glass or windows with heavy drapes. The patient must be warned to avoid precipitants of parasomnias, including unusual stress, sleep deprivation, and ingestion of substances such as alcohol (which increases slow-wave sleep and may promote such parasomnias as sleepwalking) and caffeine-containing products (which have been implicated in parasomnias such as RBD). Often for the less severe presentations, behavioral and safety precautions are sufficient. However, when symptoms are severe or result in injury, the use of pharmacologic therapy is indicated. Pharmacologic therapy relies primarily on the use of benzodiazepines, such as clonazepam, diazepam, and alprazolam. Other treatment options may include tricyclic antidepressants, particularly in cases of sleep terrors. Treatment options for the common parasomnias are listed in Table 2. SUGGESTED READING
Aldrich MS: Sleep medicine, New York, 1999, Oxford University Press. Avidan ACR: Confusional arousal. In Gilman S, editor: Neurology MedLink, San Diego, 2004, MedLink. Boeve B: Melatonin for treatment of REM sleep behavior disorder: response in eight patients [abstract], Sleep 24(Suppl):A35, 2001. Boeve BF, Silber MH, Ferman T: REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease, Neurology 51:363-370, 1998. Broughton R: Behavioral parasomnias, Boston, 1998, ButterworthHeinemann, 635-660. Broughton R: NREM arousal parasomnias, Philadelphia, 2000, WB Saunders, 693-706. Dyken ME, Yamada T, Lin-Dyken DC: Polysomnographic assessment of spells in sleep: nocturnal seizures versus parasomnias, Semin Neurol 21:377-390, 2001. Ferini-Strambi L, Zucconi M: REM sleep behavior disorder, Clin Neurophysiol 111(Suppl):S136-S140, 2000. Guilleminault C, Palombini L, Pelayo R, Chervin RD: Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics 111:e17-25, 2003.

Evaluation of Nocturnal Arousals


The clinical evaluation of a patient presenting with symptoms of parasomnia involves a careful neurologic, medical, psychiatric, and sleep history; an interview with a bed partner or family member; and complete physical examination. Some useful screening questions to ask include the following: Are you or your bed partner aware that you move your arms, legs, or body during sleep? Do you have unusual, vigorous, or violent behaviors during sleep? Do you physically act out your dreams? Have you hurt yourself or a bed partner during sleep? Do you shout, scream, or walk in your sleep? When the observers and the patient are interviewed, the following issues may be addressed: Timing of the event during the night Description of the behaviors Preservation of consciousness versus unresponsiveness Preservation of memory for the event versus amnesia Potential psychosocial factors Presence or absence of family history of similar events

In children with arousal disorders who have a normal neurologic and physical examination, further laboratory
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The International Classification of Sleep Disorders. 2005, Westchester, IL: American Academy of Sleep Medicine. Hobson JA, Silvestri L: Parasomnias, Harvard Mental Health Lett 15:3-5, 1999. Kales A, Soldatos CR, Kales JD: Sleep disorders: insomnia, sleepwalking, night terrors, nightmares, and enuresis, Ann Intern Med 106:582-592, 1987. Kavey NB, Whyte J, Resor SR Jr, Gidro-Frank S: Somnambulism in adults, Neurology 40:749-752, 1990. Klackenberg G: Incidence of parasomnias in children in a general population, New York, 1987, Raven Press, 99-113. Kowey PR, Mainchak RA, Rials SJ, et al: Things that go bang in the night, N Engl J Med 327:1884, 1992. Llorente MD, Currier MB, Norman SE, Mellman TA: Night terrors in adults: phenomenology and relationship to psychopathology, J Clin Psychiatry 53:392-394, 1992. Mahowald MW: Overview of parasomnias. In National sleep medicine course, Westchester, IL, 1999, American Academy of Sleep Medicine. Mahowald MW, Ettinger MG: Things that go bump in the night: the parasomnias revisited, J Clin Neurophysiol 7:119-143, 1990. Mahowald MW, Rosen GM: Parasomnias in children, Pediatrician 17:21-31, 1990. Mahowald MW, Schenck CH: Diagnosis and management of parasomnias, Clin Cornerstone 2:48-57, 2002. Mahowald MW, Schenck CH: NREM sleep parasomnias, Neurol Clin 14:675-696, 1996. Mahowald MW, Schenck CH: REM sleep behavior disorder, Philadelphia, 1994, WB Saunders, 574-588. Masand P, Popli AP, Weilburg JB: Sleepwalking, Am Family Physician 51:649-654, 1995. Milliet N, Ummenhofer W: Somnambulism and trauma: case report and short review of the literature, J Trauma Injury Infect Crit Care 47:420-422, 1999. Ohayon MM, Guilleminault C, Priest RG: Night terrors, sleepwalking, and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders, J Clin Psychiatry 60:268-276, 1999. Parkes JD: The parasomnias, Lancet 2:1021-1025, 1986. Plazzi G, Corsinin R, Provini F: REM sleep behavior disorders in multiple system atrophy, Neurology 48:1094-1097, 1997. Reid WH, Ahmed I, Levie CA: Treatment of sleepwalking: a controlled study, Am J Psychother 35:27-37, 1981. Rosen GM, Mahowald MW, Ferber R: Sleepwalking, confusional arousals, and sleep terrors in the child. In Ferber A, Kryger M, editors: Principles and practice of sleep medicine in the child, Philadelphia, 1995, WB Saunders, 99-106. Schenck CH, Bundlie SR, Mahowald MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder, Neurology 46:388-393, 1996. Schenck CH, Bundlie SR, Patterson AL, Mahowald MW: Rapid eye movement sleep behavior disorder: a treatable parasomnia affecting older adults, JAMA 257:1786-1789, 1987. Schenck CH, Mahowald MW: REM sleep parasomnias, Neurol Clin 14:697-720, 1996. Schenck CH, Mahowald MW: Two cases of premenstrual sleep terrors and injurious sleepwalking, J Psychosom Obstet Gynaecol 16:79-84, 1995. Shneerson J: Handbook of sleep medicine, Malden, 2000, Blackwell Science, 136-162. Takeuchi N, Uchimura N, Hashizume Y, et al: Melatonin therapy for REM sleep behavior disorder, Psychiatry Clin Neurosci 55:267-269, 2001. Tassi P, Muzet A: Sleep inertia, Sleep Med Rev 4:341-353, 2000. Thorpy MJ, Glovinsky PB: Parasomnias, Psychiatr Clin North Am 10:623-639, 1987. Wise MS: Parasomnias in children, Pediatr Ann 26:427-433, 1997.

Narcolepsy
Scott Fromherz, M.D., and Emmanuel Mignot, M.D., Ph.D.

Together with obstructive sleep apnea (OSA), insufficient sleep, and idiopathic central nervous system hypersomnia, narcolepsy is a common cause of excessive daytime sleepiness. Even when narrowly defined by the presence of cataplexy, narcolepsy is not rare and affects 1 in 2000 individuals in North America and Western European countries.

Definition and Pathophysiology


The classic narcolepsy tetrad includes daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Cataplexy, a sudden loss of muscle tone, triggered by strong emotions, is almost pathognomonic but is not required for diagnosis. Other symptoms include disrupted night-time sleep and automatic behaviors. Narcolepsy is associated with human leukocyte antigen (HLA) DQB1*0602. Postmortem studies have shown a selective loss of 50,000 to 100,000 posterior hypothalamic neurons, producing the neuropeptide hypocretin (orexin). The HLA association and associated hypocretin deficiency is particularly strong (>90%) in patients with definite cataplexy. This association lends support to the hypothesis that narcolepsy is an autoimmune disorder. Hypocretin has tight functional interactions with cholinergic and monoaminergic systems regulating sleep. Without hypocretin, narcoleptic patients have sleepiness, inappropriate rapid eye movement (REM) paralysis during wakefulness (cataplexy, sleep paralysis), REM dreaming before falling asleep (hypnagogic hallucinations), and disorganized night-time sleep. Rapid transitions into REM sleep (REM latency below 20 minutes) called sleep-onset REM periods (SOREMPs) can be observed during nocturnal sleep and while napping.

Clinical Characteristics
Cataplexy is a sudden, short-lived (seconds, rarely more than minutes), bilateral loss of muscle tone elicited by emotions. The existence of a typical trigger is crucial to the recognition of genuine cataplexy. It is usually produced by humor or laughter, especially when the patient himself or herself is telling a joke or relating a funny story. Less commonly, anger, surprise, elation, playful excitement may be involved. There is no sensory component or loss of consciousness. Attacks can be mild, such as an inability to retain facial muscle tone, or severe, leading to complete collapse. Reflexes are abolished, but the episodes are rarely long enough to evaluate by physical examination. Respiration can be hampered by position or made slightly more difficult, but it is always maintained.
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Narcolepsy

The International Classification of Sleep Disorders. 2005, Westchester, IL: American Academy of Sleep Medicine. Hobson JA, Silvestri L: Parasomnias, Harvard Mental Health Lett 15:3-5, 1999. Kales A, Soldatos CR, Kales JD: Sleep disorders: insomnia, sleepwalking, night terrors, nightmares, and enuresis, Ann Intern Med 106:582-592, 1987. Kavey NB, Whyte J, Resor SR Jr, Gidro-Frank S: Somnambulism in adults, Neurology 40:749-752, 1990. Klackenberg G: Incidence of parasomnias in children in a general population, New York, 1987, Raven Press, 99-113. Kowey PR, Mainchak RA, Rials SJ, et al: Things that go bang in the night, N Engl J Med 327:1884, 1992. Llorente MD, Currier MB, Norman SE, Mellman TA: Night terrors in adults: phenomenology and relationship to psychopathology, J Clin Psychiatry 53:392-394, 1992. Mahowald MW: Overview of parasomnias. In National sleep medicine course, Westchester, IL, 1999, American Academy of Sleep Medicine. Mahowald MW, Ettinger MG: Things that go bump in the night: the parasomnias revisited, J Clin Neurophysiol 7:119-143, 1990. Mahowald MW, Rosen GM: Parasomnias in children, Pediatrician 17:21-31, 1990. Mahowald MW, Schenck CH: Diagnosis and management of parasomnias, Clin Cornerstone 2:48-57, 2002. Mahowald MW, Schenck CH: NREM sleep parasomnias, Neurol Clin 14:675-696, 1996. Mahowald MW, Schenck CH: REM sleep behavior disorder, Philadelphia, 1994, WB Saunders, 574-588. Masand P, Popli AP, Weilburg JB: Sleepwalking, Am Family Physician 51:649-654, 1995. Milliet N, Ummenhofer W: Somnambulism and trauma: case report and short review of the literature, J Trauma Injury Infect Crit Care 47:420-422, 1999. Ohayon MM, Guilleminault C, Priest RG: Night terrors, sleepwalking, and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders, J Clin Psychiatry 60:268-276, 1999. Parkes JD: The parasomnias, Lancet 2:1021-1025, 1986. Plazzi G, Corsinin R, Provini F: REM sleep behavior disorders in multiple system atrophy, Neurology 48:1094-1097, 1997. Reid WH, Ahmed I, Levie CA: Treatment of sleepwalking: a controlled study, Am J Psychother 35:27-37, 1981. Rosen GM, Mahowald MW, Ferber R: Sleepwalking, confusional arousals, and sleep terrors in the child. In Ferber A, Kryger M, editors: Principles and practice of sleep medicine in the child, Philadelphia, 1995, WB Saunders, 99-106. Schenck CH, Bundlie SR, Mahowald MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder, Neurology 46:388-393, 1996. Schenck CH, Bundlie SR, Patterson AL, Mahowald MW: Rapid eye movement sleep behavior disorder: a treatable parasomnia affecting older adults, JAMA 257:1786-1789, 1987. Schenck CH, Mahowald MW: REM sleep parasomnias, Neurol Clin 14:697-720, 1996. Schenck CH, Mahowald MW: Two cases of premenstrual sleep terrors and injurious sleepwalking, J Psychosom Obstet Gynaecol 16:79-84, 1995. Shneerson J: Handbook of sleep medicine, Malden, 2000, Blackwell Science, 136-162. Takeuchi N, Uchimura N, Hashizume Y, et al: Melatonin therapy for REM sleep behavior disorder, Psychiatry Clin Neurosci 55:267-269, 2001. Tassi P, Muzet A: Sleep inertia, Sleep Med Rev 4:341-353, 2000. Thorpy MJ, Glovinsky PB: Parasomnias, Psychiatr Clin North Am 10:623-639, 1987. Wise MS: Parasomnias in children, Pediatr Ann 26:427-433, 1997.

Narcolepsy
Scott Fromherz, M.D., and Emmanuel Mignot, M.D., Ph.D.

Together with obstructive sleep apnea (OSA), insufficient sleep, and idiopathic central nervous system hypersomnia, narcolepsy is a common cause of excessive daytime sleepiness. Even when narrowly defined by the presence of cataplexy, narcolepsy is not rare and affects 1 in 2000 individuals in North America and Western European countries.

Definition and Pathophysiology


The classic narcolepsy tetrad includes daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Cataplexy, a sudden loss of muscle tone, triggered by strong emotions, is almost pathognomonic but is not required for diagnosis. Other symptoms include disrupted night-time sleep and automatic behaviors. Narcolepsy is associated with human leukocyte antigen (HLA) DQB1*0602. Postmortem studies have shown a selective loss of 50,000 to 100,000 posterior hypothalamic neurons, producing the neuropeptide hypocretin (orexin). The HLA association and associated hypocretin deficiency is particularly strong (>90%) in patients with definite cataplexy. This association lends support to the hypothesis that narcolepsy is an autoimmune disorder. Hypocretin has tight functional interactions with cholinergic and monoaminergic systems regulating sleep. Without hypocretin, narcoleptic patients have sleepiness, inappropriate rapid eye movement (REM) paralysis during wakefulness (cataplexy, sleep paralysis), REM dreaming before falling asleep (hypnagogic hallucinations), and disorganized night-time sleep. Rapid transitions into REM sleep (REM latency below 20 minutes) called sleep-onset REM periods (SOREMPs) can be observed during nocturnal sleep and while napping.

Clinical Characteristics
Cataplexy is a sudden, short-lived (seconds, rarely more than minutes), bilateral loss of muscle tone elicited by emotions. The existence of a typical trigger is crucial to the recognition of genuine cataplexy. It is usually produced by humor or laughter, especially when the patient himself or herself is telling a joke or relating a funny story. Less commonly, anger, surprise, elation, playful excitement may be involved. There is no sensory component or loss of consciousness. Attacks can be mild, such as an inability to retain facial muscle tone, or severe, leading to complete collapse. Reflexes are abolished, but the episodes are rarely long enough to evaluate by physical examination. Respiration can be hampered by position or made slightly more difficult, but it is always maintained.
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Narcolepsy

19
Disorders of Consciousness

This definition allows one to rule out possible mimics. Syncope, sleep attacks, and generalized seizures all involve a loss of consciousness. The bilateral distribution of weakness and temporal course are inconsistent with most strokes. The short duration and lack of correlation with intense exercise are inconsistent with episodic or fluctuating neuromuscular disorders. The lack of positive phenomena rules out most seizures. Because startle alone is not a typical trigger, hyperekplexia can be excluded. It is also important to differentiate genuine cataplexy from normal physiologic reactions. For example, a person may laugh so hard that his face hurts or feels weak. When laughing hard, non-narcoleptic patients might also feel rubber knees or roll onto the floor. In true cataplexy, muscle weakness is obvious and must occur more than a few times in a lifetime. Sleepiness in narcolepsy is usually more severe than in other sleep disorders; however, contrary to popular belief, it is not easy to differentiate from sleepiness due to insufficient sleep or OSA. Napping is common, and short naps are typically refreshing. A misperception in narcolepsy is the nature of sleep attacks. Some have a mistaken impression that the term sleep attack refers to sudden sleep that is so severe it may cause extraordinary events such as falling asleep into a soup bowl. Others are confusing cataplexy and sleep attacks. The correct definition of sleep attack is an irresistible desire to fall asleep that can lead to unintentional sleep. It can present rapidly, but its onset is not as acute as cataplexy. For example, people with narcolepsy may feel awake and nonsleepy until they are in a sedentary or nonstimulating situation, at which point they may rapidly fall asleep. It is not an attack so much as an unexpected nap. Other symptoms are more straightforward to identify but lack diagnostic specificity. Sleep paralysis is an inability to move that occurs at sleep onset or on awakening. Hypnagogic and hypnopompic hallucinations are dreamlike visual or auditory perceptions that occur at sleep onset and on awakening, respectively. Hallucinations and sleep paralysis may occur in combination and are typically frightening. Automatic behaviors are actions that occur without full awareness or memory, for example continuing to talk on the phone without making sense, because of sleepiness or microsleep. It is merely an indication of the severity of daytime sleepiness independent of any etiology. Disturbed nocturnal sleep is present in approximately 50% of patients and can be quite disabling. In narcolepsy, it is usually not characterized by a difficulty falling asleep but rather by recurrent night-time awakenings and a feeling of restlessness during the night. All symptoms except cataplexy can also be found in normal individuals, idiopathic hypersomnia, and OSA in some circumstances.

Diagnosis
The diagnosis of narcolepsy is primarily clinical, but confirmatory tests are usually necessary to verify the diagnosis (Figure 1). The presence of definite cataplexy is
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most important (see later). Questions about sleep patterns, medications that cause somnolence, signs of sleep apnea such as snoring, symptoms of restless leg syndrome, and evidence of sleep insufficiency or a circadian rhythm disturbance must be asked. If there is suspicion of OSA, an overnight polysomnogram (PSG) is mandatory. Finally, evaluation must include questions about sleep paralysis, hypnagogic and hypnopompic hallucinations, automatic behaviors, and disrupted night-time sleep. Because of its importance to the diagnosis, questions regarding cataplexy should be asked carefully to avoid leading the patient. Cataplexy is rarely observed during interviews, although small facial attacks are sometimes observed when severely affected patients recount emotional events. A question like Does anything unusual happen when you are laughing? is more appropriate than Do you feel weak when you are laughing? Similarly, the clinician should not be satisfied with a simple affirmative response. Rather, the patient should be asked to recall the specific circumstances. In this regard, it is useful to ask for a description of the first or last episode experienced. Patients describing unclear events or events that have occurred only once should be considered without cataplexy for the purpose of further evaluation and treatment strategies (Figure 2; see also Figure 1). If a patient has both hypersomnia and definite cataplexy, a clinical diagnosis can be made. However, it is still recommended that a PSG followed by a multiple sleep latency (MSL) test be done to document sleepiness and evaluate comorbid sleep disorders. Proper documentation also permits more aggressive treatment in the future. Approximately 15% of patients with cataplexy do not display typical MSL test abnormalities, so the diagnosis must remain clinically based. If there is no cataplexy, an MSL test (preceded by PSG) is mandatory (see Figure 1). The MSL test objectively quantifies daytime sleepiness. It consists of five 20-minute daytime naps at 2-hour intervals. The amount of time it takes to fall asleep (sleep latency) and the occurrence of REM sleep is recorded. An MSL of less than 8 minutes and two or more SOREMPs is diagnostic for narcolepsy. The MSL test must always be preceded by a PSG to rule out other causes of short MSL or SOREMPs such as OSA, insufficient sleep, or delayed sleep phase syndrome. At least 6 hours of sleep must have occurred prior to the MSL test. Sleep logs or actigraphy for the preceding 2 weeks can be helpful to exclude chronic sleep deprivation. It must also be conducted after withdrawal of psychotropic medications (generally > 2 weeks). Antidepressants, most notably, suppress REM sleep and/or may create REM rebound if stopped too recently prior to testing. The PSG may also show a short sleep latency (< 10 minutes) and a SOREMP (< 20 minutes on the PSG). Periodic limb movements, fragmented sleep and low sleep efficiency are often observed. The MSL test may be difficult to interpret in the presence of disturbed nocturnal sleep or in patients with combined sleep pathologies (e.g., OSA or severe periodic limb movements and narcolepsy). When conducted

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Narcolepsy

Hypersomnia

Clinical evaluation: Ask about cataplexy, evaluate severity of sleepiness and presence of sleep paralysis, hypnagogic hallucinations, or automatic behaviors. Rule out more common causes of hypersomnia such as obstructive sleep apnea, insufficient sleep syndrome, or a circadian rhythm disorder. Also, confirm that it is primarily a problem of sleepiness rather than fatigue.

Definite cataplexy

No cataplexy or atypical cataplexy

Diagnosis of narcolepsy Proceed with PSG/MSLT to objectively document a firm diagnosis and allow for more aggressive treatment later. Treat comorbid sleep disorders if needed (e.g. OSA, but rarely PLMs) If MSLT is negative (MSL > 8 or < 2 SOREMPs) the results should be interpreted within the context of the clinical history as the presence of cataplexy is sufficient to diagnose narcolepsy. If necessary, the MSLT can be repeated Consider LP for CSF hypocretin-1 levels if patient: 1. is already being treated with psychotropic medications 2. has clinically significant associated sleep disorders 3. has disabling neurological or psychiatric disorders, confounding the clinical picture or disrupting the ability to conduct an MSLT 4. is very young and cannot follow MSLT instructions properly

MSLT Must be preceded by PSG to rule out comorbid sleep disorders and document adequate nocturnal sleep. If significant sleep disorder detected on PSG, then disorder must be treated before proceeding with MSLT.

MSL > 8 minutes or < 2 SOREMPs

MSL < 8 minutes or 2 SOREMPs

Not narcolepsy (If clinical suspicion high, consider repeat MSLT or LP for CSF hypocretin-1 levels)

Diagnosis of narcolepsy

FIGURE 1. Evaluation of narcolepsy. MSLT, Multiple sleep latency test; MSL, mean sleep latency; PSG, polysomnogram; SOREMP, sleep-onset rapid eye movement period; OSA, obstructive sleep apnea; PLM, periodic limb movement; LP, lumbar puncture; CSF, cerebrospinal fluid.

in the absence of sleep deprivation or delayed sleep phase, it is considered to be a highly predictive test. Large sample populationbased MSL test evaluations in controls are lacking, but it is estimated that only a small percentage of the general population has SOREMPs during MSL testing. Cerebrospinal fluid (CSF) hypocretin-1 measurements can also be used to diagnose narcolepsy. In patients with cataplexy, CSF hypocretin-1 levels are absent or very low in more than 90% of the cases. In patients with various other neurologic disorders, only 2% have low CSF hypocretin-1, mostly in the context of severe neurologic conditions. Levels are normal in controls independent of psychotropic treatment and/or presence of other sleep disorders. Unfortunately, the test is less predictive in patients without cataplexy, with only 16% having low levels, often in younger subjects who may later develop cataplexy.

Positive MSL test findings may be absent in some narcoleptics, especially young children. Approximately 15% of patients with definite narcolepsy and hypocretin deficiency have a negative first-time MSL test. If the MSL test is negative, but clinical suspicion for narcolepsy is high, repeat the MSL testing or measure CSF hypocretin-1. Serum HLA typing for DQB1*0602 is positive in many patients with narcolepsy, but it is also positive in approximately 20% to 25% of normal subjects. DQB1*0602 positivity does not confirm narcolepsy.

Pharmacologic Treatments
Modafinil is now first-line standard-of-care treatment for sleepiness associated with narcolepsy. Headache can be a problematic side effect, but that usually resolves with time and can often be avoided by slowly increasing
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Narcolepsy

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Disorders of Consciousness

Diagnosis of narcolepsy

Definite cataplexy

Behavioral methods: Scheduled naps Fixed wake-up time Regular sleep schedule

No cataplexy or atypical cataplexy

Disrupted nighttime sleep

No disrupted nighttime sleep

Sodium oxybate: Starting dose 4.5 grams split in two nightly doses (at bedtime and 2 hours later). Dose can be increased by 1.5 grams every two weeks, up to a maximum of 9 grams per night. Consider adding modafinil and anticataplectics on a short-term basis until sodium oxybate has full effect (up to 6 months later). If successful treatment, consider decreasing or stopping dose of anticataplectics and stimulants.

Treat cataplexy with anticataplectic monoamine reuptake inhibitors: Venlafaxine 75300 mg/day Atomoxetine 18100 mg qd or split bid Fluoxetine 2060 mg/day Clomipramine 25200 mg qhs Protriptyline 2.520 mg/bid If no (or minimal) response, consider reevaluating presence of true cataplexy. An LP for CSF hypocretin-1 levels may be necessary to confirm diagnosis. If patient responds to anticataplectics, but sideeffects are limiting, effect is insufficient, or disrupted nighttime sleep appears, consider sodium oxybate.

Treat daytime sleepiness with modafinil 200600 mg/day (if insufficient, can add two pulse doses of 5 mg methylphenidate at peak times of sleepiness)

Use caution before proceeding to stronger CNSstimulating agents, given the potential for abuse and tolerance. Confirm MSLT results and consider LP for CSF hypocretin-1. If patient is hypocretin-1 deficient, consider sodium oxybate.

Methylphenidate SR 20 mg in am with two pulse doses of 5 mg methylphenidate (non-SR) at peak times of sleepiness Dextroamphetamine SR 1015 mg in am with 5 mg pulse dosing as with methylphenidate

If onset is recent, adjust treatment with appearance of new symptoms Evaluate stable patients every six months Watch for weight gain and development of OSA or additional sleepiness FIGURE 2. Treatment of narcolepsy. CNS, Central nervous system; MSLT, multiple sleep latency test; CSF, cerebrospinal fluid; LP, lumbar puncture; OSA, obstructive sleep apnea.

the dose. The safest starting dose for modafinil is 100 mg in the morning, which can be gradually increased to a maximum of 400 to 600 mg. This may be split into a morning and a noon dose. Amphetamine-like stimulants, such as methylphenidate, dextroamphetamine, amphetamine racemic mixture, and methylamphetamine, can also be used but have a number of disadvantages. They are potentially addictive and should be reserved for patients with a well-established diagnosis. Additionally, side effects such as palpitations, hypertension, and nervousness may occur because of their action on the autonomic nervous system. The mode of action of amphetamine-like stimulants and modafinil on
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wakefulness is thought to involve increase dopaminergic transmission. The most important concept in using stimulants for treating daytime sleepiness is timing. A typical scenario is to use modafinil or an extended-release amphetamine formulation in the morning, with pulse dosing of shortacting medication at appropriate times throughout the day. For example, a student who still has problems with sleepiness after lunch might take 5 to 15 mg of shortacting methylphenidate at that time in addition to the morning modafinil. Although stimulants are used primarily for daytime sleepiness, amphetamines (not modafinil) also have some effect on cataplexy at high doses.

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Narcolepsy

Antidepressants are commonly used to treat cataplexy. They are also effective for sleep paralysis and hypnagogic hallucinations, a sometime disabling symptom. Tricyclic antidepressants are highly effective but have anticholinergic side effects. Selective serotonin reuptake inhibitors are efficacious, but relatively high doses are generally needed. Newer medications targeting norepinephrine reuptake, such as venlafaxine and atomoxetine, are most effective. The dual serotoninergic/noradrenergic reuptake inhibitor venlafaxine, 75 to 300 mg/day, is now a typical first-line treatment. If this is not helpful, atomoxetine, 18 to 100 mg daily or split to twice daily; fluoxetine, 20 to 60 mg/day; or even tricyclic antidepressants (e.g., protriptyline, 2.5 to 20 mg/day, or clomipramine, 25 to 200 mg/day) can be used. Atomoxetine is unique in being the only U.S. Food and Drug Administration approved medication that selectively blocks norepinephrine reuptake. Patients should be warned that rebound cataplexy usually occurs when medications are discontinued, changed, or skipped. Sodium oxybate (gamma-hydroxybutyrate [GHB]) is unique because it is efficacious on all symptoms. This naturally occurring compound is a potent but shortacting hypnotic that consolidates slow-wave and REM sleep, most likely via gamma-aminobutyric acid type B agonistic effect. It has been available since the 1970s but was only recently approved for the treatment of cataplexy. It is thought that the consolidation of nocturnal sleep and REM sleep leads to decreased daytime symptoms. The starting dose is 4.5 gm per night, divided in two nightly doses (before bedtime and 2 to 3 hours later, once the first dose has metabolized). The patient should prepare both doses, lie down after taking the drug, and possibly set up an alarm for the second dose. The dose can be increased every 2 weeks by 1.5-gm increments to a maximum of 9 gm per night. The most common side effects are dizziness, nausea, and, at a higher dose, enuresis. Sodium oxybate should not be taken with alcohol or other central nervous system depressants. Narcolepsy is frequently associated with other sleep disorders. OSA is common and must be treated, especially if GHB is to be used. Periodic limb movements are also common but rarely need treatment unless associated with restless leg syndrome.

The risk of driving while sleepy, especially prior to adequate therapy, must be discussed and if appropriate, regulatory agencies notified. Patients with narcolepsy must avoid jobs that put others in danger and should consider activities that are less sedentary. Jobs that involve repetitive tasks or sitting down and looking at a computer all day can be difficult. Employers or teachers should be asked to accommodate 15- to 30-minute scheduled naps. SUGGESTED READING
Dauvilliers Y, Billiard M, Montplaisir J: Clinical aspects and pathophysiology of narcolepsy, Clin Neurophysiol 114:2000-2017, 2003. Lammers GJ, Overeem S: Pharmacological management of narcolepsy, Expert Opin Pharmacother 4:1739-1746, 2003. Mignot E, Lammers GJ, Ripley B, et al: The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias, Arch Neurol 59:1553-1562, 2002. Mignot E, Lin L, Rogers W, et al: Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups, Am J Hum Genet 68:686-699, 2001. Taheri S, Zeitzer JM, Mignot E: The role of hypocretins (orexins) in sleep regulation and narcolepsy, Annu Rev Neurosci 25:283-313, 2002.

PATIENT RESOURCES
American Academy of Sleep Medicine One Westbrook Corporate Center, Suite 920 Westchester, IL 60154 Phone: 708-492-0930 http://www.aasmnet.org/ Narcolepsy Network, Inc. 10921 Reed Hartman Highway, Suite 119 Cincinnati OH 45242 Phone: 513-891-3522 E-mail: narnet@narcolepsynetwork.org http://www.narcolepsynetwork.org/ National Organization for Rare Disorders 55 Kenosia Avenue P.O. Box 1968 Danbury, CT 06813-1968 Phone: 800-999-6673 Email: orphan@rarediseases.org http://www.rarediseases.org/ National Sleep Foundation 1522 K Street NW, Suite 500 Washington, DC 20005 Phone: 202-347-3471 E-mail: nsf@sleepfoundation.org http://www.sleepfoundation.org/ Stanford Center for Narcolepsy Department of Psychiatry and Behavioral Sciences Psychiatry and Behavioral Sciences Building 401 Quarry RoadRoom 3354 Stanford, CA 94305-5730 Phone: 650-725-6512 http://www.med.stanford.edu/school/psychiatry/narcolepsy/ Talk About Sleep, Inc. P.O. Box 146 Chaska, MN 55318 Phone: 952-448-5511 http://www.talkaboutsleep.com/

Behavioral Treatments
Good sleep hygiene, education, and treatment compliance are important to the management of narcolepsy. Referral to support groups such as the Narcolepsy Network is helpful. Fixed wake-up times, sleep diaries, and regular sleep schedule are recommended. Obesity may develop, especially in young children when disease onset is abrupt. It is useful to restrict the diet, encourage exercise, and treat sleepiness aggressively at this stage.

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SECTION 2

Seizures
Neonatal Seizures and Infantile Spasms
Tallie Z. Baram, M.D., Ph.D.
is uncommon. If you add benzodiazepines, be prepared to intubate. If the seizures or the cause are focal, phenytoin may be considered. Here, if a dose of phenytoin, 20 mg/kg, with serum levels greater than 20 g/mL is ineffective, then further doses are unlikely to be helpful.

Infantile Spasms
Infantile spasms (Wests syndrome) are a severe, relatively common (~1:2400 births), and often missed diagnosis. It is important to recognize infantile spasms because they respond poorly to conventional anticonvulsants, but remit in most infants when treated with high-dose adrenocorticotropic hormone (ACTH) (see later) (Figure 2). A broad consensus suggests that cognitive outcome is better in infants with infantile spasms who are treated successfully. Infantile spasms are considered a form of myoclonic seizures that occur in clusters. They are prevalent in 3- to 12-month-old infants and are associated with a highly abnormal (interictal), chaotic electro-encephalogram (EEG) (hypsarrhythmia). This pathognomonic EEG pattern is most commonly observed during sleep. The seizures may be flexor, extensor, or mixed, subtle, or massive, and flattening of the EEG during a spasm is typical. Most infantile spasms are symptomatic, resulting from a large variety of insults or genetic causes. A variant associated with tuberous sclerosis may be particularly responsive to vigabatrin (100 to 150 mg/kg/day). This medication is available outside the United States, and the side effects of visual-restrictive retinal changes should be considered. In some cases the causes of infantile spasms may be treatable, with seizure remittance. Mostly, treatment of the spasms with a goal of eliminating them and normalizing the EEG is required. Early, successful therapy seems to improve cognitive outcome. The latter is grim in symptomatic cases but excellent in remitting idiopathic cases. The most efficacious treatment is high-dose ACTH, with greater than 85% success. A 2-week treatment with this potent hormone results in unpleasant but rarely dangerous side effects such as acne, hypertension, voracious appetite, and irritability. Long-lasting treatment may lead to immunosuppression or gastric bleeding. Because efficacy is a function of the dose, and 23

Neonatal Seizures
Most seizures in a newborn are symptomaticthey are caused by acute or remote insults to the developing brain. Some of these may be eliminated or reversed; others may require concurrent treatment. Therefore, a diagnostic evaluation should precede or coincide with therapeutic intervention (see later). A second unique feature of many neonatal seizures is their unusual or subtle nature compared with seizures later in life. In addition to tonic, clonic, focal, or apparent generalized motor seizures, neonatal seizures may consist of fragmented, nonrhythmic movements, eye blinking, singleextremity posture, or electroencephalographic seizures without overt motor manifestations. Thus, the clinician should have a high level of suspicion for seizures in an ill neonate. Tachycardia or bradycardia, unexplained oxygen desaturation, or abnormal mental status may signify ongoing seizures. Finally, the outcome of neonatal seizures is best predicted by their cause. For example, hypocalcemia-induced seizures in an otherwise normal fullterm infant typically remit, with good outcome. In contrast, seizures following severe hypoxia/ ischemia, severe neonatal infection, or congenital brain malformation may respond to treatment, but the infants prognosis would be guarded. TREATMENT (Figure 1) There is no absolute best drug. Phenobarbital is recommended here because it is both rapid and long acting and has no ceiling; repeated boluses can be used in severe cases as monotherapy with high likelihood of success. Ignore serum levels; in any event, they are not steady-state. Use remission as your guideline. With phenobarbital monotherapy, respiratory depression
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Neonatal Seizures and Infantile Spasms

ALGORITHM FOR MANAGEMENT OF NEONATAL SEIZURES 1. Assure adequate airway protection and oxygenation 2. Initiate diagnostic evaluation: History/physical for obvious causes (placenta previa, multiorgan failure with hypoxic ischemic encephalopathy (HIE), severe prematurity, etc). Metabolic: Glucose (in an infant of diabetic mother, give oral or iv glucose), calcium, electrolytes Infection: CBC, cultures, chest x-ray. Spinal tap mandatory (consider metabolic causes of low CSF glucose). Evaluate for congenital infection, particularly if petechiae, liver enlargement, cataracts or other clues present. CT/MRI: periventricular hemorrhage in severe prematurity, malformation, tuberous sclerosis, infarcts, abnormal basal ganglia signal indicating HIE, etc. Obtain EEG, if infant ill or seizures subtle consider continuous EEG to monitor results of therapy. 3. Treat A. Address treatable causes (calcium, glucose, infection) B. Give phenobarbital 20 mg/kg. This is a loading dose that should lead to barely therapeutic serum levels.

Seizures remit

Seizures persist

Cause transient or resolved: stop treatment Cause persistent or unknown, baby abnormal: continue treatment

Repeat PB at 1020 mg/kg* Obtain EEG. If seizures focal consider phenytoin (20 mg/kg) Barbiturates have no ceiling effect. May be used at very high doses, to seizure remission Mixing barbiturates and benzodiazepines should be done with caution in unintubated infants, because of potential respiratory depression.

Seizures remit

More PB or benzodiazepine. Reassess diagnostic workup. Consider intubation.

Seizures persist

FIGURE 1. Algorithm for management of neonatal seizures. CBC, Complete blood count; CSF, cerebrospinal fluid; EEG, electroencephalogram; PB, phenobarbital.

ALGORITHM FOR MANAGEMENT OF INFANTILE SPASMS 1. Establish the diagnosis History/physical: to rule out (sleep) myoclonus, myoclonic seizures, GE reflux The age, clusters of spasms, hypsarrhythmic EEG are diagnostic Consider treatable causes (mass lesion, metabolic derangement). Try to establish diagnosis, particularly tuberous sclerosis, infection, other genetic/acquired insult (CT/MRI, basic metabolic workup). Normal baby = idiopathic IS: prognosis better Abnormal baby with diagnosis (symptomatic IS), or no diagnosis (cryptogenic) prognosis for cognitive outcome guarded 2. Treat A. Address treatable causes (hydrocephalus, infection) B. Give ACTH depot (ACTHARGEL): 150 units/square meter per day (~ 80 U per 10 kg baby) in two daily divided doses for 2 weeks.

Spasms remit (>80%)

Spasms persist

Obtain EEG or video-EEG to verify. Often hypsarrhythmia will disappear revealing other abnormalities.

Verify that medication given as directed. Try another batch of ACTH.

Spasms persist No spasms, no hypsarrhythmia Consider vigabatrin 100 mg/kg/day. Consider topiramate, valproate, B-6, ketogenic diet.

Taper ACTH over 2 weeks

FIGURE 2. Algorithm for management of infantile spasms. EEG, Electroencephalogram; GE, gastroesophageal; IS, infantile spasm; ACTH, adrenocorticotropic hormone. Johnson: Current Therapy in Neurologic Disease (7/E)

Febrile Seizures

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Seizures

side effects are a function of the duration of treatment, it is best to initiate ACTH treatment at the high dosage and limit duration to 2 weeks, with a 2-week taper. Complete dramatic remission of the spasms typically occurs during the first week. Note that twice-daily dosing at the high (ActharGel, 150 U/m2 of body surface area) is required. Occasional bad batches of the hormone have been described. In infants with a strong focal element of the spasms, particularly with focal lesion (e.g., tuber) and focal EEG, surgical therapy should be considered. A trial of ACTH may still be indicated and may convert apparent infantile spasms to focal seizures. Other therapies may be successful at a much lower rate. Consider pyridoxine (to exclude pyridoxinedependent seizures, or as therapy), 100-150 mg/day; valproate; topiramate; and the ketogenic diet. If seizures remit and recur, verify that these are indeed infantile spasms rather than a new seizure type with focal EEG. A second course of ACTH may be effective for infantile spasm recurrence. New seizure types, instigated by the original disorder, may respond to appropriate anticonvulsant therapy.

TABLE 1 Risk of Experiencing a Febrile Seizure


Factor General population Child in daycare Slow development Prolonged nursery stay (>28 days) Febrile seizure in first-degree relative (mother, father, sibling) Febrile seizure in two first-degree relatives Any two risk factors Risk of Febrile Seizure (%) 2 7 10 12 10 33 28

Adapted from Bethune P, Gordon K, Dooley J, et al: Which child will have a febrile seizure? Am J Dis Child 147:35-39, 1993.

What Is the Chance That My Child Will Have Febrile Seizures?


Families with a history of febrile seizures may ask this question, particularly when there are siblings with febrile seizures. Febrile seizures are more common in some families, and 10% to 20% of siblings of children with febrile seizures will also experience them. Certain other children may have an increased risk, as high as 25% if the child had a prolonged nursery stay, slow development, or daycare attendance. These factors suggest susceptibility to febrile seizures in a child who may have experienced some subtle neurologic changes and who is exposed on a more consistent basis to a wide range of infections in the daycare setting. When two or more of these factors exist, it may be appropriate at one of the early well-child visits to discuss management of fever and what to do if a febrile seizure occurs (Table 1).

Febrile Seizures
Adam L. Hartman, M.D., and Eileen P. G. Vining, M.D.

Febrile seizures occur in approximately 3% of children, making them the most common type of seizure in this age group. They are seizures in infancy or childhood (typically between 3 months and 5 years of age) associated with fever and without evidence of central nervous system infection or other defined cause, such as metabolic abnormalities due to dehydration. Ordinarily, they are generalized (tonic-clonic or tonic) in nature and brief. The fact that they are common to pediatric practices (and often to neurologic consultation) makes it important to understand many of the concerns associated with their occurrence and to understand the information that has reshaped our approach to this problem. In fact, this has resulted in reconsideration of our overall approach to seizures. Given the generally benign prognosis in febrile seizures, counseling the family is the primary form of therapy. One way to consider the issues involved in febrile seizures is to organize the information in a format that answers parents questions and provides a framework for providing ongoing care. This can even include anticipatory guidance, which is so vital to the practice of pediatrics.
Johnson: Current Therapy in Neurologic Disease (7/E)

What Should We Do If Our Child Has a Febrile Seizure?


Most febrile seizures are brief and do not need medical intervention. If, however, the seizure has persisted longer than 5 minutes, Emergency Medical Services (i.e., 911) should be called. Less than 5% of febrile seizures occur as status epilepticus, and it is likely that the seizure will end before medications can be given. The usual intervention is either lorazepam, 0.1 mg/kg intravenously (IV), up to 4 mg, or diazepam, 0.3 mg/kg IV given slowly at less than 1 mg/kg/min. Health care providers in emergency settings should recall that diazepam could be given rectally.* In essence, care during a febrile seizure should be the same as for any other generalized convulsion. When the seizure is over and the child has returned to baseline (often sleepiness if the seizure has occurred at night), a decision must be made concerning the
*Diastat, 0.5 mg/kg rectally for children 2 to 5 years, 0.3 mg/kg rectally for children 6 to 11 years, 0.2 mg/kg rectally for children older than 11 years, all rounded to the nearest syringe size; one dose may be repeated after 30 minutes, if necessary.

Febrile Seizures

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Seizures

side effects are a function of the duration of treatment, it is best to initiate ACTH treatment at the high dosage and limit duration to 2 weeks, with a 2-week taper. Complete dramatic remission of the spasms typically occurs during the first week. Note that twice-daily dosing at the high (ActharGel, 150 U/m2 of body surface area) is required. Occasional bad batches of the hormone have been described. In infants with a strong focal element of the spasms, particularly with focal lesion (e.g., tuber) and focal EEG, surgical therapy should be considered. A trial of ACTH may still be indicated and may convert apparent infantile spasms to focal seizures. Other therapies may be successful at a much lower rate. Consider pyridoxine (to exclude pyridoxinedependent seizures, or as therapy), 100-150 mg/day; valproate; topiramate; and the ketogenic diet. If seizures remit and recur, verify that these are indeed infantile spasms rather than a new seizure type with focal EEG. A second course of ACTH may be effective for infantile spasm recurrence. New seizure types, instigated by the original disorder, may respond to appropriate anticonvulsant therapy.

TABLE 1 Risk of Experiencing a Febrile Seizure


Factor General population Child in daycare Slow development Prolonged nursery stay (>28 days) Febrile seizure in first-degree relative (mother, father, sibling) Febrile seizure in two first-degree relatives Any two risk factors Risk of Febrile Seizure (%) 2 7 10 12 10 33 28

Adapted from Bethune P, Gordon K, Dooley J, et al: Which child will have a febrile seizure? Am J Dis Child 147:35-39, 1993.

What Is the Chance That My Child Will Have Febrile Seizures?


Families with a history of febrile seizures may ask this question, particularly when there are siblings with febrile seizures. Febrile seizures are more common in some families, and 10% to 20% of siblings of children with febrile seizures will also experience them. Certain other children may have an increased risk, as high as 25% if the child had a prolonged nursery stay, slow development, or daycare attendance. These factors suggest susceptibility to febrile seizures in a child who may have experienced some subtle neurologic changes and who is exposed on a more consistent basis to a wide range of infections in the daycare setting. When two or more of these factors exist, it may be appropriate at one of the early well-child visits to discuss management of fever and what to do if a febrile seizure occurs (Table 1).

Febrile Seizures
Adam L. Hartman, M.D., and Eileen P. G. Vining, M.D.

Febrile seizures occur in approximately 3% of children, making them the most common type of seizure in this age group. They are seizures in infancy or childhood (typically between 3 months and 5 years of age) associated with fever and without evidence of central nervous system infection or other defined cause, such as metabolic abnormalities due to dehydration. Ordinarily, they are generalized (tonic-clonic or tonic) in nature and brief. The fact that they are common to pediatric practices (and often to neurologic consultation) makes it important to understand many of the concerns associated with their occurrence and to understand the information that has reshaped our approach to this problem. In fact, this has resulted in reconsideration of our overall approach to seizures. Given the generally benign prognosis in febrile seizures, counseling the family is the primary form of therapy. One way to consider the issues involved in febrile seizures is to organize the information in a format that answers parents questions and provides a framework for providing ongoing care. This can even include anticipatory guidance, which is so vital to the practice of pediatrics.
Johnson: Current Therapy in Neurologic Disease (7/E)

What Should We Do If Our Child Has a Febrile Seizure?


Most febrile seizures are brief and do not need medical intervention. If, however, the seizure has persisted longer than 5 minutes, Emergency Medical Services (i.e., 911) should be called. Less than 5% of febrile seizures occur as status epilepticus, and it is likely that the seizure will end before medications can be given. The usual intervention is either lorazepam, 0.1 mg/kg intravenously (IV), up to 4 mg, or diazepam, 0.3 mg/kg IV given slowly at less than 1 mg/kg/min. Health care providers in emergency settings should recall that diazepam could be given rectally.* In essence, care during a febrile seizure should be the same as for any other generalized convulsion. When the seizure is over and the child has returned to baseline (often sleepiness if the seizure has occurred at night), a decision must be made concerning the
*Diastat, 0.5 mg/kg rectally for children 2 to 5 years, 0.3 mg/kg rectally for children 6 to 11 years, 0.2 mg/kg rectally for children older than 11 years, all rounded to the nearest syringe size; one dose may be repeated after 30 minutes, if necessary.

26

Febrile Seizures

evaluation of the precipitating fever. The American Academy of Pediatrics has published guidelines outlining the approach to these patients, summarized here and in Figure 1. If this is the patients first febrile seizure (particularly if in a young infant or toddler), the child should be examined immediately to detect and/or treat the cause of the fever. A seizure in the setting of a fever must be excluded from a seizure resulting from meningitis. Generally this is not difficult since an alternative source can be found or the child is acting normally without evidence of significant illness. A lumbar puncture (LP) should be done whenever there is concern about the possibility of meningitis. It is usually performed in children younger than 1 year of age who have had a first febrile seizure and in settings where there is concern about the reliability of remaining in contact with the medical care providers. There are certain indications that increase the likelihood that an LP will be positive: (1) a physician visit within the 48 hours preceding the seizure, (2) seizure occurring or persisting in the emergency department setting, (3) focal seizure, or (4) suspicious findings on either physical or neurologic examination. Additional laboratory work should be done depending on the nature of the illness and the questions being asked. A computed tomographic scan or magnetic resonance imaging is not necessary in simple febrile seizures. An EEG is also not necessary; if done within a
Simple FS, no meningeal signs

week of the seizure, it is often minimally abnormal, displaying evidence of the postictal features of the brain. There is no evidence that these findings are predictive of an outcome, either of recurrent seizures or of epilepsy. Usually, the child can be discharged from the emergency department without ongoing medications (other than those appropriate for infection). It is critical that followup be arranged to discuss the meaning of the febrile seizure and how the situation should be managed in the future. If the seizure is recurrent and brief, the physician should be called and plans should be made to assess the source of fever.

What Else Could It Have Been Besides a Febrile Seizure? What Causes Febrile Seizures?
The differential diagnosis of febrile seizures includes the first presentation of epilepsy unmasked by a lowered seizure threshold caused by the fever and illness. The distinction between a febrile seizure and new-onset epilepsy need not be made on the first presentation. There are a number of reasons for this. First, the pathophysiologic relationship between febrile seizures and epilepsy later in life is debated (see later). Second, tests that help make the diagnosis of certain epilepsy syndromes (e.g., EEG) are not predictive after a first simple febrile seizure. Epilepsy will declare itself over time. Even experienced epileptologists can be challenged when making the distinction between a first febrile seizure and a first seizure with fever. Recent work has shown that some patients with a combination of febrile and afebrile seizures, known as generalized epilepsy and febrile seizures plus (GEFS+) have mutations in voltage-gated sodium channel subunits. If there is a family history of febrile and afebrile seizures (particularly severe myoclonic epilepsy of infancy), referral can be made to research groups interested in the genetics of these conditions. Meningitis can manifest as seizures and fevers, as previously discussed. Toxic ingestions of certain medications and substances with anticholinergic properties can also cause seizures and hyperthermia, though there are other historical and clinical signs that should suggest their presence. The same is true for neuroleptic malignant syndrome. In the appropriate setting, intentional exposures (e.g., chemical exposures or bioterrorism) should be considered. Associations have been made between certain pathogens (e.g., human herpesvirus 6) and febrile seizures. Investigation for these viruses is not ordinarily indicated in otherwise healthy children. Certain pathogens can cause encephalopathies that include seizures and fevers. Encephalopathic patients need extensive investigations and are not the subject of this chapter.

Routine imaging, EEG, blood studies not indicated if first simple FS

Age < 12 months? Age 1218 months?

Age > 18 months?

Strongly consider LP

Consider LP

LP unnecessary

1. Manage concurrent illness (e.g., UTI or otitis media). 2. Manage fever, pain, and discomfort. 3. Counsel family at the appropriate time (preferably at office visit) about risk factors, recurrence risk, management of another seizure, risk of epilepsy.

First FS or duration < 15 min.?

Recurrent FS or duration > 15 min.?

No treatment necessary

Discuss option of rectal diazepam with caregivers

Did the Seizure Hurt My Child?


FIGURE 1. Neurology-centered management of febrile seizures (FS). EEG, Electroencephalogram; LP, lumbar puncture; UTI, urinary tract infection.

Parents witnessing a febrile seizure fear that their child will die. We must acknowledge this emotional turmoil,
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but their fears and worries can be allayed only by solid information. There is no evidence that a typical febrile seizure hurts the child. Parents need to know about the National Collaborative Perinatal Project, in which children were followed from birth to 7 years of age. Much was learned about the natural history of febrile seizures from this study. Three percent of a cohort of 54,000 children had a febrile seizure (1800 youngsters). No child died of a febrile seizure; no child developed mental retardation from a febrile seizure; and no child developed cerebral palsy from a febrile seizure. There is good evidence from this study that febrile seizures do not lower intelligence. Since the cohort was so large, establishing controls was possible (siblings without febrile seizures) for those who had febrile seizures. The IQ at age 7 years of children with febrile seizures, even recurrent febrile seizures, was not lower than their siblings who had not experienced febrile seizures. More recent studies have confirmed these findings. Parents need to be able to grasp the reality of this information as we help them understand the benign nature of febrile seizures and as they assess interventions.

occurred at a lower temperature (<101F) than if the seizure occurred with a fever higher than 105F. These two observations suggest that there are some children whose threshold for having a febrile seizure is lower than others. It takes a shorter exposure to fever and less of a fever to make them have a febrile seizure. Recurrences are also more likely (40% vs. 20%) if there is a family history of febrile seizures. Recurrence of febrile seizures is not more likely if the seizure is focal or prolonged or even if the child is neurologically or developmentally abnormal before the seizure occurred. About 50% recur in the first 6 months, and 90% will have recurred within the first year.

If the Seizure Is Very Long, Will It Hurt My Child?


There are no data to support the fear that a prolonged febrile seizure will harm the child. Most episodes of febrile status epilepticus occur as the first febrile seizure. Only about 10% of febrile seizures last longer than 15 minutes. Children do not die of febrile status epilepticus, and they do not experience new neurologic problems from it. In fact, they do not have a significantly greater risk of recurrence of simple febrile seizures than the population at large. Only children who have underlying neurologic abnormalities have an increased risk of recurrence of febrile seizures and febrile status epilepticus. These children are also at increased risk for developing afebrile seizures.

Will My Child Have Another Febrile Seizure? If So, When?


Unfortunately, febrile seizures recur in many children. One third of the children will have a second one, and there is a 50% chance that there will be a recurrence if the child is younger than 1 year of age. Parents should be told that there is no reason to expect that a subsequent febrile seizure will be worse than the first. In fact, the first febrile seizure is usually the worst one. There is an increased risk for recurrence under a variety of circumstances (Table 2). The risk of recurrence is increased to almost 50% if the febrile seizure happened in the first hour of fever and is only 15% if the febrile seizure happened more than 24 hours into the fever. The risk of recurrence is also higher (40%) if the febrile seizure

Will My Child Have Epilepsy?


Whether a child will develop epilepsy after a febrile seizure is a concern of families and of physicians and has certainly been one of the motivating forces for initiating prophylactic therapy, hoping to ward off not only recurrent febrile seizures but also epilepsy. Recurring afebrile seizures (epilepsy) is not a consequence of febrile seizures, even recurrent febrile seizures. In the National Collaborative Project, there was no significant increase in the incidence of epilepsy if children had febrile seizures (0.5% vs. 0.9%). The only group that had a significantly increased risk of developing epilepsy by 7 years of age was those children who had two or more risk factors. These risk factors included (1) family history of epilepsy in a first-degree relative; (2) abnormal neurodevelopmental status prior to the first febrile seizure; and (3) complex febrile seizure defined as any one or more of the following features: focal, lasting longer than 15 minutes, or recurring in 24 hours. A child who had a focal febrile seizure that lasted 20 minutes has only one risk factor. Figure 2 graphically demonstrates the overlap between risk factors. Only 6% of the cohort had two or more risk factors, and only 9% of these children developed epilepsy by 7 years os age. Thus, even when the risks appear great, more than 90% of children will not develop epilepsy. Other studies that were not prospective suggest that risks may be higher if people are assessed in their 20s.

TABLE 2 Risk of Recurrence of Febrile Seizure


Factor Overall First febrile seizure <1 yr old Duration of fever <1 hr >24 hr Temperature <101F >105F Family history of febrile seizures Negative family history of febrile seizures Risk of Recurrence (%) 30 50 46 15 42 12 40 23

Adapted from Berg AT, Shinnar S, Hauser WA, et al: A prospective study of recurrent febrile seizures, N Engl J Med 327:1122-1127, 1992.

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Febrile Seizures

Positive family history 5.3%

10%

Abnormal development 3.3%

23% 13% 8%

Complex febrile seizure 4.1%

FIGURE 2. Risks of developing epilepsy after a febrile seizure based on associated factors. (Data from Nelson KB, Ellenberg JH: Prognosis in children with febrile seizures, Pediatrics 61:720-727, 1978.)

These risks include more emphasis on the cumulative effects of a number of factors including the focality of the seizure, whether a Todds paralysis existed, the number of febrile seizures, the age at which the febrile seizure occurred, and the duration of the febrile seizure. Many physicians are worried that febrile seizures will lead to intractable complex partial epilepsy (temporal lobe epilepsy). This issue was raised long ago because of observations made in the setting of surgery to control complex partial seizures. Falconer noted that in the setting of finding mesial temporal sclerosis, there was an increased history of prolonged febrile seizures. Others have disputed these observations. There has been no objective evidence of this process, and many have postulated that prolonged febrile seizures may occur in the setting of an already abnormal mesial temporal lobe. This would need to be studied using magnetic resonance imaging at the time of the initial prolonged or atypical febrile seizure. It is this fear that febrile seizures will lead to intractable epilepsy that has fueled the fire to prevent febrile seizures. There is no evidence, however, that prophylaxis of febrile seizures actually prevents the development of epilepsy.

Can You Prevent These Seizures from Coming Back?


Febrile seizure recurrence can probably be prevented, but why should we even try? For more than 20 years we have known that chronic prophylaxis with phenobarbital levels maintained at more than 17 mg/L will decrease the risk of recurrence to about 10%. Higher levels might prevent more.

There are no convincing data demonstrating that assiduous use of antipyretics can prevent febrile seizure recurrences. We do not even understand enough about the role of fever in provoking the seizure to recommend appropriate antipyretic therapy. Many have believed that it was the rate of rise of fever that provoked the seizure, but this is probably not correct. More likely, the height of the fever itself, the cause of the fever, and other factors unique to the child during the illness (amount of rest, fluids, and so on) determine the predisposition for seizures. Other methods to try to prevent recurrence have been suggested. Other medications, with perhaps fewer side effects than phenobarbital, have been suggested. However, phenytoin and carbamazepine do not appear to prevent febrile seizure recurrences. The potential risks of valproic acid in younger children outweigh the fact that it seems as effective as phenobarbital. About 10 years ago, there was renewed interest in intermittent prophylaxis with diazepam. The results of one study were highly informative in describing why this can be a challenge. The lack of availability of a rectal preparation in the United States at that time led to the study of oral diazepam, 0.33 mg/kg orally every 8 hours, during the febrile illness. Rosman and colleagues showed a 44% reduction in febrile seizure recurrence but found many problems with adherence to the medication regimen. The reasons for this included the following: the temperature was not taken or the presence of illness was not recognized until the seizure occurred; the child was not with the parent when it happened; directions were misunderstood; the child vomited or did not tolerate the medicine; and fear of side effects. In addition, almost 40% of those treated with diazepam had side effects including ataxia, lethargy, and irritability. A recent meta-analysis by Rantala and associates concluded that prophylaxis was difficult to justify in the face of adverse events. An option newly available in the United States is rectal diazepam gel (Diastat) (see earlier). Europeans have used this technique for many years and have had some reasonable success. There are situations where this form of diazepam may be appropriate. This might include neurologically abnormal children who have experienced febrile status epilepticus and children who have a history of recurring, prolonged febrile seizures, especially those who live far from care. This could prevent a prolonged seizure and perhaps diminish the likelihood of recurrence within the next few hours. Unfortunately, large studies of its use have not been undertaken. It has been our anecdotal experience that just having the medicine available and caregivers knowledgeable in its use can lower anxiety levels at home, in the appropriate setting. In managing a patient over the phone, an inquiry should be made about whether rectal diazepam has been prescribed; some caregivers seek a physicians permission to use it, because they fear adverse reactions to the medicine. Physicians seeing children with recurrent febrile seizures should inquire about its use prior to arrival in an acute care setting, since it can alter the patients clinical presentation.
Johnson: Current Therapy in Neurologic Disease (7/E)

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How Will the Treatment Affect My Child?


This depends on the treatment. Phenobarbital may have significant side effects. For decades we have known that it may make children hyperactive, inattentive, and irritable and that it may interfere with sleep. Studies have consistently found that phenobarbital appears to diminish cognitive function (on the average, 4 or 5 IQ points) and that behavior is adversely affected. It is not clear that this impact disappears when the medication has been discontinued, and this is a source of continuing concern since it is administered to children at such a vulnerable developmental period. The risks of intermittent prophylaxis with diazepam are less. Any source of anxiety about the seizures themselves or their treatment leads to strained interactions and increased vulnerability of the child to overprotectiveness.

be a slightly increased incidence of sleep problems, such as parasomnias.

Where Can We Learn More About This?


Parents, caregivers, and often the extended family, should be given an opportunity to learn more. They can accomplish this through several mechanisms. We have written a book specifically for parents that discusses these issues in detail (see Patient Resource). They can be referred to the Abilities Network, which maintains a toll-free hotline (1-800-EFA-1000). Parents will be sent appropriate literature and will be notified if there is a local affiliate that can probably provide even more services such as family counseling and focus groups. Frequently parents need to hear from other parents who have been through this difficult period that the outcome is truly good and that brief febrile seizures have not damaged their child. SUGGESTED READING

What Shall I Do If My Child Has Another Seizure?


The advice to give a family about what to do if the child has another febrile seizure is straightforward. Remember that everything was fine after the first seizure. Remember basic first aid. Provide supportiveprotective care. Stay calm. A child recovering from a seizure and perhaps feeling ill from the fever and cranky at being wakened from sleep does not need to see a panicked parent. Reassure the child that everything is fine. Be soothing. As in the first seizure, the childs pediatrician should be consulted so that they can properly manage the illness. The discussion about whether to use prophylaxis will resurface. Nevertheless, the risks and benefits have not really changed. There is still no significant risk from a febrile seizure. The risk of epilepsy does not substantially increase with recurrent febrile seizures, and there are no data to make us believe we can prevent epilepsy anyway. The risks from treatment remain the same: exposure to medication, the side effects, the constant observation, and the daily reminder that there is something wrong that needs constant medication. Most of these children will outgrow these seizures and experience no disability from having had febrile seizures. On the other hand, those parents who have been sensitized to be frightened of illness and those children who have been medicated over a protracted period may have problems. The risks of treatment generally are worse than the possible benefits that might accrue from therapy.

American Academy of Pediatrics. Committee on Quality Improvement, Subcommittee on Febrile Seizures: Practice parameter: long-term treatment of the child with simple febrile seizures, Pediatrics 103:1307-1309, 1999. American Academy of Pediatrics. Provisional Committee on Quality Improvement, Subcommittee on Febrile Seizures: Practice parameter: the neurodiagnostic evaluation of the child with a first simple febrile seizure, Pediatrics 97:769-772, 1996. Berg AT, Shinnar S, Hauser WA, et al: A prospective study of recurrent febrile seizures, N Engl J Med 327:1122-1127, 1992. Bethune P, Gordon K, Dooley J, et al: Which child will have a febrile seizure? Am J Dis Child 147:35-39, 1993. Farwell JR, Lee YJ, Hirtz DG, et al: Phenobarbital for febrile seizures: effects on intelligence and seizure recurrence, N Engl J Med 322:364-369, 1990. Maytal J, Shinnar S: Febrile status epilepticus, Pediatrics 86:611-616, 1990. Nelson KB, Ellenberg JH: Predictors of epilepsy in children who have experienced febrile seizures, N Engl J Med 295:1029-1033, 1976. Nelson KB, Ellenberg JH: Prognosis in children with febrile seizures, Pediatrics 61:720-727, 1978. Rantala H, Tarkka R, Uhari M: A meta-analytic review of the preventive treatment of recurrences of febrile seizures, J Pediatr 131:922-925, 1997.

PATIENT RESOURCES
Freeman JM, Vining EPG, Pillas DJ: Seizures and epilepsy in childhood: a guide for parents, Baltimore, 2003, Johns Hopkins University Press. Abilities Network: Hotline: 800-332-1000

What Else Can Happen to Children with Febrile Seizures?


Intellectual development is normal in previously developmentally normal children with febrile seizures. Some children can develop some behavioral problems, but this may not be due to the febrile seizures. There may
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Absence Seizures

Absence Seizures
Nathan E. Crone, M.D.

Diagnosis
Although patients and physicians often refer to absence seizures as petit mal, absence is the preferred term to describe seizures with staring, unresponsiveness, and characteristic generalized epileptiform discharges on electroencephalogram (EEG). Absence seizures may be differentiated into typical absence and atypical absence. Typical absence seizures are characterized by a brief lapse of consciousness and responsiveness, usually lasting less than 10 seconds, associated with characteristic generalized 3-Hz spike-and-wave discharges that abruptly appear and disappear against the background of an otherwise normal EEG. The EEG abnormalities are readily elicited by hyperventilation and less frequently by intermittent photic stimulation. Typical absence seizures have no auras or postictal confusion. Although amnestic for events during the seizure, patients may continue with activities that were temporarily interrupted by the seizure, often continuing where they left off mid-sentence. Typical absence seizures may be further subdivided into simple and complex absence seizures according to whether there are associated orofacial or limb automatisms, or other motor signs such as clonic, tonic, or atonic movements. Atypical absence seizures are most readily distinguished from typical absence seizures by their longer duration (usually > 20 seconds), slower generalized spikewave discharges (2 to 2.5 Hz), and their association with mental retardation and other seizure types, particularly atonic and tonic seizures. These seizures are clinically less stereotyped than typical absence seizures, with a less abrupt onset and offset and a longer duration, lasting up to several minutes. In addition, these seizures are often not precipitated by hyperventilation or photic stimulation. Atypical absence seizures are best known for their occurrence in Lennox-Gastaut syndrome (see later). Yet another type of absence seizure, myoclonic absence, is accompanied by rhythmic clonic jerking of bilateral upper and lower limbs. It is important to distinguish absence seizures from complex partial seizures, which may superficially resemble absence seizures in some patients. Patients may refer to either seizure type as a staring spell, and patients with complex partial seizures may refer to their seizures as petit mal simply because they are less severe than their grand mal seizures. Some complex partial seizures consist only of staring, behavioral arrest, and unresponsiveness, and absence seizures are often accompanied by automatisms that are more commonly seen in complex partial seizures. However, complex partial seizures can usually be clinically differentiated from absence seizures by their longer duration and the presence of auras and/or postictal confusion. The diagnosis of absence seizures can usually be confirmed by the characteristic

ictal and interictal discharges seen on EEG. The distinction between these seizure types is clinically relevant because absence seizures may be exacerbated by some medications used to treat complex partial seizures. In addition to carbamazepine, gamma-aminobutyric acid agonists such as tiagabine and vigabatrin may also exacerbate absence seizures by modulating the abnormal thalamocortical circuits that appear to be responsible for the characteristic 3-Hz spike-and-wave discharges. Absence seizures often present in children as deteriorating school performance and may be misdiagnosed as attention deficit disorder or other behavioral disturbances. Typical absence seizures often go unrecognized because of their brevity and subtle clinical appearance in otherwise normal children, but they may occur hundreds of times per day. If left untreated these brief but frequent lapses of consciousness can interrupt learning. Therefore, the academic performance of patients with newly diagnosed absence seizures should be closely monitored, and remedial instruction should be recommended if necessary. The EEG is a critical component in the diagnostic work-up for possible absence seizures. The ictal and interictal EEG abnormalities associated with typical absence seizures are stereotyped and diagnostic, consisting of high-voltage, rhythmic 3-Hz spike-and-wave complexes over widespread head regions, maximal over frontal regions and usually, but not always, bilaterally symmetrical. Briefly displacing an otherwise normal background EEG, these spike-wave complexes coincide with the abrupt onset and offset of ictal clinical manifestations. Brief interictal discharges may not be associated with appreciable clinical manifestations, but runs of spike-wave complexes lasting more than a few seconds are often associated with typical clinical absence seizures. Both interictal and ictal discharges, as well as typical absence seizures, may be evoked by hyperventilation and, less commonly, by intermittent photic stimulation. Atypical absence seizures are most commonly associated with slow spike-and-wave complexes (1.5 to 2.5 Hz) that often appear less stereotyped and symmetrical. This pattern usually occurs against an abnormal background of diffuse slowing with focal or multifocal spikes. Effective therapeutic decision making relies on a correct diagnosis of not only the seizure type but also the associated epilepsy syndrome. The most common syndromes presenting with absence seizures are childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME). CAE usually begins before 10 years of age, with peak incidence at 5 years of age, and usually remits (is outgrown) within a few years after onset. Remission occurs in 90% of cases before 12 years of age, and attempts to taper medications can be initiated during adolescence, before the patients driving license becomes an issue. JAE begins after 10 years of age, but unlike CAE, it does not usually remit and is often lifelong. Although CAE is manifest only by absence seizures, JAE may also be associated with myoclonic and generalized tonic-clonic seizures, which are the more common seizure types seen in JME. Absence seizures typically occur with much
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Seizures

lower frequency in JAE than in CAE, and typical spikewave discharges are not as reliably induced by hyperventilation in JAE. Infrequent absence seizures may also occur in 30% to 50% of patients with JME. A substantial minority of patients with typical absence seizures and generalized discharges on EEG does not fit the aforementioned syndromes. In addition, rare but well-recognized syndromes with absence seizures include myoclonic absence epilepsy, eyelid myoclonia with absences, and perioral myoclonia with absences. Atypical absence seizures are commonly seen in Lennox-Gastaut syndrome, which consists of mental retardation in association with mixed seizure types, including atypical absence, atonic, myoclonic, tonic, and/ or generalized tonic-clonic seizures. The peak age at onset is 3 to 5 years of age, and 20% of patients have a history of infantile spasms. This is considered a symptomatic epilepsy syndrome because it is often associated with preexisting cerebral insults, including hypoxic-ischemic and other perinatal brain injuries, central nervous system infections, developmental malformations, and neurogenetic diseases such as tuberous sclerosis. The diagnosis of typical absence seizures may be confirmed with careful clinical history and EEG, without additional ancillary tests. CAE, JAE, and JME appear to be genetic in origin with highly variable penetrance; therefore, a family history of similar seizures is helpful but not necessary for the diagnosis. Clinicians can often make the diagnosis in the office by observing clinical seizures during hyperventilation. However, a history of atypical absence seizures should prompt a search for an underlying neurologic disease, and the work-up should include magnetic resonance imaging of the brain, as well as screening for neurogenetic diseases. Absence status epilepticus usually presents as persistent confusion or stupor associated with characteristic 1- to 4-Hz spike-and-wave or polyspike-and-wave discharges on EEG, usually without other typical clinical manifestations of absence seizures. It may occur in patients with a history of typical or atypical absences with their attendant epilepsy syndromes. This emergency can usually be resolved with intravenous lorazepam or diazepam, or sodium valproate (Depacon).

Management
The mainstays of pharmacotherapy for typical absence seizures are ethosuximide and valproic acid. These drugs appear to be equally effective as monotherapy, controlling more than 80% of patients. Ethosuximide has been considered the first choice because of its lack of the serious, yet rare, side effects associated with valproic acid. By reducing low-threshold T-type calcium currents that play a role in the generation of 3-Hz spike-and-wave rhythms in thalamocortical neurons, ethosuximide is highly effective against absence seizures. However, there is no evidence that it has other common antiepileptic mechanisms of action, and it is not usually effective in monotherapy for generalized tonic-clonic seizures. Its use as monotherapy is therefore largely limited to CAE, but it may be used as an adjunctive
Johnson: Current Therapy in Neurologic Disease (7/E)

antiepileptic drug in patients with absence seizures in addition to other seizure types. Ethosuximide may also be effective against absence seizures in JME, epilepsy with myoclonic absences, and eyelid myoclonia with absences, as well as atypical absence seizures in Lennox-Gastaut syndrome. The most common doserelated side effects are nausea, drowsiness, and other gastrointestinal complaints, which are usually mild and most prevalent at the onset of therapy. Headaches and behavioral disturbances, including psychosis, can be caused or exacerbated by ethosuximide in rare instances. Valproic acid is effective not only against absence seizures but also against generalized tonic-clonic, myoclonic, and atonic seizures; therefore, it is particularly useful in the treatment of patients with mixed seizure types. It is usually the drug of choice for atypical absence seizures, particularly in patients with LennoxGastaut syndrome. However, valproic acid therapy is frequently associated with weight gain, hair loss, and tremor. These side effects are somewhat dose related and can sometimes be ameliorated with an exercise program, vitamin supplementation, or dose reduction, respectively. Relatively rare but serious idiosyncratic side effects include hepatic failure, bone marrow suppression, and pancreatitis. Valproic acid at higher doses can cause an encephalopathy with hyperammonemia and triphasic waves on EEG. Valproate-induced carnitine deficiency can be addressed with carnitine supplementation (L-carnitine, 50 to 100 mg/kg/day). Valproic acid may also be useful in patients with comorbid conditions for which it is also effective (i.e., migraine headache and bipolar disorder). Lamotrigine may also be considered a potential first-line medication. It has already been shown in a double-blind, placebo-controlled trial to be effective as monotherapy in 64% of children with newly diagnosed typical absence seizures, but a head-to-head comparison with ethosuximide or valproic acid has not been made. Nevertheless, lamotrigine is generally considered to have a low incidence of side effects, and in some studies it has been better tolerated than other antiepileptic drugs. Although there were early concerns about lamotrigines association with serious rash, including Stevens-Johnson syndrome, it has since been learned that the incidence of rash is greatly reduced by initiating this medication at lower dosages and titrating the dosage more slowly (Table 1). Dosage titration must be particularly careful when lamotrigine is given in combination with valproic acid because it inhibits the hepatic metabolism of lamotrigine. The initial and target dosages of lamotrigine (see Table 1) are much lower for patients already taking valproic acid. If given in monotherapy, the dosage of lamotrigine may also require a significant reduction if valproic acid is later added. In contrast, serum lamotrigine levels are reduced by enzyme-inducing antiepileptic drugs, and target dosages of 600 to 1000 mg/day may be required to achieve therapeutic blood levels of lamotrigine. Aside from the risk of rash, the most common dose-related side effects are diplopia, dizziness, and ataxia, which may be worse when lamotrigine is given with drugs that have similar neurotoxic side effects. Because lamotrigine

32

Absence Seizures

TABLE 1 Antiepileptic Drugs for Treatment of Absence Seizures


Medication Ethosuximide (Zarontin) Form Available Capsules: 250 mg Syrup: 50 mg/mL Dosage Initiate slowly at 10-20 mg/ kg/day (bid), increasing q 2 wk according to clinical response; optimal dosage in children is usually 20-40 mg/kg/day (bid) Maintenance dose in adults ranges 500-1500 mg/day (bid) Adverse Effects Usual Target Level 40-100 g/mL

Valproic acid (Depakote)

Depacon Depakene

Tablets: 125, 250, 500 mg; Sprinkles: 125 mg ER (extended release) tablets: 250, 500 mg IV solution: 100 mg/mL Capsules: 250 mg Syrup: 250/mL

Initiate at 10-15 mg/kg/day and increase daily dosage by 5-10 mg/kg/day q wk up to 30-60 mg/kg/day, divided bid-qid Maintenance dose in adults ranges 750-4000 mg/day (bid-qid)

Lamotrigine (Lamictal)

Tablets: 25, 100, 150, 200 mg Chewable dispersible tablets: 2, 5, 25 mg

Children 2-12 yr of age Note: Round all dosages down from recommended mg/kg/day to nearest whole tablet denominations Also taking valproate: Weeks 1 and 2: 0.15 mg/kg/day (bid) Weeks 3 and 4: 0.3 mg/kg/day (bid) Then increase dose by 0.3 mg/kg/day every 1-2 wk up to 1-5 mg/kg/day or maximum of 200 mg/day (bid) Not also taking valproate: Weeks 1 and 2: 0.6 mg/kg/day (bid) Weeks 3 and 4: 1.2 mg/kg/day (bid) Then increase dose by 1.2 mg/kg/day every 1-2 wk up to 5-15 mg/kg/day or maximum of 400 mg/day (bid) Patients > 12 yr of age Also taking valproate: Weeks 1 and 2: 25 mg qod Weeks 3 and 4: 25 mg qd Then increase dose by 25-50 mg every 1-2 wk up to 100-400 mg/day (bid)

Dose-related: nausea, vomiting, anorexia, epigastric pain, diarrhea, headache, drowsiness, dizziness, euphoria, mood and thought disorders Non-dose-related: leukopenia, skin rash, Stevens-Johnson syndrome, systemic lupus erythematosus, aplastic anemia Dose-related: nausea, vomiting, abdominal pain, drowsiness, tremor, increased appetite and weight gain, hair loss, ataxia Non-dose-related: hepatic failure (increased risk with polypharmacy and age <2 years), hyperammonemia, thrombocytopenia, leukopenia, pancreatitis, amenorrhea, polycystic ovarian syndrome (associated with weight gain and insulin resistance) Dose-related: ataxia, dizziness, diplopia, nausea, headache, sedation Non-dose-related: skin rash, StevensJohnson syndrome

50-120 g/mL

4-18 g/mL

Johnson: Current Therapy in Neurologic Disease (7/E)

Treatment of Newly Diagnosed Complex Partial Seizures

33
Seizures

TABLE 1 Antiepileptic Drugs for Treatment of Absence Seizurescontd


Medication Form Available Dosage Adverse Effects Usual Target Level

Methsuximide (Celontin)

Capsules: 150, 300 mg

Not also taking valproate: Weeks 1 and 2: 50 mg/day (bid) Weeks 3 and 4: 100 mg/day (bid) Then increase dose by 100 mg/day every 1-2 wk up to 300-500 mg/day 5-20 mg/kg/day (qd-bid) Usual adult maintenance dosage: 1200-1500 mg/day (qd-tid)

Acetazolamide (Diamox)

Tablets: 125, 250 mg SR (sustainedrelease) capsules: 500 mg

Initiate at 10-25 mg/kg/day (tid) and gradually increase to 1000 mg/day (tid)

Clonazepam (Klonopin)

Tablets: 0.5, 1, 2 mg

Initiate at 0.01-0.03 mg/kg/day and titrate according to seizure control up to 0.1-0.5 mg/kg/day (tid)

Nausea, vomiting, diarrhea, anorexia, abdominal pain, drowsiness, dizziness, mood and thought disorders, rash, Stevens-Johnson syndrome, leukopenia, pancytopenia Acral paresthesias, altered taste, hearing disturbance (tinnitus), lethargy, dizziness, rash, Stevens-Johnson syndrome, nausea, vomiting, fever, leukopenia, aplastic anemia, nephrolithiasis Dose-related: lethargy, sedation, ataxia, behavioral disturbances

10-50 g/mL of N-desmethylmethsuximide

Not established

2
10-50 ng/mL

has exacerbated myoclonic seizures in some patients, its use should be monitored closely in patients with JME and Lennox-Gastaut syndrome, in which it can otherwise serve as a useful adjunctive antiepileptic drug. Methsuximide, chemically related to ethosuximide, is effective against absence seizures, as well as complex partial and generalized tonic-clonic seizures, but tolerance to its anticonvulsant effect is frequent, as are drug-drug interactions with other antiepileptic drugs. It should be considered for patients who are allergic or unresponsive to the first-line agents. Acetazolamide is effective against absence seizures, but tolerance develops rapidly. Its usefulness is therefore limited to intermittent adjunctive therapy, particularly appropriate for brief seizure exacerbations or catamenial epilepsy. Atypical absence seizures are usually more difficult to treat than typical absence seizures because they are associated with more refractory seizure types and have greater neurologic comorbidity. Valproic acid is usually the drug of first choice, but lamotrigine, clonazepam, and topiramate have also been shown to be effective. In medically refractory cases of Lennox-Gastaut syndrome, felbamate and/or the ketogenic diet may be considered, and adrenocorticotropic hormone or prednisone may serve as a last resort. Carbamazepine, vigabatrin, and tiagabine should be avoided because of their potential for exacerbating absence seizures, particularly atypical absence. The prognosis of absence seizures depends largely on the underlying epilepsy syndrome. Seizures spontaneously
Johnson: Current Therapy in Neurologic Disease (7/E)

remit in up to 90% of patients with CAE, and medication should be withdrawn after the patient has been seizure free for 1 to 2 years. However, the likelihood of remission is much lower in JAE, and JME is usually a lifelong condition. Atypical absence seizures, particularly those associated with Lennox-Gastaut syndrome, are often lifelong and refractory to medication. In these patients the vagus nerve stimulator and/or the ketogenic diet may also be considered.

Treatment of Newly Diagnosed Complex Partial Seizures


Susan T. Herman, M.D., and Jacqueline A. French, M.D.

Complex partial seizures (CPSs) are stereotyped episodes characterized by alteration in consciousness and amnesia for some or all of the event. CPSs are often preceded by an aura, or simple partial seizure, which may indicate the ictal onset zone. The clinical manifestations of CPSs are varied, including motionless staring,

Treatment of Newly Diagnosed Complex Partial Seizures

33
Seizures

TABLE 1 Antiepileptic Drugs for Treatment of Absence Seizurescontd


Medication Form Available Dosage Adverse Effects Usual Target Level

Methsuximide (Celontin)

Capsules: 150, 300 mg

Not also taking valproate: Weeks 1 and 2: 50 mg/day (bid) Weeks 3 and 4: 100 mg/day (bid) Then increase dose by 100 mg/day every 1-2 wk up to 300-500 mg/day 5-20 mg/kg/day (qd-bid) Usual adult maintenance dosage: 1200-1500 mg/day (qd-tid)

Acetazolamide (Diamox)

Tablets: 125, 250 mg SR (sustainedrelease) capsules: 500 mg

Initiate at 10-25 mg/kg/day (tid) and gradually increase to 1000 mg/day (tid)

Clonazepam (Klonopin)

Tablets: 0.5, 1, 2 mg

Initiate at 0.01-0.03 mg/kg/day and titrate according to seizure control up to 0.1-0.5 mg/kg/day (tid)

Nausea, vomiting, diarrhea, anorexia, abdominal pain, drowsiness, dizziness, mood and thought disorders, rash, Stevens-Johnson syndrome, leukopenia, pancytopenia Acral paresthesias, altered taste, hearing disturbance (tinnitus), lethargy, dizziness, rash, Stevens-Johnson syndrome, nausea, vomiting, fever, leukopenia, aplastic anemia, nephrolithiasis Dose-related: lethargy, sedation, ataxia, behavioral disturbances

10-50 g/mL of N-desmethylmethsuximide

Not established

2
10-50 ng/mL

has exacerbated myoclonic seizures in some patients, its use should be monitored closely in patients with JME and Lennox-Gastaut syndrome, in which it can otherwise serve as a useful adjunctive antiepileptic drug. Methsuximide, chemically related to ethosuximide, is effective against absence seizures, as well as complex partial and generalized tonic-clonic seizures, but tolerance to its anticonvulsant effect is frequent, as are drug-drug interactions with other antiepileptic drugs. It should be considered for patients who are allergic or unresponsive to the first-line agents. Acetazolamide is effective against absence seizures, but tolerance develops rapidly. Its usefulness is therefore limited to intermittent adjunctive therapy, particularly appropriate for brief seizure exacerbations or catamenial epilepsy. Atypical absence seizures are usually more difficult to treat than typical absence seizures because they are associated with more refractory seizure types and have greater neurologic comorbidity. Valproic acid is usually the drug of first choice, but lamotrigine, clonazepam, and topiramate have also been shown to be effective. In medically refractory cases of Lennox-Gastaut syndrome, felbamate and/or the ketogenic diet may be considered, and adrenocorticotropic hormone or prednisone may serve as a last resort. Carbamazepine, vigabatrin, and tiagabine should be avoided because of their potential for exacerbating absence seizures, particularly atypical absence. The prognosis of absence seizures depends largely on the underlying epilepsy syndrome. Seizures spontaneously
Johnson: Current Therapy in Neurologic Disease (7/E)

remit in up to 90% of patients with CAE, and medication should be withdrawn after the patient has been seizure free for 1 to 2 years. However, the likelihood of remission is much lower in JAE, and JME is usually a lifelong condition. Atypical absence seizures, particularly those associated with Lennox-Gastaut syndrome, are often lifelong and refractory to medication. In these patients the vagus nerve stimulator and/or the ketogenic diet may also be considered.

Treatment of Newly Diagnosed Complex Partial Seizures


Susan T. Herman, M.D., and Jacqueline A. French, M.D.

Complex partial seizures (CPSs) are stereotyped episodes characterized by alteration in consciousness and amnesia for some or all of the event. CPSs are often preceded by an aura, or simple partial seizure, which may indicate the ictal onset zone. The clinical manifestations of CPSs are varied, including motionless staring,

34

Treatment of Newly Diagnosed Complex Partial Seizures

unresponsiveness, oral or limb automatisms, focal limb posturing or clonus, and postictal confusion or focal neurologic deficits. CPSs typically last less than 2 to 3 minutes. Most patients with CPSs will at some time in their course also experience secondarily generalized tonic-clonic seizures. Most CPSs arise from the temporal lobe. Seizure frequency may range from one per year to many per day. It may be difficult to diagnose a CPS after a single event given the varied clinical manifestations. Most patients have had several CPSs by the time they present to a physician for evaluation. A careful history for previous episodes suggestive of seizures, such as stereotyped auras, episodes of loss of time or confusion, or witnessed staring spells, may help confirm the diagnosis. The differential diagnosis includes syncope, sleep disorders, anxiety and panic disorders, migraine headache, narcolepsy, and nonepileptic psychogenic events. CPSs may be idiopathic (presumed genetic), cryptogenic (no known cause), or remote symptomatic (known prior brain insult). A specific cause can be determined in fewer than 50% of patients. Common etiologic factors include mesial temporal sclerosis, tumor, cortical dysplasia, stroke, complicated febrile seizures, mental retardation, cerebral palsy, central nervous system infections, and traumatic brain injury. Diagnostic evaluation should include complete blood count (CBC), electrolytes, serum glucose, blood urea nitrogen and creatinine, and liver function tests (LFTs) to screen for potential etiologies and establish a baseline prior to initiation of AEDs. Urine toxicology and serum ethanol levels may be useful if substance abuse is suspected. Electroencephalography is an essential part of the work-up. It is most likely to be diagnostic within 24 hours after a suspected seizure. The hallmark abnormality of CPSs is the focal epileptiform discharge (spike or sharp wave), usually over one temporal region. A single electroencephalogram (EEG) shows focal spikes in only approximately 50% of patients, but repeat EEGs and sleep deprivation increase the yield to 70% to 90%. Neuroimaging should be performed for all patients with CPSs. Head computed tomography (CT) may be appropriate in emergency situations, but magnetic resonance imaging (MRI) has greater yield for structural abnormalities. A high-quality 1.5-tesla MRI should be performed. Gadolinium contrast does not increase the yield. Thin T2-weighted and fluid-attenuated inversion recovery (FLAIR) coronal cuts perpendicular to the long axis of the hippocampus are necessary to detect mesial temporal sclerosis, whereas high-resolution spoiled gradient recall images are sensitive for cortical dysplasia. Patients and their families should be fully educated about the risk for seizure recurrence, the potential implications of further seizures, first aid measures for seizures, and common seizure precipitants such as sleep deprivation and alcohol use. Safety precautions include restrictions on swimming alone, working at heights or near open water, operating heavy machinery, participating in contact sports, driving, and other high-risk behaviors. Most states impose driving limitations on patients with episodes of loss of consciousness. Patients usually must be seizure free for 3 to 12 months before

driving privileges are restored. Exceptions may be made for patients with only simple partial seizures (no impairment of consciousness), prolonged stereotyped auras, exclusively nocturnal seizures, or a single seizure with a normal EEG. The physicians responsibility is to instruct the patient about the relevant state laws and to report to the Department of Motor Vehicles when mandated by law. Mortality rates are increased among patients with partial seizures owing to accidents (drowning and motor vehicle accidents), sudden unexplained death, and suicide, particularly in patients with difficult-to-control epilepsy. Treatment should not be initiated unless it is clear that the episode in question was actually an epileptic seizure and only when the recurrence risk is high. Overall, the risk of seizure recurrence after a single seizure is 30% to 40% over 2 years. Patients with no epilepsy risk factors, normal neurologic examinations, normal EEGs, and normal neuroimaging have a recurrence risk of only approximately 20% to 30%. Such patients do not usually require treatment with antiepileptic drugs (AEDs), unless the consequences of a second seizure outweigh the potential adverse effects of the AED. Epileptiform discharges on EEG or a structural abnormality on neuroimaging increases the risk of a second seizure to 60% to 70%. Many epileptologists consider occurrence of a clear-cut CPS in an adult as a strong indication of structural abnormality and treat after a single event. Adults with high likelihood of seizure recurrence require treatment with AEDs because of the potential adverse consequences of a second seizure on driving, independence, and employment. Treatment after a single seizure is not as imperative in children, since the consequences of a second seizure are less problematic. Once a patient has had two or more seizures, a diagnosis of epilepsy can be made. The risk of continued seizures is then greater than 70% to 80%, and most patients should be treated with AEDs. The goal of treatment with AEDs is complete seizure control without side effects. Almost all of the currently available AEDs (Table 1) are effective for the treatment of partial-onset seizures. The choice of the initial AED should be tailored to the individual patient (Table 2). Nearly 50% of patients will achieve complete control of seizures with their first AED and will remain on this therapy for several years to a lifetime. There is no evidence to support efficacy differences among AEDs, so treatment decisions focus on potential adverse effects and other AED characteristics. Patient factors to consider in drug selection include age, gender, concomitant medical disorders, and coadministered medications. AED factors include spectrum of activity, pharmacokinetics, titration rate, drug metabolism and elimination, adverse effect profile, and cost. The longer-established AEDs are less expensive but have more drug interactions and may produce long-term complications. As a group, the newer AEDs have simpler pharmacokinetics, fewer drug interactions, fewer serious idiosyncratic side effects, and less dose-related toxicity. Chronic adverse effects, such as cosmetic changes, bone disease, and teratogenicity, may also be less problematic with the newer AEDs.
Johnson: Current Therapy in Neurologic Disease (7/E)

TABLE 1 Doses and Adverse Effects of AEDs for Complex Partial Seizures
Total Daily Dose Range Adults 600-2400 mg 15-35 mg/kg bid-qid (bid for XR and Carbatrol) bid-tid Ataxia, dizziness, diplopia, hyponatremia Aplastic anemia, agranulocytosis, rash, SJS, hepatitis Aplastic anemia, hepatotoxicity, rash, SJS Children Dose Schedule Common Adverse Effects Rare or Idiosyncratic Side Effects

Initial Dose and Escalation Children

Agent

Adults

Carbamazepine (Tegretol, Tegretol XR, Carbatrol) 2400-4800 mg 100-125 mg/kg

100 mg bid, increase 100 mg bid q 3-5 days

Felbamate (Felbatol)

300 mg tid, increase 300 mg tid q 7 d 900-6000 mg 20-60 mg/kg tid-qid

Seizures

Johnson: Current Therapy in Neurologic Disease (7/E)

Gabapentin (Neurontin)

Insomnia, headache, weight loss, nausea, vomiting Weight gain

Lamotrigine monotherapy (Lamictal) 300-800 mg 5-15 mg/kg bid

100-500 mg

1-5 mg/kg

bid

Headache, dizziness, insomnia

Movement disorders, behavioral disturbance (children) Rash, SJS

Lamotrigine + EI-AED 100-300 mg 0.5-2 mg/kg qd-bid

300 mg qd, increase 300 mg daily to 300 mg tid, then 300 mg tid q 7 days 25 mg qd, increase 25-50 mg q 2 wk 50 mg qd, increase 50 mg q 2 wk

Lamotrigine + VPA

25 mg qod, increase 25 mg q 2 wk 1000-4000 mg 30-100 mg/kg

Levetiracetam (Keppra) 900-2400 mg

bid

Irritability, fatigue bid-tid Dizziness, GI disturbance, hyponatremia

Psychosis

Oxcarbazepine (Trileptal) 60-240 mg

20-50 mg/kg

Rash, SJS

Phenobarbital (Luminal)

4-8 mg/kg

qd-bid

Rash, SJS, hepatitis, connective tissue disturbance 200-500 mg 4-8 mg/kg qd-bid Rash, SJS, hepatitis, lupus-like reaction

Treatment of Newly Diagnosed Complex Partial Seizures

Phenytoin

250 mg bid, increase 250-500 mg bid q wk 150 mg bid, increase 150-300 mg bid q wk 30-60 mg qd, increase 30-60 mg q 1-2 wk 200-300 mg qd (oral load 6-7 mg/kg q 8 hr for three doses)

5 mg/kg/day divided bid, increase 5 mg/kg/day q 3-5 days 15 mg/kg/day divided tid, increase 15 mg/kg/day q 7 day 5 mg/kg/day divided tid, increase 5 mg/kg/day q 7 days 0.2 mg/kg/day divided bid, increase 0.2 mg/ kg/day q 2 wk 0.6 mg/kg/day divided bid, increase 0.6 mg/ kg/day q 2 wk 0.15 mg/kg/day divided bid, increase 0.15 mg/kg/day q 2 wk 5 mg/kg/day divided bid, increase 5 mg/ kg/day q wk 5 mg/kg/day divided bid, increase 5 mg/ kg/day q wk 1-2 mg/kg/day, increase 1-2 mg/kg/day q 1-2 wk 4 mg/kg/day (oral load 6 mg/kg q 8 hr for three doses) Sedation, somnolence, irritability, depression Ataxia, difficulty concentrating, hirsutism, coarse facial features, gingival hyperplasia

35
Continued

36

TABLE 1 Dosing and Adverse Effects of AEDs for Complex Partial Seizurescontd
Total Daily Dose Range Adults 32-56 mg 0.1-0.4 mg/kg bid-tid Irritability, anxiety, weakness Children Dose Schedule Common Adverse Effects

Initial Dose and Escalation Children

Agent

Adults

Rare or Idiosyncratic Side Effects Spike-wave stupor

Tiagabine (Gabitril) 100-600 mg 5-15 mg/kg bid

Treatment of Newly Diagnosed Complex Partial Seizures

Topiramate (Topamax)

4 mg qd, increase 4-8 mg divided bid-tid q wk 25-50 mg qd, increase 25-50 mg divided bid q 1-2 wk

0.1 mg/kg/day divided tid, increase 0.1 mg/ kg/day q wk 0.5 mg/kg/d divided bid, increase 0.5-1 mg/kg/day q 1-2 wk

Acute-angle closure glaucoma, renal calculi

1000-4000 mg

15-60 mg/kg

bid-tid (qd for ER) qd-bid

Hepatotoxicity, pancreatitis, thrombocytopenia Rash, SJS, renal calculi

Valproate (Depakote, Depakene, Depakote ER) Zonisamide (Zonegran) 200-600 mg 8-12 mg/kg

125-250 mg bid, increase 125-250 mg bid q wk 100-200 mg qd, increase 100-200 mg qd q wk

5 mg/kg/day divided bid-tid, increase 5 mg/kg/day 2 mg/kg/day, increase 2 mg/kg/day q wk

Decreased verbal fluency, impaired memory, weight loss, paresthesias, hypohidrosis (mostly children) Tremor, weight gain, hair loss, GI disturbance, diarrhea Headache, GI disturbance, difficulty concentrating, hypohidrosis (mostly children)

Johnson: Current Therapy in Neurologic Disease (7/E)

AED, Antiepileptic drug; CNS, central nervous system; GI, gastrointestinal; SJS, Stevens-Johnson syndrome. EI-AED, enzyme-inducing antiepileptic drug VPA, valproate QOD, every other day

Treatment of Newly Diagnosed Complex Partial Seizures

37
Seizures

TABLE 2 Selection of AEDs for Complex Partial Seizures*


CBZ Monotherapy efficacy established Pediatric efficacy established, good side effect profile in children Oral contraceptives Pregnancy Bone health Taking other AEDs* Taking other medications High cognitive functioning Age > 60 yr Obesity Renal dysfunction Hepatic dysfunction Psychosis, behavior problems, depression Noncompliance Rapid titration possible Patient example (totaled) 1 1 GBP 1 1 LTG 1 1 LVT 2 2 OXC 1 1 PB 1 3 PHT 1 1 PRM 1 3 TPM 1 2 TGB 2 2 VPA 1 1 ZNS 2 2 Example X

3 3 3 3 3 2 2 3 1 3 1 2 3 9

1 2 2 1 1 1 1 3 2 1 2 3 1 7

1 2 2 2 1 1 1 2 1 1 1 2 3 5

1 2 2 1 1 1 1 2 2 1 3 2 1 7

2 2 2 2 1 2 2 2 1 2 2 2 1 7

3 3 3 3 3 3 3 2 2 3 3 1 2 9

3 3 3 3 3 2 3 2 2 3 2 1 1 8

3 3 3 3 3 3 3 2 2 3 3 2 3 9

2 2 2 2 1 3 2 1 2 2 2 2 3 7

1 2 2 2 1 2 2 2 1 2 3 3 2 8

1 3 3 3 1 2 2 3 1 3 1 1 1 9

1 2 2 2 1 2 2 1 2 2 2 X

X X

2
1 1 7

See text for instructions for use and example. 1 = good profile; 2 = neutral or unknown; 3 = adverse profile. CBZ, Carbamazepine; GBP, gabapentin; LTG, lamotrigine; LVT, levetiracetam; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; PRM, primidone; TPM, topiramate; TGB, tiagabine; VPA, valproate; ZNS, zonisamide. *P-450 enzyme-inducing or -inhibiting AEDs. Relative contraindication in adolescent girls due to teratogenicity. Alter lamotrigine metabolism; OK if dose is stable. Long-acting formulation (Tegretol XR, Carbatrol, Depakote ER). OCP, Oral contraceptive pills

AEDs may be categorized into three broad groups for the initial treatment of CPSs. Group 1 drugs (phenytoin, carbamazepine, valproate, gabapentin, lamotrigine, oxcarbazepine, and topiramate) have demonstrated efficacy as monotherapy in randomized controlled trials in patients with partial-onset or partial and generalized seizures. Carbamazepine and phenytoin have long been considered drugs of first choice, and valproate is also widely used. Chronic adverse effects and complex pharmacokinetics of carbamazepine, phenytoin, and valproate, however, make these less attractive choices. The superior tolerability and adverse effect profiles of gabapentin, lamotrigine, oxcarbazepine and topiramate support the use of these AEDs as initial monotherapy in many patients. Group 2 drugs (tiagabine, levetiracetam, and zonisamide) are effective as adjunctive therapy but have not yet been demonstrated to be efficacious in monotherapy. Such medications can be used as secondline agents or as initial agents in specific patients. Group 3 drugs (phenobarbital, primidone, and felbamate), although equally efficacious, have significant adverse effects that limit their usefulness. These drugs
Johnson: Current Therapy in Neurologic Disease (7/E)

are not appropriate for use as initial monotherapy of CPSs. Table 1 summarizes initial dosing, titration schedules, and serious adverse effects of currently available AEDs. Therapy should be initiated with a single drug. Using a low dose and slow titration schedule minimizes adverse effects, but frequent seizures necessitate more rapid dose escalations. Polytherapy increases the risk for adverse effects and is not appropriate for new-onset seizures. A reasonable approach is to select two or three appropriate AEDs for presentation to the patient, discuss their potential side effects, and then choose an AED based on patient preference. Avoidance of side effects and use of twice-daily formulations improves compliance with chronic therapy and thereby seizure control. Table 2 presents a tool to select potential best therapies among the wide range of AED options. To determine AED options for an individual patient, choose all relevant patient factors on the left; then add the numbers in the selected rows for each drug. AEDs with the lowest total score may offer a good adverse effect profile for that patient, although the physician must still weigh the

38

Treatment of Newly Diagnosed Complex Partial Seizures

relative importance of each factor individually. The last row and column show an example of a 26-year-old woman executive, weighing 200 lb, who is planning her first pregnancy. Lamotrigine (safety in pregnancy, weight neutrality) would be a reasonable first choice for this patient, but several of the other newer AEDs would also be options. The dose of the initial AED should be gradually increased until seizures are completely controlled or until side effects occur. If the first AED fails, a second AED should be substituted and the first AED withdrawn. Combinations of AEDs, the vagus nerve stimulator, and epilepsy surgery are possible options if seizures remain difficult to control (see Chapter 11). Serum AED levels may be useful in assessing compliance, maintaining stable levels during pregnancy or after initiation of a second AED, assessing the presence of drug interactions, or determining the etiology of side effects. Routine monitoring of serum AED levels is not necessary in patients with well-controlled seizures. Many of the newer AEDs do not have well-established therapeutic ranges. CBC, chemistry panel, and LFTs should be checked 1 to 2 months after initiating a new AED. Repeated monitoring of laboratory tests is indicated for some AEDs but not others. For example, more frequent monitoring is indicated early in treatment with valproate due to potential for thrombocytopenia and hepatic failure. CBC and LFTs should be monitored during the first 6 months of carbamazepine and phenytoin use, due to remote risk of aplastic anemia and hepatic failure. Several sodium levels should be drawn for patients receiving carbamazepine/oxcarbazepine to check for hyponatremia. After the first 6 months, serial monitoring rarely detects new clinically significant abnormalities, but annual blood work may still be reasonable. The choice of an AED for women with new-onset CPSs should take into consideration potential effects on contraception, reproductive health, and pregnancy. AEDs that induce the hepatic P-450 enzyme system (phenytoin, carbamazepine, primidone, and, to a lesser extent, topiramate and oxcarbazepine) reduce the efficacy of hormonal contraception, resulting in increased risk of unplanned pregnancy. Oral contraceptive pills, estrogen patches, and depot progesterone all may be affected. Women taking enzyme-inducing AEDs should take an oral contraceptive pill containing at least 50 g of estrogen or use a barrier contraceptive method. Of note, hormonal contraceptives induce the metabolism of lamotrigine. Women should be counseled to report any change in contraception. Both enzyme-inducing and enzyme-inhibiting (e.g., valproate) AEDs may be associated with reproductive dysfunction, such as anovulatory menstrual cycles, infertility, and polycystic ovaries. These effects appear to be most problematic with valproate. Symptoms and signs of reproductive endocrine dysfunction include hirsutism, weight gain, irregular menstrual cycles, and infertility and should trigger a gynecologic evaluation. Many of the AEDs are teratogens. The risk of congenital malformations in children of women with epilepsy taking AEDs is 4% to 8%, compared with 2% to 3% in the general population. The risk is increased with high AED doses and with polytherapy. Malformations can include cardiac, midline facial, neural

tube, genitourinary, and gastrointestinal anomalies. Minor anomalies of the face and digits may be seen in another 10% to 15% of children. Effect of these AEDs on cognitive development is in the early stages of investigation, but there is increasing evidence that some AEDs, valproate in particular, may lead to increased risk of learning disabilities. Because folate administration may protect against some malformations, at least 1 mg of folate daily should be prescribed to all women taking AEDs. Phenytoin, carbamazepine, valproate, phenobarbital, and primidone are pregnancy class D medications, associated with a known teratogenic risk in humans. The newer AEDs are pregnancy class C medications, showing no teratogenicity in animals but unknown safety in humans. Preliminary results from a lamotrigine pregnancy registry suggest low teratogenicity, but final results are pending. Prospective pregnancy registries in the United States and Europe will help to define the risks of the newer AEDs. At this point, we favor the use of the newer AEDs, particularly lamotrigine, in women of reproductive age because of fewer effects on the hormonal milieu and probable lower teratogenicity. Drug interactions are common with AEDs as a class. When initiating AEDs, physicians should consider current concomitant medications as well as potential future needs. One of the most problematic interactions is that of hepatic enzyme induction, which occurs with use of phenytoin, carbamazepine, primidone, and phenobarbital. Hepatic induction increases the clearance of many commonly prescribed medications. Increased clearance of oral contraceptives has already been discussed. Many cholesterol-lowering agents, anticoagulants, antihypertensives, and antiarrhythmics are also subject to induction, as are chemotherapeutic agents. For patients who may require these medications, selection of a noninducing AED may be preferable. Many patients who experience their first seizure are evaluated in the emergency department and may be started on phenytoin. Often, the patient will be referred to a neurologist within the next few weeks. At this visit, it is appropriate to reassess the individual needs of that particular patient and make changes as necessary, including discontinuation if treatment is not indicated or selection of an alterative agent. AED withdrawal may be considered when a patient has been seizure free for at least 2 years. Unfortunately, seizure recurrence rates are relatively high40% to 50%after drug withdrawal. Patients with normal neurologic examinations, neuroimaging, and EEG have a lower recurrence risk. Focal structural lesions or epileptiform abnormalities on EEG, however, indicate a recurrence risk of greater than 70%. Many patients elect to continue AEDs rather than run the risk of a seizure recurrence. If patients decide to discontinue AEDs, the drug should be tapered slowly to avoid withdrawal seizures. Patients should not drive for 3 to 6 months after AED discontinuation. SUGGESTED READING
French JA, Kanner AM, Bautista J, et al: Efficacy and tolerability of the new antiepileptic drugs: I. treatment of new-onset epilepsy. Johnson: Current Therapy in Neurologic Disease (7/E)

First Generalized Seizure Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004. Hirtz D, Berg A, Bettis D, et al: Practice parameter: treatment of the child with a first unprovoked seizure. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 60:166-175, 2003. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Tatum WO, Liporace J, Benbadis SR, Kaplan PW: Updates on the treatment of epilepsy in women, Arch Intern Med 164:137-145, 2004. Zahn CA, Morrell MJ, Collins SD, et al: Management issues for women with epilepsy: a review of the literature, Neurology 51:949-956, 1998.

39
Seizures

The neurologists initial assessment of a patient with an apparent new seizure should systematically address the following questions: Was the event in question truly an epileptic seizure? If the event was a seizure, did it start focally and become secondarily generalized, or was it a manifestation of a primary generalized epilepsy, or secondary generalized epilepsy (typically a question in young children)? Is the risk of recurrence sufficient to justify committing the patient to chronic treatment, and if so, with which agent? Evaluation should include a detailed history, including a personal or telephone interview with any available witness of the event, general and neurologic examination, and typically magnetic resonance (MR) imaging and EEG recording. The goals of this process are to determine the seizure type and the cause of the seizure and to evaluate the risk of recurrence, which will determine the need for ongoing treatment. Additional important goals are to detect systemic conditions that may provoke seizures and to assess the individual with special attention to characteristics that might influence the choice of long-term treatments. Ultimately, the neurologist faces the decision of whether to initiate treatment, or if treatment was already started in the acute setting, whether to continue, change, or discontinue it. Whereas the ED physician was most concerned with acute efficacy and patient safety, the neurologist must be concerned with efficacy, effectiveness (a term encompassing efficacy, tolerability, and compliance), and long-term health consequences of what is likely to be a chronic therapy.

PATIENT RESOURCES
Epilepsy Foundation of America http://www.epilepsyfoundation.org/ American Epilepsy Society http://www.aesnet.org/ The Epilepsy Project www.epilepsy.com

First Generalized Seizure


Andrew J. Cole, M.D., F.R.C.P.(C)

Individuals who develop new seizures, especially generalized tonic-clonic attacks, are frequently initially evaluated in an emergency department (ED) setting. When family members are not available, ED physicians obtain historical information from paramedics and from the patient who may still be confused in the postictal state. A general examination and a basic neurologic examination, in combination with computed tomographic (CT) scanning, are typically performed to rule out acute structural processes, whereas standard laboratory testing including electrolytes, blood count, and toxin screens are used to asses potential metabolic etiologies. At the completion of testing, the ED physician faces a two-part treatment decision: Should the patient be treated, and if so, with which antiepileptic drug (AED)? In making these decisions, ED physicians are particularly concerned with the short-term goal of preventing early seizure recurrence and keeping the patient safe until definitive evaluation can be accomplished. Additional factors influencing treatment choices include the time necessary to obtain a therapeutic blood level; ease of drug delivery, including available routes of administration; and their own familiarity and comfort with specific agents. In this context, phenytoin is the most commonly used AED in the ED setting. In the face of the acute issues, less attention is paid to the cognitive and long-term toxicities of potential treatments, which may properly be considered the province of neurologists. On discharge from the ED, referral to the patients internist or to a neurologist is typically suggested.
Johnson: Current Therapy in Neurologic Disease (7/E)

Evaluation and Diagnosis


The value of a detailed history cannot be overemphasized. Although the initial history might describe a generalized tonic attack, careful questioning might reveal the presence of a warning or evidence of focal onset of motor activity pointing to a focal seizure with secondary generalization. By contrast, a history of absence lasting less than 20 seconds, myoclonic jerks on awakening, and an early morning convulsion without warning suggest the diagnosis of a primary generalized seizure disorder, especially in teenagers and young adults. As a rule, the older the patient, the less likely that the seizure is truly of generalized origin, and for practical purposes new-onset seizures in patients older than 30 years of age should be considered to be focal unless proven otherwise. A careful history may reveal that the event in question was not in fact the first seizure, since the patient had been having minor spells for some time, or that there was a clear provocative factor such as significant sleep deprivation, use of a proconvulsant medication such as tramadol, or withdrawal from an anxiolytic such as alprazolam. In the former case, need for treatment seems clear, whereas in the latter case, many neurologists would attempt to manage the patient with lifestyle modification or avoidance of the offending agents.

First Generalized Seizure Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004. Hirtz D, Berg A, Bettis D, et al: Practice parameter: treatment of the child with a first unprovoked seizure. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 60:166-175, 2003. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Tatum WO, Liporace J, Benbadis SR, Kaplan PW: Updates on the treatment of epilepsy in women, Arch Intern Med 164:137-145, 2004. Zahn CA, Morrell MJ, Collins SD, et al: Management issues for women with epilepsy: a review of the literature, Neurology 51:949-956, 1998.

39
Seizures

The neurologists initial assessment of a patient with an apparent new seizure should systematically address the following questions: Was the event in question truly an epileptic seizure? If the event was a seizure, did it start focally and become secondarily generalized, or was it a manifestation of a primary generalized epilepsy, or secondary generalized epilepsy (typically a question in young children)? Is the risk of recurrence sufficient to justify committing the patient to chronic treatment, and if so, with which agent? Evaluation should include a detailed history, including a personal or telephone interview with any available witness of the event, general and neurologic examination, and typically magnetic resonance (MR) imaging and EEG recording. The goals of this process are to determine the seizure type and the cause of the seizure and to evaluate the risk of recurrence, which will determine the need for ongoing treatment. Additional important goals are to detect systemic conditions that may provoke seizures and to assess the individual with special attention to characteristics that might influence the choice of long-term treatments. Ultimately, the neurologist faces the decision of whether to initiate treatment, or if treatment was already started in the acute setting, whether to continue, change, or discontinue it. Whereas the ED physician was most concerned with acute efficacy and patient safety, the neurologist must be concerned with efficacy, effectiveness (a term encompassing efficacy, tolerability, and compliance), and long-term health consequences of what is likely to be a chronic therapy.

PATIENT RESOURCES
Epilepsy Foundation of America http://www.epilepsyfoundation.org/ American Epilepsy Society http://www.aesnet.org/ The Epilepsy Project www.epilepsy.com

First Generalized Seizure


Andrew J. Cole, M.D., F.R.C.P.(C)

Individuals who develop new seizures, especially generalized tonic-clonic attacks, are frequently initially evaluated in an emergency department (ED) setting. When family members are not available, ED physicians obtain historical information from paramedics and from the patient who may still be confused in the postictal state. A general examination and a basic neurologic examination, in combination with computed tomographic (CT) scanning, are typically performed to rule out acute structural processes, whereas standard laboratory testing including electrolytes, blood count, and toxin screens are used to asses potential metabolic etiologies. At the completion of testing, the ED physician faces a two-part treatment decision: Should the patient be treated, and if so, with which antiepileptic drug (AED)? In making these decisions, ED physicians are particularly concerned with the short-term goal of preventing early seizure recurrence and keeping the patient safe until definitive evaluation can be accomplished. Additional factors influencing treatment choices include the time necessary to obtain a therapeutic blood level; ease of drug delivery, including available routes of administration; and their own familiarity and comfort with specific agents. In this context, phenytoin is the most commonly used AED in the ED setting. In the face of the acute issues, less attention is paid to the cognitive and long-term toxicities of potential treatments, which may properly be considered the province of neurologists. On discharge from the ED, referral to the patients internist or to a neurologist is typically suggested.
Johnson: Current Therapy in Neurologic Disease (7/E)

Evaluation and Diagnosis


The value of a detailed history cannot be overemphasized. Although the initial history might describe a generalized tonic attack, careful questioning might reveal the presence of a warning or evidence of focal onset of motor activity pointing to a focal seizure with secondary generalization. By contrast, a history of absence lasting less than 20 seconds, myoclonic jerks on awakening, and an early morning convulsion without warning suggest the diagnosis of a primary generalized seizure disorder, especially in teenagers and young adults. As a rule, the older the patient, the less likely that the seizure is truly of generalized origin, and for practical purposes new-onset seizures in patients older than 30 years of age should be considered to be focal unless proven otherwise. A careful history may reveal that the event in question was not in fact the first seizure, since the patient had been having minor spells for some time, or that there was a clear provocative factor such as significant sleep deprivation, use of a proconvulsant medication such as tramadol, or withdrawal from an anxiolytic such as alprazolam. In the former case, need for treatment seems clear, whereas in the latter case, many neurologists would attempt to manage the patient with lifestyle modification or avoidance of the offending agents.

40

First Generalized Seizure

General and neurologic examinations are focused on searching for coexisting conditions that may cause or predispose the patient to seizures and detecting evidence of focal or diffuse central nervous system dysfunction. Particular attention should be focused on examination of the skin; a search for endocrine or metabolic disturbances; evidence of malignancy; and especially in older patients, evidence of cerebrovascular disease. At the same time, general characteristics of the individual such as body weight, complexion, cognitive function, and even reproductive capacity should be duly noted. We routinely obtain electroencephalographic recordings without sleep deprivation as part of our initial evaluation. The goals are to search for generalized spike-and-wave discharge that is typically frontally predominant at 2.5 4 Hz, supporting a diagnosis of primary generalized epilepsy, or to find focal abnormalities including slowing or epileptiform abnormalities that support the diagnosis of focal epilepsy. This distinction is critical in therapeutic decision making (see later). A negative electroencephalogram (EEG) does not rule out the diagnosis of epilepsy, and positive findings must always be interpreted in the context of available clinical information. All adults with new-onset seizures should have highquality MR imaging, even if a negative CT scan is available. Our protocol includes axial and coronal T2-weighted fast-spin echo (FSE) sequences, axial and coronal fluid-attenuated inversion recovery (FLAIR) sequences, and a T1-weighted coronal volumetric data set with 1.2- to 1.5-mm thick cuts without skip. We do not routinely use gadolinium contrast in the assessment of new seizures, especially in patients younger than 50 years of age, although we do use contrast material to characterize foreign tissue lesions that are discovered on noncontrast scans. In patients with a history of trauma, we frequently obtain gradient echo (susceptibility) sequences as well to search for old blood products. Images should be directly reviewed by the neurologist in the context of all available information, including historical information, findings on examination, and EEG findings. It is not unusual for a neurologist to detect a lesion that had been overlooked by the radiologist, perhaps because the neurologist is in a position to formulate a hypothesis about where to look for the likely causative lesion based on clinical information not readily available to the radiologist.

frequently in this situation, and our practice is supported by considerable published data. General statements about the risk of recurrence can be based on population studies, but their relevance to the specific patient at hand is uncertain. In this context it is difficult to be doctrinaire about the need for treatment, and patient preference should play a substantial role in decision making. Although there are little data to guide patients and physicians with respect to the optimal duration of treatment, experienced neurologists are typically reluctant to discontinue treatment that is well tolerated, even after many years, for fear of seizure recurrence. To the extent that treatment is thus likely to be of long duration, particular attention to the long-term consequences of chronic treatment should be considered at the time of treatment initiation and not, as commonly happens, after some predictable adverse consequence of treatment becomes apparent after months or years (e.g. weight gain, osteoporosis, adverse medication interactions). Treatment of a first generalized seizure is particularly problematic because seizure frequency cannot be used as an endpoint to determine optimal treatment intensity. Dose selection must therefore be determined by an educated guess as to what dose is likely to have a high probability of suppressing recurrent events, even without definitive knowledge of whether seizures will recur in specific patient. The temptation to use a low dose of medication thus seems ill advised. Most drugs should be started at a modest dose and then advanced over weeks to the target dose to avoid undue toxicity. Given the long-term nature of AED treatment, minor differences in the titration rates of available agents should not be a predominant factor in drug selection. After all, the goal is to establish an effective, well-tolerated treatment plan that will continue for years, so whether that takes 6 days or 6 weeks seems of little importance. In situations where the risk of early recurrence is high, patients can be covered with a rapidly titrated agent (often already the case after an ED visit) while titration of the ultimate treatment is underway.

Counseling
The diagnosis of a new seizure disorder raises a series of issues that may be anxiety provoking and psychologically traumatic to consider for patients. Neurologist should have a calm, orderly, and systematic approach to discussing these issues with patients and their families. We begin by emphasizing that the goal of treatment is to allow the patient to live a normal life without undue restrictions. For example, unless there is a history of excessive alcohol consumption and abuse, we do not routinely prohibit the consumption of an occasional beer, glass of wine, or cocktail, although we do counsel moderation. We emphasize the importance of regular sleep habits and compliance with treatment schedules. Rules on driving and reporting vary by state. We advise patients of the rules in their home state and document that information has been provided and that the patient appears to understand. Driving laws in each state can
Johnson: Current Therapy in Neurologic Disease (7/E)

Treatment Initiation
Treatment decisions should be undertaken largely independent of previous decisions made by non-neurologists. Our algorithm for whether or not to initiate or continue treatment and specific agents to be used is shown in the accompanying diagram (Figure 1). Treatment agents are numbered according to whether they constitute first-line, second-line, or third-line choices. Within groups, agents are listed alphabetically, and choices should be made according to the characteristics of the individual patient. While many of the newer agents do not have a U.S. Food and Drug Administrationapproved indication for use as initial monotherapy, we use them

First Generalized Seizure

41
Seizures

Grand mal tonic clonic seizure

History Examination EEG MRI

Epileptic

Non-epileptic

Classification Cardiac Unknown Primary (idiopathic) generalized epilepsy Partial seizure with secondary generalization Yes

Vasovagal/ neurocardiogenic

Psychiatric/ behavioral

Refer/treat as appropriate

Age > 30 and no previous history? No

Review history, sleep-deprived EEG Identifiable provocative factors? Yes No Rx: conservative management

No

Risk/benefit analysis for Rx: EEG or MRI or exam abnl? Patient unwilling to accept 2040% risk of recurrence?

No

No Rx: observe

Yes

Partial seizures with or without secondary generalization: 1. Lamotrigine 300500 mg/d 1. Levetiracetam 20003000 mg/d 1. Oxcarbazepine 6001200 mg/d 2. Carbamazepine 400800 mg/d 2. Phenytoin 30000 mg/d 2. Topiramate 200400 mg/d 2. Valproate 10001500 mg/d 3. Gabapentin 15002400 mg/d 3. Zonisamide 300400 mg/d 4. Mysoline 500750 mg/d 4. Phenobarbital 60120 mg/d

Consider patient characteristics: Age Sex Reproductive status Body habitus Medical co-morbidities Psychiatric co-morbidities Co-medications Cognitive function Financial concerns Select treatment

Primary (idiopathic) generalized epilepsy: 1. Lamotrigine 300500 mg/d 1. Valproate 750500 mg/d 2. Topiramate 200400 mg/d 3. ?Levetiracetam 15003000 mg/d 3. ?Zonisamide 200400 mg/d

FIGURE 1. Flowchart illustrating our approach to the evaluation and treatment of a first convulsion. Drugs are numbered as first-line, second-line, third-line, or fourth-line choices. Within category, drugs are listed alphabetically without implying a specific order of preference. Specific selections should be made based on individual patient characteristics. Dose ranges shown are approximate. All drugs should be titrated no faster than the manufacturers recommendations to avoid excessive initial toxicity. Johnson: Current Therapy in Neurologic Disease (7/E)

42

Recurrent Generalized and Partial Seizures

be accessed at http://epilepsyfoundation.org/answerplace/ Social/driving/statedrivinglaws.cfm. We discuss the effects of medications on the efficacy of oral contraceptives when appropriate, and we recommend supplemental folic acid, 1 mg daily, to all women of childbearing age, although the optimal dose has not been determined.

Treatment Monitoring
We routinely see patients 2 to 3 months after treatment initiation or sooner if problems arise. Although there is little information available on optimal drug levels for many of the newer agents, we measure levels after a stable dose has been achieved to have an individual baseline against which comparisons can be made in the event problems arise in the future. We check routine laboratory tests (complete blood count, electrolytes, liver function tests, clotting parameters) at the initiation of treatment if recent values are unavailable, but we recheck these parameters only in specific cases (e.g., serum sodium in patients on oxcarbazepine, electrolytes in patients on topiramate, platelets and liver function tests in patients on valproate) unless there is a clinical indication. Some authors recommend measuring bone density at the initiation of treatment, but definitive studies supporting the value of this measurement are presently lacking. SUGGESTED READING
French JA, Kanner AM, Bautista J, et al: Efficacy and tolerability of the new antiepileptic drugs: I. Treatment of new-onset epilepsy. Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004.

abnormality or focal slowing the probability of a second seizure is 40% to 60%. The EEG may not be a good predictor of pharmacoresistant epilepsy, and additional clinical biomarkers of treatment resistance are needed to improve the care of persons with recurrent seizures. Epilepsy is a chronic condition that requires years, if not lifelong, of treatment for most affected persons. The disability commonly associated with epilepsy begins on the day of the first seizure, because most adult and adolescent patients will receive a driving restriction. Work restrictions, social limitations, and public stigma significantly increase the disability experienced by many persons with epilepsy. Serious injuries such as fractures or burns may occur in up to 10% of patients with recurrent seizures per year. In addition, adverse antiepileptic drug (AED) side effects and the presence of comorbid depression have emerged as important predictors of poor quality of life with epilepsy.

Initial Treatment Considerations


Based on available data from the Centers for Disease Control and Prevention and pharmacy registries, epilepsy care has changed very little during the past 30 years. Phenytoin remains the most frequently prescribed AED, and with carbamazepine, valproate, and phenobarbital, accounts for the large majority of prescriptions for epilepsy in the United States. The eight AEDs approved by the U.S. Food and Drug Administration (FDA) during the past 11 years account for less than 20% of prescriptions for epilepsy treatment in the United States. This may be considered surprising by some clinicians caring for persons with epilepsy, considering that the investigators in the largest randomized double-blind comparison of carbamazepine, phenobarbital, phenytoin, and primidone concluded:
The outcome of this project underscores the unsatisfactory status of antiepileptic therapy with the medications currently available. Most patients whose epilepsy is reasonably controlled must tolerate some side effects. These observations emphasize the need for new AEDs and other approaches to treatment.

Recurrent Generalized and Partial Seizures


Frank G. Gilliam, M.D., M.P.H.

Epilepsy is defined as two or more unprovoked seizures and has been described as a tendency toward recurrent seizures. The factors that determine whether a single seizure recurs, or whether recurrent seizures are preventable by medications, have not been clearly established. Understanding of both the genetic predisposition related to specific receptor/neurotransmitter system defects and characteristics of the acquired injury or dysfunction in a particular brain is required to explain a unique individuals risk of epilepsy or pharmacoresistance. Although electroencephalography was developed in the 1930s, it remains the most accurate predictor of the probability of seizure recurrence, as well as epilepsy classification. After a single seizure, less than 30% of patients with a normal electroencephalogram (EEG) will have a second seizure. If the EEG shows an epileptiform

The characteristics of an optimal AED may be described based on pharmacokinetic properties, tolerability, and cost, as presented in Table 1. Considering that newer AEDs tend to have less hepatic enzyme induction and fewer drug interactions, but are generally more

TABLE 1 Optimal Attributes of an Antiepileptic Drug


Simple, linear kinetics Minimal adverse side effects No drug-drug interactions (minimal hepatic enzyme induction and serum protein binding) Long half-life for once-a-day dosing and potential for extended seizure protection after a missed dose (>24-hour elimination half-life) Inexpensive
Johnson: Current Therapy in Neurologic Disease (7/E)

42

Recurrent Generalized and Partial Seizures

be accessed at http://epilepsyfoundation.org/answerplace/ Social/driving/statedrivinglaws.cfm. We discuss the effects of medications on the efficacy of oral contraceptives when appropriate, and we recommend supplemental folic acid, 1 mg daily, to all women of childbearing age, although the optimal dose has not been determined.

Treatment Monitoring
We routinely see patients 2 to 3 months after treatment initiation or sooner if problems arise. Although there is little information available on optimal drug levels for many of the newer agents, we measure levels after a stable dose has been achieved to have an individual baseline against which comparisons can be made in the event problems arise in the future. We check routine laboratory tests (complete blood count, electrolytes, liver function tests, clotting parameters) at the initiation of treatment if recent values are unavailable, but we recheck these parameters only in specific cases (e.g., serum sodium in patients on oxcarbazepine, electrolytes in patients on topiramate, platelets and liver function tests in patients on valproate) unless there is a clinical indication. Some authors recommend measuring bone density at the initiation of treatment, but definitive studies supporting the value of this measurement are presently lacking. SUGGESTED READING
French JA, Kanner AM, Bautista J, et al: Efficacy and tolerability of the new antiepileptic drugs: I. Treatment of new-onset epilepsy. Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004.

abnormality or focal slowing the probability of a second seizure is 40% to 60%. The EEG may not be a good predictor of pharmacoresistant epilepsy, and additional clinical biomarkers of treatment resistance are needed to improve the care of persons with recurrent seizures. Epilepsy is a chronic condition that requires years, if not lifelong, of treatment for most affected persons. The disability commonly associated with epilepsy begins on the day of the first seizure, because most adult and adolescent patients will receive a driving restriction. Work restrictions, social limitations, and public stigma significantly increase the disability experienced by many persons with epilepsy. Serious injuries such as fractures or burns may occur in up to 10% of patients with recurrent seizures per year. In addition, adverse antiepileptic drug (AED) side effects and the presence of comorbid depression have emerged as important predictors of poor quality of life with epilepsy.

Initial Treatment Considerations


Based on available data from the Centers for Disease Control and Prevention and pharmacy registries, epilepsy care has changed very little during the past 30 years. Phenytoin remains the most frequently prescribed AED, and with carbamazepine, valproate, and phenobarbital, accounts for the large majority of prescriptions for epilepsy in the United States. The eight AEDs approved by the U.S. Food and Drug Administration (FDA) during the past 11 years account for less than 20% of prescriptions for epilepsy treatment in the United States. This may be considered surprising by some clinicians caring for persons with epilepsy, considering that the investigators in the largest randomized double-blind comparison of carbamazepine, phenobarbital, phenytoin, and primidone concluded:
The outcome of this project underscores the unsatisfactory status of antiepileptic therapy with the medications currently available. Most patients whose epilepsy is reasonably controlled must tolerate some side effects. These observations emphasize the need for new AEDs and other approaches to treatment.

Recurrent Generalized and Partial Seizures


Frank G. Gilliam, M.D., M.P.H.

Epilepsy is defined as two or more unprovoked seizures and has been described as a tendency toward recurrent seizures. The factors that determine whether a single seizure recurs, or whether recurrent seizures are preventable by medications, have not been clearly established. Understanding of both the genetic predisposition related to specific receptor/neurotransmitter system defects and characteristics of the acquired injury or dysfunction in a particular brain is required to explain a unique individuals risk of epilepsy or pharmacoresistance. Although electroencephalography was developed in the 1930s, it remains the most accurate predictor of the probability of seizure recurrence, as well as epilepsy classification. After a single seizure, less than 30% of patients with a normal electroencephalogram (EEG) will have a second seizure. If the EEG shows an epileptiform

The characteristics of an optimal AED may be described based on pharmacokinetic properties, tolerability, and cost, as presented in Table 1. Considering that newer AEDs tend to have less hepatic enzyme induction and fewer drug interactions, but are generally more

TABLE 1 Optimal Attributes of an Antiepileptic Drug


Simple, linear kinetics Minimal adverse side effects No drug-drug interactions (minimal hepatic enzyme induction and serum protein binding) Long half-life for once-a-day dosing and potential for extended seizure protection after a missed dose (>24-hour elimination half-life) Inexpensive
Johnson: Current Therapy in Neurologic Disease (7/E)

Recurrent Generalized and Partial Seizures

43
Seizures

expensive, the benefits of better pharmacokinetic properties and potential for improved tolerability must be weighed against greater monetary costs. In addition to pharmacokinetic properties, tolerability, and costs, the epilepsy syndrome being treated and clinically important comorbid conditions should be considered in the decision for initial AED treatment. As presented in Figure 1, partial seizures (with or without secondary generalizations), idiopathic generalized seizures, and symptomatic generalized seizures (secondary to prior brain injury) are the major categories that guide AED selection. Some drugs appear to have a broad spectrum of efficacy across multiple seizure categories and might be considered when the classification is not certain. Emerging evidence from clinical trials and aggregate clinical experience suggest that certain AEDs have efficacy for common comorbid conditions. For example,

migraine is more common in persons with epilepsy than the general population; valproate and topiramate have received indications for migraine prophylaxis from the FDA and may be particularly useful in persons with both diagnoses. Lamotrigine at low to moderate doses has been found to have fewer adverse cognitive and fatigue effects compared with carbamazepine and may be advantageous to students and for people in professions requiring sustained concentration or mental vigilance. Valproate and lamotrigine are approved by the FDA for the treatment of bipolar disorder, and carbamazepine and oxcarbazepine may be effective as well. Some clinical trial data suggest that topiramate and zonisamide may facilitate weight loss, as opposed to a tendency toward weight gain with valproate. The lack of hepatic enzyme induction by gabapentin, levetiracetam, and lamotrigine is a consideration for women on

Recurrent seizures (epilepsy)

Thorough history (including witness) + EEG

Seizure (epilepsy) classification

Generalized seizures

Partial seizures (localization-related epilepsy)

Symptomatic or cryptogenic

Idiopathic (e.g., childhood absence, juvenile myoclonic epilepsy, etc.)

Consider patient preferences and comorbidity

1. valproate 2. lamotrigine 3. topiramate 4. levetiracetam 5. zonisamide 6. phenobarbital 7. felbamate

Absence only

Absence + GTC; or GTC only

Absence + GTC + myoclonic

1. ethosuxamide 2. valproate 3. lamotrigine 4. levetiracetam

1. valproate 2. topiramate 3. lamotrigine 4. levetiracetam

Pregnancy

Headaches Oral contraception

Cognition/fatigue Overweight 1. lamotrigine 2. oxcarbazepine 1. topiramate 2. zonisamide

Cost

Avoid valproate and phenobarbital; consider lamotrigine

1. topiramate 2. valproate 1. gabapentin 2. levetiracetam 3. lamotrigine

Generic carbamazepine valproate phenobarbital phenytoin

FIGURE 1. Suggested sequence of medications for recurrent unprovoked seizures (i.e., epilepsy). EEG, Electroencephalogram; GTC, generalized tonic-clonic. Johnson: Current Therapy in Neurologic Disease (7/E)

44

Recurrent Generalized and Partial Seizures

hormonal birth control. However, recent study data indicate that lamotrigine metabolism is significantly affected by hormonal birth control. Early results of systematic birth registries indicate that valproate and phenobarbital should be avoided in women who are considering pregnancy if medically feasible. The long half-life of zonisamide and phenobarbital may provide benefit to persons whose schedule or motivation limit compliance. The recommended maintenance doses of most AEDs are derived from clinical studies performed before optimal dosing strategies were determined. Recent evidence suggests that most people whose seizures can be controlled by AEDs will require doses in the lower end of a recommended range. For example, most persons with epilepsy will require less than 1000 mg/day of carbamazepine, 2000 mg/day of valproate, 400 mg/day of lamotrigine, or 300 mg/day of topiramate. Most AEDs require two- or three-times-a-day dosing, and the package insert should be consulted for specific recommendations. Fewer daily doses improve compliance, but multiple doses during the day may reduce peak serum concentrations and subsequent adverse effects. In general, the starting dose should be approximately one fourth of the initial target dose

with increases every 1 to 2 weeks by one fourth of the target dose. Lamotrigine has a slower titration rate due to the risk of rash, and topiramate has a slower rate to improve tolerability of adverse cognitive effects; the FDA-approved dosing information should be consulted for both of these AEDs. Systematic screening with a reliable and valid instrument, such as the Adverse Events Profile, may be necessary after each dosage adjustment to accurately identify significant side effects.

Treatment of Pharmacoresistant Epilepsy


Most patients will be controlled by moderate doses of their first AED, but approximately 40% will not be controlled or will relapse after an initial response. There is no clear consensus in the epilepsy community about the treatment approach after failure of the initial AED, and as previously emphasized, the treatment decisions should be made in consideration of the individual patients unique situation. A suggested stepwise approach to epilepsy care is shown in Figure 2.

Two or three failed optimal antiepileptic drug (AED) regimens

1. Video/EEG 2. High-resolution MRI

Localized EEG or MRI abnormality

Yes

No

Consider presurgical evaluation: 1. Neuropsychological testing. 2. Functional neuroimaging?

Sensitivity to AED side effects

Yes

No

Good surgical candidate

Consider vagus nerve stimulator

Additional AEDs as mono or dual therapy

Yes

No

Seizure-free without adverse AED effects

Surgical resection* * Some patients may need additional testing such as intracarotid amobarbital test or intracranial EEG monitoring No Yes

Consider vagus nerve stimulator or If injurious tonic or atonic seizures: Consider corpus callosotomy or Additional testing to attempt to localize a focal epileptogenic region

Continue AEDs

FIGURE 2. Comprehensive approach to epilepsy care. EEG, Electroencephalogram. Johnson: Current Therapy in Neurologic Disease (7/E)

Status Epilepticus

45
Seizures

If seizures recur after the initial target dose of an AED is achieved, the dose should be increased at a tolerable rate to the most effective dose. The decision to increase to the next dosage increment, versus titrating to the highest tolerated dose, should be made in consultation with the patient. If seizures recur on the highest tolerated dose, then a second AED should be added in a similar approach to the initial drug. Frequently the dose of the initial AED will need to be reduced to improve tolerability of increased doses of the adjunctive AED. If seizures do not occur on the combination of two AEDs, the option to wean the first AED for convenience and cost should be reviewed with the patient. The decision to wean to monotherapy versus continuing effective combination therapy can be made only by weighing the overall risks and benefits to the specific patients situation. Similarly, the decision to consider a third medication after two have failed, versus proceeding to a presurgical evaluation, can be made only in consultation with the patient. Some patients may want to know if they have unilateral mesial temporal sclerosis, which may have a 75% chance for surgical success, whereas other patients will want to consider additional AEDs regardless of their surgical candidacy. The most important consideration to ensure optimal epilepsy care is that the patient be fully informed regarding the details of their options at each stage of treatment. Available evidence indicates that after three medications have failed due to lack of efficacy, as opposed to tolerability, the probability of achieving long-term remission is less than 10%. Alternative treatments, such as resective surgery or the vagus nerve stimulator, should be discussed in detail with the patient at this juncture. Although most patients who have a potential for complete seizure control, and the subsequent opportunity to drive a car and return to a more normal lifestyle, will elect to proceed with a presurgical evaluation as outlined in Figure 2, some patients may elect to try additional AEDs or the vagus nerve stimulator (VNS). Patients who have not tolerated three or more AEDs due to adverse effects may find the option of the VNS appealing, although less than 10% of patients will have complete seizure control after VNS implantation. Evaluation of patients at a comprehensive epilepsy center with epilepsy surgery capability is required for all patients with pharmacoresistant epilepsy and disabling seizures, as recommended by the published practice guidelines of the American Academy of Neurology. SUGGESTED READING
Engel J Jr, Wiebe S, French J, et al: Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society; American Association of Neurological Surgeons, Neurology 4:53847, 2003. Gilliam F: Optimizing health outcomes in active epilepsy, Neurology 58(Suppl 5):S9-S19, 2002. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Mattson RH, Cramer JA, Collins JF, et al: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures, N Engl J Med 313:145-151, 1985. Johnson: Current Therapy in Neurologic Disease (7/E)

Status Epilepticus
Jehuda Sepkuty, M.D.

Status epilepticus (SE) is a common neurologic emergency. There are approximately 100,000 to 200,000 episodes of SE in the United States annually. The term status epilepticus generally refers to the occurrence of a single unremitting seizure or frequent clinical seizures without an interictal return to normal consciousness. An operational definition as proposed by Lowenstein and Alldredge accords the diagnosis after 5 minutes of continuous seizure activity or 2 or more seizures without full recovery of awareness between seizures. Older definitions considered 30 minutes as the time criterion, based on experimental animal data suggesting that seizure activity of this length is associated with significant neuronal damage. The sooner treatment is initiated, the better the outcome; however, the treatment for prolonged seizures versus SE is essentially the same initially anyway, so that the exact definition is less important practically, as long as preparations for the worst-case scenario are carried out early. SE can cause injury due to the intense neuronal activity within the central nervous system (CNS) and due to the metabolic stress of repeated muscular convulsions. Respiratory failure, aspiration pneumonitis, neurogenic pulmonary edema, rhabdomyolysis, and lactic acidosis may complicate convulsions, and neuronal death can occur after 30 to 60 minutes of continuous seizure activity. Classification of the type of SE is crucial because it is a major factor in determining morbidity and therefore the aggressiveness of the required treatment; generalized tonic-clonic or partial-complex SE poses the greatest risk. The most common forms of SE are the following: Simple partial: characterized by repeated or continuous focal seizures that could be motor (twitching of one extremity), sensory (the sensation of numbness and tingling of one extremity), or cognitive (aphasia, dyslexia, and so forth) without impaired consciousness Complex partial: characterized by repeated or continuous episodes of focal motor, sensory, or cognitive symptoms as earlier, but with impaired consciousness, and can be associated with automatisms like swallowing, licking lips, staring, and so forth; could be difficult occasionally to differentiate from other acute confusional states Generalized tonic-clonic: always associated with impaired consciousness; tonic-clonic seizures may be the initial manifestation of SE or may represent secondary generalization from a partial seizure The following are a number of less common but important forms that need to be recognized: Absence: characterized by altered awareness, but not necessarily unconsciousness. Patients are typically confused or stuporous, and there may be associated eye blinking, perseveration, small automatism,

Status Epilepticus

45
Seizures

If seizures recur after the initial target dose of an AED is achieved, the dose should be increased at a tolerable rate to the most effective dose. The decision to increase to the next dosage increment, versus titrating to the highest tolerated dose, should be made in consultation with the patient. If seizures recur on the highest tolerated dose, then a second AED should be added in a similar approach to the initial drug. Frequently the dose of the initial AED will need to be reduced to improve tolerability of increased doses of the adjunctive AED. If seizures do not occur on the combination of two AEDs, the option to wean the first AED for convenience and cost should be reviewed with the patient. The decision to wean to monotherapy versus continuing effective combination therapy can be made only by weighing the overall risks and benefits to the specific patients situation. Similarly, the decision to consider a third medication after two have failed, versus proceeding to a presurgical evaluation, can be made only in consultation with the patient. Some patients may want to know if they have unilateral mesial temporal sclerosis, which may have a 75% chance for surgical success, whereas other patients will want to consider additional AEDs regardless of their surgical candidacy. The most important consideration to ensure optimal epilepsy care is that the patient be fully informed regarding the details of their options at each stage of treatment. Available evidence indicates that after three medications have failed due to lack of efficacy, as opposed to tolerability, the probability of achieving long-term remission is less than 10%. Alternative treatments, such as resective surgery or the vagus nerve stimulator, should be discussed in detail with the patient at this juncture. Although most patients who have a potential for complete seizure control, and the subsequent opportunity to drive a car and return to a more normal lifestyle, will elect to proceed with a presurgical evaluation as outlined in Figure 2, some patients may elect to try additional AEDs or the vagus nerve stimulator (VNS). Patients who have not tolerated three or more AEDs due to adverse effects may find the option of the VNS appealing, although less than 10% of patients will have complete seizure control after VNS implantation. Evaluation of patients at a comprehensive epilepsy center with epilepsy surgery capability is required for all patients with pharmacoresistant epilepsy and disabling seizures, as recommended by the published practice guidelines of the American Academy of Neurology. SUGGESTED READING
Engel J Jr, Wiebe S, French J, et al: Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society; American Association of Neurological Surgeons, Neurology 4:53847, 2003. Gilliam F: Optimizing health outcomes in active epilepsy, Neurology 58(Suppl 5):S9-S19, 2002. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Mattson RH, Cramer JA, Collins JF, et al: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures, N Engl J Med 313:145-151, 1985. Johnson: Current Therapy in Neurologic Disease (7/E)

Status Epilepticus
Jehuda Sepkuty, M.D.

Status epilepticus (SE) is a common neurologic emergency. There are approximately 100,000 to 200,000 episodes of SE in the United States annually. The term status epilepticus generally refers to the occurrence of a single unremitting seizure or frequent clinical seizures without an interictal return to normal consciousness. An operational definition as proposed by Lowenstein and Alldredge accords the diagnosis after 5 minutes of continuous seizure activity or 2 or more seizures without full recovery of awareness between seizures. Older definitions considered 30 minutes as the time criterion, based on experimental animal data suggesting that seizure activity of this length is associated with significant neuronal damage. The sooner treatment is initiated, the better the outcome; however, the treatment for prolonged seizures versus SE is essentially the same initially anyway, so that the exact definition is less important practically, as long as preparations for the worst-case scenario are carried out early. SE can cause injury due to the intense neuronal activity within the central nervous system (CNS) and due to the metabolic stress of repeated muscular convulsions. Respiratory failure, aspiration pneumonitis, neurogenic pulmonary edema, rhabdomyolysis, and lactic acidosis may complicate convulsions, and neuronal death can occur after 30 to 60 minutes of continuous seizure activity. Classification of the type of SE is crucial because it is a major factor in determining morbidity and therefore the aggressiveness of the required treatment; generalized tonic-clonic or partial-complex SE poses the greatest risk. The most common forms of SE are the following: Simple partial: characterized by repeated or continuous focal seizures that could be motor (twitching of one extremity), sensory (the sensation of numbness and tingling of one extremity), or cognitive (aphasia, dyslexia, and so forth) without impaired consciousness Complex partial: characterized by repeated or continuous episodes of focal motor, sensory, or cognitive symptoms as earlier, but with impaired consciousness, and can be associated with automatisms like swallowing, licking lips, staring, and so forth; could be difficult occasionally to differentiate from other acute confusional states Generalized tonic-clonic: always associated with impaired consciousness; tonic-clonic seizures may be the initial manifestation of SE or may represent secondary generalization from a partial seizure The following are a number of less common but important forms that need to be recognized: Absence: characterized by altered awareness, but not necessarily unconsciousness. Patients are typically confused or stuporous, and there may be associated eye blinking, perseveration, small automatism,

46

Status Epilepticus

or other symptoms. Absence SE typically occurs in patients with chronic epilepsy and frequently requires electroencephalogram (EEG) for confirmation Myoclonic: characterized by frequent myoclonic jerks in the setting of altered mental status. This typically occurs in patients with one of the generalized epilepsies, such as juvenile myoclonic epilepsy. This condition needs to be differentiated from the patient who has metabolic encephalopathy (particularly uremic or hepatic encephalopathy) and may have also some myoclonic activity. EEG recordings can differentiate the two Psychogenic: should be considered in situations where there are bilateral motor movements with preserved consciousness or side-to-side head movements as part of the convulsion. An EEG recording without seizure activity during motor events can help establish this diagnosis, although the EEG may also appear relatively normal during simple partial SE. It is important to refrain from the whole SE protocol, which has inherent iatrogenic risks, if there is a clinical suspicion for this diagnosis. The nonconvulsive types of SE may pose a greater clinical problem: Patients with complex partial or absence SE may exhibit confusional states that are not easily recognized as seizures. Also, patients who have had recurrent seizures may be considered postictal rather than in nonconvulsive SE; in this situation, subtle signs of ongoing seizures such as rhythmic papillary dilation or breathing may be the only evidence of seizure activity. The patient with possible SE requires rapid evaluation and treatment. Although there are differences in efficacy and side effect profile among effective agents, it is important to become familiar with one reasonable treatment method and use it. In general, more convulsive activity is associated with more systemic complications. Neither focal nor nonconvulsive SE should be considered non-life threatening, because they can progress to full convulsive SE, but they can be treated somewhat slower to minimize iatrogenic side effects. I divide the initial management into three phases: assessment and supportive treatment, initial pharmacotherapy, and pharmacotherapy for refractory seizures.

on medications for chronic epilepsy. A rapid fingerstick glucose should confirm hypoglycemia. Measurement of arterial blood gases is often valuable and may suggest a need for intubation and mechanical ventilatory support. Cardiac monitoring, frequent measurement of blood pressure, and pulse oximetry should be instituted. Before the administration of pharmacologic treatment, administer thiamine, 100 mg, followed by 50 mL of 50% dextrose by direct push into the IV line. This phase usually lasts approximately 5 to 10 minutes (see our suggested protocol in Figure 1).

Initial Pharmacologic Therapy


Lorazepam, 0.02 to 0.03 mg/kg, should be administered IV, and its effect should be assessed after a minute. If seizures continue, additional doses of lorazepam (up to a cumulative dose of 0.1 mg/kg) should be infused at a maximum rate of 2 mg/min, and a second IV catheter should be placed (if not in yet) to begin a concomitant phenytoin (or fosphenytoin) loading infusion.* Even if seizures terminate after the initial lorazepam dose (which happens in more than half of the patients presenting with SE), therapy with phenytoin or fosphenytoin is generally indicated to prevent the recurrence of seizures. As many as half of cases of treated generalized convulsive SE show evidence of persistent seizures on continuous EEG monitoring performed after clinically detectable seizures were abolished. Thus, continuing with administration of a standard anticonvulsant agent such as phenytoin is indicated even if overt seizures stopped with lorazepam. Also, follow-up EEG should be obtained as soon as possible to rule out the presence of nonconvulsive SE. A phenytoin infusion of 20 mg/kg (or 20 mg/kg phenytoin equivalents [PE] for fosphenytoin) should be started at 50 mg/min (or 100 to 150 mg PE/minute for fosphenytoin) and reduced if significant adverse effects of the infusion are seen. Heart rate and blood pressure must be watched closely because phenytoin can cause cardiac arrhythmias and hypotension. Another possible complication is local phlebitis resulting from the sclerotic effect of extravasated phenytoin. Phenytoin must be administered in saline because fluids containing glucose can cause the precipitation of phenytoin. This phase of treatment usually lasts approximately 30 minutes. In specific cases where IV access is not immediately obtained, rectal diazepam in children and intramuscular (IM) fosphenytoin injection in adults is indicated as a first step till an IV access is available. The option of IM administration of fosphenytoin is one of the three major differences between fosphenytoin and phenytoin, the other two being the option of two or three times faster administration compared with phenytoin and the reduced likelihood of causing local vein irritation. The major obstacle to the use of fosphenytoin is the high cost.

Assessment and Support


Once a situation of a prolonged seizure is encountered, it is important to begin with performing a rapid neurologic examination to establish a preliminary classification of the type of SE and its probable etiology. The patient should also undergo a rapid systemic evaluation, with particular attention to circulatory and respiratory status and the possible need for supportive therapy (oxygen, mechanical ventilation). During this time, intravenous (IV) catheters should be placed and blood obtained for electrolytes, serum calcium, magnesium, phosphorus, glucose, toxicology studies, a complete blood count with differential, liver and kidney function studies, prothrombin time, and partial thromboplastin time. Anticonvulsant levels should be obtained if the patient is

*Phenytoin and any of the benzodiazepines are incompatible and will precipitate if infused through the same IV line. Johnson: Current Therapy in Neurologic Disease (7/E)

Status Epilepticus

47
Seizures

Ongoing seizure activity

05 min.

History while watching seizure

Basic ABCs

Examination while placing intravenous lines

530 min.

Consider the diagnosis of SE and draw the necessary bloods. Initial pharmacologic therapy. Consider EEG if possible without delaying treatment unless necessary to verify diagnosis.

Lorazepam 0.1 mg/kg IV at 12 mg/min

Ongoing seizure activity?

Yes

No

Phenytoin 20 mg/kg IV (or 20 mg/kg phenytoin equivalents (PE) for fosphenytoin) at 50 mg/min (or 100150 PE/min for fosphenytoin) and reduced if significant adverse effects of infusion seen.

Phenytoin 20 mg/kg IV (or 20 mg/kg phenytoin equivalents (PE) for fosphenytoin) over 23 hours then end of protocol

Ongoing seizure activity?

2
3060 min. Yes: treatment of refractory seizures (definite SE) No

End of protocol Phenytoin: additional 10 mg/kg IV (or 10 mg/kg phenytoin equivalents (PE) of fosphenytoin) and consider another 0.05 mg/kg of lorazepam if pt. is stable. Correct metabolic derangements, intubate and get continuous EEG recording if possible.

Ongoing SE?

Yes

No

Phenobarbital 20 mg/kg IV at 50 mg/min

End of protocol

Ongoing SE? 60120 min. Yes No

If the patient is hemodynamically very unstable you may consider midazolam 0.2 mg/kg bolus, then 0.050.5 mg/kg per hour for 45 minutes trial prior to pentobarbital. If the patient is at high risk for prolonged mechanical ventilation you may consider propofol 2 mg/kg IV over 10 min. If seizure stops, discontinue bolus and continue infusion at 412 mg/kg/hour while closely monitoring EEG and blood pressure. If seizures do not stop within 45 minutes, stop and start pentobarbital 515 mg/kg rapid IV bolus, then 16 mg/kg/min IV. Continuous EEG monitoring until pattern is isoelectric.

End of protocol

Proceed with further evaluation

FIGURE 1. Evaluation and pharmacologic treatment of status epilepticus (SE). ABC, Airway, breathing, circulation; IV, intravenous; EEG, electroencephalogram. Johnson: Current Therapy in Neurologic Disease (7/E)

48

Status Epilepticus

Treatment of Refractory Seizures


Infuse another 10 mg/kg of phenytoin (or 10 mg/kg PE of fosphenytoin) and consider another 0.05 mg/kg of lorazepam if the patient is stable. Metabolic abnormalities from initial laboratory studies should be appropriately addressed. It is critical to provide adequate ventilatory and hemodynamic support: Patients with refractory seizures should be endotracheally intubated because the combination of benzodiazepines and barbiturates is likely to cause respiratory failure. The primary drugs used in this setting are pentobarbital, midazolam, and propofol; a systematic review of drug therapy for refractory SE assessed data on 193 patients from 28 trials in an attempt to clarify this issue. Overall mortality was 48%, but there was no association between drug selection and the risk of death. Pentobarbital was more effective than either propofol or midazolam in preventing breakthrough seizures (12% vs. 42%), but was associated with a significantly increased incidence of hypotension, defined as a systolic blood pressure below 100 mm Hg (77% vs. 34%). I select further pharmacologic therapy at this point according to the old school (phenobarbital followed by pentobarbital) but may modify treatment if the patient is very unstable hemodynamically or at great risk for prolonged mechanical ventilation (see Figure 1). Treatment with high-dose barbiturates remains the treatment of choice because of the greatest experience with its use. Continuous EEG monitoring should be instituted if possible, along with continuous pulse oximetry and blood pressure monitoring via an arterial catheter. Vasopressors should be available at the bedside. An initial dose of 20 mg/kg of phenobarbital should be infused at a maximum rate of 100 mg/min. If seizure activity continues, pentobarbital coma should be induced. A dose of 10 mg/kg of pentobarbital should be infused while careful attention is paid to the EEG and hemodynamic status. Additional doses of pentobarbital at rates of 1 to 6 mg/kg/min should be infused until seizures stop (and the EEG shows isoelectric pattern). Almost all patients at this point require vasopressor support (typically phenylephrine or dopamine) as well as crystalloid infusions. The mortality rate associated with barbiturate coma reaches 80% in patients older than 70 years of age because of adverse hemodynamic effects and the severity of the underlying neurologic process. If seizures are terminated with pentobarbital, then an infusion at 1 to 4 mg/kg/hr should be maintained for 48 to 96 hours and tapered over the following 24 hours. During this time therapeutic phenytoin and phenobarbital concentrations must be maintained. If EEG is not available emergently, the maintenance dose of pentobarbital should be increased until all visible evidence of seizure activity has been abolished, including subtle signs such as pupillary dilation. Recent studies on the use of pentobarbital coma for treatment of SE shows that patients treated with sufficient dosing to produce isoelectric EEG did better than those whose EEG pattern showed burst suppression only. Also, continuation of the barbiturate anesthesia for longer time, namely 4 days, resulted in better outcome.

HEMODYNAMICALLY UNSTABLE PATIENTS Treatment with barbiturates or propofol may significantly worsen the unstable patients. Therefore, in extreme cases of hemodynamic instability one may proceed with a midazolam infusion because it is the besttolerated treatment in this setting. Generally, therapy is initiated with a 0.2 mg/kg bolus, followed by a continuous infusion of 0.05 to 0.5 mg/kg/hr. If this is unsuccessful within 45 to 60 minutes, a pentobarbital infusion should be started. PATIENTS AT HIGH RISK FOR PROLONGED MECHANICAL VENTILATION Patients who are at high risk for prolonged mechanical ventilation (e.g., with chronic obstructive pulmonary disease, severe debilitation, or cancer) could be treated with propofol in an attempt to minimize the duration of sedation. Blood pressure and EEG should be monitored closely, and pressors should be ready at the bedside, while 2 mg/kg of propofol is administered over 10 minutes. If the seizures stop prior to the infusion of the entire bolus, the bolus should be discontinued and a continuous infusion begun at 4 to 12 mg/kg per hour. This infusion should be titrated over the next 20 to 60 minutes to maintain burst suppression on the EEG and a seizurefree state. If seizures are controlled with propofol, the effective infusion rate should be maintained for 24 hours and then tapered at a rate of 5 percent per hour. This prevents rebound seizures that commonly occur with too fast propofol taper. It is critical that high therapeutic levels of anticonvulsants are obtained prior to tapering the propofol to reduce the risk of seizure recurrence. If seizure activity does not stop within 45 minutes, then the treatment with propofol should be considered unsuccessful. In this case, pentobarbital coma should be considered. Propofol infusions for refractory SE are relatively new in comparison with midazolam or high-dose barbiturates. However, as clinical experience with propofol sedation in the intensive care setting grows, this agent is increasingly used in patients with refractory status persisting after intubation. It remains critical that propofol be employed cautiously and by individuals familiar with its use in this context.

Further Evaluation after Controlling Seizures


Once seizures are under control, other causes of SE should be excluded. Noncontrast brain computed tomography (CT) scan should be obtained to rule out acute CNS hemorrhage and a subsequent lumbar puncture should be done if the CT scan is negative to rule out acute infection. Urinalysis, urine culture, and blood cultures should be obtained in all patients because it may be impossible to discern the cause of existing fever as infection versus seizure related. The cause of a given episode of SE is important to determine for prognosis as well as for acute management. The most common causes for SE in adults are stroke, low anticonvulsant levels in
Johnson: Current Therapy in Neurologic Disease (7/E)

Psychogenic Nonepileptic Seizures

49
Seizures

chronic epilepsy patients, toxic or metabolic derangements, anoxia or hypoxia, infection, tumor, trauma, or drug withdrawal. These causes can be identified relatively by simple tests, and treatment of the underlying cause can shorten the duration of SE, thereby improving outcome. While the patient is in barbiturate coma, systemic metabolic abnormalities should be managed aggressively. In particular, blood pressure fluctuations require pressors for control, and maintenance of normoglycemia is vital. In addition, as mentioned before, blood levels of phenytoin and phenobarbital should be kept in the high therapeutic ranges before gradual withdrawal of phenobarbital. After several days of barbiturate anesthesia, of which at least 2 days should be free of epileptiform activity on EEG, a gradual pentobarbital taper should be initiated by decreasing 1 mg/min every 6 hours with continuous EEG monitoring. If at any point epileptiform activity is seen, the infusion should be increased back to achieving isoelectric pattern. If, however, infusion can be tapered to zero, EEG monitoring should be continued continuously or intermittently for at least 4 more days to monitor for possible relapse. Good prognostic factors in recovery from SE are history of epilepsy, infectious etiology, lack of multiorgan system failure, and age younger than 40 years. Anoxia, stroke, and tumor are less favorable prognostic factors. SUGGESTED READING
Chapman MG, Smith M, Hirsch NP: Status epilepticus, Anaesthesia 56:648, 2001. Claassen J, Hirsch LJ, Emerson RG, Mayer SA: Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review, Epilepsia 43:146, 2002. DeLorenzo RJ, Hauser WA, Towne AR, et al: A prospective populationbased epidemiologic study of status epilepticus in Richmond, Virginia, Neurology 46:1029-1035, 1996. Krishnamurthy KB, Drislane FW: Relapse and survival after barbiturate anesthetic treatment of refractory status epilepticus, Epilepsia 37:863-867, 1996. Lowenstein DH: Status epilepticus: an overview of the clinical problem, Epilepsia 40(Suppl 1):53-58, 1999. Lowenstein DH, Alldredge BK: Status epilepticus, N Engl J Med 338:970, 1998. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of Americas Working Group on Status Epilepticus, JAMA 270:854, 1993. Treiman DM: Status epilepticus. In Resor SR Jr, Kutt H, editors: The medical treatment of epilepsy, New York, 1992, Marcel Dekker.

Psychogenic Nonepileptic Seizures


Allan Krumholz, M.D., and Tricia Ting, M.D.

Psychogenic nonepileptic seizures (PNESs) are among the most common and serious of all psychogenic neurologic disorders. They account for approximately 20% of all intractable seizure disorders referred to comprehensive epilepsy centers and present with a reported annual incidence of about 4% of true epilepsy. Moreover, patients with PNESs are seriously ill. PNESs may not be real epilepsy, but their adverse consequences are very real, resulting in severe disability and even death. Compared with patients with real epilepsy, patients with PNES exhibit more frequent, severe, and disabling seizures and a poorer quality of life. Although advances in video-electroencephalogram (EEG) monitoring have much improved our ability to correctly diagnose PNESs, diagnosis and management remain major problems. Consequently, here we emphasize strategies for both correct diagnosis and proper therapy in the management of patients with PNES.

Terminology
There is no uniform standardized definition or classification for psychogenic disorders such as PNESs. We prefer the currently popular term psychogenic nonepileptic seizures. The more general term nonepileptic seizures (NESs) is used to encompass both physiologic and psychological causes for disorders that are mistaken for epilepsy (Table 1). NESs are operationally defined as disorders that mimic epilepsy but are not due to abnormal electrical discharges in the brain; and there are two types, physiologic and psychogenic. Physiologic NESs are physical disorders that are confused or mistaken for epilepsy. The specific causes vary
TABLE 1 Classification of Nonepileptic Seizures
I. Physiologic Nonepileptic Seizures or Events* A. Pure B. Mixed (with psychological exaggeration or embellishment) II. Psychogenic Nonepileptic Seizures A. Somatoform disorders 1. Somatization disorders 2. Conversion disorder or reactions B. Dissociative disorders C. Factitious disorder (e.g., Munchausens syndrome) D. Malingering
*Age dependent, e.g., night terrors or breath-holding spells in children; other syncopes, complicated migraine, and transient ischemic attacks in adults.

PATIENT RESOURCE
Epilepsy Foundation of America 4351 Garden City Drive Landover, Maryland 20785-7223 Phone: 800-332-1000 http://www.epilepsyfoundation.org/

Johnson: Current Therapy in Neurologic Disease (7/E)

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Seizures

chronic epilepsy patients, toxic or metabolic derangements, anoxia or hypoxia, infection, tumor, trauma, or drug withdrawal. These causes can be identified relatively by simple tests, and treatment of the underlying cause can shorten the duration of SE, thereby improving outcome. While the patient is in barbiturate coma, systemic metabolic abnormalities should be managed aggressively. In particular, blood pressure fluctuations require pressors for control, and maintenance of normoglycemia is vital. In addition, as mentioned before, blood levels of phenytoin and phenobarbital should be kept in the high therapeutic ranges before gradual withdrawal of phenobarbital. After several days of barbiturate anesthesia, of which at least 2 days should be free of epileptiform activity on EEG, a gradual pentobarbital taper should be initiated by decreasing 1 mg/min every 6 hours with continuous EEG monitoring. If at any point epileptiform activity is seen, the infusion should be increased back to achieving isoelectric pattern. If, however, infusion can be tapered to zero, EEG monitoring should be continued continuously or intermittently for at least 4 more days to monitor for possible relapse. Good prognostic factors in recovery from SE are history of epilepsy, infectious etiology, lack of multiorgan system failure, and age younger than 40 years. Anoxia, stroke, and tumor are less favorable prognostic factors. SUGGESTED READING
Chapman MG, Smith M, Hirsch NP: Status epilepticus, Anaesthesia 56:648, 2001. Claassen J, Hirsch LJ, Emerson RG, Mayer SA: Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review, Epilepsia 43:146, 2002. DeLorenzo RJ, Hauser WA, Towne AR, et al: A prospective populationbased epidemiologic study of status epilepticus in Richmond, Virginia, Neurology 46:1029-1035, 1996. Krishnamurthy KB, Drislane FW: Relapse and survival after barbiturate anesthetic treatment of refractory status epilepticus, Epilepsia 37:863-867, 1996. Lowenstein DH: Status epilepticus: an overview of the clinical problem, Epilepsia 40(Suppl 1):53-58, 1999. Lowenstein DH, Alldredge BK: Status epilepticus, N Engl J Med 338:970, 1998. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of Americas Working Group on Status Epilepticus, JAMA 270:854, 1993. Treiman DM: Status epilepticus. In Resor SR Jr, Kutt H, editors: The medical treatment of epilepsy, New York, 1992, Marcel Dekker.

Psychogenic Nonepileptic Seizures


Allan Krumholz, M.D., and Tricia Ting, M.D.

Psychogenic nonepileptic seizures (PNESs) are among the most common and serious of all psychogenic neurologic disorders. They account for approximately 20% of all intractable seizure disorders referred to comprehensive epilepsy centers and present with a reported annual incidence of about 4% of true epilepsy. Moreover, patients with PNESs are seriously ill. PNESs may not be real epilepsy, but their adverse consequences are very real, resulting in severe disability and even death. Compared with patients with real epilepsy, patients with PNES exhibit more frequent, severe, and disabling seizures and a poorer quality of life. Although advances in video-electroencephalogram (EEG) monitoring have much improved our ability to correctly diagnose PNESs, diagnosis and management remain major problems. Consequently, here we emphasize strategies for both correct diagnosis and proper therapy in the management of patients with PNES.

Terminology
There is no uniform standardized definition or classification for psychogenic disorders such as PNESs. We prefer the currently popular term psychogenic nonepileptic seizures. The more general term nonepileptic seizures (NESs) is used to encompass both physiologic and psychological causes for disorders that are mistaken for epilepsy (Table 1). NESs are operationally defined as disorders that mimic epilepsy but are not due to abnormal electrical discharges in the brain; and there are two types, physiologic and psychogenic. Physiologic NESs are physical disorders that are confused or mistaken for epilepsy. The specific causes vary
TABLE 1 Classification of Nonepileptic Seizures
I. Physiologic Nonepileptic Seizures or Events* A. Pure B. Mixed (with psychological exaggeration or embellishment) II. Psychogenic Nonepileptic Seizures A. Somatoform disorders 1. Somatization disorders 2. Conversion disorder or reactions B. Dissociative disorders C. Factitious disorder (e.g., Munchausens syndrome) D. Malingering
*Age dependent, e.g., night terrors or breath-holding spells in children; other syncopes, complicated migraine, and transient ischemic attacks in adults.

PATIENT RESOURCE
Epilepsy Foundation of America 4351 Garden City Drive Landover, Maryland 20785-7223 Phone: 800-332-1000 http://www.epilepsyfoundation.org/

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depending on age (see Table 1). If these episodes are uncomplicated by psychological or emotional features, they can be called pure physiologic nonepileptic events. However, sometimes a patients physiologic events are psychologically exaggerated, embellished, or misinterpreted and may be thought of as mixed physiologic nonepileptic events (see Table 1). Physiologic NESs account for only a small proportion of all patients with NESs. Most patients with NESs have PNESs (see Table 1). In general any patient with a psychological disorder that causes symptoms that are mistaken for epilepsy can be said to have PNESs. It is useful to classify psychogenic seizure patients into four major psychopathologic categories based on Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-4) system (see Table 1): A. Somatoform disorders B. Dissociative disorders C. Factitious disorders D. Malingering Somatoform disorders account for the great majority of patients and can be further subclassified (see Table 1). Dissociative disorders are increasing recognized as a significant psychopathology in some patients with PNES. Also, these categories are not mutually exclusive and may be associated with other psychological, physical, and sociologic comorbidities.

neuropsychological assessments can be useful complements to video-EEG monitoring. Diagnosis may be particularly complicated in patients with both nonepileptic and epileptic seizures. Approximately 10 to 40 percent of patients diagnosed with PNES also have been reported to have true epileptic seizures. Fortunately, in most patients with coexisting epilepsy and PNES, the epileptic seizures are usually well controlled or of only historical relevance at the time PNES present. CLINICAL OBSERVATIONS Physicians have long noted that certain overt seizure characteristics are more likely associated with PNES, whereas other features appear more indicative of epilepsy. The most commonly reported characteristics include movements and vocalizations during seizures, seizure duration, and other seizure-related associations such as injury, incontinence, and amnesia. Although variability and overlap in PNES and epileptic seizure semiology preclude relying on any single clinical sign to distinguish between the two, some clinical observations can be useful diagnostically (Table 2). PNESs often persist considerably longer than epileptic seizures, which typically last less than 3 minutes, excluding the postictal state. Some prolonged PNESs may present with nonphysiologic waxing and waning convulsive activity, or the activity may appear distractible with external stimuli. In PNES with convulsions, movements may look purposeful or semipurposeful, asymmetrical, or asynchronous (i.e., thrashing or writhing), in contrast to the synchronous tonic-clonic activity of epileptic seizures. However, it may be difficult to distinguish the semipurposeful behaviors of PNES from the automatisms of complex partial epileptic seizures, particularly frontal lobe seizures. Other distinguishing features of PNES include preservation of consciousness and responsiveness, which are frequently altered in epileptic seizures. Crying and weeping are more common to PNES, as is having the

Diagnosis
Historically, physicians have resorted to clinical observation, seizure semiology, and history for distinguishing NES from epileptic seizures. Today, clinical observation has been buttressed by video-EEG monitoring, now considered the gold standard in the differential diagnosis of seizures. Additional diagnostic techniques including seizure provocation, serum prolactin levels, single photon emission computed tomography (SPECT), and

TABLE 2 Clinical Characteristics of Epileptic versus Psychogenic Nonepileptic Seizures


Characteristics Age at onset Sex Previous psychiatric history Motor Vocalization Incontinence Duration of seizure Injury Amnesia Suggestion provokes seizure Epileptic All ages; children and adolescents more common Male and female about equal Occasionally present In generalized convulsions, bilateral movements are usually synchronous Cry at onset Frequent Usually < 2-3 min Frequent tongue biting Common, unconcious during seizure No Nonepileptic All ages; 15-35 yr most common Female more common: 3:1 Commonly noted Flailing, thrashing, and asynchronous movements more common, side to side head movements, pelvic thrusting Weeping, crying, or screaming more common Occasional Often prolonged, > 2-3 min Uncommon Variable, sometimes conscious during seizure Often
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eyes closed during a seizure. Although patients with PNES may report incontinence and self-injury, they are rarely actually witnessed or documented. Similarly, patients with PNES may report having seizures in sleep or appear to be asleep at seizure onset. However, PNESs arising from true sleep as documented by EEG are exceedingly rare. Additionally, unlike epileptic seizures, PNESs characteristically do not respond well to antiepileptic drug treatment. PNESs are much more likely to be provoked by emotional stimuli and suggestion. Thus, provocation procedures may be particularly useful for reproducing PNES during EEG recording to enable confirmation of the diagnosis. Provoking or suggesting seizures can be done in several ways, such as injecting saline or placing a tuning fork on the body or head. Hypnosis has also been used. These procedures all are accompanied by strong suggestion by the physician that this procedure is likely to bring on a typical seizure. An important diagnostic consideration is whether a provoked event truly represents the patients typical seizure. Conclusions based on an atypical induced event or on only one of a variety of seizure types can lead to a misdiagnosis, particularly in patients with coexisting PNES and epilepsy. Seizure provocation by suggestion does raise some ethical controversies. Misleading and deceiving a patient when provoking a seizure can be harmful to the patient-physician relationship and should be avoided. Nonetheless, provocative testing can be done with honesty and benefit the patient, particularly when it facilitates a correct diagnosis. VIDEO-EEG MONITORING A diagnosis of PNESs is most secure when a typical seizure is captured and shows no epileptic activity on simultaneous EEG and video monitoring. In contrast, generalized convulsive epileptic seizures invariably are associated with clear changes in the background EEG during ictal recordings. Similarly, complex partial seizures, potentially arising from small or deep seizure foci, are associated with significant ictal EEG abnormalities in perhaps 85% to 95% of such seizures. Even simple partial seizures that do not impair consciousness have associated ictal EEG abnormalities up to 60% of the time (or nearly 80% if one records multiple seizures). The ictal EEG recording is particularly important because interictal or routine EEGs occasionally may be misleading. Patients with epilepsy may have normal

interictal EEGs, whereas patients with PNES may have minor EEG abnormalities (Table 3). Clinical seizures may be captured for differential diagnosis with either outpatient or inpatient EEG monitoring. Outpatient ambulatory EEG monitoring with or without simultaneous video recording has become a more readily available option that allows patients to wear the EEG at home for several days. It is particularly useful for patients who have daily events. The advantage of home monitoring is the ability to capture typical events that may be triggered by the patients usual environment. However, physician-directed seizure provocation by suggestion is less feasible. Prolonged inpatient video-EEG monitoring may be more appropriate for patients with less frequent events, especially when antiepileptic drug tapering is considered. Simultaneous video-EEG recording offers the advantage of permitting careful observation and review of the clinical manifestations of seizures. This can be especially useful for distinguishing epileptic discharges from movement and muscle artifact when assessing patients with PNES. PROLACTIN LEVELS Detecting a rise in serum prolactin levels following a seizure can be helpful in differentiating epileptic seizures from PNES. Prolactin levels rise approximately fivefold to tenfold after generalized tonic-clonic seizures and somewhat less so but still significantly (typically at least twofold to threefold) after complex partial seizures. This increase in serum prolactin is maximum in the initial 20 minutes to 1 hour after a seizure. Although measurements of serum prolactin may be useful in distinguishing epileptic from NESs, false-negative and false-positive results do occur. Simple partial seizures or mild complex partial seizures, particularly those with little motor activity or those arising from extratemporal regions, may not significantly raise prolactin levels. In addition, serum prolactin elevations have been reported in rare instances to occur after syncope. Overall, a prolactin level elevation is fairly specific for epilepsy; however, lack of an elevation is not highly predictive of PNES. SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY Single-photon emission computed tomography (SPECT), though not a first-line choice to differentiate PNES and epileptic seizures, may provide helpful data in difficult diagnostic cases. Typically, patients with epilepsy will

TABLE 3 EEG Characteristics of Epileptic Versus Nonepileptic (Psychogenic) Seizures


EEG Interictal Preictal Ictal Postictal Epileptic Spikes and sharp waves common Spikes, sharp waves, or rhythmic ictal activity Spikes, sharp waves, or rhythmic ictal activity Slow activity Nonepileptic Normal or nonspecific abnormalities, e.g., mild slow activity (possibly medication related) Movement artifact Movement artifact Normal EEG, preserved alpha when apparently unconscious

EEG, Electroencephalogram.

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have increased cerebral blood flow in the area of the seizure focus ictally but focally decreased blood flow interictally. In contrast, patients with PNES should not show such abnormalities. NEUROPSYCHOLOGICAL TESTING The performance of PNES and epilepsy patients on various psychological and neuropsychological tests including the Minnesota Multiphasic Personality Inventory (MMPI and MMPI-2), the Weschler Adult Intelligence Scale (WAIS), and the Halstead-Reitan Test Battery have been studied. As compared to their epilepsy counterparts, PNES patients more frequently demonstrate a conversion V profile on the MMPI. A conversion V profile, defined by an elevated MMPI Scale 1 and 3 with a relative trough on Scale 2, is highly associated with somatoform disorders and conversion symptoms. Studies assessing performance on the WAIS and Halstead-Reitan Test Battery have shown that both PNES patients and epilepsy patients have more cognitive impairment compared to the normal population, but on many neuropsychological measures, there is no significant difference in performance between the two groups. These findings suggest that while neuropsychological testing may not help distinguish between patients with PNES and epilepsy, it may nevertheless provide clinically useful data by highlighting comorbid psychopathology or cognitive difficulties that could benefit from psychological or psychiatric interventions. Formal neuropsychological testing requires referral to mental health professionals who are experienced in psychometric assessment and psychotherapeutic intervention in patients with neurologic disorders. However, the distinction between PNES and epileptic seizures is best made by a neurologist, particularly one who has expertise in epilepsy, and should be based on consideration of both clinical data and neuropsychological assessments.

Treatment
PHYSIOLOGIC NONEPILEPTIC SEIZURES For patients with physiologic causes for their NESs, such as syncope, complicated migraine, or transient ischemic attacks, the treatment, clinical course, and outcome vary depending on the etiology. For example, some patients with cardiac syncope may need placement of a pacemaker, and their prognosis depends on the cardiac disease. PSYCHOGENIC NONEPILEPTIC SEIZURES Even after a diagnosis of PNES is established, neurologists can and should continue to take an active role in the care of such patients (Table 4). It is important to consider the associated psychopathology in such patients, and when appropriate, to refer patients to mental health professionals. However, mental health professionals are often uncomfortable and inexperienced with seizures

and PNES, so neurologists need to maintain an active role in the care of such patients, even if that role is simply to provide support to the mental health professional or psychiatrist. Unfortunately PNES seizure patients often fall in the cracks between psychiatry and neurology. Neurologists can be reassured that they can and should continue to be involved with PNES patients and can follow some simple guidelines for managing these types of patients. Management of patients with PNES is similar to that for patients with other types of so-called abnormal illness behavior (see Table 4). Historically, moral therapy was advocated as recognition that psychological, social, and cultural factors play an important role in these types of disorders. More recently approaches have centered on concepts such as supportive re-education. The first consideration should be the manner in which the diagnosis of psychogenic seizures is presented to the patient and family. It is important to be honest with the patient and to demonstrate a positive approach to the diagnosis. The physician should emphasize as favorable the good news that the patient does not have epilepsy and should also stress that the disorder, although serious and real, does not require treatment with antiepileptic medications and that once stress or emotional issues are resolved, the patient has the potential to gain better control of these events. Nevertheless, not all patients readily accept the diagnosis of PNES or this type of approach. Some may seek other opinions, and this should not be discouraged. An adversarial relationship with the patient should be avoided. In fact, the patient should be encouraged to return as desired, and records should be made available to avoid duplication of services. After a diagnosis of PNES is presented, supportive measures should be initiated. Regular follow-up visits for the patient are useful even if a mental health professional is involved. This allows the patient to get medical attention without demonstrating illness behavior. Moreover, it also offers support to the involved mental health professional. Patient education and support are stressed at these visits. Since family issues are often important contributing factors, family members should be involved.

TABLE 4 Management of Nonepileptic Seizure Patients


Present the diagnosis of nonepileptic seizures positively, emphasizing the potential for better seizure control. After patients are referred to mental health professionals, the diagnosing neurologist should provide some followup and support. Regular follow-up visits should be scheduled that are not contingent on persistent, new, or worsening symptoms. Give patients attention when they do well. Avoid prescribing unnecessary medications, unwarranted tests, and excessive referrals to specialists. Permit the continuation of some symptoms. A patients optimal well-being and function, rather than eradication of seizures, is the goal.
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If symptoms worsen or new ones develop, patients should get appropriate attention. However, it is important to avoid unnecessary testing, uncalled-for medication, or excessive referral to specialists. In addition, we advise that sometimes symptoms, even some PNESs, should be tolerated. Indeed, the goal of therapy should be to maximize the patients function, well-being, and quality of lifenot just to eliminate seizures. It is also important to look beyond the patients physical symptoms and apparent psychopathology. Indeed one needs to consider such factors as personality structure, coping mechanism, related psychosocial stressors, and associated cognitive problems. This approach is supported by current psychiatric theory, as emphasized in the DSM-4 classification system. For patients with coexisting epileptic and nonepileptic seizures, proper treatment is dependent on defining the nature of the seizures that are causing problems. In many patients with coexisting epileptic and nonepileptic seizures, the events are really sequential rather than truly actively coexisting or simultaneous. This means that a patient may have a history of epileptic seizures, often in the distant past or in the case of some adults, in childhood, and may be on antiepileptic medications for these, but then the patient develops different types of events that prove to be PNES. In such cases, the active problem is really not epilepsy, because the patients epileptic seizures are well controlled. Therefore, attention and treatment should be directed to the PNES, and the patient and family reassured that the epileptic seizures are controlled. Patients who present with both epileptic and nonepileptic seizures simultaneously demand more complex management. In such patients, we have found it particularly helpful to focus on the semiology of seizure manifestations as recorded by video-EEG monitoring to distinguish the NESs from the epileptic ones. We then direct our treatment of the patient according to the semiology manifesting at that time. We also have found it useful to show such epileptic or nonepileptic seizures to family members to help them understand how to respond best to a specific patients symptoms when epileptic and nonepileptic seizures coexist as active problems. A history of sexual or physical abuse is often reported among patients diagnosed with PNES. NESs occur with greater frequency in women. The exact incidence varies, but women generally account for about 70% to 80% of all individuals with NESs. In addition head injury, particularly mild head injury, is noted as a potential precipitant in a substantial proportion of these patients. These factors may represent specific psychological risk factors or the more general risk of trauma in a susceptible individual. In regard to sexual and physical abuse, these issues should be investigated and treatment directed as appropriate.

with psychogenic seizures function reasonably well after diagnosis. However, many have poor functional outcomes, and only about 30% completely stop having psychogenic seizures. When the diagnosis of psychogenic seizures is based on reliable criteria such a video-EEG monitoring, misdiagnosis is unlikely, but in patients, particularly those with unusual appearing frontal lobe seizures, it can occur. Instead, the usual cause for a poor outcome is related to a patients chronic psychological and social problems. It is noteworthy that children with psychogenic seizures appear to have a much better prognosis than adults. Children may have psychogenic seizures more related to transient stress and coping disorders, whereas adults are more likely to have psychogenic seizures within the context of more chronic psychological maladjustment, such as personality disorders. Another factor accounting for the better outcomes in children is that they are usually diagnosed earlier. Patients without evidence of serious psychiatric or personality disorders but rather symptoms more suggestive of stress and coping disorders respond relatively well to supportive, educational, or behavioral therapeutic approaches. In contrast, patients with somatoform disorders and factitious disorders more often have associated chronic personality problems and, correspondingly, a poorer prognosis. In addition, recent evidence suggests that patients with PNES may benefit from structured treatment programs and continued support by epilepsy specialists or centers. As knowledge about the nature of psychogenic seizures and their associated psychopathology is gained, better treatment strategies can be developed that will improve the care and prognosis of these difficult and challenging patients. SUGGESTED READING
Barry E, Krumholz A, Bergey C, et al: Nonepileptic posttraumatic seizures, Epilepsia 39:427-431, 1998. Bowman ES: Etiology and clinical course of pseudoseizures: relationship to trauma, depression, and dissociation, Psychosomatics 34:333-342, 1993. Cragar DE, Berry DTR, Fakhoury TA, et al: A review of diagnostic techniques in the differential diagnosis of epileptic and nonepileptic seizures, Neuropsychol Rev 12:31-64, 2002. Krumholz A: Nonepileptic seizures: diagnosis and management, Neurology 53(Suppl):S76-S83, 1999. Rueber M, Pukrop T, Bauer J, et al: Outcome in psychogenic nonepileptic seizures: one- to ten-year follow-up in 164 patients, Ann Neurol 53:305-311, 2003. Wyllie E, Friedman D, Luders H, et al: Outcome of psychogenic seizures in children and adolescents compared to adults, Neurology 41:742-744, 1991.

PATIENT RESOURCE
Epilepsy Foundation of America 4351 Garden City Drive Landover, MD 20785-7223 Phone: 800-332-1000 http://www.epilepsyfoundation.org/

Prognosis
The outcomes of patients with psychogenic seizures vary. Outcome studies show that about half of all patients
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SECTION 3

Pain
Chronic Pain Management: General Principles
Charles E. Argoff, M.D.
magnetic resonance imaging (MRI) of the lumbar spine does not routinely correlate with the degree of pain experienced by an individual. Patients with severe low back pain may have little or no structural abnormalities seen by MRI, whereas asymptomatic individuals may be noted to have disk herniations or other obvious structural problems with such imaging tools. Electrophysiologic tests may be normal in patients with severe pain, prompting some to question the legitimacy of the pain as opposed to acknowledging the limitations of the diagnostic test. Psychosocial and other factors often play a role in the chronic pain experience, adding an additional layer of complexity for both assessment and treatment. Despite these challenges, advances in our understanding of the pathophysiology of various chronic pain problems have been made that in turn have led to new pharmacotherapeutic and other treatment options for the management of chronic pain. Numerous therapeutic approaches are available that hold great promise for reducing the amount of pain that an individual has to endure, hopefully leading to functional restoration as well. The purpose of this chapter is to review the general principles of chronic pain management for the practicing neurologist. The success of the assessment and treatment of chronic pain may be enhanced by the recognition of the difference between nociceptive and neuropathic pain. Nociceptors are specialized nerve endings that are able to respond to typical normal pain producing stimuli such as thermal, chemical, mechanical, and other potential causes of tissue damage. An activated nociceptor, through C and A-delta nerve fibers, transmits its pain-producing information from the peripheral to the central nervous system, where it is processed further at spinal cord and brain levels. Nociceptive input does not become experienced by a person as pain unless the nociceptive information reaches appropriate areas of the brain. In the absence of nociceptive input, the normal nervous system does not experience pain. In contrast, neuropathic pain results from injury to the peripheral and/or central nervous system and represents abnormalities in transmission that have developed as the result of the injury. Ongoing injury is not required for these abnormalities to be expressed. There is clear evidence that neuropathic pain appears to result from the manner in which the nervous system is reorganized following injury. Peripheral and central sensitization are 55

Nearly 80 million Americans suffer from one or more types of chronic painful disorders, including chronic headache, chronic neuropathic pain, pain secondary to degenerative spinal disorders, pain secondary to nonspinal degenerative joint disease, fibromyalgia, soft tissue pain disorders such as chronic myofascial pain, cancer-related pain, and others. The pain experienced by millions of Americans is frequently associated with profound restrictions of vocational as well as nonvocational activities with devastating effects on ones quality of life. Chronic pain disables more people and adds more costs to our health care economy on an annual basis than do heart disease and cancer combined. Unlike in acute painful states such as postoperative pain or pain associated with an ankle sprain, in which the cause of the pain may be relatively easily determined, for patients with chronic pain, the exact cause of the pain may be difficult to identify even many years after the original acute injury or painful event. The term chronic pain is often defined as pain that lasts 3 months or more; however, in reality, chronic pain is pain that persists beyond the time of normal healing. By this definition, patients in certain settings might begin to experience chronic pain 1 month after the initial onset of acute pain. This is important to recognize for early treatment intervention and for the prevention of lifelong pain for the affected individual. Evaluating chronic pain poses numerous challenges to the neurologist. Although many pain assessment tools exist (see later) and new ones are being developed, the lack of a specific pain measurement tool that can prove or disprove the presence and/or the intensity of the pain may allow some practitioners to dismiss a persons complaint of pain as subjective. There are also limitations in the interpretation of available test results such as imaging and electrophysiologic tests. For example, it is well known that the degree of abnormality seen on
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key mechanisms that many lead in a neuropathic state to this reorganization such that lowered threshold to nociceptive processing that may now occur. Stimuli that may normally not be painful are, in neuropathic pain states, experienced as painful (allodynia). Stimuli that are normally painful may be more painful than usual (hyperalgesia). Any sensory stimuli, painful or otherwise, may be perceived in a more exaggerated manner (hyperesthesia). These clinical findings are the hallmark of neuropathic pain and reflect a nervous system that is now able to facilitate pain production because it is more easily excited than in a normal state. It must be emphasized that neuropathic pain may therefore be experienced even when the affected individual is not subjected to a tissue-damaging stimulus. It is important as well to recognize that a persistent nociceptive pain state may, through peripheral and central sensitization, develop into a neuropathic pain state. Although certainly not all chronic pain states are neuropathic, central nervous system changes that facilitate pain transmission have been postulated in chronic pain as well. Factors underlying this transformation are being actively studied and hold the key to the treatment and hopefully the prevention of many different chronic pain states, including postherpetic neuralgia, complex regional pain syndrome, chronic headache, chronic pain related to degenerative joint disease, chronic low back pain, and fibromyalgia, to name a few. To minimize the effect of the chronic pain on ones quality of life, it is imperative that a patient with chronic pain be assessed as early as possible. I must emphasize that chronic pain may have significant negative impact on a patients ability to function from both a physical as well as cognitive viewpoint. Work, recreational, and normal activities of daily living all may be adversely affected. Patients with chronic pain frequently develop or have exacerbation of depression, anxiety, sleep disturbances, and loss of self-esteem as the result of the pain. Lost workdays, impaired job performance, and frank absence/disability are some of the ways in which employment is often limited by the presence of chronic pain. The goals of chronic pain management must be realistic: (1) reduce pain and (2) improve quality of life and functioningeach to the fullest extent possible. The evaluation and treatment of chronic pain are not only about finding the proper medicine, nerve block, or new exercise to cure the pain: this is not likely to happen in most cases. Rather, the management of chronic pain involves a detailed assessment of the problem, including both medical and nonmedical aspects, and the development of a comprehensive treatment plan. Medical, physical rehabilitative, and psychosocial treatment strategies all are appropriate to consider in this plan. The clinical assessment is the first step in the management of any neurologic disorder, including chronic pain. The goals of the clinical assessment include not only making the diagnosis of chronic pain but also attempting to make as specific a diagnosis as possible. The clinical assessment includes obtaining the following information: When did the pain start? Was the specific onset of the pain remembered (as for example, with postherpetic

neuralgia or trauma)? Was there a specific cause to the pain (e.g., injury, surgery)? Are there already known medical or surgical conditions for the patient (e.g., diabetes, osteoarthritis, osteoporosis, connective tissue disease) that can provide clues regarding the cause of the chronic pain? For how long has the pain existed? Where is the pain? What does the pain feel like? Is it sharp, stabbing, dull, throbbing, aching, burning, knifelike, or a combination of these? What impact on physical function is associated with the pain? What makes it better? What makes it worse? Are there past medical, neurologic, or psychosocial factors that help you, the treatment provider, to understand the pain better? What diagnostic testing is required to assist in the assessment?

The clear purpose of diagnostic testing is to help make as specific a diagnosis as possible. It is not to be used nor can it be used to validate or invalidate the complaint of pain. A normal result does not suggest there is not a chronic pain problem. In my experience, I have encountered too many instances in which a negative test result, particularly a normal electrophysiologic examination (e.g., electromyography, nerve conduction velocity) or MRI was equated to the absence of legitimate pain. This practice is not only scientifically invalid but also ethically inappropriate. The assessment of pain is aided by the use of several pain questionnaires currently available. Individual patients with chronic pain often report widely different pain levels even for similar conditions and similar degrees of functional impairment. It is, therefore, important to always assess pain intensity levels as well as the degree of functional impairment in a person with chronic pain. The Brief Pain Inventory addresses not only the pain level but also the impact of that pain on various functional domains. It is a validated tool, takes only minutes to complete, and is a practical way to assess chronic pain as well as the results of treatment in a busy practice. Use of other tools, such as the Visual Analogue Scale or the Pain Intensity Scale, assess pain solely and not function. Use of the Faces scale may be appropriate for patients who are cognitively impaired or speak a foreign language that you are not conversant in. Longer and more detailed tools also are available but are not as practical or easy to use. Other tools are being developed for specific conditions such as neuropathic pain. After completing a comprehensive assessment of the chronic pain problem, an effective treatment plan needs to be developed that provides acceptable analgesia with an acceptable side effect profile. This may include pharmacologic, interventional, rehabilitative, and cognitivebehavioral approaches singly or in combination. With respect to pharmacotherapy, there is growing empirical evidence that rational polypharmacy may be most successful for patients with chronic pain. No matter how effective a single agent may be, it rarely if ever reduces pain completely; therefore, various medications
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most often based on complementary mechanisms of action may need to be combined in a rational fashion. As in other areas of medical care (e.g., cancer, hypertension, and coronary artery disease management), combinations of therapies are often believed to be more effective than a single agent. As an example, a recent open label study demonstrated that for three painful conditions (low back pain, postherpetic neuralgia, and painful diabetic neuropathy), the addition of the lidocaine 5% patch to a treatment regimen that already included gabapentin reduced pain further in all three conditions. A randomized, controlled study examining the potential benefit of combining the lidocaine 5% patch with gabapentin for postherpetic neuralgia compared with each alone is being completed. So how do you start to develop a comprehensive treatment plan? Ideally you would consider established and accepted guidelines, based on consensus unbiased expert opinion, for the condition(s) that you are treating. Regrettably, such guidelines are not uniformly available; for example, an international panel has just published guidelines for the treatment of neuropathic pain, but similar guidelines do not exist for the treatment of chronic low back pain, an even more common set of disorders. Truly whole-istic care means integrating medical care with appropriate interventional, physical rehabilitative, and behavioral pain management approaches. When considering any type of pharmacologic therapy, treatment goals need to balance efficacy, tolerability, cost, and safety. Choose among agents that have efficacy established through a variety of means, including published multicenter, randomized, controlled studies as well as significant clinical experience. Assess the tolerability of initiating and maintaining treatment, short- and long-term side effects, the likelihood of drug-drug interactions, the ease of dosage timing, and other medication use. Consider also the severity of the side effects. For example, the nonsteroidal antiinflammatory (NSAID) agent, piroxicam, although effective in reducing symptoms associated with inflammation, is also associated with potentially fatal gastrointestinal complications, thereby making it less than ideal for conditions in which an NSAID would be appropriate. Wherever possible, you should choose the approach (assuming equal efficacy and toxicities) that requires the least laboratory monitoring (e.g., to check drug levels, monitor for hepatic, renal, or bone marrow effects). Using one agent at a time, titrate for therapeutic efficacy versus side effect(s) in a manner consistent with the pharmacokinetics of the agent.* Increase the dose of the agent until acceptable analgesia is experienced or adverse effects limit further use of the agent. Remember that each patient is different. Even if both have similar radiologic findings and the same pain level, one patient with chronic low back pain may benefit from 10 mg

of valdecoxib daily, whereas another may require a 30-mg dose. Each treatment that you offer a patient (medical or otherwise) should be considered a trial therapy. Even if you just read the latest article stating that drug X is the best choice for diabetic neuropathy, you must individually assess and reassess the effect of that drug on each individual patient. If, after a period of treatment, you and the patient believe that it is both safe and effective, then continue. If not, then either amend how the treatment is offered (increase the dose, change the route of delivery) or change the treatment. Treatment goals need to be shared between you and your patient, and they need to include understanding that your patients may need to be titrated and managed with more than one agent and one type of treatment. Patients need to know that you are not married to the same treatment forever even if it does not work. They need to expect that the treatment will be altered if it is not effective. For this reason, you must have, even as you begin treatment, a plan for treatment discontinuation or an exit strategy. Whatever you are treating your patient with: an antidepressant, anticonvulsant, muscle relaxant, opiate analgesic, NSAID, topical analgesic, or any other agent, the patient and you both should have a rational sense of what treatment success or treatment failure are. A complete lack of any pain relief or functional improvement clearly constitutes treatment failure, and the patients report following treatment of minimal pain and return to work certainly suggests treatment success. Most of what we experience with our patients lies somewhere in between. In fact, this matter has been carefully studied recently in patients with postherpetic neuralgia treated with gabapentin. Substantial improvement, as reported by patients, was associated with not 100%, or even 50%, pain reduction, but with only 30% pain reduction. These data emphasize that successful treatment outcomes as defined by the patients experiences occur without absolute pain cessation and, perhaps even more important, that in chronic pain treatment it is not realistic to expect total or even 50% pain reduction.

Conclusions
The management of chronic pain should be viewed in the same way as any other chronic disease. Determine the cause to the fullest extent possible, and institute a treatment plan that has established efficacy and acceptable side effects. Assess and reassess not only the benefit of the treatment but also the possibility of adverse effects. Do not continue treatments that are ineffective or have unacceptable side effects; always be ready to exit one treatment and begin another if needed. Reduce pain and improve function as much as possible. Finally, NEVER GIVE UP. There are numerous options for the treatment of chronic pain. If you believe that all treatment strategies have been exhausted, it is

*For example, doubling the dose of the transdermal fentanyl patch daily until comfort is achieved is likely to be associated with significant side effects, because it takes far longer than 1 day to determine the effect of the patch on the patient. Johnson: Current Therapy in Neurologic Disease (7/E)

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almost certain that one of your colleagues may be able to help with a new approach. Therefore, referral to a specialized center should be considered for the difficultto-manage patientthere is always something more to be done in controlling chronic pain. PATIENT RESOURCES
American Pain Society 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4715 http://www.ampainsoc.org/ American Academy of Pain Medicine 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4731 http://www.painmed.org/ International Association for the Study of Pain 909 NE 43rd Street, Suite 306 Seattle, WA 98105 Phone: 206-547-6409 http://www.iasp-pain.org/

Failed Back Syndrome


Jacob P. Schwarz, M.D., and Neal J. Naff, M.D.
The imprecise term failed back syndrome refers broadly to the pain and disability experienced by patients whose back and/or leg pain remains refractory to surgical therapy. The frustration that these patients and their physicians experience when therapy fails can sour the patient-physician relationship and discourages many physicians from accepting the therapeutic challenge that these patients present. In every case, it is essential to determine the following about the patients prior surgical treatment: (1) Was surgical intervention indicated? and (2) Did the surgical intervention adequately treat the offending pathology? The answers to these questions will direct the appropriate work-up and treatment (Figure 1). We present here our therapeutic strategy for patients with failed back syndrome.

Initial Evaluation
Many patients who suffer from failed back syndrome have not received the diagnosis or treatment most appropriate for their constellation of symptoms. A thorough review of the patients initial history, physical examination, past imaging studies, and previous therapeutic interventions are crucial to developing the most effective treatment plan for these patients. The physical examination should include observation of muscle bulk and tone; symmetry of strength; sensation to light touch, pain, temperature, and joint position; reflexes; gait; posture; tension signs; and the range of motion of the back and legs. Perineal sensation,

a postvoid residual, and rectal tone should be examined if the history suggests injury to the sacral roots. Data regarding the onset of the pain, the circumstances provoking it, its distribution, any patterns of radiation, the effect of various postures, and ameliorating factors are particularly important aspects of the history. Pain originating in the hip joint may radiate to the low back, buttock, and groin. Hip pathology is a frequent mimic of low back pain associated with leg pain. An assessment of hip motion and tenderness should be part of every examination to evaluate back and leg pain. In the case of hip pathology, the examiner can usually provoke the patients pain with abduction, flexion, and external rotation of the hip. Tenderness over the trochanteric bursa should also be evaluated. Pain in the legs that occurs at a reproducible duration of leg activity and disappears immediately on rest is indicative of vascular disease. Neurogenic claudication from lumbar stenosis occurs at a less reproducible duration of leg activity in an erect posture. The pain may not occur at all if the patient is in a flexed posture. Typically patients with neurogenic claudication report they can walk for much longer distance if they are pushing a grocery cart. Less frequently, they may report that stationary biking does not cause the leg pain they experience when walking. Peripheral neuropathy occurs frequently in the same patient population susceptible to neurogenic claudication but is not activity dependent. Appropriate consultations should be made for those patients suspected of having vascular claudication, peripheral neuropathy, or hip pathology. These are the most frequently missed diagnosis in patients with failed back syndrome. If the commonly missed diagnoses are ruled out by history and physical examination, then sources of pain other than might not have been addressed by the patients surgical intervention should be sought. A commonly misapplied surgical intervention is lumbar laminectomy for the treatment of back pain. Patients with lumbar facet arthritis, by definition, have some radiographic evidence of lumbar stenosis. Many of those patients, however, do not have any leg pain consistent with neurogenic claudication. All too frequently, those patients may have a lumbar laminectomy for their back pain in spite of the fact that there is no anatomic reason to expect that decompressing asymptomatic compressed nerve roots will reduce the back pain associated with inflamed and degenerative facet joints. Weight loss and physical therapy, particularly water aerobics, may relieve the inciting stress on the affected facets. Failing these, more appropriate therapy for facet arthropathy would be facet joint injections with cortisone and facet median nerve rhizotomy. Psychological evaluation is critical to successful therapy in many cases. The use of psychotherapy must be introduced carefully and with sensitivity. Certainly there are patients with underlying psychopathology who develop back pain. In these circumstances, awareness of certain psychiatric vulnerabilities, such as drug dependency, may help tailor an appropriate treatment plan for each patient. The sequelae of failed back syndrome can have devastating results to the patients psyche. Appropriate psychotherapy can improve the chances
Johnson: Current Therapy in Neurologic Disease (7/E)

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almost certain that one of your colleagues may be able to help with a new approach. Therefore, referral to a specialized center should be considered for the difficultto-manage patientthere is always something more to be done in controlling chronic pain. PATIENT RESOURCES
American Pain Society 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4715 http://www.ampainsoc.org/ American Academy of Pain Medicine 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4731 http://www.painmed.org/ International Association for the Study of Pain 909 NE 43rd Street, Suite 306 Seattle, WA 98105 Phone: 206-547-6409 http://www.iasp-pain.org/

Failed Back Syndrome


Jacob P. Schwarz, M.D., and Neal J. Naff, M.D.
The imprecise term failed back syndrome refers broadly to the pain and disability experienced by patients whose back and/or leg pain remains refractory to surgical therapy. The frustration that these patients and their physicians experience when therapy fails can sour the patient-physician relationship and discourages many physicians from accepting the therapeutic challenge that these patients present. In every case, it is essential to determine the following about the patients prior surgical treatment: (1) Was surgical intervention indicated? and (2) Did the surgical intervention adequately treat the offending pathology? The answers to these questions will direct the appropriate work-up and treatment (Figure 1). We present here our therapeutic strategy for patients with failed back syndrome.

Initial Evaluation
Many patients who suffer from failed back syndrome have not received the diagnosis or treatment most appropriate for their constellation of symptoms. A thorough review of the patients initial history, physical examination, past imaging studies, and previous therapeutic interventions are crucial to developing the most effective treatment plan for these patients. The physical examination should include observation of muscle bulk and tone; symmetry of strength; sensation to light touch, pain, temperature, and joint position; reflexes; gait; posture; tension signs; and the range of motion of the back and legs. Perineal sensation,

a postvoid residual, and rectal tone should be examined if the history suggests injury to the sacral roots. Data regarding the onset of the pain, the circumstances provoking it, its distribution, any patterns of radiation, the effect of various postures, and ameliorating factors are particularly important aspects of the history. Pain originating in the hip joint may radiate to the low back, buttock, and groin. Hip pathology is a frequent mimic of low back pain associated with leg pain. An assessment of hip motion and tenderness should be part of every examination to evaluate back and leg pain. In the case of hip pathology, the examiner can usually provoke the patients pain with abduction, flexion, and external rotation of the hip. Tenderness over the trochanteric bursa should also be evaluated. Pain in the legs that occurs at a reproducible duration of leg activity and disappears immediately on rest is indicative of vascular disease. Neurogenic claudication from lumbar stenosis occurs at a less reproducible duration of leg activity in an erect posture. The pain may not occur at all if the patient is in a flexed posture. Typically patients with neurogenic claudication report they can walk for much longer distance if they are pushing a grocery cart. Less frequently, they may report that stationary biking does not cause the leg pain they experience when walking. Peripheral neuropathy occurs frequently in the same patient population susceptible to neurogenic claudication but is not activity dependent. Appropriate consultations should be made for those patients suspected of having vascular claudication, peripheral neuropathy, or hip pathology. These are the most frequently missed diagnosis in patients with failed back syndrome. If the commonly missed diagnoses are ruled out by history and physical examination, then sources of pain other than might not have been addressed by the patients surgical intervention should be sought. A commonly misapplied surgical intervention is lumbar laminectomy for the treatment of back pain. Patients with lumbar facet arthritis, by definition, have some radiographic evidence of lumbar stenosis. Many of those patients, however, do not have any leg pain consistent with neurogenic claudication. All too frequently, those patients may have a lumbar laminectomy for their back pain in spite of the fact that there is no anatomic reason to expect that decompressing asymptomatic compressed nerve roots will reduce the back pain associated with inflamed and degenerative facet joints. Weight loss and physical therapy, particularly water aerobics, may relieve the inciting stress on the affected facets. Failing these, more appropriate therapy for facet arthropathy would be facet joint injections with cortisone and facet median nerve rhizotomy. Psychological evaluation is critical to successful therapy in many cases. The use of psychotherapy must be introduced carefully and with sensitivity. Certainly there are patients with underlying psychopathology who develop back pain. In these circumstances, awareness of certain psychiatric vulnerabilities, such as drug dependency, may help tailor an appropriate treatment plan for each patient. The sequelae of failed back syndrome can have devastating results to the patients psyche. Appropriate psychotherapy can improve the chances
Johnson: Current Therapy in Neurologic Disease (7/E)

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Pain

Review initial history and diagnostic imaging

Yes

Was the initial surgery indicated?

No

Did the surgery adequately address the pathology?

Is there lumbar pathology that was not addressed?

Yes

No Re-operate

Yes Address pathology: Facet arthropathy blocks, rhizotomy Lumbar instability spinal fusion Lumbar stenosis spinal decompression

No

Is there additional pathology?

Is extra-spinal pathology present? No Nonoperative pain management Yes Address pathology: Hip arthritis Vascular disease Peripheral neuropathy No Nonoperative pain management

Yes Address pathology: Arachnoiditis spinal cord stimulator Lumbar instability spinal fusion

Consider: Nerve/nerve root injury Spinal cord stimulator Implantable drug pump FIGURE 1. Flowsheet synopsis of our approach to the work-up of failed back surgery syndrome.

that this patient will successfully comply with other treatment strategies and learn the coping mechanisms necessary to regain a reasonable quality of life. A careful review of the initial and most recent diagnostic imaging is also necessary. Plain radiographs provide important information about bone density, spinal alignment, and fractures. Standing, sitting, supine, standing flexion, and standing in extension radiographs provide invaluable information about the spine and how it changes in response to stress that is not available from any other studies. A spine that appears to have a normal radiographic appearance when the patient is standing erect may move out of alignment on flexion or extension. Disk spaces may collapse under different stresses evoked by differences in posture. In such cases mechanical instability may be provoking pain that would respond to surgical intervention. Computed tomography (CT) scans provide similar information to plain radiographs but allow for three-dimensional reconstruction and investigation. This illuminates problems related to joint hypertrophy, calcified ligaments, and osteophytes in the spinal canal or foramen that cannot be seen on plain radiograph. Finally, magnetic resonance imaging (MRI) captures data about connective tissues such as disk material, ligaments, and abnormal masses that
Johnson: Current Therapy in Neurologic Disease (7/E)

might change the architecture of the spinal column and provoke pain. It is important that all patients with failed back syndrome have an MRI with and without contrast. The contrast component of the imaging is necessary to distinguish between recurrent disk herniation and postsurgical scarring. Contrast administration is also important for the thorough evaluation for arachnoiditis.

Treatment Options
SURGICAL INTERVENTION: OPERATION AND REOPERATION Was the Surgical Intervention Indicated? To determine if the patients initial surgery was indicated, the following factors should be present. First, the patient should have had a complaint that is reliably attributable to a structural problem. Second, there should be a structural abnormality on the initial diagnostic imaging that explained the patients complaint. Third, the surgical procedure performed must have been appropriate to treat the responsible structural abnormality. In the absence of these criteria, the patients surgical intervention was misguided and was destined

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to fail. It is also a near certainty that a repeat of the same operation in this situation will also be destined to fail. If Surgery Was Indicated, Did the Surgical Intervention Adequately Treat the Pathology? It might be the case that the previous surgery failed in the presence of a surgically correctable abnormality because the wrong surgery was performed or because the appropriate surgical procedure failed or partly failed to treat the offending pathology. Common examples of the latter are residual herniated lumbar disk material or foraminal stenosis that continues to compress one or more nerve roots. In these situations the most reasonable intervention would be another operative attempt to correct the offending pathology. In these cases, repeat surgery, when properly directed at specific findings and complaints, is often successful. Success rates for reoperation vary with each report. Large series report success rates in the range of 30% to 50%. Certain features predict better outcomes. Females do better than males. Those with fewer prior surgeries are more likely to benefit from reoperation than those with multiple unsuccessful attempts. Those who have evidence of epidural scarring from previous operations are more likely to encounter bad outcomes as are those involved in litigation related to their back pain. The patient must be made aware that the risk of perioperative complications increases with reoperation and the efficacy slightly decreases. A more complicated situation is persistent lumbar instability after a lumbar fusion operation. Lumbar fusions have a mixed history of success. Most wellconducted clinical studies demonstrate no better than a 60% success rate. Therefore, 4 of 10 patients that have that operation will not benefit regardless of the technical success of the procedure. Reoperation for persisting back pain following a fusion procedure should be cautiously considered, particularly if there is no clear technical problem with the fusion construct. NO SURGICALLY CORRECTABLE PATHOLOGY PRESENT: OPTIONS WHEN NO SURGERY IS INDICATED If the determination is made that surgical intervention was not indicated, the etiology of the patients initial complaint must be determined through a careful history and physical examination. The history should reveal the specific features about the original pain that the patient had suffered and the pain that the patient experienced subsequent to each surgical intervention. This information will give important insights to the original etiology of the back pain and help to direct nonoperative therapies that might be of benefit. Physical Therapy and Rehabilitation All patients with chronic disabling back pain should be referred for physical therapy and rehabilitation regardless of other concordant therapies. Physical therapy is

important for strengthening, increasing flexibility, and helping patients learn strategies to more efficiently and safely increase their activity. Reasonable exercise has been shown not only to be safe for patients with chronic back pain but to lead to reduction in pain magnitude of 10% to 50%. Lumbar Facet Denervation Among patients whose pain is consistent with lumbar facet joint disease, facet denervation can provide measurable relief. As facet joints degenerate with time, arthritis, or instability, they gradually endure more stress and wear. This is often noticeable on diagnostic imaging where one or both facet joints demonstrate hypertrophy. These enlarged facets may cause stenosis of the lateral recess of the spinal canal and the neural foramen that contributes to radiculopathy from nerve root compression. In other cases, no radiculopathy is present, but instead severe axial back pain with radiation to the flank and hip. If this pain is worst with standing and lumbar extension, it may be that irritation of the nerves of the affected facet joints is responsible for the offending pain. When appropriately used, radiofrequency ablation of the median nerve of the facet can provide 45% to 50% of patients at least a 50% reduction in pain. Spinal Cord Stimulation Spinal cord stimulation provides pain relief by confusing the pain signaling pathways. A stimulator electrode placed over the dorsal columns of the spinal cord causes a mild vibratory sense over the dermatomes it stimulates. When targeted to the region afflicted by pain, a discomforting sensation can be overwhelmed by the vibrating sensation triggered by the stimulator. In this fashion, a constant unbearable sensation is replaced by a pleasing tingling sensation. Stimulator electrodes are designed in such a fashion that selected contact points along the electrode surface may have varying intensity. This allows the effect of the stimulator to be targeted to specific regions of the spinal cord and for the intensity of that effect to be modulated selectively. To ensure that a spinal cord stimulator will be worthwhile and to identify the ideal settings for the stimulator, surgeons conduct a temporary trial of stimulation prior to implanting it permanently. The trial uses a percutaneously placed epidural electrode that is then attached to an external computer. Over the course of the next few days, the patient is able to modulate the stimulator intensities and stimulation pattern. If an efficacious and tolerable combination arises, the surgeon then implants a permanent system. If the patient does not experience any benefit from the temporary stimulator, the electrode is simply removed and no surgery is necessary. Although this technique works best for lower extremity pain, there are many clinical series that report success with the treatment of axial back pain. Again, with careful selection, most patients receive significant pain relief from spinal cord stimulation, and as many as 78% would have the procedure again and recommend it
Johnson: Current Therapy in Neurologic Disease (7/E)

Cervical Spondylosis

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to another patient. Spinal cord stimulation is an increasingly valuable long-term solution for chronic low back pain. Implantable Drug Pumps Intrathecal or epidural administration of opioids and other pharmaceuticals has been used in the treatment of chronic low back pain with mixed success. Although the use of intrathecal drug therapy has been shown to be cost effective in the long term, patient satisfaction has been erratic from one study to the next. Most studies of implantable drug delivery are retrospective and most success has been anecdotal. Further investigation is necessary to establish which patients with failed back syndrome are most likely to benefit from this therapy.

neurosurgeons, a thoughtful methodical evaluation and treatment plan may provide benefit and ensure that all that can be done is offered for these patients. SUGGESTED READING
Kumar K, Hunter G, Demeria DD: Treatment of chronic pain by using intrathecal drug therapy compared with conventional pain therapies: a cost-effectiveness analysis, J Neurosurg 97:803-810, 2002. Loubser PG, Akman NM: Effects of intrathecal baclofen on chronic spinal cord injury pain, J Pain Symptom Manage 12:241-247, 1996. North RB, Han M, Zahurak M, Kidd DH: Radiofrequency lumbar facet denervation: analysis of prognostic factors, Pain 57:77-83, 1994. North RB, Wetzel FT: Spinal cord stimulation for chronic pain of spinal origin: a valuable long-term solution, Spine 27:2584-2591, 2002. Ohnmeiss DD, Rashbaum RF: Patient satisfaction with spinal cord stimulation for predominant complaints of chronic, intractable low back pain, Spine J 1:358-363, 2001. Rainville J, Hartigan C, Martinez E, et al: Exercise as a treatment for chronic low back pain, Spine J 4:106-115, 2004. Royal M, Wienecke G, Movva V, et al: Retrospective study of efficacy of radiofrequency neurolysis for facet arthropathy, Pain Med 2:249-250, 2001. Schwarz J, Naff N: The management of neuropathic pain, Neurosurg Clin North Am 15:231-239, 2004. van Kleef M, Barendse GA, Kessels A, et al: Randomized trial of radiofrequency lumbar facet denervation for chronic low back pain, Spine 24:1937-1942, 1999. Yoshida GM, Nelson RW, Capen DA, et al: Evaluation of continuous intraspinal narcotic analgesia for chronic pain from benign causes, Am J Orthop 25:693-694, 1996.

Conclusions
Failed back syndrome is an all-too-common problem that is disabling, demoralizing, and disruptive to a patients quality of life. A careful history of the patients initial presentation and review of the initial diagnostic studies are necessary to determine the pathology that led to the initial symptoms. Every attempt should be made to identify the initial source of the pain, and if it is determined that the initial intervention was not indicated, appropriate treatment should be offered. This may require investigation and treatment for hip pathology, vascular disease, or peripheral neuropathy. If it is determined that the patient did have a surgically remediable problem, then it must be determined if the surgical intervention adequately treated that problem. If the wrong surgical intervention was chosen initially, the best course would be to offer the patient the appropriate surgical intervention. A frequent example of this situation is the use of lumbar laminectomy for back pain when facet joint injections or median facet nerve rhizotomy would be more appropriate. If the correct surgical intervention was performed initially, then it must be determined if that intervention adequately treated the offending pathology. If the initial procedure did not adequately treat the offending pathology, then a second attempt at the same procedure would likely be the most appropriate treatment. A frequent example of this situation would be residual disk herniation or foraminal stenosis compressing a nerve root. A repeat diskectomy or foraminotomy in this situation has a high likelihood of success. If it is determined that the initial operation was indicated and that there is no residual pathology that is surgically remediable, it is then advisable that the patient pursue a comprehensive pain management program under the direction of a physician with experience in chronic pain management. A frequent example of this last situation is patients with radiculitis from pathologic or iatrogenic intrinsic nerve root injury. If these patients are inadequately treated by pharmaceutical pain management strategies, they may be ideal candidates for spinal cord stimulation or implantable morphine pumps. Although failed back syndrome is one of the more frustrating problems that confronts neurologists and
Johnson: Current Therapy in Neurologic Disease (7/E)

CERVICAL SPONDYLOSIS
Erick Scott, M.D., and Douglas Kerr, M.D., Ph.D.
Cervical spondylosis is defined as a degenerative condition compromising the spinal canal. It is an inevitable consequence of aging and is present in more than 90% of individuals older than 65 years of age. As such, it is a natural consequence of a bipedal existence and is not a disease state. However, this degenerative process may cause symptoms in up to 10% to 15% of the population and therefore is among the most common causes of patient visits to health care providers. Cervical spondylosis may cause symptoms of neck pain and restricted movement due to mechanical limitation, radicular pain and paresthesias due to compression of nerve roots, or myelopathic symptoms due to compression of the spinal cord itself. This chapter reviews the most recent advances in the diagnosis and treatment of cervical spondylosis.

Definition and Clinical Manifestations


Cervical spondylosis may cause one of three syndromes: radiculopathy, myelopathy, or mechanical neck pain. Radiculopathy is due to nerve root compression, usually from the progressive narrowing of a neural foramen, caused by hypertrophic bony changes in the anterior

Cervical Spondylosis

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Pain

to another patient. Spinal cord stimulation is an increasingly valuable long-term solution for chronic low back pain. Implantable Drug Pumps Intrathecal or epidural administration of opioids and other pharmaceuticals has been used in the treatment of chronic low back pain with mixed success. Although the use of intrathecal drug therapy has been shown to be cost effective in the long term, patient satisfaction has been erratic from one study to the next. Most studies of implantable drug delivery are retrospective and most success has been anecdotal. Further investigation is necessary to establish which patients with failed back syndrome are most likely to benefit from this therapy.

neurosurgeons, a thoughtful methodical evaluation and treatment plan may provide benefit and ensure that all that can be done is offered for these patients. SUGGESTED READING
Kumar K, Hunter G, Demeria DD: Treatment of chronic pain by using intrathecal drug therapy compared with conventional pain therapies: a cost-effectiveness analysis, J Neurosurg 97:803-810, 2002. Loubser PG, Akman NM: Effects of intrathecal baclofen on chronic spinal cord injury pain, J Pain Symptom Manage 12:241-247, 1996. North RB, Han M, Zahurak M, Kidd DH: Radiofrequency lumbar facet denervation: analysis of prognostic factors, Pain 57:77-83, 1994. North RB, Wetzel FT: Spinal cord stimulation for chronic pain of spinal origin: a valuable long-term solution, Spine 27:2584-2591, 2002. Ohnmeiss DD, Rashbaum RF: Patient satisfaction with spinal cord stimulation for predominant complaints of chronic, intractable low back pain, Spine J 1:358-363, 2001. Rainville J, Hartigan C, Martinez E, et al: Exercise as a treatment for chronic low back pain, Spine J 4:106-115, 2004. Royal M, Wienecke G, Movva V, et al: Retrospective study of efficacy of radiofrequency neurolysis for facet arthropathy, Pain Med 2:249-250, 2001. Schwarz J, Naff N: The management of neuropathic pain, Neurosurg Clin North Am 15:231-239, 2004. van Kleef M, Barendse GA, Kessels A, et al: Randomized trial of radiofrequency lumbar facet denervation for chronic low back pain, Spine 24:1937-1942, 1999. Yoshida GM, Nelson RW, Capen DA, et al: Evaluation of continuous intraspinal narcotic analgesia for chronic pain from benign causes, Am J Orthop 25:693-694, 1996.

Conclusions
Failed back syndrome is an all-too-common problem that is disabling, demoralizing, and disruptive to a patients quality of life. A careful history of the patients initial presentation and review of the initial diagnostic studies are necessary to determine the pathology that led to the initial symptoms. Every attempt should be made to identify the initial source of the pain, and if it is determined that the initial intervention was not indicated, appropriate treatment should be offered. This may require investigation and treatment for hip pathology, vascular disease, or peripheral neuropathy. If it is determined that the patient did have a surgically remediable problem, then it must be determined if the surgical intervention adequately treated that problem. If the wrong surgical intervention was chosen initially, the best course would be to offer the patient the appropriate surgical intervention. A frequent example of this situation is the use of lumbar laminectomy for back pain when facet joint injections or median facet nerve rhizotomy would be more appropriate. If the correct surgical intervention was performed initially, then it must be determined if that intervention adequately treated the offending pathology. If the initial procedure did not adequately treat the offending pathology, then a second attempt at the same procedure would likely be the most appropriate treatment. A frequent example of this situation would be residual disk herniation or foraminal stenosis compressing a nerve root. A repeat diskectomy or foraminotomy in this situation has a high likelihood of success. If it is determined that the initial operation was indicated and that there is no residual pathology that is surgically remediable, it is then advisable that the patient pursue a comprehensive pain management program under the direction of a physician with experience in chronic pain management. A frequent example of this last situation is patients with radiculitis from pathologic or iatrogenic intrinsic nerve root injury. If these patients are inadequately treated by pharmaceutical pain management strategies, they may be ideal candidates for spinal cord stimulation or implantable morphine pumps. Although failed back syndrome is one of the more frustrating problems that confronts neurologists and
Johnson: Current Therapy in Neurologic Disease (7/E)

CERVICAL SPONDYLOSIS
Erick Scott, M.D., and Douglas Kerr, M.D., Ph.D.
Cervical spondylosis is defined as a degenerative condition compromising the spinal canal. It is an inevitable consequence of aging and is present in more than 90% of individuals older than 65 years of age. As such, it is a natural consequence of a bipedal existence and is not a disease state. However, this degenerative process may cause symptoms in up to 10% to 15% of the population and therefore is among the most common causes of patient visits to health care providers. Cervical spondylosis may cause symptoms of neck pain and restricted movement due to mechanical limitation, radicular pain and paresthesias due to compression of nerve roots, or myelopathic symptoms due to compression of the spinal cord itself. This chapter reviews the most recent advances in the diagnosis and treatment of cervical spondylosis.

Definition and Clinical Manifestations


Cervical spondylosis may cause one of three syndromes: radiculopathy, myelopathy, or mechanical neck pain. Radiculopathy is due to nerve root compression, usually from the progressive narrowing of a neural foramen, caused by hypertrophic bony changes in the anterior

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Cervical Spondylosis

wall. Although the foraminal compromise is gradual, symptoms may be of sudden onset, often precipitated by a particular event such as a motor vehicle accident, a fall, or an exercise-induced injury. It is likely that the sudden nature of symptom onset is due to microtrauma, stretching or tethering of a nerve root, or inflammation within an already compromised neural foramina. Symptoms usually consist of neck pain and stiffness that evolve to include pain, paresthesias, numbness, and weakness in one arm. Neurologic examination usually reveals sensory loss and weakness in a nerve root distribution and may reveal an accompanying decrease in a deep tendon reflex (biceps reflex for C6 radiculopathy, triceps reflex for C7 radiculopathy). Cervical spondylitic myelopathy results from compression of the spinal cord, anteriorly by bony structures of the vertebral body and facets, or posteriorly by ligamentum flavum hypertrophy. Symptoms usually progress insidiously and can often be present for years prior to seeking medical attention. Occasionally, a relatively minor trauma, such as a hyperextension injury from a fall or a motor vehicle accident, precipitates sudden and severe myelopathic symptoms. Symptoms usually consist of gait difficulty and stiffness. Gait dysfunction may result from abnormal proprioceptive input due to compression of ascending sensory pathways or may be due to evolving spasticity due to compression of descending motor pathways. Bowel and bladder involvement, usually consisting of urgency, is associated with inconsistent symptoms and, if present, suggests a more advanced myelopathy. Examination findings usually consist of spasticity, hyperreflexia, and Babinskis response. Since cervical spondylitic myelopathy typically affects C6 or C7, there may be relative sparing of arm function and there may be a discord between the reflexes and tone of the upper and lower extremities. Mechanical pain due to cervical spondylosis is the most common of the three syndromes, though it is the least clearly understood and defined. In part, this is because there is poor correlation between radiologically defined spondylosis and neck pain. Also, there is no examination finding (e.g., paraspinalis spasm, limitation of neck motion or reflex asymmetry) that defines this syndrome. Typically, patients describe localized pain in the neck without radiation and often limitation in range of motion of the neck or clicks during neck movement. The pain itself likely comes from a variety of sources: new bone generation in the facets or vertebral bodies, myofascial changes, muscular spasm or the degenerating disk (diskogenic pain).

Stage 3: bridging osteophytes with immobilization of the involved segment Stage 4: compression of the spinal cord Recent studies have suggested that the dynamic nature of the cervical spinal cord is an important predictor of disability and that flexion and extension studies must be incorporated into this scheme. Magnetic resonance imaging (MRI) studies and plain radiographs done in the neutral position often do not effectively define spinal canal compromise in either the flexed or extended positions. In this study, 27% of patients in the extended position and 5% of patients in the flexed position experienced worsened spinal canal compromise compared to a neutral-position MRI. Therefore, we recommend a dynamic MRI or computed tomography (CT) myelogram to accurately evaluate cervical spondylosis.

Pathophysiology of Cervical Spondylosis


Cervical spondylosis occurs in response to dehydration or degeneration of intervertebral disks that begins in young adulthood. As a result of this degeneration, adjacent bony structures acquire new stresses as the spinal column is subjected to the dynamic movement of normal life. The disks themselves become less capable of load bearing and transfer this load to facet joints and vertebral bodies. In places where the degeneration is most advanced, adjacent bony structures contact each other, generating new bone. This results in osteophytes, bony ridges, and spurs. Additionally, the ligamentum flavum hypertrophies posterior to the spinal cord. The consequence is narrowing of the spinal canal with impingement of nerve roots or the spinal cord. If the spinal cord is compressed, myelopathic symptoms develop. If nerve roots are compressed, radicular symptoms develop. Pain may be a prominent symptom of cervical spondylosis even in the absence of neural compromise due to mechanical dysfunction.

Pathophysiology of Spondylitic Myelopathy


In some cases of spondylitic myelopathy, a dynamic compression of the spinal cord occurs. During flexion or extension of the spinal cord, a spondylitic spur compresses the spinal cord, resulting either in a direct contusion or in impaired venous drainage out of the spinal cord. Many patients demonstrate a central, high T2-weighted signal intensity on MRI. Recent studies have demonstrated that this central spinal cord abnormality represents cystic necrosis resulting from venous hypertension. Venous drainage of the spinal cord occurs via both intrinsic and extrinsic spinal cord veins. The intrinsic spinal cord veins consist of an anterior median group and a radial group. Blood in the anterior third of the spinal cord drains to the segmental central vein, then to the longitudinally oriented anterior median spinal vein, which lies on the pial surface of the spinal
Johnson: Current Therapy in Neurologic Disease (7/E)

Classification
Several classification schemes exist to quantify the degree of cervical spondylosis. These stages are defined as follows: Stage 1: diskogenic phase without osteophyte formation Stage 2: spondylosis with disk degeneration and osteophyte formation

Cervical Spondylosis

63
Pain

cord in the midline. The radial veins form in the peripheral gray matter or white matter and drain radially to the coronal plexus of veins on the pial surface. The anterior median spinal vein and the coronal plexus (termed the extrinsic venous drainage) are drained by the medullary veins that travel with nerve roots. Anterior medullary veins travel with the ventral roots, while posterior medullary veins travel with the dorsal roots. In the intervertebral foramen, a number of veins, including the anterior and posterior medullary veins, veins from the vertebral plexus, and the radicular veins, coalesce to form a plexus surrounding the spinal nerve. Appreciation of this anatomy is critical to understand how spondylitic myelopathy develops.

Diagnosis
The diagnosis of cervical spondylitic myelopathy or radiculopathy is dependent on the clinical symptoms confirmed by a detailed neurologic examination. The diagnosis of spondylitic radiculopathy can be confirmed by cervical spine radiographs. Oblique views, which are aimed to look down the neural foramina, demonstrate the encroachment by osteophytes from the anterior wall. Spiral CT scanning, especially with two-dimensional sagittal reconstructions, can also confirm foraminal stenosis. MRI images are less helpful in spondylitic radiculopathies. For spondylitic myelopathy, an MRI of the neck in neutral, extended, and flexed position is recommended (no gadolinium needed). If the anterior and posterior cerebrospinal fluid (CSF) spaces remain patent in all sequences, then conservative management is likely warranted. If the anterior and/or the posterior CSF space is impinged, especially if there is a pincer effect (anterior and posterior compression at nearby levels), then neurosurgical consultation is warranted. Cord signal change necessitates urgent neurosurgical referral.

symptoms. In a recent study, only 20% of patients experienced significant relief of symptoms. Mechanical pain from cervical spondylosis should be treated by heating pads and by stretching range-ofmotion exercises. Most patients respond well to no-no stretching of the neck for five seconds at each limit; yes-yes stretching of the neck for 5 seconds at each limit; and ear-to shoulder stretching of the neck for 5 seconds at each limit. Chiropractic therapy is often used by patients with cervical spondylosis, though there are no controlled studies that warrant this approach. Recent uncontrolled reports suggest that chiropractic manipulations may be beneficial. However, though chiropractic manipulation may be appropriate for uncomplicated mechanical pain associated with cervical spondylosis, chiropractic manipulations are not recommended for either radicular or myelopathic symptoms and may cause adverse outcomes in such patients. Shiatsu (deep massage) and acupuncture therapies are often employed by patients with anecdotally excellent response and little risk. SURGICAL APPROACH Patients with spondylitic myelopathy or radiculopathy are often offered surgical treatment that typically consists of either anterior cervical decompressions with fusion and/or instrumentation or posterior cervical laminectomy or laminoplasty. The data to support surgical intervention remain mixed. In a nonrandomized, prospective study of patients with cervical spondylitic myelopathy, surgically treated patients had a significant improvement in functional status and pain, whereas medically treated patients were worse in these areas. In a separate report, cervical laminectomy or laminoplasty was successfully used to decrease symptoms in patients with spondylitic myelopathy. Although patients younger than 65 years of age did well in the short term, they had significant deterioration between 3 and 10 years after surgery. A randomized study designed to define whether patients with mild-to-moderate spondylitic myelopathy did better with conservative or surgical treatment revealed no clear difference between the groups at 3 years follow-up. A recent Cochrane review suggested that there was not sufficient evidence from controlled trials to support surgical treatment of patients with spondylitic radiculopathy or myelopathy. Patients with persistent cord signal change after surgery had worse outcomes. T1-weighted hypointensities predicted a worse outcome.

Treatment
CONSERVATIVE MANAGEMENT For spondylitic radiculopathy, conservative measures should be attempted first. Simple soft collar immobilization often is helpful because it decreases repetitive motion and microtrauma that have precipitated the symptoms. The most effective method is the use of over-the-door cervical traction. Patients can do this at home with the use of a head halter attached to a rope that passes through a pulley set over the top of a door and is connected to a water bag for weight (5 to 10 lb). Patients should sit facing the door (to avoid hyperextension) for 30 minutes twice a day. Nonsteroidal anti-inflammatory agents and localized massage should also be employed in patients with spondylitic radiculopathy. Patients often are offered selective nerve root block for spondylitic radiculopathy. However, this approach usually results in only temporary improvement in
Johnson: Current Therapy in Neurologic Disease (7/E)

Outcomes
Although the outcomes from cervical spondylosis vary and the treatment of choice remains uncertain, the following guidelines apply: Patients with mechanical pain from spondylosis should have conservative therapy as defined earlier. Patients with spondylitic radiculopathy should be given conservative therapy, including cervical traction and

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Complex Regional Pain Syndromes

soft collar immobilization, and only later should be offered a surgical treatment. Patients with rapidly progressive spondylitic myelopathy and a clearly defined compressive etiology (either direct compression or impaired venous drainage) should be rapidly offered surgical decompression. The optimal surgical technique (laminectomy, laminoplasty, or anterior decompression with fusion/instrumentation) depends on the dynamic compressive states present. Long-term consequences of surgery remain unknown and depend on the degree of destabilization/compression of other segments of the spinal column. SUGGESTED READING
Epstein NE: Laminectomy for cervical myelopathy, Spinal Cord 41:317-327, 2003. Fouyas IP, Statham PF, Sandercock PA: Cochrane review on the role of surgery in cervical spondylitic radiculomyelopathy, Spine 27:736-747, 2002. Gillilan LA: Veins of the spinal cord: anatomic details, suggested clinical applications, Neurology 20:860-868, 1970. Handal JA, Knapp J Poletti S. The structural degenerative cascade: the cervical spine, 1995. Kirkaldy-Willis WH, Bernard TN, editors: Managing low back pain, ed 4, Philadelphia, 1999, Churchill-Livingstone. Kukurin GW: The amelioration of symptoms in cervical spinal stenosis with spinal cord deformation through specific chiropractic manipulation: a case report with long-term follow-up, J Manipulative Physiol Ther 27:E7, 2004. Mizuno J, Nakagawa H, Inoue T, Hashizume Y: Clinicopathological study of snake-eye appearance in compressive myelopathy of the cervical spinal cord, J Neurosurg 99(Suppl):162-168, 2003. Muhle C, Metzner J, Weinert D, et al: Classification system based on kinematic MR imaging in cervical spondylitic myelopathy, AJNR Am J Neuroradiol 19:1763-1771, 1998. Sampath P, Bendebba M, Davis JD, Ducker TB: Outcome of patients treated for cervical myelopathy: a prospective, multicenter study with independent clinical review, Spine 25:670-676, 2000. Slipman CW, Lipetz JS, DePalma MJ, Jackson HB: Therapeutic selective nerve root block in the nonsurgical treatment of traumatically induced cervical spondylitic radicular pain, Am J Physical Med Rehabil 83:446-454, 2004.

associated with nonspecific symptoms and signs such as altered skin color, temperature, or sudomotor activity, allodynia, disuse atrophy, or edema; and, in contrast with CRPS type 2 (formerly called causalgia), occurs in a distribution different from that resulting from injury to a single peripheral nerve. In many cases CRPS syndromes resolve over weeks or months. Even so, the unexpected finding of persistent, worsening pain, often after seemingly minor trauma or brief limb immobilization, poses a significant psychological challenge that the clinician must keep in mind from the beginning of treatment to avoid a vicious circle of pain, distress, guarding, muscle atrophy, and increased pain susceptibility. At all stages of treatment (Figure 1), effective management of CRPS depends on a threepronged approachrehabilitation, psychological support, and medicinal agentsprobably in descending order of importance. The cornerstone of management of CRPS is physical and occupational therapy. Improvement often requires a closely supervised program of continued and increasing activity of the affected limb, while the patient is under the influence of an analgesic if necessary. In additional to active exercise of the limb, physical therapy approaches can include desensitization, where progressively coarser objects are rubbed across the skin of the affected limb; spinal manipulation; myofascial

CRPS Physical therapy (e.g., active mobilization, desensitization, myofascial release) NSAID Lidocaine patch/capsaicin (local only) Corticosteroids (early only)

Resolved

Unresolved Sympathetically maintained?

Yes Sympatholytic trial e.g., clonidine, terazosin, tizanidine

No Gabapentin Opiate Mexiletine (if acute benefit from i.v. lidocaine)

Complex Regional Pain Syndromes


David S. Goldstein, M.D., Ph.D.

Resolved

Unresolved

Resolved

Unresolved

Opiate tricyclic

Resolved

Unresolved Spinal cord stimulation trial

Complex regional pain syndromes (CRPSs) come under the classification of neuropathic pain, along with entities such as postherpetic neuralgia and painful diabetic neuropathy. Distinguishing characteristics of CRPS are onset after physical trauma or limb immobilization and spread of involvement. CRPS type 1, formerly called reflex sympathetic dystrophy, refers to post-traumatic pain that spreads from the site of injury; exceeds in magnitude and duration the expected clinical course of the inciting event; progresses variably over time; is

Acute improvement Spinal cord stimulator

Unresolved

FIGURE 1. Treatment algorithm for complex regional pain syndromes. CRPS, Complex regional pain syndrome; NSAID, nonsteroidal anti-inflammatory drug; i.v., intravenous. Johnson: Current Therapy in Neurologic Disease (7/E)

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Complex Regional Pain Syndromes

soft collar immobilization, and only later should be offered a surgical treatment. Patients with rapidly progressive spondylitic myelopathy and a clearly defined compressive etiology (either direct compression or impaired venous drainage) should be rapidly offered surgical decompression. The optimal surgical technique (laminectomy, laminoplasty, or anterior decompression with fusion/instrumentation) depends on the dynamic compressive states present. Long-term consequences of surgery remain unknown and depend on the degree of destabilization/compression of other segments of the spinal column. SUGGESTED READING
Epstein NE: Laminectomy for cervical myelopathy, Spinal Cord 41:317-327, 2003. Fouyas IP, Statham PF, Sandercock PA: Cochrane review on the role of surgery in cervical spondylitic radiculomyelopathy, Spine 27:736-747, 2002. Gillilan LA: Veins of the spinal cord: anatomic details, suggested clinical applications, Neurology 20:860-868, 1970. Handal JA, Knapp J Poletti S. The structural degenerative cascade: the cervical spine, 1995. Kirkaldy-Willis WH, Bernard TN, editors: Managing low back pain, ed 4, Philadelphia, 1999, Churchill-Livingstone. Kukurin GW: The amelioration of symptoms in cervical spinal stenosis with spinal cord deformation through specific chiropractic manipulation: a case report with long-term follow-up, J Manipulative Physiol Ther 27:E7, 2004. Mizuno J, Nakagawa H, Inoue T, Hashizume Y: Clinicopathological study of snake-eye appearance in compressive myelopathy of the cervical spinal cord, J Neurosurg 99(Suppl):162-168, 2003. Muhle C, Metzner J, Weinert D, et al: Classification system based on kinematic MR imaging in cervical spondylitic myelopathy, AJNR Am J Neuroradiol 19:1763-1771, 1998. Sampath P, Bendebba M, Davis JD, Ducker TB: Outcome of patients treated for cervical myelopathy: a prospective, multicenter study with independent clinical review, Spine 25:670-676, 2000. Slipman CW, Lipetz JS, DePalma MJ, Jackson HB: Therapeutic selective nerve root block in the nonsurgical treatment of traumatically induced cervical spondylitic radicular pain, Am J Physical Med Rehabil 83:446-454, 2004.

associated with nonspecific symptoms and signs such as altered skin color, temperature, or sudomotor activity, allodynia, disuse atrophy, or edema; and, in contrast with CRPS type 2 (formerly called causalgia), occurs in a distribution different from that resulting from injury to a single peripheral nerve. In many cases CRPS syndromes resolve over weeks or months. Even so, the unexpected finding of persistent, worsening pain, often after seemingly minor trauma or brief limb immobilization, poses a significant psychological challenge that the clinician must keep in mind from the beginning of treatment to avoid a vicious circle of pain, distress, guarding, muscle atrophy, and increased pain susceptibility. At all stages of treatment (Figure 1), effective management of CRPS depends on a threepronged approachrehabilitation, psychological support, and medicinal agentsprobably in descending order of importance. The cornerstone of management of CRPS is physical and occupational therapy. Improvement often requires a closely supervised program of continued and increasing activity of the affected limb, while the patient is under the influence of an analgesic if necessary. In additional to active exercise of the limb, physical therapy approaches can include desensitization, where progressively coarser objects are rubbed across the skin of the affected limb; spinal manipulation; myofascial

CRPS Physical therapy (e.g., active mobilization, desensitization, myofascial release) NSAID Lidocaine patch/capsaicin (local only) Corticosteroids (early only)

Resolved

Unresolved Sympathetically maintained?

Yes Sympatholytic trial e.g., clonidine, terazosin, tizanidine

No Gabapentin Opiate Mexiletine (if acute benefit from i.v. lidocaine)

Complex Regional Pain Syndromes


David S. Goldstein, M.D., Ph.D.

Resolved

Unresolved

Resolved

Unresolved

Opiate tricyclic

Resolved

Unresolved Spinal cord stimulation trial

Complex regional pain syndromes (CRPSs) come under the classification of neuropathic pain, along with entities such as postherpetic neuralgia and painful diabetic neuropathy. Distinguishing characteristics of CRPS are onset after physical trauma or limb immobilization and spread of involvement. CRPS type 1, formerly called reflex sympathetic dystrophy, refers to post-traumatic pain that spreads from the site of injury; exceeds in magnitude and duration the expected clinical course of the inciting event; progresses variably over time; is

Acute improvement Spinal cord stimulator

Unresolved

FIGURE 1. Treatment algorithm for complex regional pain syndromes. CRPS, Complex regional pain syndrome; NSAID, nonsteroidal anti-inflammatory drug; i.v., intravenous. Johnson: Current Therapy in Neurologic Disease (7/E)

Complex Regional Pain Syndromes

65
Pain

release; and massage with moist heat. It is important to emphasize to the patient that physical therapy, while painful, does not worsen the injury. The distress associated with prolonged, painful treatment can exacerbate comorbid depression or anxiety; supportive psychological counseling and psychiatric drug treatments may be essential for the patient to cope with the condition and continue the rehabilitation. Psychological treatments such as relaxation, imagery, self-hypnosis, cognitive behavioral therapy, and biofeedback may help. Throughout treatment the patient should be reassured that the condition does not progress to a neurodegenerative or lethal disease and that most people with CRPS improve if they adhere to the rehabilitation program. For local pain and allodynia, topical lidocaine can be effective. Capsaicin, the alkaloid that makes red chili peppers hot, stimulates transient receptor potential vanilloid (TRPV1)-1 receptors on cutaneous nociceptor C-fibers. It is thought that prolonged stimulation of the TRPV-1 receptors suppresses hyperactive nociceptors to alleviate pain without loss of sensation. Although accepted treatment for other neuropathic painful conditions, capsaicin has not yet been established as effective for CRPS. Patients may find the burning sensation produced by capsaicin to be unacceptable. Mysteriously, the pain in CRPS can spread to the opposite limb or the ipsilateral other limb, which were not traumatized. Spread of pain over a relatively large area at sites distant from that of trauma mitigates benefits of local treatments such as with topical lidocaine or capsaicin. Chronic CRPS syndromes constitute miserable, frustrating disordersfor patients and clinicians. Pathophysiologic bases for the pain remain unclear; and since CRPS is a relatively rare consequence of physical trauma, the trauma itself might interact importantly with as yet unidentified predisposing or reactive factors. Recent reviews have emphasized traumatic sympathetic denervation, followed subacutely or chronically by secondary pathologic responses such as aberrant sprouting of regenerant sympathetic nerves. A variable proportion of patients with CRPS have sympathetically maintained pain, where the pain improves temporarily with local stellate ganglion block for an upper limb or lumbar sympathetic block for a lower limb; intravenous (IV) infusion or local injection of the alpha-adrenoceptor blocker, phentolamine; or IV infusion of the ganglion blocker trimethaphan. The finding of sympathetically maintained pain rationalizes a trial of a sympatholytic drug such as clonidine or tizanidine. These alpha2-adrenoceptor agonists act in the brain to decrease sympathetic nervous system outflows and also act at alpha2-adrenoceptors on sympathetic nerves to inhibit release of the sympathetic neurotransmitter, norepinephrine, for a given amount of sympathetic nerve traffic. The main limitation of treatment with alpha2-adrenoceptor agonists is sedation. Alpha1-adrenoceptor blockers such as terazosin may also be tried; however, these can produce substantial orthostatic intolerance or hypotension, headache, flushing, and reflexive tachycardia.
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Even in patients with repeated, temporary improvement with ganglion blocks, surgical sympathectomy does not necessarily guarantee long-term pain relief. On the contrary, patients can fail to obtain relief, the pain can recur months or years later, and the pain can spread to other limbs and body regions. By the time of establishment of chronic CRPS, mechanisms relatively independent of postganglionic sympathetic nerve traffic maintain the pain in most patients. In patients without sympathetically maintained pain, the anticonvulsant gabapentin (Neurontin) has become a first-line drug. Gabapentin can be effective to treat postherpetic neuralgia and painful diabetic neuropathy, and some uncontrolled studies have touted its value to treat CRPS. The drug has a relatively low toxicity profile, but there is a wide range of employed dosages, and no randomized, placebo-controlled trial of gabapentin for CRPS has been published yet. The same lack of controlled trials obtains for retrograde local IV injection of sympatholytic drugs, periganglionic injection of local anesthetics, systemically administered alpha-adrenoceptor antagonists, clonidine, tricyclic antidepressants, selective serotonin reuptake inhibitors, other antiepileptic drugs, ganglion blockers, mexiletine (the oral analog of lidocaine), and surgical sympathectomy; studies of these treatments have yielded disappointingly inconsistent results. Tricyclic antidepressants are often tried in CRPS. They not only can relieve pain but also can exert other beneficial effects, such as improving sleep and inducing sedation. Clinical use of tricyclics is often limited by orthostatic intolerance, dry mouth, constipation, or decreased concentration. There is recent interest in serotonin-norepinephrine reuptake inhibitors such as duloxetine in neuropathic pain, but no data are available for CRPS. Most patients with severe, chronic CRPS receive treatment with some type of opiate. Even with highdose opiate treatment, the pain, while more bearable, rarely disappears. Treatment on a continuous rather than an as-needed basis is preferred, and so long-acting agents are used, such as sustained-release oxycodone (Oxycontin), sustained-release morphine (MS Contin), methadone, and a transdermal fentanyl patch (Duragesic). Most authorities now believe that, in the absence of a history of substance abuse, neither tolerance nor addiction is an issue when opiates are prescribed for CRPS. Calcium channel blockers, beta-adrenoceptor blockers, or classic anticonvulsants are not recommended, because of lack of positive clinical experiences and frequent intolerable side effects. Stimulation of the dorsal spinal cord, via an electrode placed in the epidural space, constitutes a different treatment strategy, based on interference with transmission of impulses from the nociceptors. This approach has been used for many years in other painful conditions. A variety of ascending and descending pain pathways converge in or near the dorsal spinal cord, including a descending inhibitory noradrenergic pathway from the pontine locus ceruleus. Exactly how spinal cord stimulation relieves pain remains unclear,

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Complex Regional Pain Syndromes

and several possible mechanisms are not mutually exclusive. Previous studies have reported positive results of dorsal spinal cord stimulation in alleviating pain in CRPS, especially in patients with successful trial stimulation. A recent report provides reassuring information about the long-term efficacy of spinal cord stimulation. Briefly, in a 2-year follow-up study of a randomized, controlled trial of spinal cord stimulation with physical therapy versus physical therapy alone in patients in whom conventional treatment had failed but who had had a successful test stimulation, there was long-term improvement in pain and health-related quality of life, although functional status did not change. The results confirmed and extended those from a previously reported trial that lasted 6 months. Spinal cord stimulation, therefore, seems to be an effective long-term treatment for CRPS, in patients in whom a trial stimulation alleviates the pain.

SUGGESTED READING
Backonja MM: Anticonvulsants (antineuropathics) for neuropathic pain syndromes, Clin J Pain 16:S67-S72, 2000. Davis KD, Treede RD, Raja SN, et al: Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain, Pain 47:309-317, 1991. Drummond PD: Mechanism of complex regional pain syndrome: no longer excessive sympathetic outflow? Lancet 358:168-170, 2001. Hord ED, Cohen SP, Cosgrove GR, et al: The predictive value of sympathetic block for the success of spinal cord stimulation, Neurosurgery 53:626-632, 2003; discussion 632-633. Kemler MA, De Vet HC, Barendse GA, et al: The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years follow-up of the randomized controlled trial, Ann Neurol 55:13-18, 2004. Kingery WS: A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes, Pain 73:123-139, 1997. Kumar K, Nath RK, Toth C: Spinal cord stimulation is effective in the management of reflex sympathetic dystrophy, Neurosurgery 40:503-508, 1997; discussion 508-509. Oakley JC, Prager JP: Spinal cord stimulation: mechanisms of action, Spine 27:2574-2583, 2002.

Johnson: Current Therapy in Neurologic Disease (7/E)

SECTION 4

Headache and Facial Pain


Migraine and Cluster Headache
B. Todd Troost, M.D.
effort must be made to reduce the intake of all analgesic medication. I usually start out with a request that there be a 10% reduction each week, up to 6 weeks, when the medication is to be discontinued entirely. During this time, I prescribe a preventive therapy such as that discussed later. If patients have more than two headaches per month or are not responding well to simple analgesics, I begin one of the triptrans (Table 3). The usual dosing of triptans is one as soon as possible during the onset of a migraine attack, followed by a second, if needed, in 2 hours. The nature of the attack also makes a difference. If it is an entirely predictable migraine, a slow-onset triptan, such as frovatriptan, may be appropriate versus a faster occurring attack, when sumatriptan or rizatriptan may be the preferred triptan. Patients respond differently to the triptans, and if one does not work after two or three trials, it is appropriate to shift to another triptan. The triptans that I personally use most often are (1) eletriptan, 40 mg to repeat in 2 hours, and (2) sumatriptan, 100 mg to repeat in 2 hours. As an off-label use, if I find that patients are frequently needing a second dose, I may have them double-up on the initial dose of eletriptan and take 80 mg at the onset of the migraine. It is clear, from recent studies, that the earlier into an attack that a person takes a triptan, the more likely it is that the attack can be abolished along with cutaneous allodynia. Occasionally, patients with status migrainosus may require a variety of outpatient abortive procedures, as follows, and these are listed with doses: Valproate sodium injection (Depacon 500 mg and 50 mL saline) given intravenously (IV) over 5 minutes and repeated a single time in 1 hour. Dihydroergotamine (DHE) protocol in which patients are given, first, 10 mg of metoclopramide by slow IV push followed in 15 minutes by 0.5 mg of DHE, and this can be repeated in 1 hour. If this does not break the headache, the patient may need to be admitted for the standard IV DHE protocol. Another possibility that patients can try at home, before coming to the outpatient clinic or emergency department, is subcutaneous sumatriptan in a stat dose pack such as listed in Table 3. PREVENTIVE THERAPY The decision to use preventive therapy depends on the degree of disability and the frequency and the intensity 67

The classification of migraine and cluster headache is presented in the second edition of the International Headache Classification published in 2004 (see Suggested Reading).

Treatment of Migraine
ACUTE THERAPY A variety of acute medications may be prescribed for migraine, including the triptans, ergotamines, and analgesic medication. I avoid, as much as possible, the use of class II narcotics or excessive dependence on acetaminophen or nonsteroidal anti-inflammatory drugs. If a patient just has one headache per month that readily responds to an NSAID or two extra-strength acetaminophen, that may be sufficient. However, for more frequent acute migraine headaches, up to three per month, acute therapies may be used such as listed in Tables 1 and 2. The choice of acute treatment depends on the severity and frequency of headaches, the pattern of associated symptoms, comorbid illness, and the patient treatment response profile. The most simple treatment is with nonprescription or prescription analgesics. Most of the patients I see, however, are beyond the stage of one or two headaches per month and frequently present with chronic daily headache. I take a detailed history and attempt to verify it with a significant other of the number of analgesic medications the patient is taking. If patients are using analgesic medication more than twice a week, they tend to get rebound headache and transform their migraine into chronic daily headache. Therefore, it is imperative to determine how many extra-strength acetaminophen tablets, NSAIDs, or barbiturate-containing compounds the patient is actually consuming. Frequently, patients are taking more than 200 doses of analgesic medication per week. A determined
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Migraine and Cluster Headache

TABLE 1 Symptomatic Therapy for Migraine


Route of Administration PO PO PO, IM PO Suppository IM/IV PO Suppository PO IM IV PO PO PO

Drug NSAIDs Naproxen Ibuprofen Antiemetics* Promethazine Prochlorperazine Trimethobenzamide Metoclopramide Dimenhydrinate Mixed barbiturate analgesics Butalbital, aspirin or acetaminophen, and caffeine; butalbital and acetaminophen Narcotics (codeine-containing compounds, oxycodone, propoxyphene, meperidine)
*Given 10-20 min before ingestion of oral abortive migraine medication. NSAID, Nonsteroidal anti-inflammatory drug.

Dosage 550-750 mg with repeat in 1-2 hr; limit three times per wk 200-300 mg with repeat in 1-2 hr; limit three times per wk 50-125 mg/day 1-25 mg/day 2.5-25 mg/day 5-10 mg/day 250 mg/day 200 mg/day 5-10 mg/day 10 mg/day 5-10 mg slowly 50 mg 1 or 2 tablets q 4-6 hr; limit 4 tablets per day up to twice per wk Sparingly and infrequently, if at all, in patients with chronic headaches

of headaches in a given patient. My current regimens are listed in Table 4. Anticonvulsants I usually begin with topiramate 25 mg, increasing weekly up to 50 to 100 mg twice a day with careful monitoring of efficacy. The primary side effects are cognitive dysfunction (10% to 15%), weight loss, and paresthesias (usually mild and disappearing within a few weeks).

Rare complications include hair loss, dry eyes, kidney stones, and an idiopathic form of glaucoma occurring in roughly 8 patients per 1 million. The next anticonvulsant I prescribe is levetiracetam (Keppra), and with slow titration, as described in Table 5, the main side effect of drowsiness is avoided. Levetiracetam is an excellent anticonvulsant with no significant drug-drug interactions. It is weight neutral, and in one study we performed, we found that 70% of patients with chronic daily headache had some level of improvement.

TABLE 2 Abortive Therapy for Migraine


Route of Administration IM, SC, IV PO Sublingual Suppository PO PO IM

Drug Serotonin receptor agonists Dihydroergotamine Ergotamine derivatives Ergotamine and caffeine* Ergotamine* Ergotamine and caffeine* Sympathomimetic agents Isometheptene, acetaminophen, dichloralphenazone Corticosteroids Dexamethasone

Dosage 0.5-1 mL 2 tablets, repeat in 1 hr if necessary; limit 4 per attack 1 tablet (let dissolve), may repeat in 30 min; limit 2 per attack 1 /2-1 suppository, repeat in 1 hr if necessary; limit two doses 2 capsules, may repeat in 1 hr; limit three times per wk 2-6 mg; may repeat in 3 hr if necessary

*Wait 3 days between dosing with ergotamine in patients with frequent migraine or daily headache. For protracted migraine.

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Migraine and Cluster Headache

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Headache and Facial Pain

TABLE 3 Triptans
Trade Name Imitrex Amerge Zomig MaxAlt Frova Relpax Axert

TABLE 4 Migraine Preventive Therapy


Anticonvulsants Botulinum toxin type A injections Calcium channel blockers Beta blockers Methysergide Nonsteroidal anti-inflammatory drugs Lithium Antidepressants

Drug Sumatriptan Naratriptan Zolmitriptan Rizatriptan Frovatriptan Eletriptan Almotriptan

Dosage 25, 50, 100 mg PO 25 mg nasal spray and 6 mg SC 2.5 mg PO 2.5, 5 mg PO (oral melting tablet also available) 2.5 mg nasal spray 5, 10 mg PO (oral melting tablet also available) 2.5 mg PO 40 mg PO 12.5 mg PO

I use zonisamide at the dosage described in Table 5, lamotrigine, and gabapentin, in that order. I generally do not use divalproex sodium (Depakote) because of a significant tendency for weight gain, hair loss, and tremor. Botulinum Toxin Type A Mounting clinical evidence supports the use of botulinum type A (BoNT-A) in migraine and tension headache, particularly when there is a history or physical examination finding of neck muscle spasm. The discovery of the efficacy of BoNT-A in headache was serendipitous. Migraineurs who received BoNT-A injections for cosmetic reasons reported significant improvement in headache symptoms, and thereafter, an open-label multicenter trial suggested a high level of migraine relief. In prior studies, when we used a five-point categorical scale based on 1 = no effect to 5 = excellent improvement (90% reduction in headache) when we analyzed 436 patients, we found that most patients, who had previously failed three or more preventive pharmacologic therapies for migraine, had significant improvement after three or four injection cycles. Patients who were administered two treatments noted significantly greater improvement than those who were administered just a single treatment. We have now treated more than 650 patients with 2500 injection cycles and found that 75% to 80% reported improvement as good or excellent. It also

appeared that there was a major reduction of other analgesic medication on BoNT-A therapy. Therefore, we believe BoNT-A is a significantly promising treatment for the management of severe headache. Major placebo-controlled, double-blind studies are required to obtain U.S. Food and Drug Administration approval, and these are the results of the trials currently being analyzed. ADDITIONAL THERAPY Additional preventive therapies include calcium channel blockers and beta blockers (Table 6). For patients who have concurrent comorbidity such as Raynauds phenomenon, a calcium channel blocking drug may be efficacious. The dose can be gradually increased with verapamil or diltiazem as described in Table 6. Patients must be warned about the possibility of constipation (less with diltiazem) and should be evaluated for the possibility of cardiomyopathy or the history of congestive heart failure because these are both contraindications of the use of a calcium channel blocking drug. Beta blockers (see Table 6) such as propranolol and timolol have had the longest trial of preventive use; however, there is a significant incidence of depression in women, and I personally find the efficacy not as good as with the anticonvulsants. 4

Cluster Headache
The characteristics of cluster headache, now classified as one of the autonomic cephalalgias, is discussed in the International Headache Society publication listed in the Suggested Reading. Cluster headache is extremely

TABLE 5 Anticonvulsants for Migraine Therapy


Generic Name Topiramate Levetiracetam Zonisamide Lamotrigine Gabapentin Divalproex sodium Trade Name Topamax Keppra Zonegran Lamictal Neurontin Depakote Dosage 25 mg daily times 1 wk, increasing to 200 mg/day, average 100 mg/day 500 mg,1/2 qhs increased by 1/2 pill each week, to 11/2 pills bid, may increase up to 3000 mg 100 mg daily times 1 wk, then 200 mg/day, to be increased to 300 mg/day in single dose 25 mg, 2 tablets at night for 2 wk, then increase by 25 mg q 1-2 wk to 100-200 mg 100-300 mg, 1-3/day to 1200 mg 250 mg, 1 tablet tid to 1.5 gm/day

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TABLE 6 Additional Pharmacologic Migraine Therapy


Generic Name Calcium channel blockers Verapamil Diltiazem Beta blockers Propranolol Timolol Trade Name Inderal Cardizem Verelan Blocadren Dosage 120 mg/day, increasing to 600 mg/day 120 mg bid, increasing to 720 mg/day 10 mg tid, increasing to 180 mg/day 5 mg bid, increasing to 40 mg/day

difficult to treat. I use most of the standard preventive therapies such as calcium channel blocking drugs or anticonvulsants as initial starting therapy. Nasal oxygen (8 to 10 L/min) may be helpful at the start of a series of cluster headaches. However, I have found that most patients with recurrent cluster headache do not respond to these therapies and need to be treated with other agents such as methysergide (Sansert). The methysergide dosage should be 2 mg once to three times per day, and the patient should be given a drug-free month once every 6 months to reduce the likelihood of retroperitoneal fibrosis. Rarely, I have also used lithium in the form of Lithobid 300 mg one or two times per day. Patients may experience tremor and should have lithium levels checked at least monthly and not be on concurrent therapy with calcium channel blocking drugs. Finally, in selected patients, I have used BoNT-A with modest success in approximately 25% of the patients. SUGGESTED READING
Headache Classification Subcommittees of the International Headache Society: The international classification of headache disorders: 2nd edition, Cephalalgia 24(Suppl 1):9-160, 2004. Troost BT: Botulinum toxin type A (Botox) in the treatment of migraine and other headaches, Expert Rev Neurother 4:27-31, 2004. Goadsby PJ, Lipton RB, Ferrari MD: Migraine: current understanding and treatment, N Engl J Med 346:257-270, 2002.

Definition
What is CDH? CDH is a symptom rather than a diagnosis. CDH simply refers to the presence of headache on 15 or more days per month for more than 3 months. There are many primary and secondary causes of CDH. The International Headache Society (IHS) classification of headache disorders recently developed operational diagnostic criteria for primary and secondary CDH disorders (see Suggested Reading).

Epidemiology
The population prevalence of CDH is 3% to 5%, whereas the prevalence within U.S. headache centers approaches 80%. The annual incidence of CDH in the general population is approximately 3%. The disability associated with primary forms of CDH is substantial. These patients experience significant impairment in health-related quality of life and in physical and mental health, as well as decreased social and occupational functioning.

Approach to the Patient with Chronic Daily Headache


In most cases, CDH is attributable to primary headache disorders. However, clinicians need to be vigilant in excluding secondary causes of headaches in this population (Table 1). A thorough history is the most critical aspect of the evaluation and provides the diagnosis or guides the evaluation in most cases. Clinical evaluation should always address the possibility of elevated or low intracranial pressure, a chronic infectious or inflammatory disease, a space-occupying lesion, or symptomatic medication overuse. In the absence of red flags in the history or physical examination, a secondary cause can usually be eliminated (Table 2). Next, the question How long do the patients individual headaches last if left untreated? narrows the primary CDH subtypes into two discrete categoriesshort lasting (<4 hours) and long lasting (>4 hours) (Figure 1). By recognizing the distinctive clinical features of the common primary CDH subtypes, a specific diagnosis can be made and appropriate treatment initiated in most patients.
Johnson: Current Therapy in Neurologic Disease (7/E)

PATIENT RESOURCE
http://www.imigraine.net/

Chronic Daily Headache


Jonathan P. Gladstone, M.D., and David W. Dodick, M.D.

Chronic daily headache (CDH) is a significant public health problem affecting 3% to 5% of the population worldwide. The treatment of patients with CDH can be both challenging and immensely rewarding. Effective management requires a systematic approach to diagnosis and treatment.

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TABLE 6 Additional Pharmacologic Migraine Therapy


Generic Name Calcium channel blockers Verapamil Diltiazem Beta blockers Propranolol Timolol Trade Name Inderal Cardizem Verelan Blocadren Dosage 120 mg/day, increasing to 600 mg/day 120 mg bid, increasing to 720 mg/day 10 mg tid, increasing to 180 mg/day 5 mg bid, increasing to 40 mg/day

difficult to treat. I use most of the standard preventive therapies such as calcium channel blocking drugs or anticonvulsants as initial starting therapy. Nasal oxygen (8 to 10 L/min) may be helpful at the start of a series of cluster headaches. However, I have found that most patients with recurrent cluster headache do not respond to these therapies and need to be treated with other agents such as methysergide (Sansert). The methysergide dosage should be 2 mg once to three times per day, and the patient should be given a drug-free month once every 6 months to reduce the likelihood of retroperitoneal fibrosis. Rarely, I have also used lithium in the form of Lithobid 300 mg one or two times per day. Patients may experience tremor and should have lithium levels checked at least monthly and not be on concurrent therapy with calcium channel blocking drugs. Finally, in selected patients, I have used BoNT-A with modest success in approximately 25% of the patients. SUGGESTED READING
Headache Classification Subcommittees of the International Headache Society: The international classification of headache disorders: 2nd edition, Cephalalgia 24(Suppl 1):9-160, 2004. Troost BT: Botulinum toxin type A (Botox) in the treatment of migraine and other headaches, Expert Rev Neurother 4:27-31, 2004. Goadsby PJ, Lipton RB, Ferrari MD: Migraine: current understanding and treatment, N Engl J Med 346:257-270, 2002.

Definition
What is CDH? CDH is a symptom rather than a diagnosis. CDH simply refers to the presence of headache on 15 or more days per month for more than 3 months. There are many primary and secondary causes of CDH. The International Headache Society (IHS) classification of headache disorders recently developed operational diagnostic criteria for primary and secondary CDH disorders (see Suggested Reading).

Epidemiology
The population prevalence of CDH is 3% to 5%, whereas the prevalence within U.S. headache centers approaches 80%. The annual incidence of CDH in the general population is approximately 3%. The disability associated with primary forms of CDH is substantial. These patients experience significant impairment in health-related quality of life and in physical and mental health, as well as decreased social and occupational functioning.

Approach to the Patient with Chronic Daily Headache


In most cases, CDH is attributable to primary headache disorders. However, clinicians need to be vigilant in excluding secondary causes of headaches in this population (Table 1). A thorough history is the most critical aspect of the evaluation and provides the diagnosis or guides the evaluation in most cases. Clinical evaluation should always address the possibility of elevated or low intracranial pressure, a chronic infectious or inflammatory disease, a space-occupying lesion, or symptomatic medication overuse. In the absence of red flags in the history or physical examination, a secondary cause can usually be eliminated (Table 2). Next, the question How long do the patients individual headaches last if left untreated? narrows the primary CDH subtypes into two discrete categoriesshort lasting (<4 hours) and long lasting (>4 hours) (Figure 1). By recognizing the distinctive clinical features of the common primary CDH subtypes, a specific diagnosis can be made and appropriate treatment initiated in most patients.
Johnson: Current Therapy in Neurologic Disease (7/E)

PATIENT RESOURCE
http://www.imigraine.net/

Chronic Daily Headache


Jonathan P. Gladstone, M.D., and David W. Dodick, M.D.

Chronic daily headache (CDH) is a significant public health problem affecting 3% to 5% of the population worldwide. The treatment of patients with CDH can be both challenging and immensely rewarding. Effective management requires a systematic approach to diagnosis and treatment.

Chronic Daily Headache

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TABLE 1 Causes of Chronic Daily Headache


Primary Short lasting (<4 hr) Chronic cluster Chronic paroxysmal hemicrania SUNCT Hypnic Long lasting (>4 hr) Chronic migraine Chronic tension type Hemicrania continua New daily persistent type Secondary Medication related Medication overuse Drug side effects Vascular Giant cell arteritis Subdural hematoma Ischemic or hemorrhagic stroke Venous sinus thrombosis Arterial dissection Severe arterial hypertension Infectious Meningitis (viral, bacterial, tubercular, fungal, parasitic) Sinusitis (sphenoid) Disorders of intracranial pressure Increased intracranial pressure (primary or secondary tumor, idiopathic intracranial hypertension, hydrocephalus) Decreased intracranial pressure (spontaneous intracranial hypotension, post-lumbar puncture headache) Structural Attributable to cervical spine disorders Attributable to TMJ/dental pathology Post-traumatic Attributable to head injury Attributable to neck injury or whiplash Metabolic Hypoxia, hypercarbia Obstructive sleep apnea Carbon monoxide Thyroid disease
TMJ, Temporomandibular joint; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

TABLE 2 Daily Headache: Red Flags for Secondary Causes


Factor Onset age >50 years Comments Consider giant cell arteritis, brain tumor (primary or secondary), or subdural hematoma Chronic meningitis (tubercular, fungal, or parasitic infection) Sinusitis (sphenoid sinusitis may occur without nasal symptoms) Vasculitis (primary CNS or secondary to other inflammatory/rheumatologic conditions) Giant cell arteritis If worse when standing, consider spontaneous intracranial hypotension If worse when supine, consider increased intracranial pressure and/or posterior fossa pathology Be wary of metastatic disease or intracranial infection Re-evaluate original diagnosis, and consider a secondary cause Always be on the lookout for caffeine or medication overuse headache

Presence of fever or systemic symptoms

Focal neurologic symptoms or signs Precipitated by positional changes, Valsalva maneuver, bending or coughing

History of cancer, immunocompromise, or HIV infection Progressive headache or escalating medication requirements

CNS, Central nervous system; HIV, human immunodeficiency virus.

Primary CDH
SHORT-DURATION (<4 HOURS) PRIMARY CHRONIC DAILY HEADACHE The prototypical short-lasting primary CDH is cluster headache. It is characterized by severe pain in the orbital or temporal region and cranial autonomic features (e.g., lacrimation, rhinorrhea, conjunctival injection, ptosis). Chronic paroxysmal hemicrania and SUNCT syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) are classified together with cluster headache as the trigeminal autonomic cephalgias because of the trigeminal
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distribution of the pain and the accompanying cranial autonomic features. These syndromes must be differentiated from each other because they are each treated in a different manner (Table 3). The important treatment implications are the exquisite response of chronic paroxysmal hemicrania to indomethacin, and the preferred use of second- or third-generation anticonvulsants (gabapentin, lamotrigine, topiramate) for SUNCT syndrome. Cluster Headache Cluster headache is extremely debilitating and requires thoughtful and aggressive management. Nonpharmacologic management includes eliminating alcohol and tobacco use and directing patients to the helpful support groups available for cluster headache sufferers. The pharmacologic management of cluster headache can be separated into acute, transitional, and prophylactic therapy. Subcutaneous sumatriptan (6 mg) is the fastest acting and most effective medication for the relief of a

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Headache 15 or more days per month

Exclude secondary headaches

Treat secondary headache

Classify based on duration

Short duration (< 4 hours)

Long duration (> 4 hours)

Chronic cluster headache (CCH) Chronic paroxysmal hemicrania (CPH) Hypnic headache (HH) SUNCT syndrome

Chronic migraine (CM) Chronic tension type headache (CTTH) New daily persistent headache (NDPH) Hemicrania continua (HC)

Autonomic

+ Autonomic

Autonomic

+ Autonomic

Hypnic Headache

CCH CPH* SUNCT

CM CTTH NDPH

HC*

Onset < 3 days

Gradual onset

See Table 3

NDPH

* Indomethacin responsive Autonomic cranial autonomic symptoms

CM CTTH

FIGURE 1. Approach to chronic daily headache: narrowing the differential diagnosis based on the duration of individual headaches. SUNCT, Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

cluster headache. Recently, trials in patients with episodic cluster headache demonstrated good efficacy with intranasal sumatriptan (20 mg) and intranasal zolmitriptan (5 mg). Inhalational oxygen, administered via face mask at 10 to 15 L/min for at least 15 minutes, is effective in up to 70% of patients. Practically, the need for an oxygen canister and regulator makes this modality cumbersome for some patients. Dihydroergotamine (DHE) administered intravenously (IV), subcutaneously, or intranasally is also effective, although there are few data from randomized, controlled trials. For some patients, especially those who cannot use or tolerate

vasoconstrictive drugs such as triptans or DHE, intranasal lidocaine 4% may be effective. Prescription analgesics or opioids are not effective and may lead to medication overuse headache and central nervous system side effects. An effective preventive regimen for patients with cluster headache is crucial because attacks often occur daily for months or years (Table 4). Corticosteroids usually provide swift relief from attacks. Prednisone can be initiated at 60 mg/day for 3 days followed by 10-mg decrements every 3 days. Blockade of the ipsilateral occipital nerve can suppress attacks for up to 2 weeks in as many

TABLE 3 Differentiating Features of the Trigeminal Autonomic Cephalalgias


Feature Gender (male/female) Attack duration Attack frequency Autonomic features Alcohol ppt First-line treatment Cluster 4:1 15-180 min 1-8/day ++ ++ Verapamil CPH 1:3 2-45 min 1-40/day ++ + Indomethacin SUNCT 4:1 5-250 sec 1/day-30/hour ++ + Lamotrigine gabapentin

CPH, Chronic paroxysmal hemicrania; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

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TABLE 4 Treatment for Cluster Headache


Transitional (1-2 wk) Prednisone 60 mg qd for 3 days, then 10-mg decrements q 3 days (18 days) Ergotamine tartrate 1-2 mg PO/suppository qd (qhs or divided dosage) D.H.E-45 0.5-1 mg SC/IM q 8-12 hr Occipital nerve blockade (e.g., 3-5 mL 0.5% bupivacaine + 10-20 mg Depo-Medrol) Maintenance (duration of cluster period, usually 2-3 mo) Verapamil 80 mg tid or 240 mg SR; up to 720 mg/day Methysergide 2 mg tid; up to 12 mg/day Lithium carbonate 150-300 mg tid or 450 mg SR Valproic acid 500-2000 mg/day in divided dosages Topiramate 50-150 mg in divided daily dosages Adjunctive Melatonin 10 mg PO qhs Indomethacin 25-50 mg tid Gabapentin 300-1200 mg tid

as two thirds of patients and avoid the potential side effects associated with oral corticosteroids. Occipital nerve blockade can be achieved with 3 mL of 0.5% bupivacaine combined with 10 to 20 mg of methylprednisolone or another long-acting corticosteroid. IV DHE with repetitive infusions every 8 to 12 hours over a 1- to 2-day period can provide significant relief; however inpatient admission or an outpatient infusion center is required. Verapamil should be considered the first-line preventive agent for both episodic and chronic cluster headache. After a baseline electrocardiogram (ECG) the initial starting dose is 80 mg three times a day, or one can titrate to this dose over 3 to 5 days. Titration, as needed, should occur in 80-mg intervals every 3 to 7 days. For doses above 480 mg/day, an ECG is required prior to each dose escalation. If partial benefit is obvious at this dose, some patients may become cluster free at higher dosages (720 mg). If side effects occur (significant constipation, fatigue, gastrointestinal symptoms, hypotension, edema), we recommend decreasing the dose and adding a second-line agent such as melatonin, topiramate, or gabapentin. Although two open-label studies with divalproic acid for chronic cluster headache were encouraging, a recent placebo-controlled study failed to show a significant difference (though the placebo response in this study was unusually high). Beta blockers and tricyclic antidepressants have no role in the treatment of chronic cluster headache. Although quite effective, lithium carbonate and methysergide are typically reserved as third-line agents due to their potential for significant side effects and systemic toxicity, difficulty with dose titration, and access issues (methysergide is no longer available in the United States). Patients on methysergide require a 1-month drug holiday every 6 months and regular screening for retroperitoneal/ pleural/pericardial fibrosis. Testing usually requires an echocardiogram, computed tomographic scan of the chest and abdomen, serum creatinine, erythrocyte sedimentation rate, and urinalysis.
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A number of other agents have been reported in small open-label studies or within case reports to have demonstrated efficacy in patients with cluster headache. These include methylphenidate, pizotifen, indomethacin, antispasticity drugs (tizanidine and baclofen), clonidine, diltiazem, flunarizine, histamine, somatostatin, and intranasal capsaicin. There is a paucity of clinical experience with most of these drugs in patients with cluster headache, and because of the lack of data, further evidence is needed before recommendations can be made to support their routine use in cluster headache. However, consideration of all medical options should be given in patients with treatment-resistant cluster headache before an ablative surgical procedure is attempted. For individuals who fail medical management or develop unacceptable side effects and are psychologically stable, surgical options are available. Multiple surgical interventions have been proposed, but the results are best and experience is greatest with those procedures directed at the sensory portion of the trigeminal nerve. These include percutaneous radiofrequency, glycerol or balloon rhizolysis, and trigeminal root sectioning. Each of these procedures is irreversibly destructive with the potential for significant neurologic morbidity. Two emerging surgical options for patients with refractory chronic cluster headache are available in select research centersdeep brain stimulation and occipital nerve stimulation. Ipsilateral posteroinferior hypothalamic stimulation has been found to be relatively safe and effective in patients with medically intractable chronic cluster headache. However, fatal iatrogenic cerebral hemorrhage occurred in one patient, reminding us of the potential for serious neurologic morbidity and mortality associated with this procedure. Occipital nerve stimulation may represent an effective and minimally invasive procedure for patients with chronic cluster headache. Thus far, only two patients with chronic cluster headache have been treated, both with good results, and further investigation into the effectiveness of occipital nerve stimulation for patients with chronic migraine and cluster headache is under way. Chronic Paroxysmal Hemicrania and Hemicrania Continua Chronic paroxysmal hemicrania and hemicrania continua are typically responsive to indomethacin in dosages ranging between 25 and 75 mg three times a day. Hemicrania continua is a continuous exclusively unilateral headache that is punctuated by severe exacerbations lasting hours to days. These patients also experience one or more cranial autonomic symptoms, often during painful exacerbations. Patients typically notice complete relief within 48 hours, and once a stable dose is obtained, patients can be switched to a once-daily dosage with the slow-release formulation. If indomethacin is not effective, the diagnosis should be revisited. If indomethacin is poorly tolerated or contraindicated, alternative treatment options include other nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen, sulindac, diclofenac, aspirin, cyclooxygenase-2 inhibitors, and verapamil, and brief courses of corticosteroids.

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SUNCT Until recently, SUNCT syndrome has been notoriously difficult to treat effectively. An initial trial of indomethacin, especially if there is diagnostic uncertainty, is warranted. Lamotrigine should be considered first-line therapy. Second-line therapies include gabapentin and topiramate. Hypnic Headache Hypnic headache is a unique headache entity occurring mainly in the elderly and exclusively during sleep. The headache is generally bilateral, moderately severe, and lasts between 15 and 120 minutes. Patients generally feel better upright, and there are no cranial autonomic symptomsfeatures that distinguish this disorder from cluster headache, which can also awaken patients from sleep. Paradoxically, caffeine before bed is often effective and should be tried initially either in the form of a caffeinated beverage or tablet. Lithium, melatonin, and indomethacin all have demonstrated benefit in patients with hypnic headache. LONG-DURATION (>4 HOURS) CHRONIC DAILY HEADACHES Chronic Migraine and Transformed Migraine Chronic migraine is characterized by headaches fulfilling the criteria for migraine without aura on more than 15 days per month for more than 3 months in the absence of medication overuse. Most headache specialists in North America use the Silbsertein-Lipton criteria for transformed migraine (TM) since they are more sensitive and relevant to the CDH patients seen in U.S. clinics (Table 5). Patients with transformed migraine usually have a history of episodic migraine that gradually transforms to chronic migraine, although this transformation may be abrupt in up to 15% of patients.

Patients with transformed migraine often require aggressive management with both nonpharmacologic and pharmacologic treatment modalities. Migraineurs are often exquisitely sensitive to internal and external stimuli. Therefore, regulating daily activities (e.g., regular mealtimes and sleep schedules) and avoiding identifiable triggers are important. Anxiety and attention to pain results in inhibition of antinociceptive brainstem structures such as the periaqueductal gray matter. Therefore, training in relaxation, biofeedback, stress management, and cognitive-behavioral therapy allow patients to exert control over physiologic responses that may influence pain modulation. The efficacy of these techniques has been demonstrated in multiple welldesigned clinical trials in patients with episodic migraine and received a grade A recommendation in the U.S. Headache Consortium Guidelines and American Academy of Neurology Practice Parameter. Preventive therapy should be considered for patients with transformed migraine whether or not symptomatic medication overuse is present. Although the most frequently prescribed preventive medications for episodic migraine in North America continue to be the beta blockers and tricyclic antidepressants, evidence has emerged over the last decade for novel formulations of older anticonvulsants (divalproic acid extended-release); for newer, second-generation anticonvulsants (e.g., topiramate, gabapentin); and for botulinum toxin type A (BoNT-A) for the treatment of both episodic and chronic migraine. Although most studies have been with episodic migraine, these agents are, and will continue to be, widely used in practice to treat patients with chronic migraine in the absence of evidence from randomized, controlled data to the contrary. Medication Overuse Headache Medication overuse headache (rebound headache) is a common and disabling headache disorder characterized by the generation, perpetuation, or maintenance of CDH, caused by the frequent and excessive use of immediaterelief (symptomatic) medications. Patients with medication overuse headache frequently have a history of episodic migraine that has been transformed into CDH as a result of symptomatic medication overuse. In susceptible individuals the frequent, neardaily, or daily use of simple analgesics (aspirin or acetaminophen), combination analgesics (containing caffeine, codeine, or barbiturates), opioids, ergotamine, or triptans may transform an episodic pattern of headache into one that occurs daily. Characteristic features of medication overuse headache have been well described (Table 6) and the IHS has developed operational criteria for the diagnosis of medication overuse headache (Table 7). Medication overuse headache is a retrospective diagnosis made when the offending agent is withdrawn and the headache pattern ceases to be daily. This process generally takes weeks to months. However, daily headache is not synonymous with analgesic overuse, and many patients with transformed migraine, chronic tensiontype headache, and new daily persistent headache do not overuse symptomatic medications. It is these patients
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TABLE 5 Transformed Migraine: Silberstein-Lipton Criteria


Type A B C Description Daily or almost daily (>15 days/mo) head pain for > 1 mo Average headache duration of > 4 hr/day (if untreated) At least one of the following: (1) History of any form of episodic migraine meeting IHS criteria 1.1-1.6* (2) History of increasing headache frequency with decreasing severity of migrainous features over at least 3 mo (3) Headache at some time meets HIS criteria for migraine other than duration Does not meet criteria for new daily persistent headache or hemicrania continua

*IHS criteria refers to International Headache Society classification (see Suggested Reading).

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TABLE 6 Features of Medication Overuse Headache


Frequency of headaches increases insidiously over time Patients often awake in the early morning with headache A proportion of individual headache attacks may become nondescript (lose the characteristic migrainous features) Lowered threshold for precipitating headache exacerbations (concentration, minimal exertion, anxiety) Escalating doses of symptomatic medications required for headache relief Headaches occur within a predictable period after the last consumption of symptomatic medication, usually with reduced efficacy

who continue to have daily headache even after analgesics are discontinued. Familiarity and comfort with drug withdrawal and detoxification strategies are essential for the treatment of patients with medication overuse headache (Table 8). Patients with CDH who overuse acute symptomatic medications must discontinue or taper the overused medication due to the possibility of tolerance; habituation and dependence; the potential for renal, hepatic, or gastrointestinal side effects; and the possibility that medication overuse may neutralize the effectiveness of prophylactic medications. In the absence of prospective, placebo-controlled, randomized studies evaluating the different treatment modalities for medication overuse headache or the efficacy of medication withdrawal alone, treatment strategies are based on case reports, case series, retrospective chart reviews, and expert opinion. Treatment of medication overuse headache may occur in the outpatient setting or at an infusion center, or it may require hospitalization. Hospitalization is

typically reserved for patients overusing opioids, barbiturates, or benzodiazepines; those with severe psychiatric comorbidity; or those who have failed previous withdrawal attempts as an outpatient (Table 9). Most patients can be managed as outpatients. The first stage of treatment involves headache education, particularly regarding the role of medication overuse in the patients CDH. Comorbid depression and anxiety need to be addressed concurrently. Biobehavioral education with training in relaxation techniques and biofeedback is often helpful to allow patients to achieve an internal locus of control. Modifications of lifestyle habits must be made including, but not limited to, decreasing caffeine consumption, increasing exercise, incorporating stress management strategies, and improving sleep hygiene. Patients should always be provided with support and close follow-up and provided with the realistic expectation that they may feel worse before they feel better. In parallel, simple analgesics, ergotamines, triptans, and most combination analgesics can be abruptly discontinued, whereas opioids and butalbital containing analgesics should be gradually tapered. To alleviate potential side effects from barbiturate withdrawal, a long-acting barbiturate alternative (phenobarbital) may be substituted and tapered; similarly to avoid complications from opioid withdrawal, low doses of clonidine may be considered. Patients should be provided with

TABLE 8 Treatment of Medication Overuse Headache


Education and support with follow-up Encourage healthful behavior (smoking, exercise, meals, sleep, caffeine) Biobehavioral therapy (relaxation therapy, biofeedback) Abrupt withdrawal of overused acute medications except barbiturates, opioids, or benzodiazepines Butalbital overuse (taper over 2-4 wk; if concern for withdrawal syndrome, provide tapering course of phenobarbital 30 mg bid for 2 wk followed by 15 mg bid for 2 wk) Opioid overuse (taper over 2-4 wk; if concern for withdrawal, clonidine transdermal patch for 1-2 wk) Relief of worsening/breakthrough headache Prednisone 60 mg for 3 days; decrease by 10 mg q 3 days NSAIDs (ketoprofen 50-100 mg; naproxen sodium 550 mg; ibuprofen 600-800 mg) Antiemetics (metoclopramide 10-20 mg, prochlorperazine 10 mg or 25 mg suppository) SC or IM DHE 1 mg Triptans (if not drug being overused ) Preventive drug therapy Amitriptyline 25-100 mg qhs Divalproex sodium ER 500-2000 mg Topiramate 50-200 mg Gabapentin 900-3600 mg Botulinum toxin type A Tizanidine 4-16 mg qhs Fluoxetine 20-60 mg
NSAID, Nonsteroidal anti-inflammatory drug; DHE, dihydroergotamine.

TABLE 7 Headache Attributed to Medication Overuse: IHS Criteria*


Type A B Comments Headache present on >15 days/mo, fulfilling criteria C and D Characteristics depend on drug Regular overuse of a medication for > 3 mo Ergotamine, triptans, opioids, and combination analgesics 10 days/mo Simple analgesics 15 days/mo Total exposure to symptomatic medications 10 days/mo Headache has developed or markedly worsened during medication overuse Headache resolves or reverts to its previous pattern within 2 mo after discontinuation of overused medication

C D

*IHS criteria refers to International Headache Society classification (see Suggested Reading).

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TABLE 9 Treatment of Medication Overuse Headache


Indications Failure of outpatient treatment High consumption of opioids, butalbital, or benzodiazepines Significant psychological or behavioral disturbances Significant coexistent medical illnesses Protocols Repetitive IV infusions q 8 hr for 2-4 days Dihydroergotamine 0.5-1 mg plus metaclopramide 10-20 mg or prochlorperazine 10 mg Prochlorperazine 10 mg Divalproex sodium 6.4 mg/kg Methylprednisolone 250-500 mg q 12 hr Initiate taper/withdrawal symptomatic medications overused (clonidine, phenobarbital) Initiate preventive therapy

as well as pharmacologic therapy with tricyclic antidepressants. New Daily Persistent Headache New daily persistent headache is characterized by a constant and unremitting headache of acute onset (developing over <3 days). Clinically, the headache features may be indistinguishable from chronic tension-type headache; however, contrary to the IHS diagnostic criteria, our experience suggests that migrainous symptoms (nausea, vomiting, photophobia) may occur in these patients and the pain can be debilitating. Patients can pinpoint the calendar date of onset, unlike chronic tension-type headache. In these patients, an exhaustive search for secondary causes is mandatory. There is no available evidence on which to base therapeutic decisions for new daily persistent headache; unfortunately, many patients with new daily persistent headache who present for subspecialty consultation are particularly refractory to treatment. In the absence of alternative evidence, treatment strategies should mirror those used for chronic migraine (and for medication overuse headache when applicable).

symptomatic agents in limited doses (e.g., long-acting NSAIDs, DHE, triptans, or steroids) from drug classes other than those which they are overusing to alleviate withdrawal symptoms (headache, nausea, vomiting, arterial hypotension, tachycardia, sleep disturbances, restlessness, and nervousness). Withdrawal symptoms typically last from 2 to 10 days. For patients requiring more aggressive treatment, various strategies have been advocated including parenteral DHE, methylprednisolone, neuroleptics, or divalproex sodium acid. After initial detoxification, alternative acute medications to treat breakthrough attacks are provided in strictly limited doses. Prophylactic pharmacotherapy is initiated from the outset. There is no evidence base on which to make prophylactic therapy decisions in the medication overuse headache population, but reasonable options include amitriptyline, divalproex sodium, topiramate, botulinum toxin type A, fluoxetine, and tizanidine (see Table 4). The goal of withdrawal or detoxification therapy for medication overuse headache is to eliminate daily or neardaily medication use, to restore an episodic pattern of headache, and to establish an effective preventive and acute (symptomatic) treatment strategy. In patients with a long-standing history of near-daily or daily headache, it may be unrealistic to expect restoration of pain-free intervals. In these patients, the objective becomes to reduce the intensity of daily pain, to restore the patients ability to function, and to provide an effective strategy for acute management of severe headaches. Significant relapse rates estimated at 1 (20%) and 5 years (50%) highlights the need for ongoing follow-up care. Chronic Tension-Type Headache Chronic tension-type headache is seen much less commonly in neurologic practice than chronic migraine. Typically the syndrome evolves after years of episodic tension-type headache. First-line treatments for chronic tension-type headache include nonpharmacologic therapy such as relaxation, stress reduction, and biofeedback

Conclusion
Although CDH can be challenging to manage, considerable clinical experience over the past decade has led to the development of operational diagnostic criteria and a better understanding of the clinical features, pathogenesis, and treatment requirements for these patients. Most of these patients can be effectively treated in clinical practice with existing therapies; however, the recidivism rate in those with medication overuse and the unacceptably high number of patients that are refractory to medical management illustrate the importance of further research in this area. As emerging evidence from ongoing randomized, controlled clinical trials becomes available, future improvements in treatment are undoubtedly around the corner. SUGGESTED READING
Bigal ME, Tepper S J, Sheftell FD, et al: Chronic daily headache: correlation between the 2004 and the 1988 International Headache Society diagnostic criteria, Headache 44:684-691, 2004. Dodick DW: Indomethacin-responsive headache syndromes, Curr Pain Headache Rep 8:19-26, 2004. Dodick DW, Mosek AC, Campbell JK: The hypnic (alarm clock) headache syndrome, Cephalalgia 18:152-156, 1998. Dodick D, Rozen T, Goadsby P, Silberstein S: Cluster headache, Cephalalgia 20:787-803, 2000. Evers S, Goadsby PJ: Hypnic headache: clinical features, pathophysiology, and treatment, Neurology 60:905-909, 2003. Gladstone JP, Eross E, Dodick DW: Chronic daily headache: a rational approach to a challenging problem, Semin Neurol 23:265-276, 2003. Headache Classification Subcommittees of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgia, and facial pain: 2nd edition, Cephalalgia 24(Suppl 1):9-160, 2004. Mathew NT: Chronic refractory headache, Neurology 43(Suppl 3): S26-S33, 1993. Rozen TD: Interventional treatment for cluster headache: a review of the options, Curr Pain Headache Rep 6:57-64, 2002. Johnson: Current Therapy in Neurologic Disease (7/E)

Headaches in Children Scher AI, Stewart WF, Liberman J, et al: Prevalence of frequent headache in a population sample, Headache 38:497-506, 1998. Scher AI, Stewart WF, Ricci JA, Lipton RB: Factors associated with the onset and remission of chronic daily headache in a populationbased study, Pain 106:81-89, 2003. Silberstein SD: Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 55:754-762, 2000. Silberstein SD, Lipton RB, Solomon S, Mathew N: Classification of daily and near-daily headaches in the headache clinic: proposed revision to the International Headache Society criteria. In Olesen J, editor: Frontiers in headache research, vol 4: headache classification and epidemiology, New York, 1994, Raven Press, 117-126.

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PATIENT RESOURCES
American Council for Headache Education http://www.ache.org/ National Headache Foundation http://www.headaches.org/ OUCHThe Organization for the Understanding of Cluster Headache http://www.clusterheadaches.org/

Headaches in Children
Eric H. Kossoff, M.D.

Headaches in the pediatric population are surprisingly common, much to the surprise of parents but not to pediatric neurologists. By 7 years of age, half of all children have experienced a headache at some time. Migraines are also quite common, with a prevalence of 3.2% by age 7, and 11% by age 15. Despite this, children tend to be referred to ear, nose, and throat physicians for sinusitis and ophthalmologists for myopia before seeing a neurologist. Males tend to be more likely to be affected in the prepubertal age group, followed by the more traditional female predominance after age 11. Headaches are a major source of morbidity and can lead to school failure and emotional problems. The accurate diagnosis and swift institution of appropriate therapy can be crucial.

pallor or autonomic symptoms with their headaches, frequent motion sickness, or unexplained vomiting at very young ages. Children with periodic migraines tend to be high functioning and on honor rolls, perhaps indicating the triggering factor of stress in migraines. Typically the mother bringing in the child for evaluation has migraines herself, which are occasionally unrecognized. One quick and convenient method of distinguishing migraine from other headaches in a less verbal child is by the use of drawings of how the child feels during a headache. It is important to distinguish a headache caused by tension or migraine from that of a potentially lifethreatening neurologic condition such as meningitis or malignancy. This can often be difficult in children, especially in those prior to school age. All children complaining of headache should have a careful history obtained, with strong consideration to neuroimaging if the headache severity is increasing rapidly, they are awakening the child from sleep, or are different from a usual pattern. The presence of focal deficits, seizures, or increased intracranial pressure on neurologic examination should lead to an immediate magnetic resonance imaging (MRI). Most neurologists obtain an MRI in patients with complicated migraine (e.g., confusional, hemiplegic) to ensure that no structural abnormalities exist. Neuroimaging should also be considered in those patients with risk factors such as ventriculoperitoneal shunt, head trauma, human immunodeficiency virus, or systemic malignancy. However, when the history is consistent with migraine and the examination is normal, neuroimaging is not required, regardless of age. There is no indication for electroencephalography, lumbar puncture, or routine laboratory studies in children with migraine.

Treatment
BASIC PRINCIPLES It is important for all physicians to be honest and realistic with children and their families as early in the course of treatment as possible. Migraines are typically a lifelong diagnosis with a fluctuating severity over the years. A promise or expectation of migraine freedom is often followed by disappointment and frustration. Setting appropriate goals, such as a 50% to 75% reduction in severity and frequency in combination with advising patience, often leads to better therapeutic success. To fully treat the patient with headaches, both acute (abortive) and preventive (prophylactic) therapies must be provided at the same time (Figure 1). ACUTE THERAPY The role for nonpharmacologic abortive therapies for childhood migraine is limited but should always be advised. Children may occasionally continue activities such as video games or television during the onset of a migraine; this should be discouraged, and the child should rest in a quiet, dark room. Ice packs can be applied to

Diagnosis
Migraine symptoms can be similar between children and adults, but there are distinct differences. The International Headache Society (IHS) criteria from 1988 are not particularly specific for the pediatric patient. Several potential recommendations have been made by experts to alter the diagnostic criteria for children, specifically to reduce the duration of migraine to less than 1 hour, eliminate the requirement for unilaterality (because many childhood migraines are frontal or bilateral), and allow either phonophobia or photophobia (not necessarily both). Many children have a history of facial
Johnson: Current Therapy in Neurologic Disease (7/E)

Headaches in Children Scher AI, Stewart WF, Liberman J, et al: Prevalence of frequent headache in a population sample, Headache 38:497-506, 1998. Scher AI, Stewart WF, Ricci JA, Lipton RB: Factors associated with the onset and remission of chronic daily headache in a populationbased study, Pain 106:81-89, 2003. Silberstein SD: Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 55:754-762, 2000. Silberstein SD, Lipton RB, Solomon S, Mathew N: Classification of daily and near-daily headaches in the headache clinic: proposed revision to the International Headache Society criteria. In Olesen J, editor: Frontiers in headache research, vol 4: headache classification and epidemiology, New York, 1994, Raven Press, 117-126.

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PATIENT RESOURCES
American Council for Headache Education http://www.ache.org/ National Headache Foundation http://www.headaches.org/ OUCHThe Organization for the Understanding of Cluster Headache http://www.clusterheadaches.org/

Headaches in Children
Eric H. Kossoff, M.D.

Headaches in the pediatric population are surprisingly common, much to the surprise of parents but not to pediatric neurologists. By 7 years of age, half of all children have experienced a headache at some time. Migraines are also quite common, with a prevalence of 3.2% by age 7, and 11% by age 15. Despite this, children tend to be referred to ear, nose, and throat physicians for sinusitis and ophthalmologists for myopia before seeing a neurologist. Males tend to be more likely to be affected in the prepubertal age group, followed by the more traditional female predominance after age 11. Headaches are a major source of morbidity and can lead to school failure and emotional problems. The accurate diagnosis and swift institution of appropriate therapy can be crucial.

pallor or autonomic symptoms with their headaches, frequent motion sickness, or unexplained vomiting at very young ages. Children with periodic migraines tend to be high functioning and on honor rolls, perhaps indicating the triggering factor of stress in migraines. Typically the mother bringing in the child for evaluation has migraines herself, which are occasionally unrecognized. One quick and convenient method of distinguishing migraine from other headaches in a less verbal child is by the use of drawings of how the child feels during a headache. It is important to distinguish a headache caused by tension or migraine from that of a potentially lifethreatening neurologic condition such as meningitis or malignancy. This can often be difficult in children, especially in those prior to school age. All children complaining of headache should have a careful history obtained, with strong consideration to neuroimaging if the headache severity is increasing rapidly, they are awakening the child from sleep, or are different from a usual pattern. The presence of focal deficits, seizures, or increased intracranial pressure on neurologic examination should lead to an immediate magnetic resonance imaging (MRI). Most neurologists obtain an MRI in patients with complicated migraine (e.g., confusional, hemiplegic) to ensure that no structural abnormalities exist. Neuroimaging should also be considered in those patients with risk factors such as ventriculoperitoneal shunt, head trauma, human immunodeficiency virus, or systemic malignancy. However, when the history is consistent with migraine and the examination is normal, neuroimaging is not required, regardless of age. There is no indication for electroencephalography, lumbar puncture, or routine laboratory studies in children with migraine.

Treatment
BASIC PRINCIPLES It is important for all physicians to be honest and realistic with children and their families as early in the course of treatment as possible. Migraines are typically a lifelong diagnosis with a fluctuating severity over the years. A promise or expectation of migraine freedom is often followed by disappointment and frustration. Setting appropriate goals, such as a 50% to 75% reduction in severity and frequency in combination with advising patience, often leads to better therapeutic success. To fully treat the patient with headaches, both acute (abortive) and preventive (prophylactic) therapies must be provided at the same time (Figure 1). ACUTE THERAPY The role for nonpharmacologic abortive therapies for childhood migraine is limited but should always be advised. Children may occasionally continue activities such as video games or television during the onset of a migraine; this should be discouraged, and the child should rest in a quiet, dark room. Ice packs can be applied to

Diagnosis
Migraine symptoms can be similar between children and adults, but there are distinct differences. The International Headache Society (IHS) criteria from 1988 are not particularly specific for the pediatric patient. Several potential recommendations have been made by experts to alter the diagnostic criteria for children, specifically to reduce the duration of migraine to less than 1 hour, eliminate the requirement for unilaterality (because many childhood migraines are frontal or bilateral), and allow either phonophobia or photophobia (not necessarily both). Many children have a history of facial
Johnson: Current Therapy in Neurologic Disease (7/E)

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Headaches in Children

Child with frequent, debilitating headaches

Obtain history, perform neurologic examination, obtain neuroimaging as necessary

Acute therapy

Preventive therapy

Pharmacologic

Non-pharmacologic

NSAIDs Ibuprofen, naproxen early in migraine, but not more than twice/week

Rest in a dark, quiet room Clear fluids as tolerated Ice pack to forehead and occiput

If abortives are being used more than 23 per week, immediately taper or discontinue

If headache not responsive after several attempts

Triptans Use preparation acceptable to child as early as possible into the headache, but not more than twice/week can be used earlier if child has failed to respond to NSAIDs for previous headaches

Basic lifestyle changes 810 hours sleep/night Exercise 3 times/week Avoid caffeine Avoid food triggers if present No missed meals Stress reduction 30 minutes/day

Evaluate patient in 23 months if headaches are still present, are impacting quality of life, occurring weekly or biweekly, or do not respond to acute therapies

Second-line choices Intranasal DHE (Migranal) Promethazine suppositories Combination agents (Midrin, Excedrin, Fioricet)

Consider pharmacologic therapy for a 68 week time period

If the child is under age 5, begin cyproheptadine 2 mg qhs

If headache not responsive and/or the child is requiring a hospital admission

Intravenous valproate (Depacon)

If not, and the child has comorbid depression or insomnia, begin either amitriptyline 1020 mg qhs or nortriptyline 1020 mg qhs

Tylenol with codeine Intravenous DHE Steroids

If not, and the child has comorbid obesity, begin topiramate 1525 mg qhs or zonisamide 2550 mg qhs

If not, and the child has comorbid bipolar symptoms or is underweight, begin valproate 125 mg qhs or gabapentin 100 mg qhs

If none of the previously mentioned comorbid conditions apply, use propranolol 10 mg qhs or verapamil 40 mg qhs. Can also choose any other agent based on side effect profile and preparations available

FIGURE 1. Algorithm for the diagnosis and treatment of headache in children. NSAIDs, Nonsteroidal anti-inflammatory drugs; DHE, dihydroergotamine.

Johnson: Current Therapy in Neurologic Disease (7/E)

Headaches in Children

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the forehead or occipital area. If the child is not nauseated, clear fluids can be provided. First-line therapies for children with headache are nonsteroidal anti-inflammatory drugs, specifically ibuprofen (10 mg/kg) and naproxen sodium (200 mg). Gastric irritation can occur but is unusual if the NSAID is used infrequently. Should these medications prove ineffective, the triptans can be extremely valuable despite the lack of U.S. Food and Drug Administration (FDA) approval for children younger than 18 years of age. Several studies of rizatriptan and sumatriptan in adolescents have shown efficacy without major side effects. These agents are traditionally avoided in complicated migraine. All agents appear equally effective, although individual patients may respond differentially. Zolmitriptan (2.5 and 5 mg) and rizatriptan (5 and 10 mg) exist in dissolvable tablet forms, which are convenient for children who cannot swallow tablets. Sumatriptan (20 mg) and zolmitriptan (5 mg) also have nasal spray preparations, which are better tolerated if the child leans forward during administration to avoid a bitter taste from swallowing the spray. Recent evidence has demonstrated nasal sprays value over placebo in adolescents. Other abortive therapies that can be helpful include promethazine (Phenergan) suppositories or intravenous metoclopramide (Reglan), especially if vomiting is a significant component of the childs migraine. Intranasal dihydroergotamine (DHE) (Migranal) is also a potential option. Combination agents such as Midrin, Fioricet, and agents containing caffeine such as Excedrin, should be used sparingly and provided in limited amounts to avoid dependence. PREVENTIVE THERAPY Nonpharmacologic Approaches Considering the occasionally dramatic improvement seen in patients just from visiting a neurologist, the avoidance of daily preventive medications is justified at least in the initial visit. Most families are willing to allow for nonmedication improvement if the physician realistically explains the disorder, reassures the child, provides abortive options, advises lifestyle alterations, and arranges close telephone and clinic follow-up. Although it is quicker to give a prescription, it is often unnecessary to do so. Basic lifestyle recommendations include adequate sleep (8 to 10 hours per night, including weekends), aerobic exercise (two or three times per week for 30 minutes), avoidance of missed meals and triggers (e.g., aged cheese, nitrites, bright sunlight) if they should exist, elimination of caffeine from the diet, and encouragement of periods of relaxation time after school each day. Pharmacologic Approaches If the child returns in 2 to 3 months with persistent, severe migraines occurring weekly or biweekly, the use of preventive medications should be discussed. Most of these agents in children can be administered nightly to avoid sedation in school and at low doses. All therapies should be given 6 to 8 weeks before they are judged
Johnson: Current Therapy in Neurologic Disease (7/E)

ineffective and a substitution is made. The risks of polytherapy generally tend to outweigh potential benefits, so a single preventive agent at a time is advised. If effective, medications should be continued for approximately 1 year, with discontinuation during a school vacation. Therapeutic classes include antihistamines, antihypertensives, antidepressants, and anticonvulsants. The choice of therapy is typically based on comorbidity, side effect profile, and preparation (Table 1). If a choice from a therapeutic class is ineffective, it is logical to try another class before using an agent with a similar mechanism of action. Cyproheptadine (Periactin) is used most often in children younger than 5 years of age and has antihistaminergic and antiserotonergic effects. Efficacy is unproved despite years of use in children. It is typically dosed at 0.5 mg/kg and can be provided as a liquid. Allergic symptoms, if present, can be alleviated, but side effects of appetite stimulation and sedation can be limiting. Propranolol and other beta blockers are proven therapies for migraine but are contraindicated in diabetes, depression, and asthma. Verapamil can also be used, but it occasionally leads to sedation, weight gain, and constipation. This may have a particular role for familial hemiplegic migraine, in which genetically defective calcium channels may be involved in the pathophysiologic mechanisms. These medications are available only as tablets. Antidepressants are quite effective, especially when insomnia or depression are comorbid states. Amitriptyline (Elavil) and nortriptyline (Pamelor) are more effective than the newer selective serotoninreuptake inhibitors for migraine prevention. Side effects include sedation, constipation, dry mouth, and cardiac conduction problems (an electrocardiogram should be obtained if the drug is used long term). Doses should be started low and advanced slowly if necessary. Anticonvulsants are perhaps the most rapidly expanding class of migraine therapeutic agents in children, although few of them are studied and approved by the FDA despite widespread use for epilepsy. Many of them can have mood-stabilizing benefits. Because all have some teratogenic risk, folic acid, 400 g, should be recommended to all adolescent female patients. Valproic acid (Depakote) is the most studied agent and is available as sprinkle capsules, liquid, and extendedrelease tablets. It can also be administered intravenously as an abortive agent, to be continued orally on discharge from a hospital setting. Side effects include weight gain, alopecia, and hepatotoxicity. Topiramate (Topamax) has gained significant popularity due to efficacy in adult studies and the side effect of weight loss and can be administered as sprinkle capsules. It is a weak diuretic due to carbonic anhydrase inhibition, so it may have a role in patients with mildly increased intracranial pressure (e.g., pseudotumor or minimal ventriculoperitoneal shunt dysfunction). Other side effects of word finding difficulties, acidosis, and kidney stones can occur and should be discussed. Zonisamide (Zonegran) appears to be similar to topiramate in mechanism of actions as well as weight loss but perhaps

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TABLE 1 Commonly Used Preventive Drugs and Doses


Medication Cyproheptadine Propranolol Verapamil Amitriptyline Nortriptyline Fluoxetine Valproic acid Topiramate Gabapentin Zonisamide Dosages (Pediatric-Friendly Preparations) 2-4 mg qhs (liquid available) 10-40 mg qhs or bid 40-120 mg qhs 10-50 mg qhs 10-50 mg qhs 10-20 mg q AM (liquid) 125-500 mg qhs (liquid, sprinkles) 15-50 mg qhs (sprinkles) 100-600 mg qhs (liquid) 25-100 mg qhs Special Indications Allergies, anorexia Hypertension Hemiplegic migraine Depression, insomnia Depression, insomnia Depression Bipolar, anorexia Obesity, menstrual pattern Bipolar, no drug interactions Obesity Side Effects Sedation, appetite stimulant Avoid in asthma, diabetes, depression Hypotension, constipation Sedation, dry mouth, cardiac conduction Sedation, dry mouth, cardiac conduction Can be activating Weight gain, alopecia, hepatotoxicity Weight loss, renal stones, word finding difficulties Slight weight gain Weight loss, renal stones

may have less risk of cognitive changes. Gabapentin (Neurontin) is available in liquid form and has few side effects and interactions, making it an attractive option for a child with other comorbid conditions requiring many medications (e.g., malignancy). It has clinical experience for pain syndromes such as postherpetic neuralgia and recently for chronic daily headache. Other agents such as lamotrigine and levetiracetam may have a potential role as well. Other Approaches Biofeedback, psychological counseling, massage therapy, stress reduction techniques, yoga, cognitive training, botulinum toxin, and acupuncture all may have some role for individual patients and can be used early in the treatment regimen if indicated. A major benefit to these options involves the de-emphasis on pharmacologic treatments as the sole option, which can lead to rebound headache (discussed later). Chiropractic therapy can occasionally lead to carotid dissection if neck manipulation is aggressively performed; therefore, it should be avoided. REBOUND HEADACHE It is imperative to be aware of the entity of rebound headache, otherwise known as both transformed migraine and medication overuse headache. This disorder has reached epidemic proportions in the community with the increasing availability of products such as Excedrin, ibuprofen, naproxen, and other over-the-counter pain medications. The frequent use, typically two or three or more doses per week for several weeks, of almost any abortive therapies will invariably lead to an increase in headache frequency or even chronic daily headaches. Although opioids and caffeine are traditionally implicated, in my experience ibuprofen is more common. Neither acute nor preventive therapies are effective in this scenario. Despite the adult literature describing this, and television programs such as NBCs Dateline bringing it to public attention, the average pediatrician and parent are unaware of the dangers.

Discontinuation of the offending agent is the only efficacious therapy, with gradual reintroduction after several weeks to a less frequent dosing regimen. Amitriptyline and steroids have been used in some series to help with the transition.

SUMMARY
The quick and accurate diagnosis of migraines as differentiated from a more serious condition causing headache is important for all physicians caring for children. Although relatively common, the diagnosis is often missed. When it is suspected, extensive evaluations including MRI are not required. Realistic treatment strategies using both acute and preventive therapies, while cognizant of the risks of medications used inappropriately, can lead to an extremely gratified child and family. SUGGESTED READING
Lavenstein BA: Comparative study of cyproheptadine, amitriptyline, and propranolol in the treatment of preadolescent migraine, Cephalagia 11(Suppl 11):122-123, 1991. Lewis DW, Ashwal S, Dahl G, et al: Practice parameter: evaluation of children and adolescents with recurrent headaches, Neurology 59:490-498, 2002. Rothner AD, Winner P: Headaches in children and adolescents. In Wolffs headache and other facial pain, ed 7, New York, 2001, Oxford University Press. Stafstrom CE, Rostasy K, Minster A: The usefulness of childrens drawings in the diagnosis of headache, Pediatrics 109:460-472, 2002. Vasconcellos E, Pina-Garza JE, Millan EJ, Warner JS: Analgesic rebound headache in children and adolescents, J Child Neurol 13:443-447, 1998. Winner P, Rothner AD, Saper J, et al: A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents, Pediatrics 106:989-992, 2000.

PATIENT RESOURCE
American Headache Society: http://www.ahsnet.org/ Johnson: Current Therapy in Neurologic Disease (7/E)

Trigeminal and Glossopharyngeal Neuralgia

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Pharmacologic Options

Trigeminal and Glossopharyngeal Neuralgia


William P. Cheshire, Jr., M.D.

Trigeminal neuralgia is one of the most severe pain syndromes in human experience. Patients characteristically complain of paroxysmal facial pain that strikes one or more branches of the sensory division of the trigeminal nerve. Most cases involve the maxillary or mandibular territories. Evidence suggests that pulsatile indentation of the trigeminal nerve root by redundant arterial loops leads to focal demyelination and the generation of ectopic neural impulses that conduct ephaptically and spill over into adjacent fibers to yield a painful crescendo. Affected persons report repetitive, momentary attacks of unilateral pain that is typically sharp, lancinating, or electrical in quality. Occasionally more sustained burning or aching pain lasting minutes to hours may also be present. The pain is triggered by light tactile stimulation of a trigger zone usually located in the nasolabial or intraoral region. Daily activities such as washing the face, speaking, smiling, applying facial cosmetics, shaving, brushing the teeth, or exposure to wind can become intolerably painful. Bouts typically continue for weeks to months separated by pain-free remissions lasting months to years. There is a tendency for exacerbations to increase in frequency, although sustained remissions may occur. Glossopharyngeal neuralgia is an infrequent disorder consisting of pain similar in its quality and temporal characteristics, but its location lies at the base of the tongue, the tonsillar fossa, beneath the angle of the jaw, or in the auditory canal, following the distribution of the glossopharyngeal nerve or the auricular or pharyngeal branches of the vagus nerve. Swallowing, speaking, or coughing triggers the painful paroxysms. Spreading of glossopharyngeal impulses via the tractus solitarius into the vagal dorsal motor nucleus often provokes reflex bradycardia, heart block, or asystole resulting in syncope that may require insertion of a cardiac pacemaker.

Diagnosis
In both disorders the diagnosis is reached on the basis of the historical details and normal neurologic and dental examinations. Evaluation should include gadolinium-enhanced cranial magnetic resonance imaging (MRI) with high-resolution axial and coronal sectioning of the posterior fossa to exclude the possibility of a cerebellopontine angle tumor or a central demyelinating disorder. Unambiguous imaging of trigeminal vascular compression and nerve root demyelination are beyond the level of current MRI resolution.
Johnson: Current Therapy in Neurologic Disease (7/E)

Accurate diagnosis is important because trigeminal and glossopharyngeal neuralgia respond to antiepileptic medications but not to traditional analgesics. The mechanism is believed to be neural membrane stabilization or enhancement of gamma-aminobutyric (GABA)ergic trigeminal segmental inhibition. Nonsteroidal anti-inflammatory drugs, tricyclics, and opioids, for example, produce little if any relief. In most cases I initiate treatment with carbamazepine because of its superior efficacy (Figure 1). A starting dose of 100 mg two or three times daily is increased by 100 mg every other day until adequate pain relief is achieved or until intolerable side effects (usually sedation and ataxia) intervene. Typical effective maintenance doses are 300 to 800 mg daily and need not always be as high as those used to treat epilepsy. Pain can be completely controlled in some patients on 200 to 300 mg daily. Self-limited initial and dose-dependent side effects such as drowsiness, nausea, dizziness, ataxia, or diplopia can often be managed by titrating slowly. Uncommon but potentially serious adverse reactions can include allergic rash, bone marrow suppression, hepatotoxicity, lymphadenopathy, lupus erythematosus, Stevens-Johnson syndrome, and aplastic anemia. A complete blood count, serum sodium, and liver function tests should be checked within several weeks of initiating therapy and at least biannually thereafter. For the patient who, because of advanced age or medical comorbidity, is less able to tolerate carbamazepine, I may initiate treatment with gabapentin (see Figure 1). Although less efficacious than carbamazepine, gabapentin lacks serious adverse effects or drug interactions. A starting dose of 300 mg daily may be increased as tolerated by 300 mg every 3 days, divided three times a day, up to 2700 mg daily. Side effects may include dizziness, drowsiness, or peripheral edema. If pain persists, baclofen administered in combination or alone may be started at 5 to 10 mg three times a day. The daily dose is increased by 10 mg every other day as tolerated up to 60 mg daily. Common side effects are drowsiness, dizziness, asthenia, and gastrointestinal distress. If pain persists, I will promptly move on to oxcarbazepine or lamotrigine, either of which is a reasonable first- or second-line therapy. Oxcarbazepine is started at 150 mg twice daily and the daily dose increased as tolerated by 300 mg every 3 days to a typical maintenance dose of 300 to 600 mg twice daily. Side effects are similar to those of carbamazepine except that hyponatremia is more frequent. Lamotrigine is started at 25 mg twice daily and should be increased slowly by 100 mg/day every 1 to 2 weeks. Daily doses of 100 to 400 mg divided twice daily have been effective. Side effects may include diplopia, ataxia, dizziness, headache, and gastrointestinal distress. Lamotrigine should be promptly discontinued at the first sign of any rash, because serious rashes including Stevens-Johnson syndrome have occurred in approximately 0.1% of patients and usually appear within 2 to 8 weeks of starting treatment.

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Trigeminal and Glossopharyngeal Neuralgia

Paroxysmal facial pain

Normal neurological exam

Diagnosis of trigeminal neuralgia

Carbamazepine

Pain persists Add baclofen

Not tolerated Gabapentin

Pain persists or drugs not tolerated

Oxcarbazepine or Lamotrigine or Topiramate or Levetiracetam or Phenytoin Retry previously effective then other drugs Pain persists or drugs not tolerated

Surgical referral

Balloon compression or Microvascular decompression or Gamma knife

Pain recurs

FIGURE 1. Suggested scheme for treating trigeminal neuralgia. The same pharmacologic strategy may be applied to the treatment of glossopharyngeal neuralgia. The order of choices differs for individual patients.

I have found the newer anticonvulsants topiramate and levetiracetam also to be effective in occasional patients. Topiramate is started at 25 mg once or twice daily, and the daily dose may be increased by 25 mg every 3 days as tolerated to 100 to 400 mg divided twice daily. Side effects can include anorexia, weight loss, somnolence, anxiety, fatigue, psychomotor slowing, urolithiasis, and glaucoma. Levetiracetam is started at 500 mg twice daily, which can be doubled after 2 weeks. Side effects can include somnolence, asthenia, and dizziness. For the patient with refractory pain, potentially useful further options are phenytoin, clonazepam, and sodium divalproex.

the drug reaches steady state, if pain persists, the dosage should be increased within the limits of safety and tolerability. In contrast, starting at too high a dose or increasing the dose too rapidly could influence the patient to dismiss what might ultimately have proved to be a tolerable and effective drug. In such cases a retrial at a lower dose may be worthwhile. Decreased elimination half-life sometimes results in an apparent loss of efficacy over time and can be corrected by slightly increasing the drug dosage. Tachyphylaxis can develop months to years into treatment such that pain recurs despite increasing the dose of a previously effective drug. It is then time to advance to a second drug. I prefer to continue the first drug during the transition phase into the second drug, tapering the first drug once pain relief is achieved. The first drug may again prove effective if reintroduced months or years later. Since the natural history of trigeminal neuralgia consists of spontaneous remissions, I advise my patients to taper their medication once the pain has remained under control for a month. Incremental decreases on a weekly schedule are aimed at finding the lowest dose necessary to maintain freedom from pain. Medication should not be discontinued abruptly after long-term administration. I will also advise the patient who is pain free off medication to keep a ready standby supply not only at home but also when traveling in case the pain returns suddenly. I will honor the request of the occasional patient who may be in complete remission yet chooses to remain on medication for fear that excruciating pain might otherwise return, while tapering to the lowest possible dose. Neuralgia sometimes escalates to the point of crisis in the patient who presents in a state of desperate pain, losing weight and hydration because attempts to eat or drink set off more attacks. When urgent control of extreme pain is needed, treatment with intravenous fosphenytoin can provide reliable relief and usually requires a full loading dose of 14 mg/kg. Relief typically lasts 2 days and affords a window of opportunity for a simultaneously administered new oral medication to take hold or to prepare for surgical referral. Lidocaine, applied transcutaneously via patch or intraorally via viscous gel, or ophthalmic instillation of 0.5% proxymetacaine drops also may provide temporary relief.

Surgical Referral
Generally I reserve surgical referral for patients whose pain has proved refractory to a sufficient trial of at least three medications including carbamazepine. The most severe cases may warrant expedited medication trials while arranging neurosurgical backup. Some patients with pain very nearly controlled will nevertheless request surgery because they do not wish to endure the subtle cognitive side effects of long-term medication. Surgical intervention is best accomplished by a neurosurgeon who performs trigeminal nerve procedures regularly. Fluoroscopically guided ablative procedures include radiofrequency thermocoagulation and neurolysis using
Johnson: Current Therapy in Neurologic Disease (7/E)

Management Strategy
When initiating therapy, the clinician must balance the need to achieve rapid relief from pain with the need to avoid troublesome side effects. Increasing the dose too slowly can prolong the agony of neuralgia. As soon as

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glycerol, phenol, or streptomycin. First-division lesions carry the risk of corneal anesthesia, which can lead to keratitis. Third-division lesions may alter lingual sensation and affect speech. All carry the risk of anesthesia dolorosa, which is an enduring, continuous burning trigeminal pain that tends to respond poorly to medication. Among my patients I have seen the most favorable outcomes following percutaneous balloon compression of the trigeminal ganglion. Results are frequently satisfactory and long lasting, and this procedure seems to carry the least risk of compromising corneal sensation or inducing anesthesia dolorosa. Suboccipital microvascular decompression of the trigeminal nerve root is unique in that it addresses the presumed underlying pathology. Although highly effective and less likely than neurodestructive procedures to impair facial sensation, this procedure carries nontrivial risks of cranial nerve deficits, stroke, cerebellar hemorrhage, and more rarely, meningitis, air embolism, and seizures. Stereotactic gamma knife radiosurgery targeting the trigeminal nerve origin is a minimally invasive intervention that has shown promising initial results. Its main disadvantage is that the time to response is several months. Medically intractable glossopharyngeal neuralgia is likewise amenable to vascular decompression. Also helpful has been surgical sectioning of the glossopharyngeal nerve, which can be complicated by severe hypertension due to baroreflex denervation. Treating patients with trigeminal neuralgia is a rewarding part of the practice of neurology because successful treatments are available. The choice of specific treatment, whether medical or surgical, should be tailored to the individual patients needs. SUGGESTED READING
Cheshire WP: Trigeminal neuralgia: diagnosis and treatment, Curr Neurol Neurosci Rep 5:79-85, 2005. Cheshire WP: Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study, J Pain 3:137-142, 2002. Cheshire WP: Fosphenytoin: an intravenous option for the management of acute trigeminal neuralgia crisis, J Pain Symptom Manage 21:506-510, 2001. Cheshire WP: Trigeminal neuralgia: a guide to drug choice, CNS Drugs 7:98-110, 1997. Fromm GH, Sessle BJ, editors: Trigeminal neuralgia: current concepts regarding pathogenesis and treatment, Boston, 1991, Butterworth-Heinemann.

Herpes Zoster and Postherpetic Neuralgia


Ricardo Cruciani, M.D., Ph.D., and Sallu Jabati, M.D.

Definition
Herpes zoster is an acute, painful sensory mononeuropathy associated with a skin eruption due to a herpesvirus infection. In 90% of the cases it resolves in days to weeks, but 10% of patients progress into a debilitating, chronic, painful condition known as postherpetic neuralgia (PHN).

Etiology
The offending agent is the varicella zoster virus, a member of the herpes virus family that in children causes chickenpox. After the infection resolves, the virus remains dormant in the dorsal root ganglia. Years to decades after the chickenpox infection, for unclear reasons there is a reactivation of the virus in 2% of immunocompetent and 10% of immunocompromised patients. The virus replicates in the dorsal root ganglia, causing an inflammatory response with swelling, hemorrhage, areas of necrosis, and neuronal loss. Subsequently, the virus travels centrifugally along the nerve (producing in its course nerve inflammation and damage), to the skin, forming a self-limited rash known as shingles. This consists of multiple vesicular lesions with a red base from which multinucleated cells can be identified in a Tzanck smear. On occasion, the virus may travel centripetally toward the spinal cord (involving both sensory and motor areas) and the brainstem. In 50% of immunocompromised patients a generalized lifethreatening viral dissemination involving the central nervous system with a 10% to 20% mortality rate (encephalitis, angiitis) may develop, instead of the local reactivation of the virus.

Clinical Presentation
Herpes zoster usually starts with a prodromal phase characterized by pain, paresthesias (numbness/tingling), and dysesthesias (unpleasant sensations) in the affected dermatomes in a beltlike fashion followed a few days later by a maculopapular rash that evolves into vesicles. The vesicles do not cross the midline and can be quite painful, especially in the elderly. The characteristic vesicles usually scab over within 10 days and heal in a month, leaving behind a hypopigmented scar. Infrequently the prodrome is not followed by the skin lesions (zoster sine herpete), and laboratory work may be necessary to identify antibodies to herpes zoster. A fourfold increase has been used to support the

PATIENT RESOURCE
Trigeminal Neuralgia Association: http://www.tna-support.org/

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glycerol, phenol, or streptomycin. First-division lesions carry the risk of corneal anesthesia, which can lead to keratitis. Third-division lesions may alter lingual sensation and affect speech. All carry the risk of anesthesia dolorosa, which is an enduring, continuous burning trigeminal pain that tends to respond poorly to medication. Among my patients I have seen the most favorable outcomes following percutaneous balloon compression of the trigeminal ganglion. Results are frequently satisfactory and long lasting, and this procedure seems to carry the least risk of compromising corneal sensation or inducing anesthesia dolorosa. Suboccipital microvascular decompression of the trigeminal nerve root is unique in that it addresses the presumed underlying pathology. Although highly effective and less likely than neurodestructive procedures to impair facial sensation, this procedure carries nontrivial risks of cranial nerve deficits, stroke, cerebellar hemorrhage, and more rarely, meningitis, air embolism, and seizures. Stereotactic gamma knife radiosurgery targeting the trigeminal nerve origin is a minimally invasive intervention that has shown promising initial results. Its main disadvantage is that the time to response is several months. Medically intractable glossopharyngeal neuralgia is likewise amenable to vascular decompression. Also helpful has been surgical sectioning of the glossopharyngeal nerve, which can be complicated by severe hypertension due to baroreflex denervation. Treating patients with trigeminal neuralgia is a rewarding part of the practice of neurology because successful treatments are available. The choice of specific treatment, whether medical or surgical, should be tailored to the individual patients needs. SUGGESTED READING
Cheshire WP: Trigeminal neuralgia: diagnosis and treatment, Curr Neurol Neurosci Rep 5:79-85, 2005. Cheshire WP: Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study, J Pain 3:137-142, 2002. Cheshire WP: Fosphenytoin: an intravenous option for the management of acute trigeminal neuralgia crisis, J Pain Symptom Manage 21:506-510, 2001. Cheshire WP: Trigeminal neuralgia: a guide to drug choice, CNS Drugs 7:98-110, 1997. Fromm GH, Sessle BJ, editors: Trigeminal neuralgia: current concepts regarding pathogenesis and treatment, Boston, 1991, Butterworth-Heinemann.

Herpes Zoster and Postherpetic Neuralgia


Ricardo Cruciani, M.D., Ph.D., and Sallu Jabati, M.D.

Definition
Herpes zoster is an acute, painful sensory mononeuropathy associated with a skin eruption due to a herpesvirus infection. In 90% of the cases it resolves in days to weeks, but 10% of patients progress into a debilitating, chronic, painful condition known as postherpetic neuralgia (PHN).

Etiology
The offending agent is the varicella zoster virus, a member of the herpes virus family that in children causes chickenpox. After the infection resolves, the virus remains dormant in the dorsal root ganglia. Years to decades after the chickenpox infection, for unclear reasons there is a reactivation of the virus in 2% of immunocompetent and 10% of immunocompromised patients. The virus replicates in the dorsal root ganglia, causing an inflammatory response with swelling, hemorrhage, areas of necrosis, and neuronal loss. Subsequently, the virus travels centrifugally along the nerve (producing in its course nerve inflammation and damage), to the skin, forming a self-limited rash known as shingles. This consists of multiple vesicular lesions with a red base from which multinucleated cells can be identified in a Tzanck smear. On occasion, the virus may travel centripetally toward the spinal cord (involving both sensory and motor areas) and the brainstem. In 50% of immunocompromised patients a generalized lifethreatening viral dissemination involving the central nervous system with a 10% to 20% mortality rate (encephalitis, angiitis) may develop, instead of the local reactivation of the virus.

Clinical Presentation
Herpes zoster usually starts with a prodromal phase characterized by pain, paresthesias (numbness/tingling), and dysesthesias (unpleasant sensations) in the affected dermatomes in a beltlike fashion followed a few days later by a maculopapular rash that evolves into vesicles. The vesicles do not cross the midline and can be quite painful, especially in the elderly. The characteristic vesicles usually scab over within 10 days and heal in a month, leaving behind a hypopigmented scar. Infrequently the prodrome is not followed by the skin lesions (zoster sine herpete), and laboratory work may be necessary to identify antibodies to herpes zoster. A fourfold increase has been used to support the

PATIENT RESOURCE
Trigeminal Neuralgia Association: http://www.tna-support.org/

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diagnosis of subclinical herpes zoster. However, a rising titer secondary to viral exposure rather than reactivation cannot be ruled out. The elderly individual undergoing high levels of stress, and immunocompromised patients (acquired immunodeficiency syndrome, cancer, treatment with steroids, chemotherapy, transplant recipients, or immunosuppressant), are at high for herpes zoster infection. After the scab forms, the lesions are not contagious. The scarred areas are less sensitive and often anesthetic. Paradoxically the skin may exhibit marked superficial pain with light touch (allodynia) or an increased sensitivity to noxious stimulation (hyperalgesia). In most patients the resolution of the skin lesions is accompanied by decreased pain. The reactivation typically affects one thoracic dermatome unilaterally (does not cross midline), but it can affect multiple sites including limbs and cranial nerves. The more commonly affected cranial nerve is the ophthalmic branch of the fifth nerve (V1) and the infection may involve the eye, producing keratitis and/or uveitis. Aggressive treatment is crucial to avoid subsequent scarring and compromised vision. Early consultation with ophthalmology is highly recommended. Palsies of cranial nerves III, IV, and VI can also occur. When shingles affects the geniculate ganglion, it is called Ramsay Hunt syndrome and can cause facial paralysis, hearing loss, and vertigo and pain. Vesicles in the tympanic membrane may be the only observable sign. The most common complication of herpes zoster is PHN. This is usually a self-limited condition defined as pain persisting beyond 3 months of the resolution of the skin lesions. The most well-established risk factors for PHN are older age, greater severity of acute pain during zoster, more severe rash, and a prodrome of dermatomal pain before onset of the rash. Symptoms tend to abate over time. Less than one fourth of the patients still experience pain at 6 months after the herpes zoster eruption, and fewer than one in 20 has pain at 1 year. Patients may complain of a steady burning or aching pain with or without paroxysmal lancinating pain. Both may occur spontaneously and may be aggravated by even the lightest contact. It is not unusual for patients to complain that they cannot tolerate the contact of clothing or the bed sheets at night. Some have to stay away from fans or air conditioning; even the light breeze provoked by fast walking can cause significant discomfort. Physical activity, temperature change, and emotional upsets may cause the exacerbation of the pain. The patients quality of life can become severely affected, and depression may develop.

been speculated that aggressive treatment of the acute infection may prevent plastic changes in the central nervous system that may be responsible for the development of PHN. There is some evidence that the use of antiviral agents (acyclovir, valacyclovir, famciclovir) within the first 72 hours may prevent viral replication and thus reduce the severity of the acute eruption and the incidence of PHN. The use of amitryptiline (a tricyclic antidepressant), 10 to 50 mg/day, may also have a similar preventive effect. Prednisone has been used with a variable degree of success with the same objective. In at least one study, when administered close to the onset of the episode, steroids can decrease pain at 3 and 12 months. Other studies have demonstrated no benefit. However, when used in conjunction with acyclovir it has been shown to reduce the pain associated with herpes zoster. Hence, if there are no contraindications, oral prednisone can be used in the treatment of the herpes zoster episode despite unclear evidence on the prevention of PHN (Figure 1).

Treatment of Postherpetic Neuralgia


A pharmacologic approach is the standard of care. A number of antidepressants and anticonvulsants have been advocated for the treatment of this condition. There are several general concepts that may increase the success rate in the treatment of PHN that could also be applied to other forms of neuropathic pain. They include the following: The results are variable and the selection of the pharmacologic agent has to be customized to the individual patient. It is important to consider that failure to respond to an antidepressant or an anticonvulsant does not preclude response to a different agent from the same pharmacologic family. Be aware that there is a significant degree of variability in the dose range and time before pain relief is seen. Discussion of the treatment plan with the patient may increase compliance. For a trial to be considered negative, it has to cover an extensive dose range and last for at least 4 to 6 weeks. Failure of treatment is commonly associated with inadequate titration of dose and/or short trial duration. There is no correlation between plasma levels and response. It is recommended to start at a low dose to decrease the incidence of side effects, a common cause for abandonment of treatment.

Treatment of Herpes Zoster


ANTICONVULSANTS The acute pain can be treated topically and systemically. Covering the lesions with calamine lotion, petroleum jelly, local anesthetic creams, or an occlusive bandage may give some symptomatic relief. Systemic medications include nonsteroidal anti-inflammatory drugs with or without codeine, but due to the intensity of the pain, more potent opioids may be indicated. It has Gabapentin Gabapentin has been shown to be of benefit in the treatment of PHN in two double-blind, placebo-controlled studies. Owing to its low incidence and severity of side effects, it has been advocated as a first-line drug for the treatment of PHN. Although its mechanism of action
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CNS involvement (myelitis/angiitis)

Herpes zoster (shingles)

Herpes zoster ophthalmicus (keratitis/retinitis) Early referral to ophthalmology IV acyclovir 10 mg/kg every 8 h for 7 to 14 days Prevention of corneal exposure

Acyclovir 10 mg/kg q8h (adults) or 500 mg/m2 body surface (children) for 7 days. Prednisone 6080 mg/day for 35 days Stop treatment if negative zoster PCR in the CSF.

Skin lesions

No lesions (zoster sine herpete)

Topical

Acute pain

Systemic

Cover area Calamine After scab forms may use lidocaine cream or patch

Persistent pain >13 months after resolution of skin lesions

Acyclovir: PO: 800 mg five times daily for 7 to 10 days IV: 10 mg/kg every 8 hours for 7 to 10 days or Famciclovir: 500 mg orally three times daily for 7 days or Valacyclovir: 1,000 mg orally three times daily for 7 days Prednisone: 30 mg orally twice daily for 7 days then 15 mg twice daily for 7 days then 7.5 mg twice daily for 7 days Amitriptyline: elderly: 10 mg qhs, others 20 mg qhs. Titrate up to 100150 mg/day qd if needed and tolerated

Topical

Chronic pain postherpetic neuralgia (PHN)

Systemic

Lidocaine patch 5%, 12h on, 12h off; up to 3 patches at a time (minimum of 2 weeks trial) Capsaicin 0.075%. Initial exacerbation of pain limits its use.

NSAIDs + adjuvants: Gabapentin: 300 mg/day for 3 days, then b.i.d. for 3 days, then t.i.d., then double. If additional benefit then continue titration up to 3600 mg/day. If side effects Tiagabine: 150300 mg/day If no effect Amitriptyline (if already on it, titrate) elderly: 10 mg qhs, others 20 mg qhs. Titrate up to 100150 mg/day q.d. if needed and tolerated If no effect or side effects Newer anticonvulsants (topiramate, levetiracetam, lamotrigine, oxcarbazepine) or other antidepressants (desipramine, nortriptyline) Opioids: May use at initiation of treatment for intense pain. Oxycodone 5 mg tabs q 4h. Once taking >20 mg q.d. introduce long-acting form.

No response or intolerable side effects

Nerve blocks Spinal cord stimulation Intrathecal methylprednisolone

FIGURE 1. Algorithm for approach to the treatment of herpes zoster. PCR, Polymerase chain reaction; CSF, cerebrospinal fluid; CNS, central nervous system; NSAIDs, nonsteroidal anti-inflammatory drugs.

has been elusive for many years, recently it has been shown to bind to the alpha2-delta subunits of the voltage-sensitive calcium channels. Its pharmacokinetic profile (with renal excretion) makes it safe in patients taking a variety of medications. Since only 10% binds to plasma proteins, the drug has little effect on the
Johnson: Current Therapy in Neurologic Disease (7/E)

international normalized ratio in patients on warfarin (Coumadin) anticoagulation. The liver does not metabolize gabapentin; hence, it does not compete for the P-450 with the selective serotonin receptor inhibitors. The dose may need to be reduced in patients with elevated creatinine.

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Pregabalin In a double-blind, placebo-controlled clinical trial, pregabalin in doses ranging from 150 to 300 mg/day reduced pain scores by more than 50% in patients with PHN. The mechanism of action and side effect profile are similar to those of gabapentin. However, since it has a linear pharmacokinetic profile, there is less interindividual variability and the dose range is more narrow and predictable. It also may have fewer side effects than gabapentin. Other Anticonvulsants When an adequate response is not achieved or in the presence of unacceptable side effects, trials with other anticonvulsants can be attempted. Topiramate, lamotrigine, levetiracetam, zonegram, and tiagabine have been shown to be of help in certain forms of neuropathic pain, and they may be helpful in the treatment of PHN. Both carbamazepine and phenytoin have been used in the past with some degree of success, but their use has been relegated to second- or third-line agents due to the high incidence and severity of side effects. ANTIDEPRESSANTS Amitriptyline Among the tricyclic antidepressants, amitriptyline is the most extensively studied. In a double-blind, placebocontrolled clinical study, amitriptyline showed significant pain relief in patients with PHN. Unfortunately the tricyclics may cause dose-limiting side effects due to their anticholinergic activity. Side effects (dry mouth, impotence, constipation, urinary retention, tachycardia, confusion) may be ameliorated by starting at low doses, slow titration, and night administration when possible. Side effects are more prominent in the elderly. The starting dose is 10 to 20 mg and because of potential somnolence and sedation, it should be given at bedtime. This side effect may be of help in patients with insomnia, a common comorbidity in chronic pain patients. On occasion, doses of 100 to 150 mg a day may be necessary. When dosing above 75 to 100 mg a day (or lower if side effects are observed), blood levels should be determined to avoid toxicity. Desipramine, a tricyclic with less severe anticholinergic effects, and nortriptyline have also been shown to be effective in controlled studies for the treatment of PHN. OPIOIDS Depending on the intensity of the pain, opioids may need to be introduced early in the treatment plan for both herpes zoster and PHN. A placebo-controlled clinical study with the extended form of oxycodone has shown significant pain relief in patients with PHN. The opioids, when used in the right context, can be a valuable tool. The patient must be warned of the potential side effects, which include physical dependence, constipation, nausea/vomiting, sedation, and the potential for addiction. If certain guidelines are followed (patient

cannot change dosing on his or her own, only one practitioner writes the prescriptions, utilization of only one pharmacy, frequent assessments), they are safe to use. Patients with a history of drug abuse can represent a unique challenge. When treating patients who are attending a methadone program, it is advisable to discuss the plan with the methadone maintenance treatment program clinic counselor and use methadone for the treatment of pain. Methadone is an interesting drug that, due to its low cost and long half-life, has been advocated for the treatment of chronic pain. The formulation available in the United States is a racemic form. While the L-enantiomer activates mu opioid receptors inducing analgesia, the D-enantiomer blocks (weakly) N-methyl-D-aspartatemediated excitatory responses, believed to be exacerbated in neuropathic pain. Urine toxicology, pill counting, and contracts are useful tools that have to be tailored to the patient. LOCAL ANESTHETICS Topical Lidocaine Double-blind, placebo-controlled trials with lidocaine 5% in a patch form have been shown to alleviate pain in PHN. Up to three patches can be used at a given time. The patches should be used 12 hours on and 12 hours off. No significant side effects have been observed with this regimen. The patch can be used alone or in combination with other adjuvants (e.g., gabapentin). The combination of the lidocaine patch with gabapentin has proved to be more effective than the two agents separately. Intravenous Lidocaine The pain crisis may be managed with intravenous (IV) administration of lidocaine. This procedure can be done on an outpatient basis. When pain scores improve more than 50%, oral mexiletine can be initiated. The IV dose is converted into an equivalent oral dose, and the titration up can be continued by 150 mg at a time every 3 to 4 days if tolerated. Patients may require up to 400 to 500 mg a day to experience relief. Capsaicin Capsaicin 0.075% cream has been shown to decrease pain. The initial application may temporarily exacerbate pain possibly due to depletion of substance P or activation of nociceptors, which frequently results in abandonment of treatment.

Conclusion
Although the literature is not conclusive, it is recommended to treat herpes zoster infection aggressively to decrease PHN. No single best treatment for PHN is known. Both topical and systemic therapies can be initiated simultaneously. If the pain is very intense, opioids can be initiated early into the regimen.
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SUGGESTED READING
Davis PS, Gailor BS: Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia, Drugs 64:937-947, 2004. Dworkin RH, Schmader KE: Epidemiology and natural history of herpes zoster and postherpetic neuralgia. In Watson CPN, Gershon AA, editors: Herpes zoster and postherpetic neuralgia, ed 2, New York, 2001, Elsevier, 39-64. Helgason S, Petursson G, Gudmundsson S, et al: Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long-term follow-up, BMJ 321:794-796, 2000. Raja SN, Haythornthwaite JA, Pappagallo M, et al: Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebocontrolled trial, Neurology 59:1015-1021, 2002. Rowbotham M, Harden N, Stacey B: Gabapentin for the treatment of postherpetic neuralgia: a randomized, controlled trial, JAMA 280:1837-1842, 1998.

Sabatowski R, Galvez R, Cherry DA, et al, and the 1008-045 Study Group: Pregabalin reduces pain and improves sleep and mood disturbances in patients with postherpetic neuralgia: results of a randomized, placebo-controlled clinical trial, Pain 109:26-35, 2004. Tyring S, Barbarash RA, Nasklik JE: Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group, Ann Intern Med 123:89-96, 1995. Watson CP, Vernich L, Chipman M: Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial, Neurology 51:1166-1171, 1998. Whitley RJ, Shukla S, Crooks RJ: The identification of risk factors associated with persistent pain following herpes zoster, J Infect Dis 178(Suppl 1):S71-S75, 1998.

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SECTION 5

Developmental Disorders
Neonatal Encephalopathy
Steven P. Miller, M.D., C.M., F.R.C.P.C.
hypocalcemia, hyponatremia, hypoxemia, and acidosis are frequently seen and should be identified and treated. Lumbar puncture should be performed if the history is not typical for hypoxic-ischemic encephalopathy to rule out intracranial infections. Neuroimaging has become increasingly important for the accurate diagnosis of neonatal encephalopathy in the term newborn. The American Academy of Neurology practice parameter suggests that a noncontrast computed tomography (CT) scan should be performed to detect hemorrhagic lesions with a history of birth trauma, low hematocrit, or coagulopathy. If CT findings are inconclusive, magnetic resonance (MR) imaging should then be performed (on days 2 and 8 of life) to establish the pattern of injury and predict neurologic outcome. Other observations suggest that CT scan is not often helpful in making a diagnosis since it is relatively insensitive to changes in water content and because injury in the posterior fossa can be obscured by bony artifact. Given this, CT is best used to determine the extent of bleeding in an emergency situation where MR imaging is not available. MR imaging has proved to be a sensitive technique to determine injury in term neonatal encephalopathy and can help establish the diagnosis of hypoxic-ischemic injury. MR imaging helps to narrow the differential diagnosis in the evaluation of an encephalopathic neonate who might have an underlying metabolic, neurogenetic, neurovascular, or inflammatory disease requiring intervention. As the first step in caring for an encephalopathic newborn is establishing the diagnosis, MR imaging should be performed in the first week of life as the diagnostic test of choice. Additionally, MR imaging, particularly in combination with MR spectroscopy, can provide important prognostic information. Regardless of the specific etiology, the importance of the immediate management of neonatal encephalopathy cannot be overestimated. The management of moderate or severe encephalopathy should occur in a neonatal intensive care unit in close collaboration with a neonatologist. Immediate management requires securing an appropriate airway and maintaining adequate ventilation and circulation. As discussed earlier, an important component of the diagnostic work-up is to identify treatable conditions causing neonatal encephalopathy that require specific therapy. Blood tests obtained routinely are serum glucose, arterial or capillary blood gas, 89

Neonatal encephalopathy is a major cause of neurodevelopmental disability in term infants, occurring in 1 to 6 per 1000 live term births. Neonatal encephalopathy is a serious condition: 15% to 20% of affected infants will die during the newborn period, and an additional 25% will sustain permanent clinical deficits. Hypoxic-ischemic encephalopathy certainly accounts for a substantial proportion of these patients, yet many cases of neonatal encephalopathy have no documented hypoxic-ischemic insult. Furthermore, there is continuing controversy as to whether neonatal encephalopathy is primarily related to insults sustained in the antepartum or intrapartum period. For the purpose of this article, the term neonatal encephalopathy is used instead of hypoxic-ischemic encephalopathy, in recognition of the many variables in the etiology and timing of this syndrome. As many causes of neonatal encephalopathy have specific therapies, a critical part of management is to determine the diagnosis. The diagnosis is made through careful history taking and neurologic examination, with laboratory studies to exclude conditions with specific therapy. Metabolic abnormalities (including inborn errors of metabolism), infection, trauma, and malformations of cerebral development all can result in neonatal encephalopathy. The history should elicit indicators of intrauterine distress: fetal heart tracing abnormalities, passage of meconium, or difficulty in labor or delivery that may have contributed to decreased placental or fetal blood flow. Hypoxicischemic brain injury is frequently accompanied by a history of difficult resuscitation including cardiopulmonary resuscitation, medications in the delivery room, intubation, and assisted ventilation at birth. Seizures, apneic episodes, jitteriness, and abnormal cry all are indicators of brain injury but do not identify the etiology of the injury. Because the clinical signs are often not specific for an etiology, laboratory tests are critical to exclude reversible causes of neonatal encephalopathy. Metabolic complications such as hypoglycemia,
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electrolytes (including calcium and magnesium), and a complete blood count with differential. Determinations of liver enzymes and serum creatinine are performed to detect injury in other end organs. If the history or examination is atypical for hypoxic-ischemic injury, a lumbar puncture is performed to rule out intracranial infections, and serum ammonia and lactate levels are obtained to expedite the investigation of an inborn error of metabolism. If infection is suspected, ampicillin and gentamicin are empirically started in addition to acyclovir if herpes simplex virus infection is suspected. If an inborn error of metabolism is suspected based on the history, examination, and the initial laboratory investigations, early treatment is crucial. Management in this situation, in consultation with a biochemical geneticist, includes stopping feeds, correcting acidosis and hypoglycemia, and considering hemodialysis based on the specific metabolic disorder. Additional diagnostic tests such as serum amino acids and urine organic acids are required to identify the specific disorder. The diagnosis of a severe intracranial hemorrhage on neuroimaging should prompt consultation with a neurosurgeon to manage raised intracranial pressure from mass effect or hydrocephalus and confirmation of platelet levels and coagulation function. In cases where neonatal encephalopathy is caused by hypoxic-ischemic injury, it is important to point out that at this time there is no specific treatment for the injury. The specific management of neonatal hypoxic-ischemic brain injury, therefore, focuses on preventing secondary brain injury. Since the clinical syndrome evolves considerably over the first 72 hours of life, management of specific complications can often be anticipated. As the clinical signs and symptoms depend on the severity, timing, and duration of the insult, it is extremely helpful to perform serial neurologic examinations. The severity of the encephalopathy can be measured daily for the first 3 days of life using a simple bedside encephalopathy score (Table 1). Not only is this score helpful in determining prognosis but it allows the management team to monitor the evolution of the clinical syndrome. The evolution of the clinical syndrome associated with hypoxic-ischemic injury is described in detail by Volpe (see Suggested Reading). The first 12 hours after birth are dominated by a depressed level of consciousness and

breathing abnormalities, including apnea. Ventilatory support with mechanical ventilation or continuous positive airway pressure is often required. Significant bradycardia and hypotension may require treatment with agents such as dopamine. Cerebral cortical involvement may present as hypotonia with decreased movement or as jitteriness. Seizures are seen in 50% of severely affected infants by 6 to 12 hours after birth. Seizures at this stage are often subtle, manifesting as ocular movements such as tonic horizontal eye deviation, tongue or lip smacking, bicycling movements of the extremities or as recurrent apnea. It is therefore important to alert the nursing staff to identify and document paroxysmal behaviors. Multifocal or focal clonic seizures may also occur, and they often indicate focal cerebral infarction. The management of neonatal seizures is outlined later. During the 12- to 24-hour period after the injury there is an apparent increase in the level of alertness that is not accompanied by other signs of improvement in neurologic function. This should not be falsely reassuring because it is frequently accompanied by more seizures and apneic episodes. An electroencephalogram (EEG) is helpful on the first day to assess background activity and determine the presence of electrographic seizures. After 24 to 72 hours following severe brain injury the infants level of consciousness deteriorates again, often accompanied by brainstem and respiratory depression requiring ventilatory support. During this period cerebral edema resulting from hypoxia-ischemia is maximal and can further impair cerebral blood flow secondary to increased vascular pressure. Most investigators avoid treatment of cerebral edema in this setting, because many interventions such as corticosteroids, hyperventilation (PaCO2 of 20 to 25 mm Hg), furosemide, or mannitol may be harmful. Follow-up EEG during this period is used primarily to determine the progression of background activity. Infants surviving beyond 72 hours often have an improvement in level of consciousness, needing less intensive care but requiring attention to feeding because suck and swallow often remain impaired. Neonatal seizures require treatment to prevent secondary brain injury, either from the seizures themselves or from the associated impairments in respiration and hemodynamics. Anticonvulsant medication should be

TABLE 1 Neonatal Encephalopathy Score*


Encephalopathy Feature Feeding Alertness Tone Respiratory status Reflexes Seizure Total Abnormal Signs Gavage feeds, gastrostomy tube, or not tolerating oral feeds Irritable, poorly responsive, or comatose Hypotonia or hypertonia Respiratory distress (need for CPAP or mechanical ventilation) Hyperreflexia, hyporeflexia, or absent reflexes Suspected or confirmed clinical seizure Score if Abnormal 1 1 1 1 1 2 0 -7

*Because the duration of an abnormal neurologic examination is usually helpful in predicting long-term neurologic disability, newborns are scored daily for the first 3 days of life and the maximum score is considered. CPAP, Continuous positive airway pressure.

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initiated only after adequate ventilation and perfusion have been established and the blood glucose concentration has been measured. The following guidelines are presented for the treatment of neonatal encephalopathy with seizures: Ensure adequate ventilation and perfusion. Correct metabolic disturbances, in particular hypoglycemia, hyponatremia, hypocalcemia, and hypomagnesemia. Begin anticonvulsant therapy. The three main anticonvulsants for use in the newborn are the following: Phenobarbital: 20 mg/kg intravenously (IV); if necessary, administer additional 10 to 20 mg/kg IV in 10 mg/kg aliquots. Monitor blood pressure and respiration. A therapeutic drug level of 40 microgram/ml or greater is targeted. Maintenance dose is 4 to 6 mg/kg per 24 hours IV or orally (PO). Lorazepam: 0.05 to 0.1 mg/kg IV over several minutes. Again, monitor closely for respiratory depression. The half-life of lorazepam in asphyxiated newborns can be as long as 40 hours, with duration of action from 6 to 24 hours. Lorazepam can be repeated at this dose (0.05 to 0.1 mg/kg IV) every 6 to 8 hours as short-term maintenance if necessary. Phenytoin: 20 mg/kg IV (diluted in 0.9% NaCl); maximal rate is 1 mg/kg/min. Monitor cardiac rate and rhythm. Maintenance dose is 5 mg/kg IV per 24 hours. Note that phenytoin is poorly absorbed orally in the newborn and is not recommended as oral maintenance therapy. Pyridoxine deficiency is a rare cause of neonatal seizures and should be considered in any newborn with intractable seizures. The diagnosis is made by pyridoxine IV with concurrent EEG. The literature supports the use of phenobarbital as the first-line agent and phenytoin as a second-line agent for seizures associated with neonatal encephalopathy. These medications, especially phenobarbital, are frequently associated with electroclinical dissociation, with control of clinical seizures but not electrographic ones. Lorazepam may be more effective in the acute setting, particularly for control of both clinical and electrographic seizures. Lorazepam can often be used as a single agent because seizures associated with neonatal encephalopathy are often limited to the first 3 days of life. If seizures are not controlled by lorazepam, phenobarbital can be added. If seizures are not controlled after the addition of phenobarbital, phenytoin can be started. Before giving a second dose or a second medication, it is important to consider the following: Is the diagnosis correct? Are ventilation and perfusion optimal? Are metabolic disturbances recognized and corrected? The optimal duration of therapy for neonatal seizures is controversial, given the potential detrimental effects of these medicines on longer-term brain development.

If phenytoin is started, attempts to stop this medication are best done prior to the childs advancing to full oral feeds because this medication is not reliably absorbed orally. Discontinuing phenobarbital is considered when the neurologic examination is normal or, if the neurologic examination does not normalize, when the EEG is normal. Phenobarbital is discontinued as a slow taper over 6 weeks. The continued need for anticonvulsant medication should be evaluated prior to discharge and at each follow-up visit as an outpatient, in an attempt to treat for the shortest duration possible. Considerable advances continue to be made in understanding the mechanisms of neonatal encephalopathy. Preventing the conditions that underlie neonatal encephalopathy is ultimately the best treatment strategy. Several approaches, such as selective cerebral hypothermia, are now actively being evaluated to treat neonatal encephalopathy resulting from hypoxic-ischemic brain injury. The results of these forthcoming studies may substantially alter the management of affected infants. Until such strategies are proved effective and implemented, child neurologists will continue to follow survivors of neonatal encephalopathy. At follow-up, these infants and children require specific attention to language and cognitive function, motor function, feeding skills, and epilepsy. Acknowledgment The author thanks Drs. Donna Ferriero, Shannon Hamrick, and William Weiss for critical review of this chapter. SUGGESTED READING
Badawi N, Kurinczuk JJ, Keogh JM, et al: Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study, BMJ 317:1549-1553, 1998. Badawi N, Kurinczuk JJ, Keogh JM, et al: Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study, BMJ 317:1554-1558, 1998. Cowan F, Rutherford M, Groenendaal F, et al: Origin and timing of brain lesions in term infants with neonatal encephalopathy, Lancet 361:736-742, 2003. Finer NN, Robertson CM, Richards RT, et al: Hypoxic-ischemic encephalopathy in term neonates: perinatal factors and outcome, J Pediatr 98:112-117, 1981. Ment LR, Bada HS, Barnes P, et al: Neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 58:1726-1738, 2002. Miller S, Newton N, Ferriero D, et al: MRS predictors of 30-month outcome following perinatal depression: role of socio-economic factors, Pediatr Res 52:71-77, 2002. Miller SP, Latal B, Clark H, et al: Clinical signs predict 30-month neurodevelopmental outcome after neonatal encephalopathy, Am J Obstet Gynecol 190:93-99, 2004. Nelson KB, Ellenberg JH: The asymptomatic newborn and risk of cerebral palsy, Am J Dis Child 141:1333-1335, 1987. Vannucci RC, Perlman JM: Interventions for perinatal hypoxicischemic encephalopathy, Pediatrics 100:1004-1014, 1997. Volpe J: Neurology of the newborn, ed 4, Philadelphia, 2001, WB Saunders.

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Chiari Malformations and Syringomyelia


Roger W. Kula, M.D.

TABLE 1 Major Causes of Syringomyelia


Chiari I malformation Spine/spinal cord trauma Meningitis and other infections including intraspinal abscess Subarachnoid hemorrhage Tumors of spinal column or cord Diastomatomyelia Developmentally persistent central canal

Chiari malformations were traditionally known to include a complex group of disorders characterized by herniation of the cerebellum through the foramen magnum into the spinal canal. Chiari malformation type I (CMIs) was first described by the pathologist Hans von Chiari in the late 1800s and constituted the simplest and most prevalent example of this continuum of hindbrain malformations. The easily recognized Chiari II malformation was associated with spinal myelomeningocele and hydrocephalus. The much rarer Chiari III/IV malformations were associated with cervical spina bifida and encephalocele or severe cerebellar hypoplasia. These more severe congenital malformations were apparent at birth and associated with complex abnormalities of the brain and spinal cord. CMI, which forms the focus of this chapter, is now properly considered to be a malformation of the mesoderm in which a hypoplastic posterior fossa results in neural compression within the posterior fossa. Herniated cerebellar tonsillar tissue, furthermore, blocks the circulation of cerebrospinal fluid between the posterior fossa and spinal canal and results in a 20% to 70% incidence of syrinx cavity formation within the spinal cord. Likewise, CMI defined as tonsillar herniation of at least 3 to 5 mm below the foramen magnum, accounts for the predominant overall etiology of syringomyelia (SM) (70%).

diagnosis. Older characterizations based on pathologic case reviews can be seen to fall short of current clinical understanding.

Clinical Presentations
CHIARI MALFORMATION I Patients with CMI may experience no symptoms. When symptoms are present, they usually do not appear until adolescence or early adulthood. Most patients complain of severe pressure-like occipital headache and neck pain. Other common symptoms are listed in Table 2. Because of this complex symptomatology, patients with CMI are frequently misdiagnosed. At least one fourth of patients manifest symptoms following relatively minor head injury or neck injury, again frequently complicating the understanding of their underlying disorder and raising issues of malingering or secondary litigious gain. Symptoms can occasionally be seen in young children who are more likely to present with oropharyngeal dysfunction and scoliosis. A number of children younger than 3 years of age have undergone fundoplication and/or gastrostomy because of vomiting and reflux before a neurologic diagnosis was entertained. The typical posterior fossa or Chiari headache requires clearer definition. Patients describe a suboccipital pain in the head that is pressure like and more often continuous but variable rather than episodic. It is more likely to be exaggerated by bearing down with bowel movements or with laughter, crying, or orgasm than cough or sneeze, the fact of which many patients are reluctant to volunteer. The pain radiates most prominently to the retro-orbital regions and the vertex. It is explosive in character rather than throbbing or pounding. Although visual sparkles and scotomas may occur, these punctuate the peaks of headache rather than occurring as a prodrome, and the headache is almost never hemicranial. Many patients languish in headache clinics as medication-resistant or narcoticdependent chronic daily headache patients. Many, because of a longstanding history, chronic depression, and multiple symptomatic complaints in the absence of abnormal neurologic findings, have never been properly imaged. The frequent presence of neck pain without radicular features, except for evanescent hand numbness and tingling, and other generalized musculoskeletal complaints with negative rheumatologic evaluations have led to their frequent labeling as chronic fatigue or
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Epidemiology
Having so set the stage, it is appropriate to shift focus from the early pathologic characterization of these disorders to their increasingly frequent clinical presentations. Until the advent of more easily obtainable magnetic resonance (MR) scanning and more sophisticated sagittal imaging, CMI was regarded as a rare condition. Current estimates range from 200,000 to 2 million Americans affected with this condition. New genetic studies support a hereditary tendency with a transmissibility rate approaching 12%. Women are affected three times more often than men. Not surprisingly, MR imaging technology has led to the recognition of syrinx cavities that previously might have escaped even postmortem identification. A recent estimate suggests the prevalence of SM in the U.S. population to be between 140,000 to 210,000 individuals, or about 1 in 1300 to 1900 Americans, considering all causes (Table 1). Since increasingly well-defined strategies now exist to investigate, diagnose, and medically and surgically manage these patients, it is of ever greater importance to understand their clinical presentations and redefine the place of these lesions in the neurologic differential

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TABLE 2 Chiari Malformation Type I (CMI) Symptoms

From Milhorat TM, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings in 364 symptomatic patients, Neurosurgery, 44:1005-1017, 1999.

fibromyalgia patients. Many patients may be simultaneously affected by migraine headache because of its prevalence and both may be exacerbated premenstrually, but the Chiari headache responds little or not at all to common migraine treatments with antidepressants, beta blockers, and triptans. Commonly used non-narcotic medications (e.g., Fiorinal, Esgic, Midrin, and nonsteroidal anti-inflammatory drugs) may give some relief, and topiramate (Topamax) with its cerebrospinal fluid (CSF) pressure-lowering carbonic anhydrase activity may offer some falsely reassuring benefit. The patients neurologic examination is rarely objectively abnormal. The most typical finding is a vestibular-like dysequilibrium and difficulty in tandem standing and walking. Nystagmus is difficult to appreciate even with Fresnel lens examination. Objective findings frequently elude sophisticated vestibular testing, which only occasionally reveals nystagmus of possible central or peripheral etiology but which routinely fails treatment with vestibular rehabilitation. Classic downbeat nystagmus is rarely seen even with tonsillar descent as striking as 20 mm. SYRINGOMYELIA SM occurs when a tubular cavity or syrinx develops within the spinal cord resulting from an obstruction of spinal fluid circulatory pathways. In CMI, most (80%) of these occur within the cervical cord. The thoracic cord can, however, be affected in isolation, and more rarely a lumbosacral syrinx may appear associated with spinal cord tethering secondary to a thickened and restrictive filum terminale. Approximately 70% of SM cases result from CMI, with an additional small percentage associated with a hypoplastic posterior fossa as suggested by recent studies. The remaining occurrences are listed in Table 1. The syrinx cavities can give rise to painful sensory disturbances and both lower motor neuron and upper motor neuron paralytic signs. Painful neuropathic dysesthesias are most likely to occur at or adjacent to the caudal extent of the syrinx cavity.
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Symptoms are more related to the pace of evolution of the syrinx than to its absolute size. Otherwise healthy patients with slitlike syrinx cavities may present with severe localized spinal and radicular pain. Other patients with syrinx cavities displacing as much as 90% of the spinal cord mass may be virtually asymptomatic. The classic dissociated sensory loss (preserved touch sensation in the face of absent pain sensation) considered indicative of SM is rarely identifiable. The importance of identifying Chiari headache and associated CMI or its other causes (Table 3) and SM lies in the availability of sound medical and surgical approaches to treatment and the invaluable provision to these patients of an understandable explanation for their misery. The secret to their identification lies in elevating them to a level of consideration through a clear appreciation of their often insidious and subtle manifestations.

Initial Diagnostic Evaluation


In the initial evaluation of these patients, an extensive clinical history and physical examination are appropriate with an open mind toward multisymptomatic

TABLE 3 Secondary Causes of Tonsillar Descent and Chiari Headache


Hydrocephalus, obstructive Pseudotumor syndrome Arachnoid cyst of posterior fossa Basilar invagination Craniosynostosis Achondroplasia Hypophosphatemic rickets Pagets disease or other hyperostotic bone disease Chronic spinal cerebrospinal fluid leak Spinal cord tethering either congenital or secondary to trauma

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presentations (see Table 2). Once either of these conditions rises to a suspicion in differential diagnosis, appropriate imaging studies are a paramount consideration (Table 4). The diagnosis of CMI has traditionally been left in the hands of neuroradiologists identifying a threshold level of tonsillar descent usually greater than 3 to 5 mm. Although sagittal imaging of the craniocervical junction has revolutionized the detection of CMI, tonsillar structure and its radiological representation with volume averaging techniques frequently underestimate the anatomic degree of tonsillar descent. Specific radiologic criteria for the identification of tonsillar ectopia and CMI are fuzzy. Recent analyses of posterior fossa dimensions and subtle abnormalities of CSF flow at the craniocervical junction may make it possible to more easily identify a hypoplastic posterior fossa (with only minimal or no tonsillar descent) sometimes referred to as Chiari zero. This may increase diagnostic sensitivity but complicate an already controversial diagnosis. The average position of the cerebellar tonsils in normal series is approximately 3 mm above the foramen magnum. The most constant feature of CMI is a volumetrically small posterior fossa, which predisposes patients to hindbrain overcrowding. The goal of the diagnostic work-up is to establish a correct diagnosis, separate possibly concurrent or associated clinical problems (Table 5), provide a course of management, and clearly lay out the risks, benefits, and expectations of possible operative intervention. Patients with CMI frequently experience chronic fatigue (72%) or fibromyalgia-like (12%) symptoms, although only a small percentage of patients with such symptoms (<5%) actually have CMI. On the other hand, significant numbers of patients with radiographically confirmed CMI are misdiagnosed for years as suffering from conditions such as migraine, multiple sclerosis, and psychiatric disorders. A gradually developing Chiari headache exacerbated with activity and straining may have propelled the patient into a progressively sedentary lifestyle with weight gain and other attendant clinical problems including depression, central and obstructive

TABLE 5 Ancillary Conditions Frequently Complicating Management


Concurrent Conditions Migraine Cluster headache Chronic daily headache Rebound headache Occipital neuralgia Multiple sclerosis Chronic fatigue syndrome Fibromyalgia syndrome CSF leak Joint hypermobility Cervical spondylosis and stenosis Depression Lyme disease Associated Conditions Pseudotumor syndrome Hydrocephalus Sleep apnea, central and obstructive Arachnoid cysts Craniocervical instability Empty sella syndrome Klippel-Feil syndrome Dysphagia Achondroplasia Hadju-Cheney syndrome Temporomandibular joint disease Eagles syndrome Sinus arrhythmia Paroxysmal orthostatic tachycardia Neurally mediated hypotension

CSF, Cerebrospinal fluid.

sleep apnea, and neck and shoulder pain frequently mistaken for cervical spondylosis or fibromyalgia. A frequent failure to find objective causes by way of electromyographic abnormalities or responses to chronic migraine treatments frequently results in patients being labeled as drug seeking, psychosomatic, and chronically depressed. Sensitivity to the clinical aspects of this disorder should significantly increase the accuracy of its identification and the exclusion of other disorders through appropriate screening laboratory investigations (Table 6).

TABLE 6 Laboratory Studies and Other Testing


CBC, ESR, ANA, SPEP, IFE T3, T4, TSH AM and PM cortisol, prolactin, IGF-1, ACTH, FSH/LH CK, Lyme titers Lying and standing blood pressure Tilt-table testing Holter monitor Echocardiogram Vestibular testing: calorics, ENG, vestibulo-optic reflex testing Lumbar puncture: CSF pressure studies (deferred with significant tonsillar descent) ICP monitoring Noninvasive or invasive cervical traction Sleep studies Barium swallow testing
CBC, Complete blood count; ESR, erythrocyte sedimentation rate; ANA, antinuclear antibody; SPEP, serum protein electrophoresis; IFE, immunofixation electrophoresis; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; IGF-1, insulin growth factor 1; ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; CK, creatine kinase; ENG, electronystagmography; CSF, cerebrospinal fluid; ICP, intracranial pressure.

TABLE 4 Imaging Studies


Mandatory MRI Brain: T1-, T2-weighted; FLAIR (transverse, coronal, sagittal) Cervical, thoracic, lumbar spine with T2-weighted sagittal views Cine CSF flow study Three-dimensional CT with contrast: posterior fossa and cervical spine Cervical spine radiographs in flexion and extension Optional Thin-slice T2-weighted axial section of posterior fossa through C3 Flexion/extension cervical spine MRI CT myelography Isotope cisternography
FLAIR, Fluid-attenuated inversion recovery; CSF, cerebrospinal fluid.

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Management
Effective patient management frequently requires a multidimensional, if not multidisciplinary, approach. Given that the Chiari headache results from CSF flow restriction and consequent pressure differential across the craniocervical junction, strategies to decrease CSF production are frequently helpful. In practice, we prescribe acetazolamide (Diamox) in doses gradually increasing to 250 mg three times a day and, in the absence of significant side effects, progressing to maximum doses of 1500 to 2000 mg daily. (Alternately, we prescribe methazolamide [Neptazane], 50 mg three times a day, increasing to 200 to 300 mg daily.) About 15% to 20% of the time, however, the use of carbonic anhydrase inhibitors such as acetazolamide and methazolamide is frequently limited by a history of allergy to sulfa-like medications, nausea, a history of renal stone disease, or annoying perioral and limb dysesthesias associated with the mild metabolic acidosis resulting from treatment. Many patients require significant oral potassium supplements of up to 20 to 60 mEq of potassium per day. In early administration, measurements of serum potassium and electrolytes are necessary. A small but nonetheless gratifying percentage of successfully treated patients (perhaps 10% to 15% of patients) derive significant relief. As alternatives, topiramate (Topamax), zonisamide (Zonegran), tizanidine (Zanaflex), and clonidine (Catapres) as well as marijuana use may have less well-defined effects on reducing CSF pressure along with more standard loop diuretics. Both topiramate and zonisamide have cross-reacting allergy profiles with sulfa drugs. Sleeping somewhat upright with a wedge pillow or in an adjustable bed may limit early-morning headache symptoms associated with lying supine. Some female patients may successfully limit such strategies and medication use to their premenstrual period. A component of pain in most patients is related to secondary cervical muscle spasm, which can often be relieved with physical massage, ultrasound, and physical therapy in addition to the use of muscle relaxants like cyclobenzoprine (Flexeril), tizanidine (Zanaflex), carisoprodol (Soma), baclofen (Lioresal), or, in extreme cases, botulinum toxin type A (Botox). Antidepressants are also frequently helpful in managing pain in general and the secondary depressive aspects of the disorder. Amitriptyline (Elavil), nortriptyline (Pamelor), and duloxetine (Cymbalta) are most frequently used. Aside from some occasional benefit from vasoactive medications such as Midrin, pharmacologic approaches to the treatment of migraine are notoriously unproductive, including beta blockers, calcium channel blockers, and triptans. This is not to say that some thought should be given to patients who may have associated migraine simply by virtue of its frequent occurrence. Patients generally quite clearly distinguish the difference between these types of headaches, often more clearly than their physicians. Because of the frequent association (25%) of even minor traumatic events aggravating or initiating CMI symptoms, patients are appropriately cautioned to refrain from high-risk behaviors such as the recreational use of
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roller coasters, skiing, physically competitive sports, and other activities that risk head and neck injury. In patients whose clinical symptoms remain unclear in the face of borderline tonsillar descent, a detailed analysis of CSF pressures and other CSF analyses are appropriately reviewed. Occasional patients with pseudotumorlike syndromes may be thus identified and a possible CSF shunting procedure contemplated. Ventriculoperitoneal shunting with the use of a Medtronic Strata programmable valve is preferred. Pregnancy is not contraindicated, although it is suggested that patients be delivered somewhat preterm and without the use of epidural anesthesia. In the case of pregnant women with SM, a cesarean section delivery is advised to avoid long hours of intrathoracic and abdominal pressure elevations consequent to pushing. Patients with SM are additionally restricted from lifting activities involving more than 15 pounds. Activities such as lifting and severe coughing have been known to result in rupture or dissection of syrinx cavities in some patients. In the case of patients without SM, an overwhelming majority are driven to surgical treatments because of intractable pressure-like posterior fossa or Chiari headache. Approximately 3500 posterior fossa decompressions in the treatment of CMI are performed each year in the United States. In the case of patients with clearly significant tonsillar descent and with obstructed CSF pathways demonstrated by cine CSF flow studies, a surgical option is largely determined by the degree of their functional incapacity. In practice, an assessment of functional disability is provided by a Modified Karnofsky Scale score (Table 7). Surgical management is not offered to patients with scores of 70 or higher. This translates into identifying those patients whose life has been significantly altered toward a dependency on others for at least some activities of daily living. These patients can frequently not sustain fulltime employment or participation in the normal demands of everyday life. Surgery is not considered for nuisance or only moderately troublesome symptoms. Surgery is not recommended as a prophylactic measure to prevent the expectation of worsening headache or fear of syrinx progression, because the natural history of SM in Chiari malformation is incompletely understood. Surgery is recommended when one or more of the following conditions are met: MR imaging evidence of syrinx propagation Clinical evidence of neurologic progression (e.g., sleep apnea, dysphagia, vertigo, sensory loss, or paralysis) Intractable symptoms, primarily Chiari headache, which have become unbearable or utterly disabling Surgery should be in the hands of an expert team with familiarity in the management of Chiari patients. The requirements for successful surgery are (1) optimal decompression of nervous tissue; (2) reconstruction of normal-sized CSF spaces at the cisterna magna and behind the cerebellum (8- to 10-mL volume); and (3) restoration of normal CSF flow between the intracranial and spinal compartments. The recent application of real-time color Doppler monitoring has helped to tailor the extent of surgical intervention

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TABLE 7 Functional Disability Assessment Tool: Modified Karnofsky Scale*


Please circle the score that best describes your current level of functioning I I I I I I I I I feel normal. carry on normal activity. carry on most normal activity. can manage all of my needs. can manage most of my needs. can manage only some of my personal needs. am disabled. am severely disabled. am totally disabled or very ill. No complaints; no evidence of illness . . . with minor symptoms. . . . with effort and some symptoms. . . . but normal activities are limited. . . . but I require occasional assistance excluding personal care. I require considerable assistance including some personal care. I require frequent assistance for most personal care. I require full assistance for most personal care. I require full assistance for all personal care; home bound in bed or chair. I have fatal processes that are rapidly progressing; I am near death. Score 100 90 80 70 60 50 40 30 20 10

I am critically ill.
See Figure 1 where this table appears in the algorithm.

and provide maximal intraoperative confirmation of the goals of surgery. Relief of the severe pressure-like Chiari headache is the most consistent surgical benefit. All other aspects of clinical symptomatology such as vestibular disturbances, chronic fatigue, brain fog, and musculoskeletal pain are not as consistently relieved. The management of SM in association with CMI most importantly benefits from the surgical release of craniocervical pressure differentials bringing about syrinx collapse. Consideration of syringosubarachnoid or syringoperitoneal shunting should be implemented only as a last resort following unsuccessful posterior fossa decompression. The extent of posterior fossa decompression is tailored to re-establish normal CSF flow characteristics at the craniocervical junction using color Doppler ultrasonography. Tonsillar shrinkage with bipolar cautery is frequently required and a dural patch typically fashioned from locally harvested pericranium, which is an excellent autologous dural substitute. The fashioning of a protective cranioplasty plate from titanium mesh and methyl-methacrylate is determined by surgical judgment based on the size of the craniotomy defect and contraindicated only in children because of anticipated cranial growth or by the presence of a very thin and porous underlying dura, which might contribute to postoperative pseudomeningocele formation. Cranioplasty frequently limits the development of later cerebellar ptosis into the craniotomy defect and scarring of muscle and subcutaneous tissue to subjacent dural membranes later contributing to a painful local surgical site. Overall, about 85% of patients experience some significant relief of severe pressure-like Chiari headache. Nevertheless, a small percentage of patients experience a return of prior symptoms 4 to 6 months or longer postoperatively (Table 8). Under these circumstances, careful attention is paid to the documentation of CSF pressure, which in many patients is moderately elevated though rarely in excess of 250 mm H2O. Such patients who generally have small ventricular size may benefit from ventriculoperitoneal shunting. These patients tend to be extremely sensitive to CSF pressure

fluctuations, even with the advent of the more sophisticated programmable valves such as the Medtronic Strata. These patients are managed with pressure readjustments and continued attention to pain management strategies, which frequently include but are not limited to muscle relaxants, physical measures, carbonic anhydrase inhibitors, gabapentin (Neurontin), and narcotic as well as nonsteroidal analgesics. In patients with SM in the absence of CMI or hypoplastic posterior fossa, contrast MR imaging studies to rule out intramedullary tumor are necessary. In addition, CT myelographic studies may be necessary to exclude a subarachnoid block resulting from possible occult arachnoiditis, which could be related to surface spinal cord bruising or extravasated blood as the result of prior impact chest or abdominal injuries, to subarachnoid hemorrhage, or to inflammatory disorders. In such cases, surgical establishment of CSF flow around such obstructions by way of laminectomy and expansile duroplasty are attempted prior to any attempt to relieve syrinx pressure with catheter placement either within the subarachnoid space or to adjacent pleural or peritoneal cavities. Shunting of syrinx cavities is a consideration of last resort and is usually associated with some degree of surgically related sensory or motor deficit. Figure 1 provides an overall management algorithm for the treatment of symptomatic CMI and SM.

TABLE 8 Conditions Constituting Failed Posterior Fossa Decompression


Intractable or progressive symptoms from inadequate decompression Persistent or enlarging syrinx Pseudomeningocele Chronically raised cerebrospinal fluid pressure Cranial settling/basilar invagination Craniocervical instability Hydrocephalus
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Posterior fossa headache?

Laboratory studies and other testing Imaging studies

Atypical/unexplained back pain and/or limb dysesthesias?

Brain, C-, T-, LS-spine MR imaging

Cine CSF flow study

3D-CT with contrast

Cervical spine films: Flex/Ext Re-image with contrast Re-image in 612 mo

Syringomyelia

Hypoplastic posterior fossa with <5mm tonsil descent? Yes

No

CMI with >5mm tonsil descent?

No

Idiopathic syringomyelia?

Yes

Conservative/ medical treatment

No Yes
Score 100 90 Modified Karnofsky Scale: Please circle the score that best describes your current level of functioning. I feel normal. I carry on normal activity. No complaints. No evidence of illness. ...with minor symptoms.

MKS score =/> 70 No

Yes No

I carry on ...with effort and some symptoms. most normal activity. I can manage all of my needs. I can manage most of my needs. ...but normal activities are limited. ...but I require occasional assistance excluding personal care.

80 70 60 50

Progression?

I require considerable assistance I can manage only some of my personal including some personal care. needs. I am disabled. I am severely disabled. I am totally disabled or very ill. I am critically ill. I require frequent assistance for most personal care. I require full assistance for most personal care. I require full assistance for all personal care. Home bound in bed or chair. I have fatal processes that are rapidly progressing. I am near death.

MKS score < 70 Yes Syrinx propagation? Yes

5
Yes CT myelography

40 30

20

10

P r i m a r y s u r g i c a l c r i t e r i a No

No

Posterior fossa decompression Failed? Yes Continuing Chiari headache? Yes Yes Repeat complete imaging

Tethering? CSF flow obstruction?

Yes Expansile spinal duroplasty Failed?

Empty sella? Yes Pituitary function studies Continued conservative medical management (Chronic fatigue, musculoskeletal pain, and vertigo are not considered reliable indicators for surgical management)

Progressive neurological deficit? No

Intractable Chiari headache?

Continuing syrinx progression?

Yes Posterior fossa revision No Good surgical result? Yes Syringoperitoneal shunt

No

High CSF pressure >200mm and headache relief with fluid removal Yes

Lumbar puncture: CSF pressure studies

VP shunt

FIGURE 1. Management algorithm for Chiari malformation type I (CMI) and syringomyelia. C-, T-, LS=, Cervical, thoracic, lumbosacral; CSF, cerebrospinal fluid; 3D, three-dimensional; MKS, Modified Karnofsky Scale; VP, ventriculoperitoneal. Johnson: Current Therapy in Neurologic Disease (7/E)

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SUGGESTED READING
Cohen AR, Gaskill S J, topic editors: Chiari I malformation, Neurosurg Focus 11(1), 2001. http://www.aans.org/education/ journal/neurosurgical/july01/11-1-nsf-toc.asp Greenlee JDW, Donovan KA, Hasan DM, Menezes AH: Chiari I malformation in the very young child: the spectrum of presentations and experience in 31 children under the age 6 years, Pediatrics 110:1212-1219, 2002. Milhorat TH, Bolognese PA: Tailored operative technique for Chiari type I malformation using intraoperative color Doppler ultrasonography, Neurosurgery 53:899-906, 2003. Milhorat TH, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients, Neurosurgery 44:1005-1017, 1999. Milhorat TH, topic editor: Syringomyelia, Neurosurg Focus 8(3), 2000. http://www.aans.org/education/journal/neurosurgical/mar00/ 8-3-NSF-toc.asp Mueller DM, Oro JJ: Prospective analysis of presenting symptoms among 265 patients with radiographic evidence of Chiari malformation type I with or without syringomyelia, J Am Acad Nurse Pract 16:134-138, 2004. Tamaki N, Batzdorf U, Nagashima T, editors: Syringomyelia: current concepts in pathogenesis and management, Tokyo, 2001, Springer-Verlag.

the clinical result of mosaicism for NF-1 gene mutations. Other types are either allelic to NF-1 or are of unclear significance. We discuss NF-1 and NF-2 in this chapter.

Neurofibromatosis Type 1 (von Recklinghausens Disease)


NF-1 is the most common form of NF and accounts for nearly 90% of NF cases. The incidence of NF-1 is 1 per 3500 individuals. It is inherited as an autosomal dominant disorder, but 50% of cases represent new mutations. Penetrance is nearly 100%, but expression varies widely. Mutational analysis of the gene encoding neurofibromin on 17q11.2 is available commercially. Although this test enjoys high sensitivity (95%), it is expensive, and diagnosis still rests on demonstration of clinical criteria. Two of seven age-dependent clinical criteria are required to make a clinical diagnosis (Table 1). In familial cases, clinical diagnostic criteria are present in 70% of 12-month-old children with NF-1 and 100% of affected 8-year-old children. In the sporadic cases, 97% of the patients display at least two diagnostic criteria by age 8 years; 100% do so by age 20 years. Other clinical manifestations, not part of the diagnostic criteria, are listed in Table 2. DIAGNOSIS Criteria as listed in Table 1 should be used as a guide for diagnostic purposes. Young infants do not always meet the criteria, especially when the disease is sporadic. However, the characteristic features develop over time, and careful and close follow-up is necessary, especially in children who have multiple caf au lait spots (CALSs) but do not meet other criteria for the diagnosis for NF-1. They should be followed until the diagnosis can be confirmed or excluded. The usual order of appearance of the clinical features is CALSs, axillary freckles, Lisch nodules, and neurofibromas. Thorough physical, ophthalmologic, audiologic, and radiologic examinations and a team approach are essential. Subsequent investigations are determined by clinical necessity. Diagnostic criteria for NF-1 provide the clinician with a highly specific tool for clinical diagnosis. In individuals with only one criterion (usually skin lesions, parenchymal tumors, or bony changes), a differential diagnosis may be generated (Table 3). These diagnoses usually are easy to differentiate from NF-1. MANAGEMENT About 45% of individuals affected with NF-1 suffer a significant medical or neurodevelopmental complication of the disorder. Management consists of screening for treatable complications, subsequent interventions that may reduce morbidity and mortality, and patient and family education and genetic counseling. We discuss management of specific features and complications of NF-1 in the following sections.
Johnson: Current Therapy in Neurologic Disease (7/E)

PATIENT RESOURCES
American Syringomyelia Alliance Project, Inc. P.O. Box 1586 Longview, TX 75606-1586 Phone: 903-236-7079 Toll-free phone: 800-ASAP-282 Fax: 903-757-7456 E-mail: info@ASAP.org http://www.asap.org/ World Arnold-Chiari Malformation Association Contact: Bernard H. Meyer 31 Newtown Woods Road Newtown Square, PA 19073 Phone: 610-353-4737 E-mail: internautbhm2@comcast.net http://www.wacma.com/ Chiari and Syringomyelia Patient Education Foundation Contact: Chiari and Syringomyelia News 346 Valerie Drive Cranberry Township, PA 16066 E-mail: editor@chiari-syringo-news.com http://www.chiari-syringo-news.com

Neurofibromatosis
Laurence Walsh, M.D., and Bhuwan P. Garg, M.D.

Neurofibromatosis (NF) is not a single disease. The term subsumes at least two distinct disorders that share some common features. The two distinct types of NF most commonly recognized are NF-1 and NF-2. NF-1 is a single gene disorder with protean manifestations. The nervous system, blood vessels, bones, and skin all may be involved in NF-1. NF-2 likewise is a single gene disorder, with variable but more circumscribed clinical features. There are other types of NF: segmental NF usually is

98

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SUGGESTED READING
Cohen AR, Gaskill S J, topic editors: Chiari I malformation, Neurosurg Focus 11(1), 2001. http://www.aans.org/education/ journal/neurosurgical/july01/11-1-nsf-toc.asp Greenlee JDW, Donovan KA, Hasan DM, Menezes AH: Chiari I malformation in the very young child: the spectrum of presentations and experience in 31 children under the age 6 years, Pediatrics 110:1212-1219, 2002. Milhorat TH, Bolognese PA: Tailored operative technique for Chiari type I malformation using intraoperative color Doppler ultrasonography, Neurosurgery 53:899-906, 2003. Milhorat TH, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients, Neurosurgery 44:1005-1017, 1999. Milhorat TH, topic editor: Syringomyelia, Neurosurg Focus 8(3), 2000. http://www.aans.org/education/journal/neurosurgical/mar00/ 8-3-NSF-toc.asp Mueller DM, Oro JJ: Prospective analysis of presenting symptoms among 265 patients with radiographic evidence of Chiari malformation type I with or without syringomyelia, J Am Acad Nurse Pract 16:134-138, 2004. Tamaki N, Batzdorf U, Nagashima T, editors: Syringomyelia: current concepts in pathogenesis and management, Tokyo, 2001, Springer-Verlag.

the clinical result of mosaicism for NF-1 gene mutations. Other types are either allelic to NF-1 or are of unclear significance. We discuss NF-1 and NF-2 in this chapter.

Neurofibromatosis Type 1 (von Recklinghausens Disease)


NF-1 is the most common form of NF and accounts for nearly 90% of NF cases. The incidence of NF-1 is 1 per 3500 individuals. It is inherited as an autosomal dominant disorder, but 50% of cases represent new mutations. Penetrance is nearly 100%, but expression varies widely. Mutational analysis of the gene encoding neurofibromin on 17q11.2 is available commercially. Although this test enjoys high sensitivity (95%), it is expensive, and diagnosis still rests on demonstration of clinical criteria. Two of seven age-dependent clinical criteria are required to make a clinical diagnosis (Table 1). In familial cases, clinical diagnostic criteria are present in 70% of 12-month-old children with NF-1 and 100% of affected 8-year-old children. In the sporadic cases, 97% of the patients display at least two diagnostic criteria by age 8 years; 100% do so by age 20 years. Other clinical manifestations, not part of the diagnostic criteria, are listed in Table 2. DIAGNOSIS Criteria as listed in Table 1 should be used as a guide for diagnostic purposes. Young infants do not always meet the criteria, especially when the disease is sporadic. However, the characteristic features develop over time, and careful and close follow-up is necessary, especially in children who have multiple caf au lait spots (CALSs) but do not meet other criteria for the diagnosis for NF-1. They should be followed until the diagnosis can be confirmed or excluded. The usual order of appearance of the clinical features is CALSs, axillary freckles, Lisch nodules, and neurofibromas. Thorough physical, ophthalmologic, audiologic, and radiologic examinations and a team approach are essential. Subsequent investigations are determined by clinical necessity. Diagnostic criteria for NF-1 provide the clinician with a highly specific tool for clinical diagnosis. In individuals with only one criterion (usually skin lesions, parenchymal tumors, or bony changes), a differential diagnosis may be generated (Table 3). These diagnoses usually are easy to differentiate from NF-1. MANAGEMENT About 45% of individuals affected with NF-1 suffer a significant medical or neurodevelopmental complication of the disorder. Management consists of screening for treatable complications, subsequent interventions that may reduce morbidity and mortality, and patient and family education and genetic counseling. We discuss management of specific features and complications of NF-1 in the following sections.
Johnson: Current Therapy in Neurologic Disease (7/E)

PATIENT RESOURCES
American Syringomyelia Alliance Project, Inc. P.O. Box 1586 Longview, TX 75606-1586 Phone: 903-236-7079 Toll-free phone: 800-ASAP-282 Fax: 903-757-7456 E-mail: info@ASAP.org http://www.asap.org/ World Arnold-Chiari Malformation Association Contact: Bernard H. Meyer 31 Newtown Woods Road Newtown Square, PA 19073 Phone: 610-353-4737 E-mail: internautbhm2@comcast.net http://www.wacma.com/ Chiari and Syringomyelia Patient Education Foundation Contact: Chiari and Syringomyelia News 346 Valerie Drive Cranberry Township, PA 16066 E-mail: editor@chiari-syringo-news.com http://www.chiari-syringo-news.com

Neurofibromatosis
Laurence Walsh, M.D., and Bhuwan P. Garg, M.D.

Neurofibromatosis (NF) is not a single disease. The term subsumes at least two distinct disorders that share some common features. The two distinct types of NF most commonly recognized are NF-1 and NF-2. NF-1 is a single gene disorder with protean manifestations. The nervous system, blood vessels, bones, and skin all may be involved in NF-1. NF-2 likewise is a single gene disorder, with variable but more circumscribed clinical features. There are other types of NF: segmental NF usually is

Neurofibromatosis

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TABLE 1 Diagnostic Criteria for Neurofibromatosis (NF)-1


Clinical Criteria* 6 caf au lait macules > 0.5 mm in diameter in prepubertal patients and > 15 mm in postpubertal patients 2 neurofibromas of any type (intracutaneous or subcutaneous) or 1 plexiform neurofibroma Freckling in the axillary or inguinal regions (3 freckles) Optic pathway glioma 2 iris hamartomas (Lisch nodules) Distinctive osseous lesion, e.g., sphenoid wing hypoplasia or thinning of long bone cortex with or without pseudoarthrosis 1 first-degree relative with NF-1 according to the above criteria
*A diagnosis of NF-1 requires 2 of these criteria.

Usual Age of Occurrence Birth 8-12 yr Congenital 3-5 yr 3-4 yr 5-12 yr Birth

Prevalence (%) by 18 Years of Age >99 (99 by 12 mo) 84 (48 by age 10 yr) >44 (25-30 apparent in infancy, 44 by age 5 yr) >90 (by age 7 yr) 15 >70 (by age 10 yr) 7-14 50

Skin Lesions Skin lesions are the most common manifestations of NF-1. The earliest and most common cutaneous lesions are CALSs. Of infants with multiple (6) CALSs, more than 80% will develop NF-1. Cosmetic concerns may occur with multiple or very large CALSs, but they do not require medical intervention otherwise. Vitamin D analogs and laser therapy have been tried with initial success, but results await confirmation. CALSs often fade by middle age, if not earlier. Isolated CALSs (usually 3) occur in 10% to 20% of the population. They are slightly more common and are slightly more likely to be multiple in individuals of Mediterranean, African, or South Asian ancestry. Some families (with and without NF-1 gene mutations) transmit multiple CALSs as an isolated autosomal dominant trait. Multiple CALSs are also reported in children with tuberous sclerosis complex, Russell-Silver syndrome, and ataxia-telangiectasia, although there is argument concerning their specific association with those disorders. Intertriginous freckling is the second most common manifestation of NF-1. Axillary freckling is twice as common as inguinal freckling. This freckling has no medical significance other than as a criterion for diagnosis. More irregular or diffuse hyperpigmentation occurs

as well; large hyperpigmented areas, sometimes with hemangiomatous changes, may overlie an often palpable plexiform neuroma. Neurofibromas occur in 84% of people with NF-1. They are discrete and are either cutaneous or subcutaneous in location. Cutaneous neurofibromas may be violaceous or tan, and they feel soft or fleshy to palpation. Subcutaneous neurofibromas are not visibly pigmented, are firmer, and are more readily associated with peripheral nerve trunks. Either may be up to 3 to 4 cm in diameter. They usually appear in late school age or adolescence but may be present in toddlers. Although puberty may be associated with the appearance of multiple new neurofibromas, they occur throughout life. They may cause local itching and cosmetic problems and may be susceptible to repeated incidental trauma (e.g., from shaving). Angiomas and xanthomas are less commonly seen. Xanthogranulomas, rare in children with NF-1, may be associated with an increased risk of lymphoproliferative disorders; however, there currently is no specific recommendation regarding additional screening.

TABLE 3 Differential Diagnosis for Neurofibromatosis Type 1


Neurofibromatosis type 2 LEOPARD syndrome Multiple intradermal nevi Multiple lipomatosis Proteus syndrome Noonans syndrome Multiple caf au lait spots McCune-Albright syndrome Multiple endocrine neoplasia type 2B Bannayan-Riley-Ruvalcaba syndrome
LEOPARD, Lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness.

TABLE 2 Other Significant Features of Neurofibromatosis Type 1


Learning disabilities Macrocephaly Aqueductal stenosis Epilepsy Scoliosis Hypertension Ungual neurofibromas Interstitial pulmonary disease
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Pruritus is common in NF-1. The itching may be severe, but the patient may not volunteer its presence. It occurs in association with neurofibromas but also diffusely, unattached to a specific cutaneous or subcutaneous lesion. Antihistamines have been tried with mixed results. Plexiform Neuromas Plexiform neurofibromas (plexiform neuromas) are larger than neurofibromas and may cause more serious problems. They occur equally on the trunk or head and neck (40% to 45% each) and less commonly on the limbs. They are congenital but may not be apparent until they enlarge with age. Plexiform neuromas start in nerve sheaths anywhere between the spinal roots and distal nerves in the extremities and appear as either nodular or diffuse lesions. Thirty percent of people with NF-1 have plexiform neuromas; malignant change to a malignant peripheral nerve sheath tumor (MPNST) occurs in 5% of cases. Deep nodular or diffuse plexiform neuromas are most likely to degenerate to MPNSTs. Even without transformation to an MPNST, plexiform neuromas may grow to compress nerves and other vital structures. Periorbital plexiform neurofibromas not only may have cosmetic consequences but may also cause ptosis, exophthalmos, and vision loss. Intraoral tumors may cause airway obstruction. Lesions in the neck may compress nearby arteries or veins with sometimes life-threatening consequences. Cephalic or paraspinous plexiform neurofibromas may extend intracranially or intraspinally. Intra-abdominal tumors also may encase important structures such as the renal artery or aorta, causing secondary hypertension or more serious complications. Plexiform neuromas that are visible on physical examination are measured during each annual or semiannual visit. Although not routinely included as part of a screening protocol, magnetic resonance (MR) imaging reveals the extent of larger tumors and allows follow-up of noncutaneous plexiform neuromas. Indications for therapeutic intervention include indications of possible malignant degeneration (rapid growth in a previously stable tumor or pain, especially associated with new growth), and impending compromise in patient function or important structures. Therapy is limited. Radiation therapy has no role in the treatment of plexiform neuromas. Chemotherapy has shown little efficacy to date. Complete surgical excision is optimal but often difficult to achieve. Incomplete resection risks recurrence but may be necessary if the tumor is especially large or if complete resection threatens vital structures. Therapy of MPNST consists of resection and chemotherapy in consultation with oncologists. Forty percent recur within 2 years. Five-year survival with MPNST is 35%; median survival is 36 months. Ophthalmic Lesions Lisch nodules in the iris are the most common eye signs in NF-1, appearing as brown nodules. These are melanocytic hamartomas. The presence of two nodules is required to meet the diagnostic criterion. They are

age dependent, and the incidence increases with age; only about 6% of children younger than 6 years of age have them, but more than 70% patients have them by teenage years. Pulsating exophthalmos due to sphenoid wing hypoplasia is seen in some children. Buphthalmos and congenital glaucoma have also been reported. These may be associated with an underlying plexiform neuroma. Optic nerve glioma is discussed in the following section. Neurologic Complications Macrocephaly (head size greater than 2 SD above mean) occurs in nearly half of the NF-1 patients. It usually is due to megalencephaly. Signs of increased intracranial pressure require exclusion of other causes such as obstructive hydrocephalus, posterior fossa tumors, aqueductal stenosis, tectal plate gliomas, and hypothalamic tumors. In some children a cause for ventriculomegaly is not found. Epilepsy occurs in 5% to 7% of affected individuals with NF-1. Seizures occur more frequently in children with NF-1 and severe neurodevelopmental disabilities than in children with NF-1 and normal development. Appropriate anticonvulsants are used for seizure control. Attention deficit with or without hyperactivity is seen often in children with NF-1, and learning disabilities (LDs) occur in about 50% (30% to 62%) of individuals with NF-1. The IQ score of patients with NF-1 averages 10 points lower than that of their siblings. Verbal scores exceed performance scores. Common, specific NF-1associated LDs include poor visuospatial skills and specific reading and language disabilities. Mental retardation occurs less commonly in NF-1 patients and may be mutation specific. Management of children with NF-1 should include specific inquiry into learning or school difficulties. Psychoeducational testing should be sought aggressively if there is any hint of cognitive delay or school difficulty. MR imaging of the brain currently is not part of recommended screening protocols for NF-1 in otherwise asymptomatic children. However, our threshold for obtaining an MR scan in a child with NF-1 is extremely low. Indications include absolute macrocephaly (>2 SD above the mean), headaches (new or worsening), decreasing vision or unexplained nystagmus in a young child, funduscopic changes suggestive of an optic nerve glioma, developmental delay or LDs, decline in school performance, cephalic plexiform neuroma that may have intracranial extension, and abnormal neurologic examination that is not explained otherwise. Precocious puberty is an absolute indication for MR scan of the brain to include detailed study of the hypothalamus and sella. Headaches occur in one half of patients with NF-1; 10% are caused by an intracranial structural lesion. Intracranial tumors require management as discussed in the following section. Optic Pathway Glioma Optic pathway gliomas have been reported in 15% of children with NF-1. The tumor may involve the
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optic nerve, optic chiasm, and/or the optic tracts. Sometimes the tumor spreads posteriorly along the optic radiations. Optic gliomas may present with decreased visual acuity, visual field defects, ptosis, proptosis, and signs and symptoms of increased intracranial pressure, or they may be asymptomatic and found on MR scans or ophthalmologic examinations. Diencephalic syndrome and precocious puberty in patients with NF-1 require exclusion of optic chiasm or hypothalamic gliomas. Most symptomatic gliomas present by 6 years of age and often do so by 2 years of age, but only about 30% to 50% of patients with optic gliomas have symptoms. Optic gliomas may remain static and behave as hamartomas, or they may grow actively. Periodic MR scans following initial detection are helpful in determining whether the tumor is progressive or static. One suggested protocol is MR scans (including optic nerve views) and ophthalmologic examinations every 3 months for 1 year, followed by MR imaging and ophthalmologic examinations every 6 months for 2 years and yearly scans and every-6-month ophthalmologic examinations thereafter. Some protocols relax surveillance even further after 36 months, but this decision rests on the age of the child and the behavior of the tumor on previous surveillance studies. Progression of optic gliomas after 10 years of age is rare. Static tumors should be watched and need no treatment. Actively growing tumors may be treated with chemotherapy, or surgery when possible. Radiation therapy may result in serious complications in NF-1 patients. These complications, including moyamoya disease, stroke, and secondary malignant glioma formation, make radiation therapy an unappealing last choice. About 25% of patients with optic gliomas require treatment for them, whereas the tumors may spontaneously regress in some patients. Routine screening for optic gliomas in a healthy asymptomatic child with NF-1 consists of yearly eye examinations by an ophthalmologist. This said, such examinations carry only about 50% to 60% sensitivity. Astrocytomas of the cerebellum, cerebrum, and brainstem are other common intracranial tumors in NF-1. Symptoms depend on location. Brainstem gliomas in patients with NF-1 may be indolent, with very slow growth and better outcome than brainstem gliomas in children without NF-1. Most (80%) occur in the medulla; 15% to 20% require intervention beyond shunt for hydrocephalus. Meningiomas and primitive neural-ectodermal tumors occur as well. Presence of symptomatic optic nerve glioma increases the likelihood of these other central nervous system tumors by a factor of nine. Intraspinal tumors may be single or multiple. Cervical neuromas may occur in 25% of children with NF-1. They may be extradural or intradural. Intramedullary spinal tumors are rare in NF-1. Intraspinal tumors may extend through the intervertebral foramen and assume a dumbbell shape. In some patients these intraspinal tumors may be in continuity with a subcutaneous plexiform neurofibroma. A 2% to 7% risk of sarcomatous change in these tumors has been reported. Appropriate treatment is necessary in symptomatic patients (e.g., with intractable pain or focal neurologic deficits).
Johnson: Current Therapy in Neurologic Disease (7/E)

Vasculopathy Vasculopathy is an under-recognized aspect of NF-1. Renal artery stenosis is the best known, but the vasculopathy of NF-1 really is a generalized disorder. Carotid artery stenosis with moyamoya disease has been reported. Coarctation of aorta has been reported by several investigators. Other, less common associations include pheochromocytoma. Hypertension is a common complication of NF-1, occurring in at least 40% of adults and up to 20% of children with NF-1. It requires thorough evaluation and treatment. Renal artery stenosis and compression of the artery from a tumor should be excluded using abdominal MR or computed tomography (CT) scan. Hypertension caused by such structural lesions may be relatively refractory to medical management and may require surgery. Pheochromocytoma, usually after the age of 15 years, is a rare cause of hypertension in NF-1. It occurs in 0.1% to 1.5% of reported NF-1 patients and presents with initial episodic hypertension and other vasomotor phenomena. Appropriate consultation is advisable for evaluation of suspected pheochromocytoma. Data for vasculopathy-related morbidity in NF-1 are sketchy. People affected with NF-1 who die prior to age 30 years have an odds ratio of 2 to 3 of having vascular disease compared with non-NF individuals who die before 30 years of age. It has been suggested that the vasculopathy is a result of alteration of the function of neurofibromin (the NF-1 gene product) in the vascular endothelium and smooth muscle cells. Skeletal Lesions Multiple bony abnormalities have been reported in NF-1. Dysplasia of the greater wing of the sphenoid bone may cause pulsating exophthalmos and marked facial disfigurement. Dural ectasias may produce enlargement of various bony (cranial nerve) foramina and need to be distinguished from enlargement due to neurofibroma involving the nerve. Cranial CT with thin slices or MR scan is useful in evaluation. Scoliosis occurs in 12% of children with NF-1. Scoliosis in NF-1 is bimodal in onset and severity. Its presence is an indication for plain films and MR imaging of the complete spine. Scoliosis due to vertebral dysplasia begins in preschool- and school-age children; this tends to be progressive and severe. Teenage-onset scoliosis in NF-1 usually is less severe. Either age group may have scoliosis due to paraspinal or intraspinal tumors with symptoms specifically referable to the tumor site. Scalloping of the vertebral body is a common radiologic finding. Dural ectasia also occurs in the spine. Bowing of the tibia and fibula and secondary pseudoarthrosis of the tibia are other bony abnormalities in NF-1. The latter may result in significant disability and may necessitate amputation of the affected leg. Short stature is common and occurs in 25% to 43% of patients with NF-1. NF-1 patients on average are reported to fall short of their siblings height and their own predicted mid-parental height.

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Additional MR Imaging Findings In addition to the abnormalities due to tumors, there are many other unusual findings in the cranial MR scans of patients with NF-1. Hyperintense foci occur on T2-weighted images in 43% to 77%. These usually are found incidentally, and most commonly occur in the globus pallidus, followed by the cerebellum, brainstem, thalamus, and periventricular white matter. Histologic verification is lacking, though they were described in the past as hamartomas. They more likely represent transient abnormalities of myelin structure. They are age dependent and usually vanish by age 12 years. Their clinical significance is unknown. Their presence is associated with LDs and may predict other NF-1related morbidities. Genetic Considerations All families affected by NF-1 require genetic counseling. The disorder is autosomal dominant. One half of cases are sporadic and suggest a new (noninherited) mutation. This may have occurred before or after conception. A mutation before conception raises the possibility of germline mosaicism in a parent. Although a presumed new mutation might suggest sibling recurrence risk of less than 1%, the possibility of a preexisting mutation limited to a parental germ cell line slightly raises the sibling recurrence risk in de novo cases. The clinically affected individual then has a 50% risk of passing the mutation to his or her offspring, with essentially 100% penetrance. In families with a clinically affected parent, offspring recurrence is 50%. There is some evidence that there is less intrafamilial than interfamilial variability in manifestations, but many exceptions exist. Thus, although the presence of only CALSs, freckling, and Lisch nodules in a given family may be reassuring, vigilance for more serious sequelae still is required. There are several specific variant clinical subtypes (Noonan-NF syndrome, Watson syndrome, a microdeletion syndrome, familial CALSs, and spinal NF with MPNST). Medical genetic consultation may be advisable in some instances, and even in cases requiring only genetic counseling, genetic counselors often are far more effective than physicians in conveying this information to affected families.

TABLE 4 Diagnostic Criteria for Neurofibromatosis (NF)-2


Bilateral vestibular schwannomas Unilateral vestibular schwannoma and first-degree relative with NF-2 First-degree relative with NF-2 and any two of the following: Glioma Meningioma Neurofibroma Schwannoma Juvenile posterior subcapsular contract Unilateral vestibular schwannoma with any two of the following*: Meningioma Schwannoma Gliomas Neurofibroma Juvenile posterior subcapsular lenticular opacities Multiple meningiomas and one of the following*: Unilateral vestibular schwannoma Any two of schwannoma, glioma, neurofibroma, cataract
*The presence of any one of these criteria is sufficient for the diagnosis of NF-2 except as noted with the asterisk. Any one of criteria with the asterisk is sufficient for probable or presumptive diagnosis.

Neurofibromatosis Type 2
NF-2 is less common than NF-1. The major hallmark of NF-2 is the development of bilateral acoustic neuromas. Occasionally there are also other brain and spinal cord tumors. The clinical mnemonic for NF-2 is MISME (multiple inherited schwannomas, meningiomas, ependymomas). NF-2 is transmitted as an autosomal dominant trait. As with NF-1, 50% of cases are sporadic and represent new mutations. Diagnostic criteria are presented in Table 4. Most patients have few or no CALSs; Lisch nodules are generally not seen. Peripheral neurofibromas are not present. Patients have a high frequency of presenile

posterior subcapsular and nuclear cataracts. These predate the symptoms of bilateral acoustic neuromas and sometimes require surgery. Acoustic neuromas or schwannomas are the hallmark of NF-2 and usually appear in late adolescence or early adulthood. They are often bilateral. Hearing loss is the first symptom. Facial weakness is a late complication. Schwannomas of other cranial nerves may also occur and are often multiple. Meningiomas are other intracranial tumors in NF-2. Optic gliomas do not occur. Spinal schwannomas may be multiple and present management difficulties. There may be two types of NF-2: one with early onset, rapid course, and multiple other tumors in addition to bilateral vestibular schwannomas, and the second with late onset, more benign course, and usually only bilateral vestibular schwannomas. As mentioned earlier, age of presentation is late teens to mid twenties. Prognosis is worse overall than in NF-1, with historical survival usually into middle age. This likely has improved with improvement in therapy for the various tumors. The NF-2 gene has been mapped to chromosome 22. NF-2 gene product is schwannomin. This protein shows a close relationship to the family of ERM (ezrin-radixinmoesin) proteins, which serve as linkers of cytoskeleton to membrane proteins. This may be a novel class of tumor suppressor genes. Audiologic evaluation is essential. BAER is often helpful. CT scan and especially MR imaging with gadolinium enhancement are helpful in visualizing even small vestibular schwannomas or acoustic neuromas. Management is symptomatic, with surgery and radiation therapy as appropriate.
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SUGGESTED READING
DeBella K, Szudek J, Friedman JM: Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children, Pediatrics 105:608-614, 2000. Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, editors: Neurofibromatosis: phenotype, natural history, and pathogenesis, ed 3, Baltimore, 1999, Johns Hopkins University Press. http://www.genetests.org/ (search term: neurofibromatosis) North KN, Riccardi V, Samango-Sprouse C, et al: Cognitive function and academic performance in neurofibromatosis 1: Consensus statement from the NF-1 Cognitive Disorders Task Force, Neurology 48:1121-1127, 1997. Nunes F, MacCollin M: Neurofibromatosis 2 in the pediatric population, J Child Neurol 18:718-724, 2003. Ruggieri M, Husom SM: The clinical and diagnostic implications of mosaicism in the neurofibromatosis, Neurology 56:1433-1443, 2001.

the diagnosis remains difficult in individuals with subtle disease manifestations. The clinical diagnostic criteria established for TSC are highly reliable, and patients who meet the clinical diagnostic criteria for definite TSC do not require genetic testing for diagnostic purposes. It is likely that gene testing might be more useful in less obvious cases depending on the clinical situation and the age of the patient in question.

Clinical Aspects
The clinical features of TSC may involve neurologic, psychiatric, behavioral, and cognitive features including epilepsy (especially infantile spasms), mental retardation, pervasive developmental disorder and autism, renal disease and tumors, cardiac tumors, ocular lesions, and pulmonary disease. The characteristic brain lesions are unique enough to be considered part of the diagnostic criteria and include cortical tubers, subependymal glial nodules (SGNs), and subependymal giant cell astrocytomas (SEGAs). Almost any other organ system can be involved with the disease complex in some patients, though any individual usually has only a relatively limited number of organs with significant involvement. We address the most commonly encountered clinical manifestations of TSC. DERMATOLOGIC The dermatologic manifestations of TSC, which are characteristic enough to be considered major features in the diagnostic criteria, include hypomelanotic macules (ash leaf spots), ungual or periungual fibroma, facial angiofibroma (sebaceous adenomas), forehead plaques, and the shagreen patch. The confetti skin lesion is less specific and is considered only a minor feature. The hypomelanotic macules are found on the skin in more than 90% of patients with TSC. The lesions are usually present on the trunk, abdomen, back, or extremities at birth and are more easily seen on a pigmented background or with the use of an ultraviolet light in fair-skinned individuals. Because hypomelanotic macules are often present as single lesions in the normal population, the diagnostic criteria require more than three lesions. The confetti lesions may develop later, after the newborn period, and are usually on the extremities. Facial angiofibromata are fibrovascular lesions that are present in about 75% of patients. They are not present at birth and begin to develop after 2 to 4 years of age. Frequently they are mistaken for acne even though they are noted well before the usual age at which acne is seen. Beginning as small red papules, the lesions increase in number and perhaps size also as the patient ages. Puberty seems to produce the most rapid changes in the number and distribution of the lesions. The angiofibromata are generally distributed over the malar region of the face and may spread over the nasolabial folds on to the chin (frequently sparing the angle of the mouth). Although they are considered specific for TSC, the fact that they are not reliably present limits their use as a

PATIENT RESOURCES
National Neurofibromatosis Foundation 95 Pine Street, 16th Floor New York, NY 10005 Phone: 212-344-NNFF Toll-free phone: 800-323-7938 Fax: 212-747-0004 E-mail: NNFF@aol.com or NNFF@nf.org http://www.nf.org/ Neurofibromatosis, Inc. 8855 Annapolis Road, Suite 110 Lanham, MD 20706-2924 Phone: 301-577-8984 Toll-free phone: 800-942-6825 Fax: 301-577-0016 E-mail: nfinc1@aol.com http://www.nfinc.org/

Tuberous Sclerosis Complex


John B. Bodensteiner, M.D., and Vinodh Narayanan, M.D.

Tuberous sclerosis complex (TSC) is a disorder that affects many tissues in the body including brain, heart, lungs, kidneys, skin, eyes, and bone. The disease complex is a disorder of cellular differentiation and proliferation resulting in hamartomata and true neoplasms, most prominently in the brain, kidney, and heart. The disease complex results from deletion/mutation abnormalities in either of two genes that work in concert in cell growth control pathways and produce indistinguishable disease manifestations although on average, the patients with TSC2 have a somewhat greater severity of manifest disease than those with TSC1. TSC1 is found on 9q34 (hamartin) and TSC2 on 16p13 (tuberin). Abnormal migration of cerebral neurons plays a central role in the neurologic manifestations of the disease. The prevalence of TSC is estimated at 1 in 6000 to 9000 individuals. Because of the striking variability of the clinical manifestations and severity of the disease,
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SUGGESTED READING
DeBella K, Szudek J, Friedman JM: Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children, Pediatrics 105:608-614, 2000. Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, editors: Neurofibromatosis: phenotype, natural history, and pathogenesis, ed 3, Baltimore, 1999, Johns Hopkins University Press. http://www.genetests.org/ (search term: neurofibromatosis) North KN, Riccardi V, Samango-Sprouse C, et al: Cognitive function and academic performance in neurofibromatosis 1: Consensus statement from the NF-1 Cognitive Disorders Task Force, Neurology 48:1121-1127, 1997. Nunes F, MacCollin M: Neurofibromatosis 2 in the pediatric population, J Child Neurol 18:718-724, 2003. Ruggieri M, Husom SM: The clinical and diagnostic implications of mosaicism in the neurofibromatosis, Neurology 56:1433-1443, 2001.

the diagnosis remains difficult in individuals with subtle disease manifestations. The clinical diagnostic criteria established for TSC are highly reliable, and patients who meet the clinical diagnostic criteria for definite TSC do not require genetic testing for diagnostic purposes. It is likely that gene testing might be more useful in less obvious cases depending on the clinical situation and the age of the patient in question.

Clinical Aspects
The clinical features of TSC may involve neurologic, psychiatric, behavioral, and cognitive features including epilepsy (especially infantile spasms), mental retardation, pervasive developmental disorder and autism, renal disease and tumors, cardiac tumors, ocular lesions, and pulmonary disease. The characteristic brain lesions are unique enough to be considered part of the diagnostic criteria and include cortical tubers, subependymal glial nodules (SGNs), and subependymal giant cell astrocytomas (SEGAs). Almost any other organ system can be involved with the disease complex in some patients, though any individual usually has only a relatively limited number of organs with significant involvement. We address the most commonly encountered clinical manifestations of TSC. DERMATOLOGIC The dermatologic manifestations of TSC, which are characteristic enough to be considered major features in the diagnostic criteria, include hypomelanotic macules (ash leaf spots), ungual or periungual fibroma, facial angiofibroma (sebaceous adenomas), forehead plaques, and the shagreen patch. The confetti skin lesion is less specific and is considered only a minor feature. The hypomelanotic macules are found on the skin in more than 90% of patients with TSC. The lesions are usually present on the trunk, abdomen, back, or extremities at birth and are more easily seen on a pigmented background or with the use of an ultraviolet light in fair-skinned individuals. Because hypomelanotic macules are often present as single lesions in the normal population, the diagnostic criteria require more than three lesions. The confetti lesions may develop later, after the newborn period, and are usually on the extremities. Facial angiofibromata are fibrovascular lesions that are present in about 75% of patients. They are not present at birth and begin to develop after 2 to 4 years of age. Frequently they are mistaken for acne even though they are noted well before the usual age at which acne is seen. Beginning as small red papules, the lesions increase in number and perhaps size also as the patient ages. Puberty seems to produce the most rapid changes in the number and distribution of the lesions. The angiofibromata are generally distributed over the malar region of the face and may spread over the nasolabial folds on to the chin (frequently sparing the angle of the mouth). Although they are considered specific for TSC, the fact that they are not reliably present limits their use as a

PATIENT RESOURCES
National Neurofibromatosis Foundation 95 Pine Street, 16th Floor New York, NY 10005 Phone: 212-344-NNFF Toll-free phone: 800-323-7938 Fax: 212-747-0004 E-mail: NNFF@aol.com or NNFF@nf.org http://www.nf.org/ Neurofibromatosis, Inc. 8855 Annapolis Road, Suite 110 Lanham, MD 20706-2924 Phone: 301-577-8984 Toll-free phone: 800-942-6825 Fax: 301-577-0016 E-mail: nfinc1@aol.com http://www.nfinc.org/

Tuberous Sclerosis Complex


John B. Bodensteiner, M.D., and Vinodh Narayanan, M.D.

Tuberous sclerosis complex (TSC) is a disorder that affects many tissues in the body including brain, heart, lungs, kidneys, skin, eyes, and bone. The disease complex is a disorder of cellular differentiation and proliferation resulting in hamartomata and true neoplasms, most prominently in the brain, kidney, and heart. The disease complex results from deletion/mutation abnormalities in either of two genes that work in concert in cell growth control pathways and produce indistinguishable disease manifestations although on average, the patients with TSC2 have a somewhat greater severity of manifest disease than those with TSC1. TSC1 is found on 9q34 (hamartin) and TSC2 on 16p13 (tuberin). Abnormal migration of cerebral neurons plays a central role in the neurologic manifestations of the disease. The prevalence of TSC is estimated at 1 in 6000 to 9000 individuals. Because of the striking variability of the clinical manifestations and severity of the disease,
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diagnostic feature. Furthermore, though they are of no functional significance and have no malignant potential, attempted removal is commonly undertaken for cosmetic reasons. The shagreen patch can be found on the back or flank most commonly. It is an irregularly shaped, slightly raised patch of skin that has a texture resembling the surface of a football. This lesion is also found infrequently in younger patients and in only 20% to 30% of patients overall. Ungual fibromas are nodular or fleshy lesions arising at the nail bed. Not usually seen in preadolescent patients with TSC, they occur in only 15% to 20% of the patients with TSC, and though they are considered by many as specific for the disease, similar lesions can result from trauma to the nail beds. We have seen several patients who have undergone procedures to remove the lesions that have been mistaken for warts. RENAL Renal lesions occur in 75% to 80% of patients with TSC. There are two types of renal lesions: cysts (single or multiple) and tumors (angiomyolipomata). Cysts tend to appear early and may be solitary, in which case they may disappear, or the cysts may be so numerous or large as to be symptomatic. Most often the solitary cysts are only an incidental feature. The presence of multiple cysts and multiple angiomyolipomata is characteristic of TSC. Bilateral tumors with many angiomyolipomata per kidney are typical. The prevalence and size of the renal tumors increase with age, so they must be followed serially with ultrasonography. Lesions that reach more than 4 cm in diameter are more likely to become symptomatic than are the smaller ones (hemorrhage into the tumor causing pain, hematuria, or acute renal failure), and the lesions that attain that size usually are treated with embolization or surgical intervention. There is a small but definite risk (<5%) of renal cell carcinoma that may arise from an angiomyolipoma or from another source. CARDIAC Rhabdomyomata, hamartomata involving the heart, are present in almost two thirds of patients with TSC and are usually multiple. They are most often located within the muscular walls of the cardiac chambers but can also be found within the papillary muscles or attached to the valve leaflets. Often the lesions are seen on prenatal fetal ultrasound, and because they usually regress with age, if they are not symptomatic early in life they usually do not become symptomatic later in life. The most common clinical manifestation is early in life with congestive heart failure that may be due to obstruction of flow by the hamartomata within the ventricle. Congestive heart failure resistant to medical management or location such as to interfere with the normal function of one of the major heart valve leaflets is the primary indication for surgical removal of the lesion. Cerebral embolism from a cardiac rhabdomyoma can occur but appears to be quite uncommon.

PULMONARY Although lung disease develops in only 1% of patients with TSC, the clinician needs to be aware of the possibility. Pulmonary lymphangiomatosis with chylothorax, spontaneous pneumothorax, dyspnea, cough, and hemoptysis are the most frequent symptoms. Pulmonary involvement is five times as common in females and may not develop till the 3rd or 4th decade. The prognosis with pulmonary involvement in TSC is not good, since two thirds of the patients die within 5 years of the onset of the symptoms. OPHTHALMOLOGIC The likelihood of finding one of the ophthalmologic features of TSC depends on the intensity of the search. Up to 87% of patients have ocular involvement but a considerably smaller number have one or more lesions identified. The retinal astrocytoma may be detected funduscopically, as can depigmented retinal lesions that represent hamartomata in the retina. Clinically significant lesions are rare, but the astrocytomata and the hamartomata may enlarge slowly and have the potential to limit vision due to their size. Occasional patients may have visual loss from vitreous hemorrhage or retinal detachment. NEUROLOGIC The classic neurologic manifestations of TSC are seizures, mental retardation, and behavioral abnormalities. A number of mildly affected individuals may have no neurologic impairment, though the proportion of patients so affected is unknown at present. The neurologic symptoms result from the disrupted neuronal migration along radial glial fibers and abnormal proliferation of glial elements. Pathologically, the lesions include the subependymal nodules (SGN and SEGA), cortical hamartomata (tubers), areas of focal cortical hypoplasia, and gray matter heterotopias. These lesions may be demonstrated by neuroimaging. SGNs frequently are calcified when they are seen best on computed tomography (CT) scans of the brain. SEGA, cortical hamartomata, and heterotopic gray matter are most easily seen on brain magnetic resonance (MR) imaging. Seizures occur in 80% to 90% of patients with TSC and may include a variety of types. Most mentally retarded patients with TSC have seizures, but there are exceptions. There is a particular tendency for infants with TSC to develop infantile spasms with hypsarrhythmia on electroencephalogram (EEG). The children with TSC who have infantile spasms are likely to have more lesions on neuroimaging and are likely to be more impaired than others with the disease complex. Other seizures, generalized and partial or partial complex, may also occur in these patients. Although many patients with TSC respond well to standard antiepileptic drug therapy, there is clearly an increased risk of refractory epilepsy in these patients. It is not surprising that a cortical tuber can frequently be identified as an epileptic focus in some patients, but perhaps more commonly the
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seizures are multifocal or generalized and a single epileptic focus cannot be identified. Most patients with seizures and TSC are retarded, but many patients with TSC and mental retardation do not have seizures. There is a rough correlation between the severity of cognitive impairment and the number and size of the cortical tubers. There is also a rough correlation between the number and size of the cortical lesions and the likelihood of behavioral disorders including autism, hyperkinesis, frank psychosis, and particularly aggressiveness, which is likely to worsen about puberty. The percentage of patients with TSC who will manifest severe behavior disturbances is not well established, but the onset of aggressive behavior near the time of puberty is characteristic of TSC in our experience. The intracranial tubers are well-localized hamartomata and do not enlarge over time. The SGNs have the potential to enlarge as the patient ages. Most SGNs are less than 2 cm in size; however, the most common location is at the level of the foramen of Monro, which can be obstructed, leading to unilateral or bilateral ventricular obstruction and hydrocephalus, which may produce acute of subacute changes in neurologic function of the affected patient. Some people believe the SEGAs represent enlarged SGNs, but there is some evidence that they are different lesions histologically. In either case, this subependymal lesion may have the potential to enlarge, and lesions larger than 1 cm are the ones most likely to do so. The frequency of this event is not well established but is sufficient to justify longitudinal evaluation of these patients. Once a SEGA begins to grow, it can be locally invasive. Because surgical removal is curative, the identification of an enlarging SEGA before the onset of symptoms has therapeutic implications.

TABLE 1 Diagnostic Criteria for Tuberous Sclerosis Complex (TSC)


Major Features Facial angiofibromata or forehead plaque Nontraumatic ungula or periungual angiofibromata Hypomelanotic macules (>3) Shagreen patch (connective tissue nevus) Subependymal nodule Cortical tuber* Subependymal giant cell astrocytoma Multiple retinal nodular hamartomata Cardiac rhabdomyomata, single or multiple Lymphangiomyomatosis Renal angiomyolipomata Minor Features Multiple, randomly distributed dental enamel pits Hamartomatous rectal polyps Bone cysts Cerebral white matter migration tracts*, Gingival angiofibromata Nonrenal hamartomata Retinal achromic patch Confetti skin lesions Multiple renal cysts Definite TSC Either 2 major features or 1 major feature and 2 minor features Probable TSC One major feature plus 1 minor feature Suspect TSC Either 1 major feature or 2 or more minor features
*When cerebral cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of TSC. When both lymphangiomyomatosis and renal angiomyolipomas are present, other features of TSC should be present before a definite diagnosis is assigned. Histologic confirmation is suggested but not required. Radiographic confirmation is sufficient. Modified from Roach ES, Gomez MR, Northrup H: Tuberous Sclerosis Complex Consensus Conference: revised clinical diagnostic criteria, J Child Neurol 13:624-628, 1998.

Clinical Evaluation
Any patient suspected of having TSC should undergo a complete history and physical examination in an effort to match the findings to the established diagnostic criteria (Tables 1 to 4). Since the diagnosis frequently requires the documentation of lesions in the brain by neuroimaging, CT or MR imaging is generally considered part of the initial evaluation. In addition to the neuroimaging, cardiac and renal ultrasonography is also part of the initial evaluation. If the patient meets the criteria for definite TSC, one need not confirm with genetic testing. If one is unable to make a definite diagnosis at this point, ophthalmologic and dental evaluations are considered useful. We do not usually evaluate the colon for polyps unless other factors point in that direction. Genetic testing may be useful in establishing the diagnosis if the diagnosis must be made now rather than waiting for new features to develop over time. There are four clinical presentations that account for the vast majority of patients with TSC: (1) infantile spasms in the infant; (2) seizures at any age, but typically early childhood; (3) the evaluation of a mentally retarded child; and (4) the consult from the renal clinic for seizures or the dermatology clinic due to the skin lesions.
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Infantile spasms are so characteristic of TSC that they were part of the diagnostic criteria in the past. The evaluation of patients with infantile spasms always includes a careful evaluation of the integument of the patient and parents as well as family history. In this setting it is important to remember the ultraviolet light because at 4 to 6 months of age, when infantile spasms most frequently begin, the depigmented macules may not be readily apparent without the Woods light. EEG is necessary to make the diagnosis of infantile spasms but is not useful in the diagnosis otherwise. Neuroimaging is considered part of the evaluation of these seizures and generally MR imaging is considered the study of choice because a good-quality study will identify even the small uncalcified SGNs. Though vigabatrin is touted as the drug of choice for infantile spasms associated with TSC, the recently published practice parameter concluded that there was insufficient evidence to conclude

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TABLE 2 Important Aspects of the Evaluation of the Patient with TSC


Presenting Signs and Symptoms Infantile spasms Seizures in childhood Mental retardation Seizures in a renal patient Skin abnormalities: white patches, acne-like lesions, shagreen patch, wartlike lesions under nails Important History Features Family history: epilepsy, mental retardation, skin lesions, consanguinity Autistic features Cardiac tumor in infancy Renal cysts or tumors Skin lesions Seizures Important Examination Features Integument Funduscopic Nail beds Malar rash Gingival angiofibromata Diagnostic Tests EEG if appropriate for seizures MR imaging or, if necessary, CT Renal ultrasound examination Cardiac ultrasound examination, if indicated Woods lamp (ultraviolet) examination of the integument Ophthalmologic examination
TSC, Tuberous sclerosis complex; EEG, electroencephalogram.

that vigabatrin is effective in these seizures. We use adrenocorticotropic hormone (ACTH), 150 units/m2, as a once-daily injection as the primary therapy for infantile spasms. A 4-week course of everyday therapy is completed if possible. Then the patient is switched to every other day, and a taper is begun that lasts over 6 to 8 weeks. When ACTH is changed to every other day,

valproate is started with the intent that it will be used as the maintenance drug when the steroid is stopped. We do an echocardiogram at the onset of therapy and follow blood pressures weekly, and if the patient develops hypertension we repeat the echo. If the repeat echo shows thickening of the myocardium, we begin the taper of the ACTH at that point. About two thirds of the patients develop hypertension and myocardial hypertrophy, which is transient and therapy related. The child who presents with seizures may already be suspected of having TSC. Stereotypic, focal seizures in a small infant should prompt the search for focal cortical dysplasias, including the cortical tubers of TSC. The evaluation includes EEG, MR imaging, and a search for other characteristic features. The choice of AED is made on the same basis as with any other seizure patient, that is, the seizure type and the EEG findings. Diagnosis in this context frequently has a major impact on prognosis and also frequently necessitates genetic counseling. Once the diagnosis is suspected, cardiac and renal ultrasound examinations are appropriate. Features that suggest the need for further or more intensive follow-up include SGN or SEGA larger than 1 cm in diameter or located precisely at the foramen of Monro on MR imaging. Renal ultrasound revealing an angiomyolipoma greater than 4 cm in size requires intervention, but smaller lesions require periodic evaluations to follow their growth. The discovery of TSC in a patient being evaluated for mental retardation or delayed acquisition of motor milestones is a relatively frequent event in practice. The principal components of the evaluation would include a careful history and physical examination, including a search of the integument and examination of the family members. MR imaging is the imaging study most likely to provide diagnostic information. On several occasions, we have made the diagnosis in a parent who was unaware of this condition. MR is the imaging study most likely to provide diagnostic information. Cardiac and renal ultrasound studies provide a baseline and help design the serial examination schedule. The patient referred from the renal or dermatology clinic for the possible diagnosis of TSC should be

TABLE 3 Suggested Serial Examinations for Various Abnormalities in Patients with TSC
Lesion Location

Abnormal Finding MRI Identification SGN or SEGA

Size

Recommendation

Lesion < 1 cm in diameter Lesion > 1 cm in diameter

Lesion at foramen of Monro Lesion elsewhere on ependymal surface Lesion at foramen of Monro Lesion elsewhere on ependymal surface

MRI q 1-2 yr if asymptomatic MRI q 3-5 yr MRI q yr MRI q 1-2 yr if asymptomatic

Ultrasonographic Identification Renal cysts or renal angiomyolipoma

Lesion < 4 cm in diameter Lesion > 4 cm in diameter

Repeat renal ultrasound q yr Treatment advised

TSC, Tuberous sclerosis complex; SGN, subependymal glial nodule; SEGA, subependymal giant cell astrocytoma.

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approached just like the patient with seizures or mental retardation with signs of TSC. Frequently, though they may have been identified as possibly having TSC, the patients referred from other medical clinics have not had the disease, its genetics, and implications explained to them or the family. The long-term management of patients with TSC includes treatment of active neurologic problems (seizures, behavior problems, mental retardation), as well as surveillance testing to prevent complications from known hamartomata. Surveillance testing usually consists of brain MR imaging, renal ultrasonography, and ophthalmologic examination. Serial brain imaging is aimed at identifying enlarging SGNs (which might actually be astrocytomas) and SEGAs, as well as detecting ventricular obstruction at the foramen of Monro. Serial renal ultrosonography is aimed at identifying renal cysts that are at risk for rupture or renal angiomyolipamas that are larger than 4 cm and are at risk for hemorrhage and other complications (see Table 3).

TABLE 4 Genetic Testing in Tuberous Sclerosis Complex


Indications Diagnostic confirmation in a suspected case Prenatal testing in an unaffected mother with a single affected child Testing for germinal mosaicism in unaffected parents with more than one affected child Testing in familial cases for genetic counseling Current Methods Amplification of exons and screening by DHPLC Direct sequencing of selected exons Future Methods Direct sequencing of TSC1 and TSC2 genes by microarray hybridization
Resources: http://www.genetests.org/ DHPLC, Denaturing high-performance liquid chromatography.

Genetics, Genetic Testing, and Genetic Counseling


About two thirds of the cases of TSC are sporadic, and the remaining cases are familial. The inheritance pattern is autosomal dominant. In most patients, the diagnosis can be made by clinical examination and radiologic studies. Genetic testing is not a part of the routine diagnostic evaluation. More than 300 distinct mutations in the TSC1 and TSC2 genes have been identified, and these are scattered over all the exons of the two genes. This makes the job of mutation detection difficult. Research studies looking for mutations in either TSC1 or TSC2 among sporadic patients with TSC report an identification rate of between 60% and 80%. The question of looking for a mutation in one of the two TSC genes comes up in certain special circumstances, and most of these deal with genetic counseling. One of these comes about because of the phenomenon of germinal mosaicism. This might be suspected when there are two or more affected children in a family, without any evidence of the disorder in either parent or other family members. Knowing the genetic mutation in the children allows us to define the carrier status of the parents, as well as to differentiate between germinal mosaicism in a parent and different spontaneous mutations in the children. A second scenario in which genetic testing may be useful is when the diagnosis is made in the child of a young unaffected couple. Again, the problem in providing accurate genetic risk information is because of the phenomenon of germinal mosaicism in a parent. Identification of the mutation in the affected child will permit prenatal testing in future pregnancies. A third setting in which genetic testing is done is when clinical and radiologic testing is not conclusive, and early diagnosis is important (e.g., when the mother is pregnant). In this situation, identification of a genetic mutation (as distinct from a polymorphism) is helpful,
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but failure to define a gene mutation should not be interpreted as ruling out the diagnosis. This is because of the limitations of the methods used to screen for mutations, and the fact the known mutations in TSC1 and TSC2 are scattered over the entire extent of the genes. SUGGESTED READING
Kandt RS: Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases, Neurol Clin North Am 20:941-964, 2002. Mackay MT, Weiss SK, Adams-Webber T, et al: Medical treatment of infantile spasms, Neurology 62:1668-1681, 2004. Roach ES, DiMario FJ, Kandt RS, Northrup H: Tuberous Sclerosis Consensus Conference: recommendations for diagnostic testing, J Child Neurol 14:401-407, 1999. Roach ES, Gomez MR, Northrup H: Tuberous Sclerosis Complex Consensus Conference: revised clinical diagnostic criteria, J Child Neurol 13:624-628, 1998. Shevell M, Ashwal S, Donley D, et al: Evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology; Committee of the Child Neurology Society, Neurology 60:367-380, 2003.

PATIENT RESOURCE
Tuberous Sclerosis Alliance 801 Roeder Road, Suite 750 Silver Spring, MD 20910 Phone: 301-562-9890 Toll-free phone: 800-225-6872 http://www.tsalliance.org info@tsalliance.org/

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Sturge-Weber Syndrome

Sturge-Weber Syndrome
Anne Comi, M.D.

port-wine stain and new onset of complex partial seizures and a strokelike episode with hemiparesis following the event. In each case, a thorough assessment of involvement is needed so that the patient and family can be appropriately counseled and treatment initiated.

Sturge-Weber syndrome (SWS) is the third most common neurocutaneous disorder and occurs sporadically. There is typicallya facial port-wine stain in the ophthalmic distribution of the trigeminal nerve, glaucoma and vascular eye abnormalities, and a parieto-occipital leptomeningeal angioma ipsilateral to the cutaneous and ocular anomalies. The usual presentation is in infancy; however, presentation with first seizure and subsequent diagnosis is known to occur in adulthood. Somatic mutation has been proposed as a possible etiology; however, the putative gene is unknown. Patients with SWS often develop neurologic problems including seizures, migraines, strokelike episodes, learning difficulties or mental retardation, visual field cuts, and hemiparesis. These problems frequently persist into adulthood and can be further complicated by psychological problems and difficulty establishing independence from the family of origin. Multiple specialists, including a neurologist, ophthalmologist, dermatologist, medical rehabilitation specialist, occupational and physical therapists, speech and language pathologist, psychiatrist, and behavioral psychologist, are therefore often involved in the care of individuals with SWS (Figure 1).

Diagnosis and Evaluation


Any child with a facial port-wine stain in the cranial nerve V1 distribution, or an adult presenting with this and neurologic symptoms, should have a head computed tomography (CT) scan to image the calcification and magnetic resonance (MR) imaging of the brain with and without contrast to detect the angioma. The typical CT findings are cortical calcifications often in a gyral pattern and atrophy, although these findings may not be present in neonates or infants. The brain MR scan demonstrates increased T2-weighted signal in the white matter and focal meningeal enhancement. When possible, we also ask for postcontrast fluid-attenuated inversion recovery (FLAIR) imaging because this appears to have greater sensitivity for visualizing the angioma. Imaging with technetium-99m hexamethylpropyleneamine oxime single-photon emission CT (SPECT) or perfusion MR imaging is useful for assessing the extent and localization of the perfusion defects and metabolic imaging with fluorodeoxyglucose positron emission tomography (FDG-PET) or MR spectroscopy may also be helpful in characterizing the extent of brain disease in SWS. If MR imaging is negative in infancy, one may need to repeat it by the first birthday or with the onset of neurologic symptoms. Close neurologic and developmental follow-up is essential for children with SWS to diagnose and treat developmental delays, seizures, headaches, hemiparesis, learning difficulties, and behavioral issues as they arise. Most children with SWS require occupational and physical therapy for their hemiparesis and visual field cut. Developmental and neuropsychological assessments can be quite helpful for addressing attentional issues and learning difficulties. Attention deficit disorder occurs in about 20% and mental retardation in about 50% of children and adults with SWS. Screening for glaucoma should be done at birth, under anesthesia if necessary, and then at least every 3 to 4 months in the first year, every 6 months in the second year, and yearly thereafter. The peak time for diagnosis of glaucoma is in infancy, but a second smaller peak occurs in young adulthood. Ophthalmologic evaluations can determine the extent of abnormal vessel involvement with the eye. Patients with port-wine stains involving both the upper and the lower eyelids are at the greatest risk for glaucoma. Glaucoma in the young child can present with eye enlargement (buphthalmos) or with corneal clouding and vision loss at any time, and these signs and symptoms need urgent evaluation. Patients with a port-wine stain are also referred for dermatologic assessment. In infancy the port-wine stain is often pink and flat. The port-wine stain generally grows commensurate with growth and often darkens or
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Presentations
The diagnosis of SWS can frequently be suspected when an individual is noted to have a facial port-wine stain. The diagnosis of SWS means that the cutaneous port-wine stain is associated with either brain or eye involvement. The risk of an associated underlying leptomeningeal angioma and/or glaucoma is about 8% with a port-wine stain anywhere on the face. Thus, most patients with a facial port-wine stain do not have SWS. This risk increases to about 25% when the skin angioma is in the cranial nerve V1 ophthalmic distribution on the face. A careful examination of the upper eyelid may reveal cutaneous involvement of just a few millimeters in some cases. The risk of intracranial involvement increases to 33% with bilateral facial port-wine stains. In approximately 85% of individuals with SWS, the involvement is unilateral with the brain and eye involvement on the same side as the port-wine stain. However, a unilateral port-wine stain can be paired with bilateral leptomeningeal angioma involvement or vice versa. The most frequent presentation for the neurologic manifestations in SWS is focal and complex partial seizures in an infant with a facial port-wine stain. Onset of seizures is usually in the first 2 years of life but occasionally can start later in childhood or even adulthood. Other presentations for SWS include a visual field cut presenting as an infant that neglects a hemivisual space or the early onset of handedness in a child with a facial port-wine stain. An adult can present with a facial

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FIGURE 1. Evaluating a patient with facial cutaneous capillovascular malformation (port-wine stain). SPECT, Single-photon emission computed tomography; FDG-PET, fluorodeoxyglucose positron emission tomography; AED, antiepileptic drug; EEG, electroencephalogram.

Patient with facial port-wine stain including the V1 trigeminal nerve distribution

Dermatologic and ophthalmologic evaluations

Obtain MRI of the brain with and without contrast Normal Consider reimaging and metabolic imaging with perfusion MRI, SPECT or FDG-PET Abnormal Provide Diastat, anticipatory guidance for seizures, daily multivitamin, screen for iron deficiency anemia, anticipatory guidance for illness and avoidance of dehydration and close neurodevelopmental follow-up

Have seizures occurred? No Close neurologic follow-up Yes Aggressive seizure management: First line AED: Carbamazepine Second line AED: Valproic acid or topiramate Maintain high-normal blood levels of AED Diastat for seizure >5 minutes If unsuccessful, consider video EEG Monitoring and PET imaging for surgery

Have focal weakness or stroke-like episodes? No Close neurologic follow-up Yes Occupational/physical therapy Low dose aspirin 35 mg/kg/day if stroke-like episodes present

may become raised with time. It is recommended that port-wine stains be treated in infancy, before hypertrophy and blebbing develop and make treatment more difficult. Later in childhood, plastic surgery may be judiciously considered to deal with the tissue hypertrophy that can occur in the region of the port-wine stain. Presenting the diagnosis of SWS to patients and parents is complex and requires the coordinated input of multiple specialists to address the different organ systems involved in this disorder. It is essential that time is spent answering questions so that seizures, strokelike episodes, and other complications are recognized and appropriately managed to minimize brain injury.

SEIZURES Infants with SWS typically develop complex partial seizures in the first 3 years of life, most in the first year. It is essential that family members receive counseling regarding what seizures look like and how to obtain help rapidly for a first seizure. Seizures are managed acutely with benzodiazepines, phosphenytoin, and, if necessary, phenobarbital. A prolonged hemiparesis, lasting days, weeks, or months is common after a seizure episode, and a permanent hemiparesis frequently develops over time. Although controversial, there is evidence that seizures, particularly if they are frequent or prolonged, may result in increased brain injury resulting from the impairments in blood flow. Therefore, chronic anticonvulsants should be initiated after the first seizure, whether febrile or afebrile, in a patient with SWS and brain involvement. Vigorous efforts should be made to gain control of seizures. I recommend medication levels (when applicable) at least in the high-therapeutic range and regular adjustments of dose for weight gain to best maintain seizure control. Generally the first-choice anticonvulsant is carbamazepine, or phenobarbital transitioning to carbamazepine, depending on the age of the child, because

Therapy
In all patients with SWS and intracranial involvement, I advise the empirical use of a daily multivitamin. Patients with SWS should be screened for iron deficiency anemia, which is relatively common in young children and some adults and, if present, could exacerbate ischemic brain injury and should be treated.
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most seizures in SWS are complex partial. Oxcarbazine (Trileptal) may also be used. Second-line choices include topiramate and valproic acid. Rectal or oral diazepam is given to the family for use with seizures lasting longer than 5 minutes or with clusters of seizures. Seizures in SWS, as in other settings, commonly occur during illness. I advise family members and patients to treat fevers and maintain good hydration during illness, even if intravenous fluids are needed. I advise continuing the anticonvulsant for a few years, until the fifth birthday if possible, because older children appear to be less susceptible to permanent neurologic decline that may be exacerbated by seizures in the younger children. If seizures are not controlled with anticonvulsants, are occurring frequently so as to interfere with development, or deterioration in neurologic status is occurring, then children should be considered for surgical resections. Surgery may include focal resections or hemispherectomies. Most candidates for surgery have significant developmental delay and hemiparesis. Timing of surgery should be carefully weighed for risks and benefits; however, in the appropriate situation surgery can result in cessation of seizures and resumption in development. There is no evidence that surgical resection of the affected cortex is the proper course of action in the absence of intractable epilepsy. STROKELIKE EPISODES Strokelike episodes can occur in SWS and present as episodes of transient visual field cuts or weakness that can occur independent of seizures or may precede or follow seizures. It is not entirely clear what these episodes represent; however, thrombosis, hypoxia-seizure, complicated migraine, and/or seizure activity all may have some role in these episodes. Minor head trauma can trigger these events as well. I recommend prophylactic use of aspirin when strokelike episodes have occurred. Experience with its use in the prevention of pediatric stroke, and anecdotal evidence in SWS, suggest that low-dose aspirin at 3 to 5 mg/kg/day is safe and effective; however no randomized, placebo-controlled trial has been done. Children on aspirin therapy should receive varicella immunization and the yearly influenza vaccine because of the association between these illnesses, aspirin use, and Reyes syndrome in children. The international experience with low-dose aspirin use for stroke prophylaxis in children, however, suggests that this therapy is safe. Preventing severe illness with these vaccinations is probably a good idea anyway because episodes of deterioration in SWS often occur in the setting of illness. Occupational and physical therapies are prescribed when weakness is persistent to maximize function and prevent contractures. HEADACHES Headaches and migraines are also common in SWS. Acutely, antimigraine medications such as ibuprofen are used; however, the safety of triptans has not been studied in SWS. In older children and adults, it seems that seizures can provoke headaches, and headaches can

precede the onset of seizures or strokelike episodes. When frequent, valproic acid may provide prophylaxis for both seizures and recurrent headaches. Alternatively, a combination of an anticonvulsant, such as carbamazepine, and a calcium channel blocker or beta blocker may be required. COGNITIVE AND PSYCHOLOGICAL ISSUES Learning disabilities and mental retardation frequently develop in SWS and need to be evaluated and addressed educationally. Attention deficit disorder is common in SWS and should be addressed with a combination of behavioral and pharmacologic approaches. When behavioral approaches are insufficient, then treatment with either a stimulant or atomoxetine should be initiated and response closely monitored. Depression and anxiety are also common in SWS. Older children and adolescents can demonstrate a decline in function or new behavioral issues, and psychological factors should be evaluated when this occurs. Treatment with a selective serotonin reuptake inhibitor or tricyclic may be helpful. However, the safety and efficacy of these approaches have not been studied specifically in SWS.

Treatment of Ophthalmologic and Dermatologic Complications


Treatment of the port-wine stain requires a series of laser treatments. Pulsed-dye laser can improve the appearance of the vascular malformation in about 10 treatments. Without treatment, the port-wine stains often develop blebbing and hypertrophy of underlying soft tissue and bone that can lead to significant psychological and functional issues depending on the location and extent of involvement. It is unknown if infancy is the best time for treatment of SWS, given the other systems involved; however, the current practice in SWS is to treat the port-wine stain early. Laser treatments are painful and can occasionally result in scarring, and older children should therefore be included in discussions for timing for treatment. Glaucoma may occur at any age, although two peaks exist in infancy and in early adulthood. The goal of treatment is to reduce intraocular pressure to protect vision. Medical and surgical approaches are used and concentrate on either reducing the production of aqueous fluid or promoting its drainage. Medications include beta-agonist eye drops, adrenergic eye drops, and carbonic anhydrase inhibitors. Trabeculectomy and goniotomy are common surgical options. SUGGESTED READING
Bodensteiner JB, Roach ES, editors: Sturge-Weber syndrome, Mt. Freedom, NJ, 1999, Sturge-Weber Foundation. Chapieski L, Friedman A, Lachar D: Psychological functioning in children and adolescents with Sturge-Weber syndrome, J Child Neurol 15:660-665, 2000. Comi AM: Pathophysiology of Sturge-Weber syndrome, J Child Neurol 18:509-516, 2000. Johnson: Current Therapy in Neurologic Disease (7/E)

Autism Kossoff EH, Buck C, Freeman JM: Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide, Neurology 59: 1735-1738, 2002. Maria BL, Neufeld JA, Rosainz LC, et al: Central nervous system structure and function in Sturge-Weber syndrome: evidence of neurologic and radiologic progression, J Child Neurol 13:606-618, 1998. Rothfleisch JE, Kosann MK, Levine VJ, Ashinoff R: Laser treatment of congenital and acquired vascular lesions, Dermatol Clin 20:1-18, 2002.

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PATIENT RESOURCES
Sturge-Weber Foundation P.O. Box 418 Mt. Freedom, NJ 07970 Phone: 800-627-5482 Fax: 973-895-4846 http://www.sturge-weber.com/ The Kennedy Krieger Institute and Johns Hopkins Medicine Sturge-Weber Syndrome Center 707 N Broadway Baltimore, MD 21205 Phone: 443-923-9128 Fax: 443-923-9160 http://www.sturge-weberkennedy krieger.org

Neuropathologic findings in autism postmortem brain tissue include altered neuronal populations in the limbic system, decreased Purkinje cells, altered cortical minicolumns, increased white matter, and neuroglial activation. Most of the findings are consistent with abnormal developmental programs of prenatal onset. These altered programs could result in observations of altered neuropeptides at birth, accelerated brain growth during infancy, and increased platelet serotonin. In addition to genetic influences, epigenetic and environmental factors may affect selectively vulnerable neural networks through multiple mechanisms. Several neurobiologic processes have been implicated in the pathogenesis of autism, including abnormal neurotransmitters, experience-dependent synaptic plasticity, glutamate excitotoxicity, and neuroimmune mechanisms.

Diagnosis and Evaluation


Early detection of autism is important because early intensive intervention improves outcome for most children. An effective screening tool for autism is the Modified Checklist for Autism in Toddlers (M-CHAT) (available at http://www.firstsigns.org/). Clinical indicators for a more structured evaluation include (1) failure to point at objects to get anothers attention (normally present at 12 months of age); (2) impaired receptive and expressive language (e.g., failure to use single words by 18 months, 2-word phrases by 2 years, answer what, where, and who questions by 3 years); and (3) the use of sustained high-pitched sounds (eeeee) or echolalia. An exception is Aspergers syndrome, in which semantics are usually spared. Early signs of abnormal social relatedness may include difficulty engaging in peek-aboo games, making and maintaining eye contact, and showing reciprocal emotion. The child may be affectionate on his or her own terms or relate to older children and adults rather than peers. Children and adults with ASDs lack theory of mind: they are unable to perceive the thoughts and feeling states of others. Repetitive and stereotypic behaviors may include waving the hands in the lateral visual fields, flapping the hands, and ordering objects. Persons with autism exhibit an insistence on sameness without apparent meaning. Certain autistic behaviors, such as covering the ears, scratching the skin, and repeating visual patterns, may result from abnormal neurophysiologic processing of sensory inputs. A preliminary impression of ASD in preschool children, based on observation and screening tests (e.g., M-CHAT or Childhood Autism Rating Scale [CARS]), should be followed by a coordinated team evaluation (physician, speech and language pathologist, and psychologist). The diagnosis is confirmed and further defined using the Autism Diagnostic Observation Schedule (ADOS) or Autism Diagnostic Interview-Revised (ADI-R), both of which are administered by specially trained testers. Evaluations should also include assessments of cognitive functions and adaptive skills. All children should have audiologic, speech and language therapy (SLT), and occupational therapy (OT) evaluations. It is important to rule out hearing loss using age-appropriate

Autism
Andrew W. Zimmerman, M.D.

Autism is a heterogeneous group of lifelong neurobehavioral syndromes, now referred to as autism spectrum disorders (ASDs), that result from abnormal early neural development with appearance of initial symptoms by the age of 3 years. Known etiologies are detectable in up to 10% of patients, although the causes in most are still unknown. Patients typically present with delayed or disordered language development, abnormal social relatedness, and repetitive, odd behaviors. Autistic symptoms and cognitive deficits vary widely among patients in their age at onset, severity, and clinical course. Regression in previously acquired language and social skills occurs in approximately 30%, usually between 18 and 21 months. Classic, or Kanner-type, autism is grouped with other ASDs (or pervasive developmental disorders [PDDs] in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), including Aspergers syndrome and PDD/NOS (not otherwise specified). Idiopathic autism is genetic; concordance for the broad autism spectrum in monozygotic twins is 90% and in dizygotic twins, 10%. The recurrence risk for a family with one child with autism is up to 9%. The disorders typically affect boys more than girls (4:1) and occur in all cultural and racial groups. The estimated prevalence of ASDs is 1:250 to 500 and appears to be increasing. However, this may result in part from broader definition and improved recognition in recent years. In any case, autism is now the most common neurodevelopmental disorder.
Johnson: Current Therapy in Neurologic Disease (7/E)

Autism Kossoff EH, Buck C, Freeman JM: Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide, Neurology 59: 1735-1738, 2002. Maria BL, Neufeld JA, Rosainz LC, et al: Central nervous system structure and function in Sturge-Weber syndrome: evidence of neurologic and radiologic progression, J Child Neurol 13:606-618, 1998. Rothfleisch JE, Kosann MK, Levine VJ, Ashinoff R: Laser treatment of congenital and acquired vascular lesions, Dermatol Clin 20:1-18, 2002.

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PATIENT RESOURCES
Sturge-Weber Foundation P.O. Box 418 Mt. Freedom, NJ 07970 Phone: 800-627-5482 Fax: 973-895-4846 http://www.sturge-weber.com/ The Kennedy Krieger Institute and Johns Hopkins Medicine Sturge-Weber Syndrome Center 707 N Broadway Baltimore, MD 21205 Phone: 443-923-9128 Fax: 443-923-9160 http://www.sturge-weberkennedy krieger.org

Neuropathologic findings in autism postmortem brain tissue include altered neuronal populations in the limbic system, decreased Purkinje cells, altered cortical minicolumns, increased white matter, and neuroglial activation. Most of the findings are consistent with abnormal developmental programs of prenatal onset. These altered programs could result in observations of altered neuropeptides at birth, accelerated brain growth during infancy, and increased platelet serotonin. In addition to genetic influences, epigenetic and environmental factors may affect selectively vulnerable neural networks through multiple mechanisms. Several neurobiologic processes have been implicated in the pathogenesis of autism, including abnormal neurotransmitters, experience-dependent synaptic plasticity, glutamate excitotoxicity, and neuroimmune mechanisms.

Diagnosis and Evaluation


Early detection of autism is important because early intensive intervention improves outcome for most children. An effective screening tool for autism is the Modified Checklist for Autism in Toddlers (M-CHAT) (available at http://www.firstsigns.org/). Clinical indicators for a more structured evaluation include (1) failure to point at objects to get anothers attention (normally present at 12 months of age); (2) impaired receptive and expressive language (e.g., failure to use single words by 18 months, 2-word phrases by 2 years, answer what, where, and who questions by 3 years); and (3) the use of sustained high-pitched sounds (eeeee) or echolalia. An exception is Aspergers syndrome, in which semantics are usually spared. Early signs of abnormal social relatedness may include difficulty engaging in peek-aboo games, making and maintaining eye contact, and showing reciprocal emotion. The child may be affectionate on his or her own terms or relate to older children and adults rather than peers. Children and adults with ASDs lack theory of mind: they are unable to perceive the thoughts and feeling states of others. Repetitive and stereotypic behaviors may include waving the hands in the lateral visual fields, flapping the hands, and ordering objects. Persons with autism exhibit an insistence on sameness without apparent meaning. Certain autistic behaviors, such as covering the ears, scratching the skin, and repeating visual patterns, may result from abnormal neurophysiologic processing of sensory inputs. A preliminary impression of ASD in preschool children, based on observation and screening tests (e.g., M-CHAT or Childhood Autism Rating Scale [CARS]), should be followed by a coordinated team evaluation (physician, speech and language pathologist, and psychologist). The diagnosis is confirmed and further defined using the Autism Diagnostic Observation Schedule (ADOS) or Autism Diagnostic Interview-Revised (ADI-R), both of which are administered by specially trained testers. Evaluations should also include assessments of cognitive functions and adaptive skills. All children should have audiologic, speech and language therapy (SLT), and occupational therapy (OT) evaluations. It is important to rule out hearing loss using age-appropriate

Autism
Andrew W. Zimmerman, M.D.

Autism is a heterogeneous group of lifelong neurobehavioral syndromes, now referred to as autism spectrum disorders (ASDs), that result from abnormal early neural development with appearance of initial symptoms by the age of 3 years. Known etiologies are detectable in up to 10% of patients, although the causes in most are still unknown. Patients typically present with delayed or disordered language development, abnormal social relatedness, and repetitive, odd behaviors. Autistic symptoms and cognitive deficits vary widely among patients in their age at onset, severity, and clinical course. Regression in previously acquired language and social skills occurs in approximately 30%, usually between 18 and 21 months. Classic, or Kanner-type, autism is grouped with other ASDs (or pervasive developmental disorders [PDDs] in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), including Aspergers syndrome and PDD/NOS (not otherwise specified). Idiopathic autism is genetic; concordance for the broad autism spectrum in monozygotic twins is 90% and in dizygotic twins, 10%. The recurrence risk for a family with one child with autism is up to 9%. The disorders typically affect boys more than girls (4:1) and occur in all cultural and racial groups. The estimated prevalence of ASDs is 1:250 to 500 and appears to be increasing. However, this may result in part from broader definition and improved recognition in recent years. In any case, autism is now the most common neurodevelopmental disorder.
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audiometric techniques or, if necessary, brainstem auditory evoked responses. Structured behavioral therapies (e.g., applied behavioral analysis) should be considered for young children, with assisted programming based on psychological and educational testing in school-age children. Additional help with play or social skills groups may be needed. The differential diagnosis of ASD includes more than 100 conditions that show autistic behaviors. Many of these include double syndromes, in which the phenotype of autism is associated with another disorder of known cause, such as Rett, Down, and fragile X syndromes, and tuberous sclerosis. Rett syndrome results from defects in the methyl-CpG-binding protein 2 (MeCP2) gene and affects mainly females, who regress after the first year of life and often develop seizures and typical hand-wringing movements. Fragile X syndrome, due to expansion of trinucleotide repeats within the FMR1 gene, is a major cause of mental retardation and may present with autism in boys, as well as learning disabilities in girls. Autism, by itself, in most cases does not have an identifiable cause. Identification of a specific etiology can have important implications for prognosis and treatment, such as for seizures and mitochondrial dysfunction. Neurologic evaluations for ASDs should include histories of the prenatal and perinatal periods, early development, infections, gastrointestinal (GI) and immune functions, and seizures. The family history may reveal conditions concurrent with autism or elements of ASDs (e.g., difficulties with social or pragmatic language skills). The neurologic examination, often a challenge to perform, should include direct observation of the childs communication and play behaviors; evaluation of receptive, expressive, and social aspects of language; measurements of growth; notation of dysmorphic features; and Woods lamp examination.

seizure activity (atypical Landau-Kleffner syndrome). Other tests may be indicated for specific syndromes, such as 7-dehydrocholesterol for Smith-Lemli-Opitz syndrome, FISH for velocardiofacial and Angelmans syndrome, transferrin electrophoresis for congenital disorders of glycosylation, 24-hour urinary uric acid for purine autism, and serum ammonia levels. Cranial computed tomography (CT), single-photon emission CT, and magnetic resonance (MR) scans are generally not performed routinely and should be reserved for those with special indications based on the history and neurologic examination. Other imaging methods, such as positron emission tomography, functional MR imaging, and MR spectroscopy, are strictly research tools.

Treatment
Established therapies for autism include individualized special school programs and speech/language and behavioral therapies in a setting that is coordinated, structured, and predictable and contains visual supports and high degrees of reinforcement. Beginning therapies early takes advantage of potential synaptic plasticity. Although most children improve, an individual childs trajectory for improvement varies over time. Outcomes for independent functioning correlate with attainment of functional language and adaptive skills by school age. Periodic, regular assessments should include cognitive, social skills and educational testing, in additional to SLT, OT, and occasionally physical therapy. Drug therapies for ASDs (Figure 1) are symptomatic and are chosen to improve short-term function and behavior such as calming, improving attention, or reducing aggression to enable the child to remain in the classroom. There is no evidence to suggest pharmacotherapy affects long-term outcomes. In individual cases, therapy targeted to the treatment of concurrent medical disorders, such as mitochondrial dysfunction, allergy, or hypothyroidism, can be beneficial. Children with GI symptoms (recurrent loose stools or constipation in 24%) may benefit from GI evaluation and elimination diets (e.g., gluten- and casein free). Sleep is disordered in 60% of ASD patients (more in young children), and abnormal rapid eye movement arousals can be observed on sleep studies. Treatment with melatonin, up to 3 mg/day, or clonidine, 0.025 to 0.1 mg, at bedtime may help to initiate but not maintainsleep, whereas trazodone, 25 to 75 mg, may benefit both. The following steps are suggestions for drug treatment and may be selected in any order, depending on the patients symptoms. The goal is to improve function with as few agents as possible, allowing adequate time between trials to assess their efficacy. Step 1. Selective serotonin reuptake inhibitors (SSRIs) SSRIs improve function in most children with ASDs. Multiple clinical and experimental studies over 30 years have shown that altered serotonin (increased in platelets; decreased synthesis in the central nervous system [CNS]) is a critical component of ASDs in many patients and suggest that treatment may
Johnson: Current Therapy in Neurologic Disease (7/E)

Laboratory Testing
Recommendations for laboratory testing in children with autism range from no studies to a comprehensive evaluation. In my opinion basic laboratory studies in children with ASDs should include complete blood count, serum chemistries (including aspartate aminotransferase [AST]/amino alanine transferase [ALT] and creatine kinase), red blood cell lead levels, and thyroid function. Marginal or low hemoglobin levels occur frequently, especially in children with restricted food preferences. Genetic testing should include a karyotype with subtelomere screening by fluorescence in situ hybridization (FISH), and fragile X by DNA (in girls as well as boys). If there has been regression of language and other skills, further testing of mitochondrial function is indicated, including fasting lactic acid, serum carnitine, plasma amino and urinary organic acids; the ratios of plasma alanine-to-lysine should normally be less than 3:1 and serum AST/ALT less than 2:1. An overnight or extended electroencephalographic (EEG) study including deep natural sleep is also suggested, to evaluate for

Autism

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FIGURE 1. Suggested drug treatment plan over 1 year for 4- to 8-year-old children with autistic spectrum disorders. Successive treatment trials for clinical symptoms should start with smallest doses and increase slowly to assess responses and to avoid overstimulation, due to sensitivity to serotonergic agents (buspirone, selective serotonin reuptake inhibitors [SSRIs]). Regimens should be limited to one or two drugs if possible.

Anxiolytic: buspirone 2.55 mg t.i.d. 1st

(or)

(Treat anxiety, mood, attention, repetitive behaviors)

SSRI: e.g., citalopram 0.5 mg q.a.m.; increase weekly by 0.5 mg, up to 45 mg; avoid overstimulation Alpha-2 adrenergic agonists: e.g., clonidine 0.050.1 mg q.h.s.; up to 0.1 mg t.i.d.

2nd

(Sleep, calming)

(usually not together)

3rd

(Focus, attention)

Stimulants: e.g., methylphenidate 2.510 mg q.a.m. and afternoon Antiepileptics/mood stabilizers: e.g., divalproex sprinkles, 1015 mg/kg; up to 30 mg/kg; monitor labs Atypical antipsychotics: e.g., risperidone 0.25 mg q.h.s., up to 1 mg b.i.d. 9 12

4th

(Seizure activity, mood)

5th

(Mood, aggressive behaviors)

6 Months

improve outcomes. Unfortunately, currently available clinical assays of circulating serotonin are not useful to guide treatment. SSRIs decrease anxiety and repetitive behaviors and improve attention and mood. Experience shows that most children with ASDs have increased sensitivity to SSRIs and respond to small doses; a few children show decreased sensitivity and require high doses. I prefer to begin therapy with very small doses of citalopram (using liquid preparations of 0.5 to 1 mg daily, usually in the morning) and to increase weekly by a similar amount, being cautious to avoid overstimulation as the dose is increased. This may occur when the dose exceeds the individuals therapeutic window, usually in doses from 1 to 5 mg in young children. Individual responses to different SSRIs vary, so repeated trials of different medications may be needed, each over 2 to 3 months. Full therapeutic benefits may not become apparent for 6 to 8 weeks and may be superseded by side effects if the dose is increased too rapidly. Treatment should continue for 6 to 12 months and then be tapered slowly over 6 to 8 weeks. Most young children maintain their gains after the SSRI is discontinued, although loss of function may dictate restoration of drug therapy. Step 2. Sleep, calming, and attentionAlpha2-adrenergic agonists (e.g., clonidine, guanfacine) are useful agents; clonidine helps induce sleep and can be used during the day for calming and to improve focus and attention but may also induce drowsiness. Guanfacine produces less sedation and calming but may be more effective for focus and attention. Step 3. Stimulants for attentionAlthough symptoms of attention deficit hyperactivity disorder (ADHD) occur frequently, children with ASDs are less likely than typical children with ADHD to respond favorably to stimulant medications. Children with ASDs overfocus and have selective attention. Brief medication
Johnson: Current Therapy in Neurologic Disease (7/E)

trials with stimulants (e.g., methylphenidate) are indicated but may lead to irritability and increased hyperactivity. Imipramine and atomoxetine are often good alternatives. Step 4. AnticonvulsantsEEGs following language regression or seizures may reinforce a decision to treat with anticonvulsant medications, such as divalproex or carbamazepine. Although guidelines for the evaluation, treatment, and prognosis of children with abnormal EEGs (but without clinical seizures) have not been determined, experience suggests that approximately one half of these patients will improve in their behavior and language when treated with anticonvulsants. Such improvements, however, likely result from the effect of these medications as mood stabilizers and suggest that epileptiform activity on EEGs reflects, rather than causes, underlying CNS dysfunction. Approximately 30% of persons with autism develop generalized tonic-clonic epilepsy, usually during adolescence. Step 5. Atypical antipsychoticsThese medications are helpful for aggression and adverse behaviors in ASDs. Despite their demonstrated efficacy in short-term trals, risperidone and related drugs deserve cautious follow-up for side effects that include extrapyramidal movements, weight gain, and hyperprolactinemia. Olanzapine and other atypical antipsychotics may induce diabetic changes requiring glucose monitoring.

Summary
Current therapies for ASDs may take advantage of inherent CNS plasticity and lead to improved outcomes. Basic and clinical research in autism is evolving rapidly and should provide approaches based on new knowledge of the underlying pathogenesis of ASDs.

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Acknowledgment The author thanks Dr. Susan Connors for her review and helpful suggestions. SUGGESTED READING
Bauman, ML, Kemper TL, editors: The neurobiology of autism, ed 2, Baltimore, 2005, Johns Hopkins University Press. Palermo MT, Curatolo P: Pharmacologic treatment of autism, J Child Neurol 19:155-164, 2004. Tuchman R: Autism, Neurol Clin North Am 21:915-932, 2003. Zimmerman AW: Autism spectrum disorders. In Singer HS, Kossoff EH, Hartman AL, Crawford TO, editors: Treatment of pediatric neurologic disorders, New York, 2005, Marcel Dekker, pages 489-494.

EVALUATION The evaluation of an individual with suspected ADHD includes the following: 1. Identification of ADHD features that continue to impair function and fulfill diagnostic criteria. This should include information from multiple sources (individual, family member, educators, job colleagues, and friends) and from preexisting documents (report cards, school assessments, psychological testing). Rating scales can be helpful as part of the assessment of individuals with ADHD, with results interpreted in conjunction with other information. Common tools include Conners Parent and Teacher Rating Scales, ADHD Rating Scale, and Vanderbilt Assessment Scale (available as part of an ADHD Toolkit at http:// www.nichq.org/). Adult scales include Adult ADHD Self-Report Scale Wender Utah Rating Scale, Conners Adult ADHD Rating Scales, and Brown Adult ADD Scale. 2. Confirmation that the individual manifested features of ADHD during childhood, especially during or prior to the early school-age years. 3. Review of prenatal, birth, and developmental history for factors that can cause ADHD and for timing and severity of presentation. These include in utero ethanol exposure, prematurity, encephalitis and meningitis, and traumatic brain injury. Individuals with neurodevelopmental disabilities can have an increased risk for ADHD. 4. Delineation of possible alternative diagnoses (psychiatric and medical) and comorbid conditions (Figure 1). Neuropsychological testing (either through a schoolbased multifactorial evaluation or an independent evaluator) should be done when there is a question about the diagnosis or the presence of other learning problems. 5. Family history of psychiatric and neurologic conditions, including ADHD, bipolar disorder, and Tourette syndrome. ADHD may be the first feature of Tourette syndrome or chronic tic disorder, which usually presents during the school-age years in 10% to 12% of this population. Children with bipolar disorder may initially have features of ADHD with excessive mood lability prior to the overt presentation of bipolar features. 6. Physical examination for possible underlying medical condition that may mimic ADHD or impact on treatment (sleep disturbance, hypertension, endocrinopathy, medication side effect from anticonvulsant or beta adrenergic drugs) or neurologic abnormalities (dyspraxia, cerebral palsy, movement disorder).

PATIENT RESOURCES
Autism Society of America http://www.autism-society.org/ Cure Autism Now Foundation http://www.cureautismnow.org/ National Alliance for Autism Research http://www.naar.org/ Kennedy Krieger Institute http://www.kennedykrieger.org/

Attention Deficit Hyperactivity Disorder and Learning Disabilities


Max Wiznitzer, M.D.

Attention Deficit Hyperactivity Disorder


Attention deficit hyperactivity disorder (ADHD) is a common reason for consultation with primary care providers and pediatric specialists. The prevalence for this biologically based disorder is 5% to 10% in children and 2% to 4% in adults. The core symptoms of ADHD are short attention span for mental age, impulsivity (acting without thinking of consequences), easy distractibility (inability to maintain focus on a needed task), and motor overactivity (which may range from fidgetiness to continuous movement). These core features have been organized into two major groupings (inattentiveness and hyperactivity-impulsivity) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and are listed in Table 1. Features can vary by age at presentationdisruptive behavior in the preschool years; academic struggles in the school-age years; and disorganization, impulsive risk taking, social difficulties, and educational and employment challenges in adolescence and adulthood.

TREATMENT The management of ADHD requires an approach that combines behavioral and educational techniques with judicious use of medication. This conclusion is supported by the findings in the Multimodal Treatment Study of Children with ADHD, which showed that the core features of ADHD were best managed with
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Acknowledgment The author thanks Dr. Susan Connors for her review and helpful suggestions. SUGGESTED READING
Bauman, ML, Kemper TL, editors: The neurobiology of autism, ed 2, Baltimore, 2005, Johns Hopkins University Press. Palermo MT, Curatolo P: Pharmacologic treatment of autism, J Child Neurol 19:155-164, 2004. Tuchman R: Autism, Neurol Clin North Am 21:915-932, 2003. Zimmerman AW: Autism spectrum disorders. In Singer HS, Kossoff EH, Hartman AL, Crawford TO, editors: Treatment of pediatric neurologic disorders, New York, 2005, Marcel Dekker, pages 489-494.

EVALUATION The evaluation of an individual with suspected ADHD includes the following: 1. Identification of ADHD features that continue to impair function and fulfill diagnostic criteria. This should include information from multiple sources (individual, family member, educators, job colleagues, and friends) and from preexisting documents (report cards, school assessments, psychological testing). Rating scales can be helpful as part of the assessment of individuals with ADHD, with results interpreted in conjunction with other information. Common tools include Conners Parent and Teacher Rating Scales, ADHD Rating Scale, and Vanderbilt Assessment Scale (available as part of an ADHD Toolkit at http:// www.nichq.org/). Adult scales include Adult ADHD Self-Report Scale Wender Utah Rating Scale, Conners Adult ADHD Rating Scales, and Brown Adult ADD Scale. 2. Confirmation that the individual manifested features of ADHD during childhood, especially during or prior to the early school-age years. 3. Review of prenatal, birth, and developmental history for factors that can cause ADHD and for timing and severity of presentation. These include in utero ethanol exposure, prematurity, encephalitis and meningitis, and traumatic brain injury. Individuals with neurodevelopmental disabilities can have an increased risk for ADHD. 4. Delineation of possible alternative diagnoses (psychiatric and medical) and comorbid conditions (Figure 1). Neuropsychological testing (either through a schoolbased multifactorial evaluation or an independent evaluator) should be done when there is a question about the diagnosis or the presence of other learning problems. 5. Family history of psychiatric and neurologic conditions, including ADHD, bipolar disorder, and Tourette syndrome. ADHD may be the first feature of Tourette syndrome or chronic tic disorder, which usually presents during the school-age years in 10% to 12% of this population. Children with bipolar disorder may initially have features of ADHD with excessive mood lability prior to the overt presentation of bipolar features. 6. Physical examination for possible underlying medical condition that may mimic ADHD or impact on treatment (sleep disturbance, hypertension, endocrinopathy, medication side effect from anticonvulsant or beta adrenergic drugs) or neurologic abnormalities (dyspraxia, cerebral palsy, movement disorder).

PATIENT RESOURCES
Autism Society of America http://www.autism-society.org/ Cure Autism Now Foundation http://www.cureautismnow.org/ National Alliance for Autism Research http://www.naar.org/ Kennedy Krieger Institute http://www.kennedykrieger.org/

Attention Deficit Hyperactivity Disorder and Learning Disabilities


Max Wiznitzer, M.D.

Attention Deficit Hyperactivity Disorder


Attention deficit hyperactivity disorder (ADHD) is a common reason for consultation with primary care providers and pediatric specialists. The prevalence for this biologically based disorder is 5% to 10% in children and 2% to 4% in adults. The core symptoms of ADHD are short attention span for mental age, impulsivity (acting without thinking of consequences), easy distractibility (inability to maintain focus on a needed task), and motor overactivity (which may range from fidgetiness to continuous movement). These core features have been organized into two major groupings (inattentiveness and hyperactivity-impulsivity) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and are listed in Table 1. Features can vary by age at presentationdisruptive behavior in the preschool years; academic struggles in the school-age years; and disorganization, impulsive risk taking, social difficulties, and educational and employment challenges in adolescence and adulthood.

TREATMENT The management of ADHD requires an approach that combines behavioral and educational techniques with judicious use of medication. This conclusion is supported by the findings in the Multimodal Treatment Study of Children with ADHD, which showed that the core features of ADHD were best managed with
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TABLE 1 Diagnostic Criteria for Attention Deficit Hyperactivity Disorder


A. Either (1) or (2): (1) six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Inattention (a) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities (b) often has difficulty sustaining attention in tasks or play activities (c) often does not seem to listen when spoken to directly (d) often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions) (e) often has difficulty organizing tasks and activities (f) often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework) (g) often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools) (h) is often easily distracted by extraneous stimuli (i) is often forgetful in daily activities (2) six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Hyperactivity (a) often fidgets with hands or feet or squirms in seat (b) often leaves seat in classroom or in other situations in which remaining seated is expected (c) often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness) (d) often has difficulty playing or engaging in leisure activities quietly (e) is often on the go or often acts as if driven by a motor (f) often talks excessively Impulsivity (g) often blurts out answers before questions have been completed (h) often has difficulty awaiting turn (i) often interrupts or intrudes on others (e.g., butts into conversations or games) B. Symptoms that caused impairment were present before 7 years C. Impairment from the symptoms is present in two or more settings (e.g., at school, work, and home) D. Clinically significant impairment in social, academic, or occupational functioning E. The symptoms do not occur exclusively during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for by another mental disorder (e.g., Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder) Attention-Deficit/Hyperactivity Disorder, Combined Type: if both Criteria A1 and A2 are met for the past 6 months Attention Deficit/Hyperactivity Disorder, Predominantly Inattentive Type: if Criterion A1 is met but Criterion A2 is not met for the past 6 months Attention Deficit/Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type: if Criterion A2 is met but Criterion A1 is not met for the past 6 months
From American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC, 1994, American Psychiatric Association.

appropriate dosing of medication, whereas the consequences of ADHD (school performance, peer and family relations, self-esteem) best improved with combined pharmacologic and behavioral/educational intervention. For individuals with mild to moderate ADHD (especially the inattentive type), nonpharmacologic intervention may be sufficient. For those with moderate to severe symptomatology, medication is necessary to improve attention and reduce impulsivity before they can learn new learning and behavioral habits. Recommendations for nonpharmacologic intervention include: Behavioral interventions with psychosocial interventions that focus on family, school, and child; teach parenting skills; and provide support in multiple environments. Involvement with a parent support
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group can be useful. Intervention should focus on the encouragement of wanted behaviors using verbal or tangible reward techniques rather than the sole use of extinction of unwanted behaviors. Frequent changes in rewards and positive approach methods may be needed in this population. Social skills training is frequently necessary because of the social immaturity present in many children with ADHD (especially the combined type). Behavioral intervention should also focus on aggressive intervention for any comorbid condition such as oppositional-defiant disorder, anxiety, or depression. This management is usually done by a psychologist or counselor/therapist with consultation with a psychiatrist for significant psychiatric comorbidities. Academic intervention requires an organized environment, a well-trained educational staff that understands

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Referral for suspected inattention, hyperactivity and/or impulsivity presenting as: disruptive behavior, academic difficulties, social issues, work difficulties History from: family, other caregivers; school/camp personnel and reports; employers and work evaluations Physical and neurological examination Confirmation with parent and teacher rating scales Neuropsychological assessment Diagnosis of ADHD Yes No Cognitive deficiency Learning disability/style Peripheral sensory deficit Epilepsy Sleep disorder Medication effect Oppositional-defiant disorder Conduct disorder Anxiety disorder Mood disorder Autism spectrum disorder Environmental/social stressors Difficult child Medical illness

FIGURE 1. Referral for suspected inattention, hyperactivity, and/or impulsivity presenting as disruptive behavior, academic difficulties, social issues, and work difficulties. ADHD, Attention deficit hyperactivity disorder.

Behavioral Parent training (positive reinforcement) Social skills training Educational Family education School accommodations

Medication (see Table 2) Stimulant (methylphenidate or amphetamine) as first choice. Try the other if first not effective or has side effects. Extended release preparation is preferred. Atomoxetine as a first line choice: Need early AM or late PM effect History of substance abuse Stimulant nonresponder/side effects

Comorbidity monitoring Oppositional-defiant disorder Dyspraxia Learning/language disability Temperament dysregulation Anxiety disorder Mood disorder Conduct disorder Substance use disorder Tic disorder

Preschool years Mixed amphetamine salt D-Methylphenidate Clonidine

School age years 8 hour effect (methylphenidate) Only needed for school Need 16 hour effect (bid dose) 12 hour effect (stimulant, atomoxetine) Homework, behavior problems Desire once daily dosing Lower abuse potential

Adult years Long-acting stimulant Atomoxetine

Incomplete response, consider: Stimulant + Atomoxetine Stimulant + Clonidine or Guanfacine Nortriptyline

the need for structure and routine, and a defined educational approach to children with a short attention span. This can include more time for lessons and tests, smaller work units, and a decrease in external distractions. Use of a schedule, daily teacher feedback, and a positive reward mechanism can be successful. Medications can successfully improve attention span and, consequently, decrease distractibility and overactivity in more than 80% to 90% of children with ADHD. The primary medications and recommended initial starting doses are listed in Table 2. Medication use is indicated when ADHD causes a risk of physical injury, impaired family and social relationships or academic failure, and nonpharmacologic intervention has an

inadequate effect. General usage rules include to start at a low dose and increase slowly (usually every 4 to 7 days) and to titrate to maximal efficacy without undue side effects. Whether medication is needed on a daily basis or only for in-school use needs to be determined on an individual basis. Children with comorbid behavioral problems and difficulties with peer interactions should take medication on a daily basis. Medication choice is influenced by age and ability to swallow pills. Stimulants (methylphenidate and amphetamine) are first-line treatment and appear to be equally effective. If the child does not show a good response to one, another should be tried since responses can be idiosyncratic. When possible, long-acting preparations should
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TABLE 2 Medications Used in the Treatment of Attention Deficit Hyperactivity Disorders


Generic Class Stimulants Methylphenidate Daily Dose Frequency Duration Dosing*
Developmental Disorders

0.3-2 mg/kg

MethylphenidateStart with 0.3 mg/kg/dose for immediate release and 0.5-1 mg/kg/day for extended-release preparation. Increase dose every 4-7 days as tolerated by 0.15-0.3 mg/kg up to 2 mg/kg/day. Although maximum recommended dose is 60 mg/day, adolescents and adults may require higher daily doses. Monitor blood pressure, height, and weight. Side effects include insomnia, appetite suppression, headache, and nausea bid-qid q AM 3-4 hr 8 hr 8 hr 12 hr

IR ER Metadate CD Ritalin LA Concerta Amphetamine

0.15-1.5 mg/kg

AmphetamineStart with 0.15 mg/kg/dose for immediate release and 0.2-0.3 mg/kg/day for extended release preparation. Increase dose every 4-7 days as tolerated by 0.15-0.3 mg/kg up to 1.5 mg/kg/day. While maximum recommended dose is 40 mg/day, adolescents and adults may require higher daily doses. Monitor blood pressure, height and weight. Side effects include insomnia, appetite suppression, headache and nausea q q
AM-bid AM

IR ER Dexedrine Spansule Adderall XR Antidepressants Atomoxetine 1-2 mg/kg

4-6 hr 6-8 hr 12 hr

qd or bid

AtomoxetineStart with 0.5-0.7 mg/kg/day as a qd or bid dose. Increase after 4-7 days to 1-1.4 mg/ kg/day as qd or bid dose. It may take 4-6 weeks to observe the full effect. Although the maximum recommended dose is 100 mg/day, adolescents and adults may require higher doses. Slow metabolizers through CYP2D6 require lower doses. Side effects include tiredness, decreased appetite, GI upset and nausea, urinary retention, and liver dysfunction NortriptylineStart 0.5-1 mg/kg day qhs or bid and increase weekly by 0.5-1 mg/day increments to 1-3 mg/kg/day bid or tid. Electrocardiogram at baseline and with dose changes (especially at final dose) to monitor QTc. Side effects include fatigue, dizziness, constipation, tachycardia, and irritability

Imipramine Nortriptyline

2-5 mg/kg 1-3 mg/kg

bid bid-tid

Bupropion Venlafaxine Others Clonidine

2-6 mg/kg 1-3 mg/kg 3-10 g/kg

qd-tid bid-tid bid-qid 2-4 hr ClonidineStart with 0.1 mg tablets at a dose of 1/41/ 2 tablet qhs and increase by 1/4-1/2-tablet increments q wk to a tid or qid regimen with maximum dose of 10 g/kg/day. If effective, consider use of transdermal patch. Monitor blood pressure. Side effects include lethargy and irritability GuanfacineStart with 1-mg tablets at a dose of 0.25-0.5 mg qhs and increase weekly by 0.25-0.5 mg increments to a bid or tid regimen with maximum of about 100 g/kg/day. Monitor blood pressure. Side effects include lethargy and irritability

Guanfacine

30-100 g/kg

bid-tid

4-8 hr

*Goal is maximal efficacy without undue side effects. IR, Immediate release; ER, extended release; GI, gastrointestinal; QTc, QT correction.

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be used since they minimize the number of daily doses and provide more even effect throughout the day. Although atomoxetine may not be as effective as the stimulants, it should be considered as a first-line therapy in individuals who need early-morning or late-evening treatment, have a history of substance use, have failed or do not tolerate stimulants, or require combined therapy with stimulants. Stimulant side effects include transient headache and upset stomach that can be ameliorated with medication administration after a meal, a sleep disturbance that may need additional treatment, and a worsening in mood that disappears with discontinuation. As the medication effect diminishes, rebound hyperactive behavior lasting 35 to 40 minutes may occur and probably represents a return to baseline ADHD. This effect can be lessened by changing from a shorter- to longer-acting stimulant medication. Tics may occur during use of stimulant medication, although research does not suggest that de novo causation or exacerbation of tics occurs. Most children with tics have little change in tic frequency or severity over time. If tics occur within 2 weeks of stimulant initiation, a decrease in dose or change to another medication should be considered. Children with well-controlled epilepsy do not have a seizure exacerbation when placed on methylphenidate. Children on stimulants should have periodic measurement of height and weight because of potential appetite suppression and reports of possible slowing of growth, especially in children at the higher height percentile who are on daily therapy. Whether this effect is transient and will disappear during the pubertal growth spurt or whether it will produce a small but permanent blunting of growth has not been determined. Blood pressure and pulse should be checked. Effective treatment of ADHD with stimulants reduces the risk of substance use to the age-matched peer level and does not contribute to illicit drug use in this population. Diversion and use by non-ADHD individuals can occur but is not a prominent problem. Atomoxetine, a selective norepinephrine reuptake inhibitor, has become available and is useful in the management of ADHD. Its side effects include tiredness, gastrointestinal complaints, and decreased appetite. In adults, modest blood pressure and heart rate elevation, urinary retention, and sexual dysfunction can occur. Liver dysfunction with elevated aspartate aminotransferase, alanine aminotransferase, and bilirubin has been rarely reported. Since it is metabolized through CYP2D6, dosing reduction may be warranted in slow metabolizers and those on medications that inhibit CYP2D6 (such as paroxetine, fluoxetine, or quinidine). It should be considered as first-line therapy in the nonstimulant category, especially for those who do not tolerate or want a stimulant or whose history precludes use of a stimulant. Clonidine and guanfacine are alpha-adrenergic agonists that have shown some efficacy in the treatment of children with ADHD. Most frequently, they are used in conjunction with stimulant medications and for stabilization of mood and decrease in aggression and overarousal. Abrupt discontinuation is not recommended.

Learning Disabilities
Learning disabilities are a severe discrepancy between achievement and intellectual ability in one or more areas that include reading, mathematics, written language, oral expression, or listening comprehension. The prevalence is 10% to 15%, with dyslexia (reading disability) being most common. The physician is frequently the first professional who is asked to address family concerns about the childs developmental progress. The assessment includes the following: 1. History that investigates potential risk factors such as family history of learning disability, prematurity, past central nervous system insult (toxin, infection, trauma), epilepsy, or congenital syndrome and examines developmental milestones (language delay/disorder, difficulties learning letters), present academic progress (isolated difficulty in one or more academic areas with otherwise normal development), and available school records and teacher reports 2. Medical examination that identifies a syndrome that can be associated with learning disabilities (e.g., neurofibromatosis, Turners syndrome, velocardiofacial syndrome) and motor difficulties (dyspraxia) that can aggravate learning problems; office-based screening should include hearing and vision (if not yet done) and samples of reading, writing, and math skills 3. Screening for comorbid disorders such as ADHD, anxiety disorder, depression, and social skills impairment 4. No specific medical testing (e.g., electroencephalogram or other electrophysiologic tests, magnetic resonance imaging, positron emission tomography or singlephoton emission computed tomography scan) without clinical indications 5. Referral for psychoeducational testing through the school system or neuropsychological evaluation for diagnosis of a learning disability; other assessments for motor or language problems should be obtained as necessary, with the physician maintaining a position within the multidisciplinary team After identification of and intervention for the learning disability, the physicians input may be requested. Educating the child and family about the diagnosis and available resources, planning a referral for counseling, prescribing medication for comorbid conditions, and addressing questions about alternative/complementary therapies may be needed. The remaining part of the management team helps with advocacy issues and monitoring of the childs clinical course. SUGGESTED READING
American Academy of Child and Adolescent Psychiatry: Practice parameters of the use of stimulant medications in the treatment of children, adolescents and adults with attention-deficit/hyperactivity disorder, J Am Acad Child Adolesc Psychiatry 41(2 Suppl):26S-49S, 2002. American Academy of Pediatrics: Clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder, Pediatrics 105:1158-1170, 2000.

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PATIENT RESOURCES
International Dyslexia Society Chester Building, Suite 382 8600 LaSalle Road Baltimore, MD 21286 Phone: 800-ABC-D123 http://www.interdys.org/ Learning Disabilities Association of America 4156 Library Road Pittsburgh, PA 15234 Phone: 412-341-1515 http://www.ldanatl.org/

Children and Adults with Attention Deficit Hyperactivity Disorder (CHADD) 8181 Professional Place, Suite 150 Landover, MD 20785 Phone: 800-233-4050 http://www.chadd.org/ American Academy of Pediatrics: ADHD: A Complete and Authoritative Guide, Elk Grove Village, IL, 2003, AAP. National Institute for Child Health Quality (NICHQ) ADHD Practitioners Toolkit (http://www.nichq.org/resources/toolkit/) contains assessment and management documents for ADHD, including the Vanderbilt Assessment Scale.

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SECTION 6

Viral Infections
Herpesvirus Infections
Micheline McCarthy, M.D., Ph.D.
although inhibition of viral DNA polymerase is less efficient. Penciclovir achieves a much longer intracellular half-life than acyclovir, allowing for two- or three-timesa-day dosing. Ganciclovir has relatively greater potency against CMV and HHV-6, good activity against HSV, and less activity against VZV and EBV. Intravenous (IV) ganciclovir has been the first-line therapy for CMV infection in immunocompromised patients. But oral ganciclovir has poor bioavailability, making it ineffective for long-term prophylactic suppressive regimens. Valganciclovir provides an oral bioavailability for ganciclovir of 60% and is replacing IV ganciclovir as the first choice for anti-CMV maintenance. Two additional, clinically effective drugs, foscarnet and cidofovir, directly inhibit herpesvirus DNA polymerases. Both have broad-spectrum antiherpesvirus activity but require IV administration. Herpesvirus resistance to acyclovir or ganciclovir can arise through mutations in viral thymidine kinase or DNA polymerase enzymes. Drug-resistant mutants occur rarely among herpesvirus isolates from immunocompetent patients; however, among immunocompromised patients, including those treated with prophylactic courses of antiviral drugs, drug-resistant mutants are more likely to be clinically significant and occur more than ten times more frequently. Foscarnet and cidofovir are used to treat herpesvirus infections that are resistant to first-line antiviral therapy. The antiherpesvirus drugs all have varying degrees of nephrotoxic potential. Ganciclovir is also myelosuppressive. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are rare but life-threatening complications reported with high-dose (8 gm/day) valacyclovir therapy in severely immunocompromised patients. The antiherpesvirus drugs must be administered with careful attention to detailed, current prescribing information. Dosages must be adjusted for renal function. Patients should be well hydrated, and IV infusions should be administered slowly with an infusion pump. There are no standards for the use of prophylactic valacyclovir or famciclovir in children.

Human herpesviruses (HHVs) constitute a diverse group of ubiquitous viral pathogens capable of both acute and persistent infection in the host. These complex DNAcontaining viruses typically infect humans early in life and establish latent infection at the cellular level. Latent infection is clinically dormant, but reactivation of viral replication can lead to recurrent clinical illness. Primary (initial) or reactivated infection by these viruses can also cause severe neurologic illness. Neurologic complications are especially prominent in aging or immunocompromised patients, and these pose an increasing diagnostic and treatment challenge to the neurologist.

Antiherpesvirus Therapy
Among human viral infections of the nervous system, herpesvirus infections are probably the most amenable to antiviral therapy. This is largely due to the growing drug family of purine nucleoside analogs that are activated by virus-specific kinases and then interfere with herpes viral DNA replication. The prototype drug, acyclovir (acycloguanosine), was identified about 30 years ago, followed by penciclovir and ganciclovir a decade or more later. Now available are oral prodrugs of acyclovir (valacyclovir, the L-valyl ester of acyclovir), penciclovir (famciclovir, the diacetate ester of 6-deoxy-penciclovir), and ganciclovir (valganciclovir, the L-valyl ester of ganciclovir). The oral prodrug provides greater bioavailability and higher plasma levels of the active antiviral drug. Acyclovir is most active against herpes simplex viruses (HSVs), then varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus (HHV-6), in decreasing order of antiviral potency. Valacyclovir, with its greater bioavailability, allows a simpler dosing regimen than oral acyclovir. It is likely to eventually replace oral acyclovir, but currently generic oral acyclovir is much less expensive. The antiviral spectrum of penciclovir is similar to that of acyclovir,
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Herpes Simplex Viruses


Two human HSVsHSV-1 and HSV-2have similar molecular structures but tend to cause different neurologic illnesses. HSV-1 is most frequently associated with 121

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recurrent orolabial mucocutaneous lesions (cold sores), whereas HSV-2 is associated with recurrent genital mucocutaneous lesions. These viruses establish latency in the sensory ganglia subserving these anatomic locations. Either primary or reactivated HSV infection can cause neurologic illness. HERPES SIMPLEX ENCEPHALITIS (HSE) HSV-1 is the most common cause of fatal sporadic viral encephalitis in adults and children. Beyond the neonatal period, most cases of fatal encephalitis are due to HSV-1 and are more commonly reactivated rather than primary infection. The classic clinical presentation is necrotic, hemorrhagic, frontal-temporal lobe encephalitis, but the distribution of lesions can be diffuse and may involve the brainstem. HSV-2 accounts for less than 10% of frontal-temporal encephalitis in immunocompetent patients. Milder or atypical cases of HSE can also occur, particularly in immunocompromised patients. Diagnostic evaluation and treatment should be instituted speedily since delayed onset of therapy, along with coma and older age, are poor prognostic indicators. Mortality among untreated patients exceeds 70%. Polymerase chain reaction (PCR) testing for HSV DNA in the cerebrospinal fluid (CSF) is the diagnostic test of choice for herpes simplex encephalitis (HSE). Treatment should be with IV acyclovir for 14 to 21 days (Table 1). Follow-up PCR determination of HSV DNA in the CSF may be useful to monitor the adequacy of therapy. Patients treated with IV acyclovir for 14 days should have a negative CSF PCR test for HSV DNA. If not, treat an additional 14 days. Acyclovir-resistant HSE occurs almost exclusively in immunocompromised patients, particularly those with recurrent HSV infections requiring repeated courses of antiviral therapy. Treatment of acyclovir-resistant HSE is with foscarnet for 14 to 21 days (see Table 1). If HSE is resistant to both acyclovir and foscarnet, treat with cidofovir (see Table 1). When treating any HSV infection that appears resistant to acyclovir, isolate virus from CSF, if possible, or from a peripheral source (e.g., mucocutaneous lesion), and test the isolates for antiviral drug susceptibility. Even with clinical improvement after treatment of HSE, relapse or progressive neurologic impairment may occur. This may be due to reactivation of latent virus in the brain. The efficacy of long-term oral antiviral therapy to suppress viral reactivation, increase survival, and/or decrease sequelae after HSE has not been demonstrated. However, this issue is being addressed in randomized, placebo-controlled, double-blind trials of oral valacyclovir given for 3 months after IV acyclovir. These trials are being conducted by the Collaborative Antiviral Study Group (CASG), a multi-institutional collaborative network funded by the National Institute of Allergy and Infectious Diseases. NEONATAL ENCEPHALITIS Neonatal HSE is due to HSV-2 in approximately two thirds of cases and to HSV-1 in the remainder. The virus

is acquired from the female genital tract in the intrapartum interval. Neonatal HSE can be a devastating disease, associated with serious neurologic sequelae even with aggressive antiviral treatment. Neonates with HSE should receive IV acyclovir for 21 days (see Table 1). The CASG is conducting trials of oral acyclovir given for 6 months after IV acyclovir to prevent relapse in neonatal HSE. BELLS PALSY Idiopathic peripheral seventh cranial nerve palsy, or Bells palsy, is the most common cause of unilateral facial paralysis. VZV infection is known to cause Bells palsy as part of the Ramsay Hunt syndrome. More recently, studies using PCR have linked HSV-1 with Bells palsy through detection of viral DNA sequences in endoneural fluids or auricular muscle. Since HSV-1 typically establishes latency in peripheral sensory ganglia, not motor neurons, the role of HSV-1 in the pathogenesis of Bells palsy remains controversial. Appropriate diagnostic evaluation is essential. Addition of oral acyclovir to standard prednisone treatment for Bells palsy has been demonstrated to produce a moderate clinical improvement in volitional facial muscle action. Combination therapy should be started within 3 days of symptom onset and should continue for 10 days (see Table 1). To date no conclusive benefit has been demonstrated with antiviral therapy alone. HSV MENINGITIS AND MYELITIS HSV infection can cause aseptic meningitis, including benign recurrent lymphocytic meningitis. These clinical presentations are usually due to HSV-2 infection in immunocompetent patients. HSV-2 is likely the major viral agent responsible for recurrent meningitis, including many or most cases of Mollarets meningitis. Aseptic HSV-2 meningitis occurs concomitant with or after primary HSV-2 genital infection but may also occur in the absence of recent genital lesions. Rarely necrotizing meningitis has been reported in association with immunosuppression (e.g., corticosteroid treatment). The treatment of single or recurrent episodes of HSV meningitis has not been defined by clinical trials. In practice, patients presenting with acute aseptic meningitis are often treated empirically with IV acyclovir until CSF test results are available. Confirmed HSV meningitis may be treated with IV acyclovir for 5 to 7 days, followed by oral valacyclovir to complete a total 14-day course of therapy (see Table 1). With recurrent lymphocytic meningitis due to HSV-2, there is limited evidence for the efficacy of oral antiviral therapy for recurrent episodes or for continuous prophylaxis (see Table 1). Myelitis or radiculomyelitis can result from HSV infection of immunocompetent patients, with most reported cases resulting from HSV-2. In immunocompromised patients, HSV-2 central nervous system (CNS) infection may result in ascending necrotizing myelitis or myelopathy. These clinical presentations should be treated with IV acyclovir for 14 days or longer with more extensive illness (see Table 1).
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TABLE 1 Human Herpesvirus Infections: Antiviral Therapy for Neurologic Illness


Viral Infection Herpes simplex: Immunocompetent Clinical Presentation Encephalitis Adult and adolescent (12 yr) Pediatric (3 months to 12 years) Neonatal (birth to 3 months) Postencephalitis (clinical trials) HSV Neonatal Bells palsy Drug*, Acyclovir Acyclovir Acyclovir Dosage* 10-15 mg/kg IV q 8 hr for 14-21 days 500 mg/m2 or 20 mg/kg IV q 8 hr for 14-21 days 20 mg/kg IV q 8 hr for 21 days Comments These antiviral drugs are nephrotoxic; adjust dose for renal function, infuse over 1 hr Consider serial CSF PCR for HSV DNA to monitor adequacy of therapy Acyclovir-resistant HSE is rare in immunocompetent patients but is more likely to occur in patients with prior recurrent or chronic anti-HSV therapy Postencephalitis regimens are in clinical trials to evaluate efficacy Do appropriate diagnostic evaluation Role of HSV in Bells palsy etiology is controversial; more data needed to support antiviral therapy Drug therapy should be started within 3 days of symptom onset

Valacyclovir Acyclovir Prednisone plus

PO, 3-mo course PO, 6-mo course 1 mg/kg PO qd divided bid for 3-5 days, then tapered over total 10-day course 400 mg PO 5 times/ day for 10 days

Acyclovir Meningitis Single episode Acyclovir then

Recurrent episode Continuous prophylaxis Myelitis, radiculomyelitis Chronic suppression

Herpes simplex: Immunocompromised

Acyclovir resistant Acyclovir and foscarnet resistant

Varicella zoster: Immunocompetent

Zoster (shingles); herpes zoster ophthalmicus; varicella in adults, adolescents

HSV-2 is major cause of meningitis 5-10 mg/kg IV No controlled trials have established q 8 hr for 5-7 days treatment of single or recurrent then episodes of HSV meningitis Valacyclovir 1000 mg PO bid for 7-9 days to complete a 14-day course Valacyclovir 1000 mg PO tid for 10 days Valacyclovir 1000 mg PO qd Only anecdotal evidence for efficacy or of antiviral prophylaxis Acyclovir 400 mg PO bid Acyclovir 10-15 mg/kg IV q Use a longer course for more serious 8 hr for 14 days illness Valacyclovir 500 mg PO bid TTP and HUS have been reported in or severely immunocompromised patients treated with high doses Famciclovir 500 mg PO bid of valacyclovir (8 mg/day) for or extended periods Acyclovir 400-800 mg PO No standards available for bid or tid valacyclovir or famciclovir in children Foscarnet 40 mg/kg IV q 8 hr Isolate virus for antiviral susceptibility for 14-21 days testing Cidofovir 5 mg/kg IV once/wk Isolate virus for antiviral susceptibility twice, then 5 mg/ testing kg IV q 2 wk; coadminister cidofovir with probenecid (2 gm PO 3 hr prior to cidofovir; 1 gm 2 hr after cidofovir; 1 gm 8 hr after cidofovir) Valacyclovir 1000 mg PO tid for Valacyclovir preferable (higher or 5-7 days bioavailability of active drug) Start antiviral therapy within 3 days of rash
continued

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TABLE 1 Human Herpesvirus Infections: Antiviral Therapy for Neurologic Illnesscontd


Viral Infection Clinical Presentation Drug*, Acyclovir or Famciclovir Herpes zoster in patients > 50 yr of age; Ramsay Hunt syndrome (zoster oticus) Valacyclovir or Dosage* 800 mg PO 5 times/ day for 7-10 days 500 mg PO tid for 7 days 1000 mg PO tid for 7 days Comments Hospitalized zoster patients should be isolated to prevent transmission of VZV to other patients

Acyclovir therapy plus prednisone CNS complications of zoster Aseptic meningitis with rash Myelitis or myelopathy VZV vasculopathy Stroke (contralateral to zoster) Encephalomyelitis (immunemediated demyelination) Zoster sine herpete (dermatomal pain without rash) Varicella with cerebellar ataxia (postvaricella cerebellitis) Varicella (primary infection) Shingles >1 dermatome Disseminated herpes zoster Acyclovir-resistant zoster Progressive encephalitis, ventriculitis, meningoencephalitis Retinitis (systemic therapy) Valacyclovir Acyclovir Acyclovir plus prednisone Methylprednisolone Acyclovir

800 mg PO 5 times/ day for 7-10 days; prednisone, 1 mg/ kg/day, tapered over 10 days Diagnostics should include CSF for antiviral antibody and viral DNA (PCR) testing 1000 mg PO tid for 7 days 10-15 mg/kg IV q 8 hr for 7-10 days 10-15 mg/kg IV q 8 hr for 7-10 days; prednisone, 60-80 mg for 3-5 days 1000 mg IV qd divided qid or bid for 5 days, then oral steroid taper 10-15 mg/kg IV q 8 hr for 7-10 days 20 mg/kg (800 mg max) PO qid for 5 days 10 mg/kg IV q 8 hr for 7 days 10 mg/kg IV q 8 hr for 7-14 days 15 mg/kg IV q 8 hr for 7 days 40 mg/kg IV q 8 hr for 14-21 days 10 mg/kg IV q 8 hr for 10 days or longer in severely immunocompromised patients 5 mg/kg IV q 12 hr for 14-21 days 900 mg PO bid for 21 days 5 mg/kg IV once per wk twice (give 1 L normal saline IV Stroke usually delayed complication of herpes zoster ophthalmicus Postinfectious neurologic complication of VZV infection Confirm rising titers of VZV-specific antibody and VZV DNA in the CSF Efficacy of antiviral therapy reported but not established Usual course is self-limited without sequelae Antiviral therapy not proven to alter course

Acyclovir

Varicella zoster: Immunocompromised

Acyclovir Acyclovir Acyclovir Foscarnet Acyclovir

Isolate virus for antiviral susceptibility testing

Cytomegalovirus: Immunocompromised

Induction therapy Ganciclovir or Valganciclovir or Cidofovir

These antiviral drugs are nephrotoxic. Use with caution in combination with immunosuppressive drug regimens Dosages must be adjusted for renal function CMV retinitis should be diagnosed and monitored by ophthalmologic specialists

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TABLE 1 Human Herpesvirus Infections: Antiviral Therapy for Neurologic Illnesscontd


Viral Infection Clinical Presentation Drug*, Dosage* before cidofovir); give with probenecid (2 gm PO 3 hr prior to cidofovir, 1 gm 2 hr after cidofovir, 1 gm 8 hr after cidofovir) Comments Systemic therapy as adjunct to intraocular antiviral therapy can prevent CMV disease in contralateral eye and other organs Immune recovery inflammatory vitreitis may occur with inactive CMV retinitis in HIV-infected patients recovering CD4+ cell counts on HAART; this may require steroid treatment Consider discontinuing maintenance therapy with CD4+ count >100 cells/mm3 after 6 mo HAART and retinitis is inactive

Maintenance therapy Valganciclovir or Ganciclovir or


Cidofovir Ganciclovir resistant Foscarnet Induction

900 mg PO qd 5 mg/kg IV qd or 6 mg/kg IV qd 5 days per wk 5 mg/kg IV q 2 wk; give with probenecid

Monotherapy resistant Nervous system complications Lumbosacral polyradiculitis, myelitis

60 mg/kg IV q 8 hr or 90 mg/kg IV q 12 hr for 14-21 days Maintenance 90-120 mg/kg IV qd Ganciclovir 5 mg/kg IV qd plus Foscarnet 90-125 mg/kg IV qd

Induction therapy Ganciclovir Maintenance therapy Valganciclovir or Ganciclovir

5 mg/kg IV q 12 hr for 14-21 days 900 mg PO qd 5 mg/kg IV qd or 6 mg/kg IV qd 5 days/wk 5 mg/kg IV q 12 hr for 14-21 days 60 mg/kg IV q 8 hr for 14-21 days 5 mg/kg IV qd or 6 mg/kg IV qd 5 days/wk 90-120 mg/kg IV qd

Polyradiculitis most likely to be seen in AIDS patients Consider combination ganciclovir and foscarnet if patient develops symptoms despite prior anti-CMV therapy

Encephalitis, ventriculoencephalitis

Induction therapy Ganciclovir plus (?) Foscarnet Maintenance therapy Ganciclovir plus (?)
Foscarnet

Serial CSF PCR for CMV DNA may be useful to monitor response to anti-CMV therapy Long-term maintenance therapy may be necessary in patients who remain profoundly immunosuppressed Consider combined therapy in HIV-infected patients with low CD4+ counts (<100 cells/mm3) and/or in immunocompromised patients with poor response to monotherapy In most reports, HHV-6 encephalitis occurs in the setting of severe immunosuppression, particularly bone marrow transplantation Several published reports find successful treatment in this setting, but no clinical trial data setting, but no clinical trial data are available
continued

Human herpesvirus 6 (HHV-6, B variant)

Encephalitis: focal features and/or demyelination

Foscarnet

60 mg/kg IV q 8 hr for 14 days Maintenance 90 mg/kg IV qd for or 1-4 wk

Induction

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TABLE 1 Human Herpesvirus Infections: Antiviral Therapy for Neurologic Illnesscontd


Viral Infection Clinical Presentation Drug*, Ganciclovir Induction Dosage* 5 mg/kg IV q 12 hr for 3 wk 5 mg/kg IV qd 900 mg PO qd Acyclovir significantly reduced oropharyngeal Epstein-Barr virus shedding in clinical trials but did not have statistically significant clinical effectiveness in either mild or severe illness Comments

Epstein-Barr virus: Immunocompetent

Infectious mononucleosis Aseptic meningitis

Maintenance or maintenance with valganciclovir No antiviral treatment Acyclovir

800 mg PO 5 times/day for 7-10 days 10 mg/kg IV q8h for 10 days 0.4 gm/kg/day for 5 days 5 mg/kg IV q 12 hr for 4 wk then 900 mg PO qd 1000 mg PO tid for 14 days 800 mg PO 5 times/ day for 14 days 5 mg/kg IV q 12 hr for 14 days 15 mg/kg IV q 8 hr for 14 days 1000 mg PO tid 800 mg PO 5 times/day

Encephalitis Neuropathy: GuillainBarr syndrome, small-fiber sensory or autonomic Transverse myelitis, meningoencephalitis Postexposure (monkey bite)

Acyclovir IV immune globulin Ganciclovir then Valganciclovir Valacyclovir or Acyclovir

Epstein-Barr virus: Immunocompromised B virus (Cercopithecine herpesvirus 1)

Symptomatic CNS disease

Ganciclovir or Acyclovir

Successful therapy reported but not established by controlled clinical trials Start therapy within 5 days of exposure Culture wound or exposure site for virus Repeat serologic testing at 3-6 wk and 3 mo postexposure Neurologic complications include necrotizing myelitis and hemorrhagic encephalitis Duration of suppressive therapy not established but should be at least 6 mo to 1 yr

Chronic suppression

Valacyclovir or Acyclovir

*Consult current, detailed prescribing information provided by the manufacturer before prescribing and administering any drug. The drug names are generic. The trade names are listed in parentheses as follows: acyclovir (Zovirax); valacyclovir (Valtrex); famciclovir (Famvir); cidofovir (Vistide); foscarnet (Foscavir) ganciclovir (Cytovene); valganciclovir (Valcyte). HSV, Herpes simplex virus; HHV, human herpesvirus; EBV, Epstein-Barr virus; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; HSE, herpes simplex encephalitis; TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic-uremic syndrome; VZV, varicella zoster virus; CMV, cytomegalovirus; HIV, human immunodeficiency virus; HAART, highly active anti-retroviral therapy; CNS, central nervous system.

CHRONIC SUPPRESSION OF HSV REACTIVATION Chronic oral antiviral therapy with acyclovir, valacyclovir, or famciclovir may be used to suppress HSV reactivation in immunocompromised patients, particularly those with human immunodeficiency virus (HIV)-1 infection. The doses used in this setting are higher than those used to suppress recurrent oral or genital ulcers (see Table 1). There is no established advantage of either valacyclovir or famciclovir in this setting, and acyclovir is less costly. Long-term therapy does raise concern for the selection of acyclovir-resistant HSV strains.

Varicella Zoster Virus (Herpes Zoster Virus)


VZV is familiar to the neurologist as the cause of shingles and postherpetic neuralgia. VZV primary infection (varicella or chickenpox) typically occurs in childhood, and the virus then becomes latent in cranial nerve and dorsal root ganglia. In the immunocompetent, otherwise healthy child, varicella is generally not treated. Since varicella can be more complicated in adults and adolescents, oral antiviral therapy (see Table 1) may be more beneficial for these patients. Oral antiviral therapy has also been used to treat varicella with cerebellar
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ataxia (varicella cerebellitis). However, the usual course of this neurologic presentation is benign, and antiviral therapy has not been proved to alter the course. Reactivation of latent viral infection (herpes zoster) results in a cutaneous vesicular rash, itching, dysesthesias, and pain localized along affected dermatomes (shingles). Shingles is more frequent or more extensive as virus-specific immune responses decline, such as occurs with aging or in immunocompromised states. In the severely immunocompromised patient, disseminated zoster may occur, with lesions covering the body surface. Varicella or herpes zoster occasionally leads to CNS complications, and these are much more common in immunocompromised patients. HERPES ZOSTER Herpes zoster includes shingles, cranial neuropathies such as Ramsay Hunt syndrome (zoster oticus and ipsilateral peripheral facial weakness), radiculoneuropathy, or ganglionitis. Herpes zoster ophthalmicus involves the first division of the trigeminal nerve and can result in ocular complications (e.g., iritis, keratopathy) leading to loss of sight. Zoster of cranial nerves may also cause ophthalmoplegia or optic neuritis. Radicular zoster may cause focal extremity weakness, bowel or bladder dysfunction, and, rarely, diaphragmatic paralysis. For the treatment of these neurologic presentations, oral valacyclovir provides higher plasma acyclovir concentrations than does oral acyclovir therapy, with a simpler daily dosing schedule (see Table 1). Valacyclovir may be more effective than acyclovir in resolving zosterassociated pain for patients older than 50 years of age. An alternative therapy for these older patients or for patients with peripheral facial weakness associated with Ramsay Hunt syndrome includes oral acyclovir combined with oral prednisone over a 10-day course (see Table 1). This combination may decrease acute zoster pain or enhance clinical improvement in facial movement. Rarely, zoster can manifest as dermatomal pain without rash (zoster sine herpete). This can be diagnosed by detecting rising titers of VZV-specific antibody and VZV DNA in the CSF. The efficacy of antiviral therapy has not been established, but successful treatment with IV acyclovir (see Table 1) has been reported. In immunocompromised patients, varicella or zoster can be more extensive, involving multiple dermatomes or disseminated throughout the body. IV acyclovir (see Table 1) should be used for these patients. Acyclovir-resistant zoster is treated with foscarnet (see Table 1). VZV MENINGITIS AND MYELITIS Aseptic meningitis associated with VZV DNA in CSF occurs in immunocompetent patients in approximately 1% of cases, of which approximately half may have associated rash. With benign, self-limited courses of aseptic meningitis due to VZV, antiviral therapy may be dictated by the presence of rash, since specific viral diagnosis may lag behind the resolution of symptoms when rash is not present. First-choice therapy is valacyclovir
Johnson: Current Therapy in Neurologic Disease (7/E)

(see Table 1). Myelitis may occur 1 to 2 weeks after rash in immunocompetent patients, but acute or, rarely, recurrent myelopathy may occur without rash. Direct viral infection of the brain or spinal cord parenchyma usually occurs with immunosuppression, which can be caused to varying degrees by cancer, steroid use, HIV infection, or immunosuppressive drug regimens. In immunocompromised patients, myelopathy may be slower and progressive, with severe inflammation and necrosis of the spinal cord. With these neurologic presentations, detection of VZV DNA and VZV-specific antibody in the CSF mandates aggressive treatment with IV acyclovir (see Table 1). VZV VASCULITIS IN THE CENTRAL NERVOUS SYSTEM VZV is unique among the human herpesviruses (HHVs) in the extent to which viral infection of large and small blood vessels causes variable clinical neurologic syndromes. Encephalitis related to VZV infection is frequently due to viral vasculopathy. Arteritis of the large vessels in the brain (granulomatous arteritis) occurs in immunocompetent patients, causing stroke due to bland or, infrequently, hemorrhagic infarction. Stroke often presents as motor weakness occurring weeks to months after prior, contralateral zoster ophthalmicus. Small-vessel disease occurs more frequently in immunocompromised patients, presenting clinically as chronic progressive encephalitis or, unusually, as ventriculitis or meningoencephalitis. CNS vasculopathies are treated with IV acyclovir for 7 to 10 days or longer in severely immunocompromised patients (see Table 1). With stroke, IV acyclovir may be combined with a 3- to 5-day course of oral prednisone. An encephalitis presentation associated with varicella or herpes zoster in immunocompetent patients may also result from postinfectious immune-mediated demyelination (encephalomyelitis). This would be treated with a course of IV methylprednisolone (see Table 1).

Cytomegalovirus
Human CMV is a ubiquitous herpesvirus that typically infects in utero, childhood, or young adult life. More than 50% of persons in urban American populations carry antibody to CMV. The virus establishes latency in hematogenous cells, primarily monocytes, and may reactivate to produce asymptomatic infection in immunocompetent hosts. Primary or reactivated infection may occur during pregnancy, posing a risk for intrauterine or perinatal mother-to-child viral transmission and congenital CMV infection. In immunocompetent patients, CMV primary infection after the neonatal interval is either subclinical or manifest as infectious mononucleosis, with less pharyngitis and lymphadenopathy than the similar illness associated with EBV infection. Infrequently (1% of cases) this illness is complicated by aseptic meningitis, or, even less frequently, by encephalitis, myelitis, or acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barr syndrome). Given the toxicity

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of anti-CMV drugs, CMV illness in the otherwise healthy, immunocompetent patient is generally not treated with antiviral therapy. Clinical neurologic illness due to reactivated or occasionally primary CMV infection occurs predominantly in immunocompromised patients, particularly those with acquired immunodeficiency syndrome (AIDS) or those with organ transplants on immunosuppressive drug regimens. CMV antiviral therapy in these patients usually involves two stages: induction therapy to suppress viremia followed by maintenance therapy to suppress viral reactivation. In HIVinfected patients, the use of highly active antiretroviral therapy (HAART) to recover immune function may indirectly suppress CMV viremia and improve the response to anti-CMV therapy. CONGENITAL CMV INFECTION Asymptomatic congenital CMV infection can eventually lead to hearing loss or mental retardation in about 10% to 20% of cases. Approximately 5% of infected newborns have cytomegalic inclusion disease, with microcephaly, chorioretinitis, sensorineural deafness, and organomegaly with jaundice. This is more likely the result of primary rather than recurrent maternal infection. There is no safe and effective antiviral treatment for CMV maternal infection or for symptomatic congenital illness in the newborn. Though ganciclovir has been used and studied in symptomatic congenital CMV infection, the clinical efficacy (e.g., hearing improvement) may be countered by significant toxicity (e.g., neutropenia) in affected infants. Future therapy for congenital CMV infection will likely involve a combination of CMV hyperimmune globulin with antiviral drugs of lower toxicity than occurs with ganciclovir or foscarnet. CMV retinitis is the most common manifestation of CMV in HIV-infected patients, though its incidence has been declining since the introduction of HAART. CMV retinitis should be diagnosed and monitored by ophthalmologic specialists. Systemic anti-CMV therapy with ganciclovir or valganciclovir (see Table 1), used adjunctively with intraocular therapy, can prevent CMV disease in the contralateral eye or visceral organs. Cidofovir (see Table 1) is used as alternative systemic therapy if ganciclovir is not tolerated, although cidofovir may have the same antiviral resistance profile as ganciclovir. Ganciclovir-resistant CMV retinitis is treated with foscarnet or combination foscarnet plus ganciclovir (see Table 1). Immune recovery inflammatory vitreitis may occur in HIV-infected patients with inactive CMV retinitis whose CD4+ cell counts increase with HAART. Vitreitis may require steroid treatment. Current National Institutes of Health guidelines suggest discontinuing maintenance therapy for HIV-infected patients with CD4+ counts higher than 100 cells/mm3 after 6 months on HAART, if CMV retinitis is inactive. PERIPHERAL NERVE DISEASE CMV can infect the peripheral nervous system, causing mononeuritis multiplex associated with vasculitis of epineural arteries. A fairly common syndrome causing

back pain, ascending weakness, and sphincter dysfunction in AIDS patients is due to CMV infection in lumbosacral nerve roots (lumbosacral polyradiculitis), or the lumbosacral roots plus the conus medullaris (lumbosacral myelopathy). This is treated by induction therapy with IV ganciclovir, followed by maintenance therapy with oral valganciclovir, or, alternatively, IV ganciclovir (see Table 1). CNS complications of CMV infection in immunocompromised patients include encephalitis, ventriculoencephalitis, and myelitis. CMV encephalitis in AIDS may present as a rapidly progressive dementia, often with fluctuating sensorium and focal neurologic signs. CMV encephalitis is also a major cause of CMV-related morbidity in organ transplant patients, particularly after bone marrow transplantation. In both settings, encephalitis with prior or concurrent evidence of CMV disease, such as retinitis and CMV viremia, raises a high index of suspicion for CMV encephalitis. Ventriculoencephalitis, distinguished by ventriculomegaly with subependymal enhancement on magnetic resonance brain imaging, may result from CSF rather than hematogenous spread of CMV. No specific treatment for encephalitis has been established. In immunocompromised patients with established CMV infection, IV ganciclovir should be used, with induction at 5 mg/kg IV every 12 hours for 14 to 21 days followed by maintenance therapy at 5 mg/kg IV daily or 6 mg/kg IV daily 5 days per week. Combined anti-CMV therapy with ganciclovir and foscarnet (see Table 1) has been studied and reported to improve or stabilize the neurologic course in approximately 75% of HIV-infected patients with low CD4+ counts (<100 cells/mm3) and no use of HAART. In treating CMV-associated CNS disease, serial CSF PCR for CMV DNA may be useful to determine when to switch from induction to maintenance therapy. Long-term maintenance therapy may be necessary for patients who remain profoundly immunocompromised. Oral valganciclovir may replace IV ganciclovir for this purpose as more clinical experience accumulates.

Other Herpesviruses
HHV-6 is another ubiquitous human herpesvirus (HHV) that typically infects in childhood and establishes latency in peripheral blood mononuclear cells. HHV-6 is the viral cause of childhood roseola (exanthem subitum), which is associated with febrile convulsions in about one third of primary HHV-6 infections. In the immunocompetent patient population, the virus is generally silent throughout life. However, HHV-6 is increasingly recognized as an agent of opportunistic infection causing clinical neurologic illness in immunocompromised patients. Most reports in the past decade have documented HHV-6 as a cause of viral encephalitis after organ transplantation, particularly bone marrow, kidney, or liver transplantation. HHV-6 encephalitis may show focal features and/or demyelination and should be suspected in encephalitis patients with febrile exanthema. HHV-6 has antiviral susceptibility similar to that of CMV. Both foscarnet and ganciclovir (see Table 1) have been reported to
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successfully treat HHV-6 encephalitis in immunocompromised patients. EBV is a lymphotro phic HHV that typically causes asymptomatic primary infection in childhood or infectious mononucleosis in adolescence or young adult life. Virus replicates in the pharyngeal lymphoid tissue and may be persistently or recurrently shed into oral secretions. In immunocompetent patients with infectious mononucleosis, neurologic complications occur rarely (<1% frequency). These complications include aseptic meningitis, encephalitis, or neuropathy, including small-fiber sensory or autonomic neuropathy or Guillain-Barr syndrome. EBV replication is sensitive to acyclovir, and both oral and IV regimens have been used to treat neurologic illness (see Table 1). However, a meta-analysis of several clinical trials that used acyclovir to treat EBV illness showed that acyclovir therapy does not have statistically significant clinical efficacy. Acyclovir therapy does reduce oropharyngeal EBV shedding, which may reduce the duration and severity of illness by limiting viral reinfection. The neuropathic complications of EBV infection may respond to IV immunoglobulin (see Table 1). In immunocompromised patients, more severe CNS illness has been reported, including transverse myelitis and meningoencephalitis. Ganciclovir induction therapy has been reported to successfully treat meningoencephalitis, but the incidence of these EBV neurologic presentations is low, so no clinical trials have established efficacy. For ganciclovir-treated patients who improve neurologically but remain severely immunocompromised, maintenance therapy with oral valganciclovir should be considered. Herpes B virus (Cercopithecine herpesvirus 1 or Herpes simiae) produces infection in macaque monkeys that is similar to human HSV infection. The B virus may be transmitted to humans via monkey bites, scratches, or percutaneous inoculation of infected materials. The bloodborne transmission of B virus can cause severe, often necrotizing myelitis or encephalitis, which may progress rapidly to death. Prophylaxis with antiviral therapy is recommended after skin or mucosal exposure to a high-risk source, such as an infected macaque monkey, and wound or exposure sites should be cultured for B virus. The first choice for postexposure prophylaxis is oral valacyclovir; alternatively, oral acyclovir (see Table 1). This should be instituted within 5 days of exposure and continued for 2 weeks, then discontinued if the patient is clinically asymptomatic. Postexposure serologic testing should be repeated 3 to 6 weeks and again 3 months after initial exposure for patients receiving antiviral prophylaxis. If wound cultures are initially positive for B virus, then repeat cultures should be obtained 1 to 2 weeks after antiviral prophylaxis is stopped. IV ganciclovir is recommended for patients with symptoms and signs of CNS involvement (see Table 1). This should be continued for at least 14 days and until the symptoms resolve and two or more sets of cultures are negative for B virus growth. Postexposure prophylaxis with oral therapy, preferably oral valacyclovir, should continue for 6 months to 1 year. Some authorities hold that lifelong suppressive therapy is needed since the B virus could reactivate months to years after primary infection.
Johnson: Current Therapy in Neurologic Disease (7/E)

SUGGESTED READING
Brady RC, Bernstein DI: Treatment of herpes simplex virus infections, Antivir Res 61:73-81, 2004. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, et al: Neurologic complications of the reactivation of varicella-zoster virus, N Engl J Med 342:635-645, 2000. Naesens L, DeClercq E: Recent developments in herpesvirus therapy, Herpes 8:12-16, 2001. Redington JJ, Tyler KL: Viral infections of the nervous system, 2002: update on diagnosis and treatment, Arch Neurol 59:712-718, 2002. Singh N, Paterson DL: Encephalitis caused by human herpesvirus-6 in transplant recipients, Transplantation 69:2474-2479, 2000. Sissons JGP, Carmichael AJ: Clinical aspects and management of cytomegalovirus infection, J Infect 44:78-83, 2002.

PATIENT RESOURCES
http://www.webmd.com/This well-known site has a broad appeal and is relatively easy to navigate. It is widely referenced by patients. The site includes educational materials and links to patient support organizations. http://www.virology.net/Comprehensive site claiming all the virology on the World-Wide Web. Information and links to research, education, clinical, and patient support sites as well as comprehensive educational material on the human herpesviruses. http://www.gsu.edu/~wwwvir/National Herpes B Virus Resource Center

Arthropod-Borne Virus Infections


James J. Sejvar, M.D., and Grant L. Campbell, M.D., Ph.D.

Arboviruses (arthropod-borne viruses) include several families of viruses that share the feature of transmission by arthropod vectors and are the most common etiologic agents of epidemic encephalitis worldwide. Nearly 100 such viruses are recognized to cause clinical illness in humans. The most common arboviruses causing neurologic illness in North America include the following families and their members: FlaviviridaeWest Nile virus (WNV), St. Louis encephalitis virus (SLEV), Powassan viruses (POWV) BunyaviridaeCalifornia encephalitis virus (CEV); LaCrosse virus (LACV); Jamestown Canyon, snowshoe hare, and Cache Valley viruses Togaviridaeeastern equine encephalitis virus (EEEV) and western equine encephalitis virus (WEEV) ReoviridaeColorado tick fever virus (CTFV) Severe neuroinvasive disease from North American arboviruses generally occurs sporadically at low incidence, with occasional mosquito-borne epidemics occurring predominantly during the late summer and fall. Following its initial arrival in North America in 1999, WNV, a flavivirus in the Japanese encephalitis antigenic complex, quickly became the most important etiologic

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successfully treat HHV-6 encephalitis in immunocompromised patients. EBV is a lymphotro phic HHV that typically causes asymptomatic primary infection in childhood or infectious mononucleosis in adolescence or young adult life. Virus replicates in the pharyngeal lymphoid tissue and may be persistently or recurrently shed into oral secretions. In immunocompetent patients with infectious mononucleosis, neurologic complications occur rarely (<1% frequency). These complications include aseptic meningitis, encephalitis, or neuropathy, including small-fiber sensory or autonomic neuropathy or Guillain-Barr syndrome. EBV replication is sensitive to acyclovir, and both oral and IV regimens have been used to treat neurologic illness (see Table 1). However, a meta-analysis of several clinical trials that used acyclovir to treat EBV illness showed that acyclovir therapy does not have statistically significant clinical efficacy. Acyclovir therapy does reduce oropharyngeal EBV shedding, which may reduce the duration and severity of illness by limiting viral reinfection. The neuropathic complications of EBV infection may respond to IV immunoglobulin (see Table 1). In immunocompromised patients, more severe CNS illness has been reported, including transverse myelitis and meningoencephalitis. Ganciclovir induction therapy has been reported to successfully treat meningoencephalitis, but the incidence of these EBV neurologic presentations is low, so no clinical trials have established efficacy. For ganciclovir-treated patients who improve neurologically but remain severely immunocompromised, maintenance therapy with oral valganciclovir should be considered. Herpes B virus (Cercopithecine herpesvirus 1 or Herpes simiae) produces infection in macaque monkeys that is similar to human HSV infection. The B virus may be transmitted to humans via monkey bites, scratches, or percutaneous inoculation of infected materials. The bloodborne transmission of B virus can cause severe, often necrotizing myelitis or encephalitis, which may progress rapidly to death. Prophylaxis with antiviral therapy is recommended after skin or mucosal exposure to a high-risk source, such as an infected macaque monkey, and wound or exposure sites should be cultured for B virus. The first choice for postexposure prophylaxis is oral valacyclovir; alternatively, oral acyclovir (see Table 1). This should be instituted within 5 days of exposure and continued for 2 weeks, then discontinued if the patient is clinically asymptomatic. Postexposure serologic testing should be repeated 3 to 6 weeks and again 3 months after initial exposure for patients receiving antiviral prophylaxis. If wound cultures are initially positive for B virus, then repeat cultures should be obtained 1 to 2 weeks after antiviral prophylaxis is stopped. IV ganciclovir is recommended for patients with symptoms and signs of CNS involvement (see Table 1). This should be continued for at least 14 days and until the symptoms resolve and two or more sets of cultures are negative for B virus growth. Postexposure prophylaxis with oral therapy, preferably oral valacyclovir, should continue for 6 months to 1 year. Some authorities hold that lifelong suppressive therapy is needed since the B virus could reactivate months to years after primary infection.
Johnson: Current Therapy in Neurologic Disease (7/E)

SUGGESTED READING
Brady RC, Bernstein DI: Treatment of herpes simplex virus infections, Antivir Res 61:73-81, 2004. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, et al: Neurologic complications of the reactivation of varicella-zoster virus, N Engl J Med 342:635-645, 2000. Naesens L, DeClercq E: Recent developments in herpesvirus therapy, Herpes 8:12-16, 2001. Redington JJ, Tyler KL: Viral infections of the nervous system, 2002: update on diagnosis and treatment, Arch Neurol 59:712-718, 2002. Singh N, Paterson DL: Encephalitis caused by human herpesvirus-6 in transplant recipients, Transplantation 69:2474-2479, 2000. Sissons JGP, Carmichael AJ: Clinical aspects and management of cytomegalovirus infection, J Infect 44:78-83, 2002.

PATIENT RESOURCES
http://www.webmd.com/This well-known site has a broad appeal and is relatively easy to navigate. It is widely referenced by patients. The site includes educational materials and links to patient support organizations. http://www.virology.net/Comprehensive site claiming all the virology on the World-Wide Web. Information and links to research, education, clinical, and patient support sites as well as comprehensive educational material on the human herpesviruses. http://www.gsu.edu/~wwwvir/National Herpes B Virus Resource Center

Arthropod-Borne Virus Infections


James J. Sejvar, M.D., and Grant L. Campbell, M.D., Ph.D.

Arboviruses (arthropod-borne viruses) include several families of viruses that share the feature of transmission by arthropod vectors and are the most common etiologic agents of epidemic encephalitis worldwide. Nearly 100 such viruses are recognized to cause clinical illness in humans. The most common arboviruses causing neurologic illness in North America include the following families and their members: FlaviviridaeWest Nile virus (WNV), St. Louis encephalitis virus (SLEV), Powassan viruses (POWV) BunyaviridaeCalifornia encephalitis virus (CEV); LaCrosse virus (LACV); Jamestown Canyon, snowshoe hare, and Cache Valley viruses Togaviridaeeastern equine encephalitis virus (EEEV) and western equine encephalitis virus (WEEV) ReoviridaeColorado tick fever virus (CTFV) Severe neuroinvasive disease from North American arboviruses generally occurs sporadically at low incidence, with occasional mosquito-borne epidemics occurring predominantly during the late summer and fall. Following its initial arrival in North America in 1999, WNV, a flavivirus in the Japanese encephalitis antigenic complex, quickly became the most important etiologic

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agent of epidemic viral encephalitis in the Western hemisphere and, in the span of 6 years, has become endemic in most of the continental United States and large areas of Canada and Mexico. Since 1999, WNV has caused thousands of cases of severe human neuroinvasive disease and has had tremendous public health impact. Large WNV epidemics are likely to recur annually for the foreseeable future; therefore, much of this chapter focuses on WNV. Although the spectrum of clinical illness associated with WNV and other arboviral infections in humans is still emerging, infection has been associated with a number of clinical syndromes, including aseptic meningitis, encephalitis, and an acute poliomyelitis-like syndrome. Treatment remains supportive; however, a number of investigational therapeutics are currently under assessment, and a human vaccine for WNV is undergoing early clinical trials.

is variable, but persistence of weakness and functional deficits is the rule; development of respiratory muscle weakness often necessitates prolonged endotracheal intubation and ventilatory support and is associated with high mortality. Clinical illness due to other North American arboviral infections varies with respect to the population and age groups at highest risk for infection, neurotropism and illness severity, and primary clinical manifestations (Table 1). In particular, EEE results in high mortality and high rates of neurologic sequelae among survivors.

Diagnosis
Infection with WNV or another arbovirus should be suspected in patients developing acute meningitis, encephalitis, or asymmetrical flaccid paralysis during the summer and fall months or other periods of mosquito activity. The gold standard for diagnosis of arboviral infections is virus isolation from clinical specimens (e.g., blood, serum, cerebrospinal fluid [CSF], or tissue) followed by demonstration of seroconversion of virusspecific neutralizing antibodies in serum. However, because virus isolation of WNV and many other arboviruses is technically difficult and lacks sensitivity, serology remains of central importance. A presumptive diagnosis of recent infection may be made by detection of virus-specific IgM antibodies in serum or CSF; however, with some arboviruses, including WNV, diagnosis of a recent infection is complicated by prolonged persistence of IgM antibodies in some previously infected persons. The observation of at least a fourfold rise in virus-specific neutralizing antibody titers in serial serum samples is considered confirmatory. Serologic crossreactivity between closely related arboviruses (e.g., WNV and SLEV) complicates the issue of what is virus specific, and this usually requires the demonstration of specific neutralizing antibody using a battery of geographically and epidemiologically appropriate arboviruses or arboviral antigens. Plaque reduction neutralization, the most widely used test method for detecting arboviral neutralizing antibody, requires the use of live virus and is not commercially available at present but can be performed at the Centers for Disease Control and Prevention and some state health department and other reference laboratories. Nucleic acid amplification tests (e.g., polymerase chain reaction) are also available for detecting WNV and several other arboviruses in clinical samples, but these tests have limited sensitivity and generally cannot substitute for serology. Head computed tomography is generally normal in arboviral encephalitis and is useful only in excluding other causes of acute encephalopathy. Magnetic resonance (MR) imaging in patients with WNE, although frequently normal, sometimes displays signal abnormalities in the basal ganglia, posterior thalami, and brainstem, best visualized on T2-weighted, diffusion-weighted images (DWI), or fluid-attenuated inversion recovery (FLAIR) sequences; the sensitivity and specificity of these findings are unknown, and similar findings have occasionally been noted with SLE. In WNP cases,
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Clinical Arboviral Illness in Humans


Human infections with most arboviruses, including WNV, are usually asymptomatic. Symptomatic infections may range from mild systemic febrile illness to more severe neuroinvasive disease, manifesting as aseptic meningitis, encephalitis, or myelitis. WNV infection provides a good example of the spectrum of neurologic illness associated with arboviral infection. Self-limited febrile illness (West Nile fever) is characterized by an incubation period of 2 to 14 days, followed by the abrupt onset of fever, chills, myalgias, and fatigue; nausea and vomiting are common. West Nile meningitis (WNM) is similar to other aseptic meningitides and is characterized by fever, headache, and meningismus. Early in the course of infection, pleocytosis may be neutrophilic, with the lymphocytic pleocytosis more commonly seen in viral infections predominating later, sometimes obscuring the diagnosis. Outcome is generally favorable, though patients occasionally experience persistent headache and fatigue. West Nile encephalitis (WNE) occurs more commonly in elderly persons. Recent evidence suggests that immunosuppressed persons are also at greater risk for WNE. Severity of WNE may range from a mild confusional state to coma and death; mortality occurs in approximately 10% to 15% of those with severe illness and increases with age. Various neurologic signs, including pronounced postural and intentional tremor, focal myoclonus, and parkinsonism, are seen frequently and may persist. Poliomyelitis (West Nile poliomyelitis) is a particularly severe manifestation of WNV infection and, less frequently, infection with other arboviruses. Weakness may occur in the absence of meningitis, encephalitis, or even fever, headache, or other symptoms suggestive of WNV infection. Diaphragmatic and intercostal muscle weakness can result in acute respiratory failure; patients developing early lower bulbar findings, particularly dysarthria and dysphagia, are at high risk for impending respiratory failure and should be closely monitored. Outcome in patients with paralysis

TABLE 1 Geographic Distribution, Primary Arthropod Vectors, and Main Clinical and Epidemiologic Features of the Main Arboviral Agents of Neurologic Disease in North America

Family/ Virus Mosquitoes (Culex spp.) Birds Urban/ suburban/ rural Epidemic Currently, the most important cause of epidemic encephalitis in North America: during 1999-2003, >14,000 total human cases reported in the United States, including 6000 neuroinvasive disease cases and 600 deaths

Geographic Distribution

Primary Vectors

Primary Vertebrate Hosts Main Human Risk Areas

Main Epidemiologic Pattern

Incidence (All Clinical Categories)

Main Clinical/ Demographic Features

Known NonarthropodBorne Modes of Transmission to Humans

Viral Infections

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Flaviviridae West Nile

Continental United States, southern Canada, Central America, Caribbean (also widely distributed in the eastern hemisphere)

St. Louis encephalitis

Continental United States, southern Canada, Central and South American, Caribbean

Mosquitoes (Culex spp.)

Birds

Urban/ suburban/ rural

Epidemic

Arthropod-Borne Virus Infections

Most (80%) Blood infections subclinical; transfusion, mild, self-limited organ febrile illness (West transplantation, Nile fever) in ~20% intrauterine, of infections (mainly laboratory young adults); accidents neuroinvasive disease in <1% of infections: meningitis (mainly young adults), encephalitis (mainly elderly, immunocompromised), poliomyelitis-like syndrome (mainly young adults, elderly), neuritis; case fatality in encephalitis 10-15% increases with age During 1964Most infections Laboratory 2002, 4589 subclinical; frequency accidents cases were of mild, self-limited reported to febrile illness unknown; the CDC, for neuroinvasive disease a national in <1% of infections: average of meningitis (mainly 118 cases/yr children, young adults), (median, 26; encephalitis (mainly range, 2-1967). elderly); case fatality In the 1975 10-15% in epidemic encephalitis cases, involving much increases with age of the eastern United States, 2000 cases and 200 deaths were reported
continued

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TABLE 1 Geographic Distribution, Primary Arthropod Vectors, and Main Clinical and Epidemiologic Features of the Main Arboviral Agents of Neurologic Disease in North Americacontd

Family/ Virus Ticks (Ixodes spp.) Small to mediumsized mammals (e.g., woodchucks) Rural; most cases from northeastern United States and Canada Endemic/ sporadic Rare (<35 cases documented)

Geographic Distribution

Primary Vectors

Primary Vertebrate Hosts Main Human Risk Areas

Main Epidemiologic Pattern

Incidence (All Clinical Categories)

Main Clinical/ Demographic Features Frequency of Laboratory subclinical or mild accidents illness unknown; neuroinvasive disease (<35 cases ever recognized): meningitis, encephalitis, poliomyelitis-like illness (symptomatic illness more frequently recognized in adults, elderly); case fatality in encephalitis ~20%; encephalitis may be associated with focal lesions on neuroimaging

Known NonarthropodBorne Modes of Transmission to Humans

Arthropod-Borne Virus Infections

Powassan

United States (especially northern), southern Canada

Bunyaviridae La Crosse

Eastern United States Small mammals (e.g., squirrels, chipmunks) Suburban, especially near oak woodlands Endemic/ sporadic and small case clusters

Aedes triseriatus (eastern treehole mosquito)

Most Most infections important subclinical; frequency cause of of mild illness endemic unknown; arboviral neuroinvasive encephalitis in disease: meningitis United States. and encephalitis During the (mainly children); 39-year encephalitis may be period of associated with 1964-2002, seizures; fatalities 3077 rare California serogroup viral CNS disease cases (nearly all presumed to be due to La Crosse virus

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Viral Infections

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Jamestown Canyon

United States (including Alaska), Canada

Mosquitoes (Aedes spp.?, Culiseta spp.?)

Large mammals (e.g., deer, elk)

Rural/ suburban

Endemic/ sporadic

Snowshoe hare

Northern United States, southern Canada

Mosquitoes (Aedes spp.?, Culiseta spp.?)

Small Rural/ mammals suburban (e.g., hares, rabbits)

Endemic/ sporadic

California encephalitis

Western United States

Mosquitoes (Aedes spp.)

Small mammals (e.g., ground squirrels, hares) Large mammals (e.g., deer, elk) Endemic/ sporadic

Endemic/ sporadic

Cache Valley

North America

Mosquitoes (spp. undetermined)

Rural/ suburban, especially in the California Central Valley Rural/ suburban

infection) were reported to the CDC, for a national average of 79 cases/yr (median, 67; range, 29-167) Rare Most infections (<40 cases subclinical; documented) frequency of mild illness unknown; neuroinvasive disease: meningitis more common than encephalitis (mainly adults) Rare Most infections (<15 cases subclinical; documented) frequency of mild illness unknown; neuroinvasive disease: meningitis, encephalitis (mainly adults) Rare Subclinical infections (<10 cases common in some documented) areas; neuroinvasive disease: meningitis, encephalitis (children and younger adults) Rare (only Most infections 1 case ever subclinical; recognized: frequency of mild fatal illness unknown; encephalitis neuroinvasive in an adult) disease: encephalitis (adult) Endemic/ sporadic During 19642002, 200 human cases were reported to the CDC, for a national Most infections subclinical; frequency of mild illness unknown; neuroinvasive disease: meningitis and encephalitis Laboratory accidents

Arthropod-Borne Virus Infections

Togaviridae Eastern equine encephalitis Mosquitoes (Culex spp., Aedes spp.) Birds

Eastern United States and Canada (especially in coastal states)

Rural/ suburban, mainly near freshwater hardwood swamps

continued

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TABLE 1 Geographic Distribution, Primary Arthropod Vectors, and Main Clinical and Epidemiologic Features of the Main Arboviral Agents of Neurologic Disease in North Americacontd

Family/ Virus average of 5 cases/yr (median, 4; range, 0-14) Mosquitoes (Culex tarsalis) Birds Rural/ suburban, especially in irrigated agricultural areas During 19642002, 640 human cases were reported to the CDC, for a national average of 16 cases/yr (median, 2; range, 0-172). For unknown reasons, the number of reported cases has declined dramatically since the late 1980s During 19872001, a total of 777 Colorado tick fever case reports were received by nine western state health departments, with Colorado (32), Utah (8), and Montana (7) Most infections subclinical; frequency of mild illness unknown; neuroinvasive disease: meningitis and encephalitis (children and elderly; extremes of age); case fatality <5% (higher in infants than adults) (children and elderly; extremes of age); case fatality ~30%; survivors often have severe sequelae

Arthropod-Borne Virus Infections

Geographic Distribution

Primary Vectors

Primary Vertebrate Hosts Main Human Risk Areas

Main Epidemiologic Pattern

Incidence (All Clinical Categories)

Main Clinical/ Demographic Features

Known NonarthropodBorne Modes of Transmission to Humans

Western equine encephalitis

Midwestern and western United States and Canada

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Reoviridae Colorado tick fever

Western United States and Canada Small mammals (e.g., squirrels, chipmunks)

Dermacentor andersoni (Rocky Mountain wood tick)

Rural, Endemic/ mountainsporadic ous areas, at elevations >3000 ft

Rates of subclinical and mild illness unknown. Most clinical infections are nonspecific, self-limited febrile illnesses. Neuroinvasive disease is rare: meningitis, encephalitis (mainly children). Virus is sequestered in red blood cells

Blood transfusion, laboratory accidents

Viral Infections

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reporting the greatest annual averages. For unknown reasons, the number of reported cases has declined steadily during the past 2 decades. Nevertheless, the disease is almost certainly greatly underrecognized and underreported

throughout their normal lifespan, protected from immune response; patients should not donate blood for at least 6 mo following clinical recovery

CDC, Centers for Disease Control and Prevention; CNS, central nervous system.

Arthropod-Borne Virus Infections

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spinal MR imaging may display anterior cord signal hyperintensity, and patients with respiratory weakness sometimes show signal abnormality in the lower medulla and high cervical cord. Electromyography/ nerve conduction studies generally display decreased or absent compound muscle action potentials with relative preservation of sensory nerve action potentials, widespread denervation changes, and reduced recruitment, consistent with a motor axonal or anterior horn cell process.

Options for Management


There is currently no definitive treatment for arboviral infections; therefore, prevention is critical and is possible only through protection from arthropod bites. Patients should be educated about WNV and other arboviral diseases in their home areas and about the importance of vector avoidance and personal protection measures. In the absence of definitive antiviral treatment, management remains supportive. Patients with severe arboviral meningitis may require hospital admission for headache pain control and for rehydration secondary to severe nausea and vomiting. Severe headache in the acute phase of WNM often responds to a brief course of analgesic, such as nonsteroidal anti-inflammatory agents (ketorolac, 10-30 mg intramuscularly [IM] or intravenously [IV] every 6 hours), codeine (15 to 60 mg orally [PO] every 4 to 6 hours when necessary), or morphine (10-30 mg PO/2-10 mg/70 kg body weight IM or IV, or the lowest dosage achieving pain relief, every 4 to 6 hours. These drugs should be discontinued as soon as possible to avoid rebound headache or dependence. Nausea and vomiting frequently respond to antiemetics such as promethazine (12.5 to 25 mg IM or IV every 4 hours) or prochlorperazine (2.5 to 10 mg IM or IV every 3 to 4 hours) without exacerbation of the parkinsonian features of WNE. In patients with arboviral encephalitis, attention to level of alertness and ability to protect the airway is obviously important. Seizures have been infrequently reported with WNE but are seen more commonly in LACV encephalitis and should be managed appropriately with anticonvulsants. Elevated intracranial pressure and cerebral edema has likewise been infrequently reported but should be suspected if suggested by neuroimaging, CSF opening pressures, or neurologic features (e.g., papilledema, Cheyne-Stokes/apneustic/ataxic respiratory patterns, posturing) and managed appropriately with hyperventilation or mannitol. Patients developing flaccid paralysis may not have concurrent meningitis or encephalitis; thus, WNV infection may not initially be suspected, and inappropriate diagnostic procedures or treatment modalities, such as anticoagulation for suspected acute stroke or muscle biopsy for suspected myopathy, may be rendered. It is important to suspect WNV infection in persons developing acute asymmetrical paralysis. As mentioned previously, patients developing early dysarthria and dysphagia are at higher risk for subsequent acute respiratory failure; for this reason, hospitalization and observation of patients with flaccid paralysis are advised, and development of dysarthria and dysphagia should be viewed

with concern. Experience in the management of paralysis is limited; management of poliomyelitis due to poliovirus infection suggests that initiation of aggressive physical activity during the acute febrile period of illness is associated with more profound and persistent weakness. In the absence of additional data, avoidance of aggressive physical therapy during the acute febrile illness or during the initial 48 to 72 hours of weakness seems a reasonable approach. Physical and occupational therapy should probably be initiated soon thereafter; the most effective rehabilitation strategies for improvement of limb strength are currently unknown. Definitive treatment of infection with WNV or other arboviruses is complicated by the fact that viremia is generally short-lived, and clinical illness may not develop until viremia has essentially ended; thus, to be efficacious, administration of a therapeutic agent may need to occur prior to the development of clinical neurologic disease. Recently, several therapeutic modalities, including use of antiviral agents, nucleic acid analogs, and immunomodulating agents, have been explored as potential treatments for WNV disease; unfortunately, data from animal studies are sparse, and the large number of human cases combined with the clinical desire to intervene medically has led to the empirical use of a number of agents. Anecdotal information suggesting the benefit of these agents in the treatment of severe WNV neuroinvasive disease has perpetuated such usage among many clinicians; however, the efficacy of these drugs is difficult to substantiate in the absence of randomized, blinded, placebo-controlled trials. It is clear, however, that no single therapy appears to have a dramatic impact on outcome. The antiviral agent ribavirin has been used empirically in the United States to treat WNE, but no clinical trials have been conducted. Ribavirin was used in an uncontrolled, nonblinded fashion in a group of patients with neuroinvasive WNV disease in Israel and was found to be ineffective and potentially harmful; for this reason, its use is discouraged. The immunoregulatory protein interferon- has shown in vitro inhibition of cytotoxicity due to WNV, SLEV, and EEEV infections but has not been fully evaluated in animal models. Results of an open-label trial in humans have not been encouraging; data from a blinded, placebo-controlled trial in the treatment of Japanese encephalitis failed to demonstrate efficacy, suggesting that interferon is likely to be ineffective in WNE and other flaviviral encephalitides. Based on mouse model data suggesting the benefit of early administration of high-titer WNV-specific IV immune globulin (IVIG) from Israel (Omr-IgG-am), as well as anecdotal reports of therapeutic efficacy in immunocompromised patients, a phase I/II randomized, double-blinded, placebo-controlled trial to evaluate the safety and efficacy of this product was initiated in 2003 by the Collaborative Antiviral Study Group and the National Institutes of Health. Experimental human WEEV, EEEV, and VEEV vaccines currently exist, but the low associated rates of human illness and the lack of licensure by the U.S. Food and Drug Administration make them impractical and
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unavailable for general public use. Human WNV vaccines are under development, but licensure is likely many years away. SUGGESTED READING
Agrawal AG, Peteresen LR: Human immunoglobulin as a treatment for West Nile virus infection, J Infect Dis 188:5-12, 2003. Calisher CH: Medically important arboviruses of the United States and Canada, Clin Microbiol Rev 7:89-116, 1994. Petersen LR, Marfin AA, Gubler DJ: West Nile virus, JAMA 290: 524-528, 2003.

Systemic Diagnostic Syndromes


The most common (>50%) systemic manifestation of an EV infection is a nonspecific febrile illness, with a fever of 38.5 to 40C, and lasting 2 to 4 days. Less frequent EV-specific systemic syndromes may be seen and can provide additional clues for diagnosis (Table 3).

Viral (Aseptic) Meningitis


CLINICAL MANIFESTATION Viral meningitis manifests with headache (may be intense), photophobia, nausea, fever, stiff neck, and general irritability. Onset can be abrupt. The presentation of viral meningitis is strongly influenced by age, and in younger children signs are much less specific (Table 4). Generally children younger than 3 years of age are most susceptible to viral meningitis. DIAGNOSTIC STRATEGIES The neurologic manifestations of viral meningitis are not diagnostically useful for differentiating among the causes. Therefore, systemic manifestations (see Table 3) combined with other clues (see Table 2) are useful in making the diagnosis. The differential diagnosis includes other viral infections (arbovirus, herpes simplex 2, mumps, varicella, LCM), Rocky Mountain spotted fever (RMSF), Lyme disease, bacterial meningitis, tuberculous meningitis, and fungal meningitis. DIAGNOSTIC TESTS Once viral meningitis is suspected, a number of tests can be performed to confirm the diagnosis, basically by ruling out other causes of meningitis. Computed tomography (CT), magnetic resonance (MR) imaging, and electroencephalography (EEG) are usually normal (Figure 1).

PATIENT RESOURCE
http://www.casg.uab.edu/: Collaborative Antiviral Study Group clinical trial of West Nile virus-specific high-titer intravenous immune globulin.

Enterovirus Infections
Burk Jubelt, M.D., and Stacie L. Ropka, Ph.D.

The human enterovirus (EV) genus, so called because the primary site of entry and replication is the gastrointestinal tract, includes the polioviruses (PVses), coxsackieviruses, echoviruses, and the unclassified EV-68 through EV-71. EVs are the etiologic agents of about a dozen neurologic syndromes, but from a practical standpoint, the important ones are meningitis, encephalitis, flaccid paralysis, and chronic infection. Although each of these syndromes can be caused by most of the different EVs, there are predominant species responsible for each syndrome (Table 1).

Epidemiologic Diagnostic Considerations


In tropical climates EVs are endemic. In temperate climates, however, most infections occur as epidemics from May through October. Because of this epidemic behavior, EVs are often referred to as summer viruses. People with EV infections shed virus for about a week in oral secretions and about a month in feces. Infection is spread primarily by the fecal-hand-oral route. EVs are spread horizontally in the community and are usually introduced into the household by young children. Therefore, transmission within a community depends on a number of factors, which are useful in diagnosing an enteroviral infection, especially host age, hygiene, crowded conditions, and overall sanitation (Table 2).
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TABLE 1 Common Enteroviral (EV) Neurologic Syndromes*


Syndrome Meningitis Encephalitis Predominant Etiology Echoviruses Coxsackieviruses EV-71 Echoviruses Coxsackieviruses EV-71 Polioviruses Polioviruses EV-70 EV-71 Echoviruses Polioviruses, vaccine like

Flaccid paralysis Chronic infection

*Syndromes that are rarely caused by or have been related to EV include cranial nerve palsies, opsoclonus-myoclonus, febrile convulsions, cerebellar ataxia, transverse myelitis, Guillain-Barr syndrome, and rhabdomyolysis.

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Viral Infections

unavailable for general public use. Human WNV vaccines are under development, but licensure is likely many years away. SUGGESTED READING
Agrawal AG, Peteresen LR: Human immunoglobulin as a treatment for West Nile virus infection, J Infect Dis 188:5-12, 2003. Calisher CH: Medically important arboviruses of the United States and Canada, Clin Microbiol Rev 7:89-116, 1994. Petersen LR, Marfin AA, Gubler DJ: West Nile virus, JAMA 290: 524-528, 2003.

Systemic Diagnostic Syndromes


The most common (>50%) systemic manifestation of an EV infection is a nonspecific febrile illness, with a fever of 38.5 to 40C, and lasting 2 to 4 days. Less frequent EV-specific systemic syndromes may be seen and can provide additional clues for diagnosis (Table 3).

Viral (Aseptic) Meningitis


CLINICAL MANIFESTATION Viral meningitis manifests with headache (may be intense), photophobia, nausea, fever, stiff neck, and general irritability. Onset can be abrupt. The presentation of viral meningitis is strongly influenced by age, and in younger children signs are much less specific (Table 4). Generally children younger than 3 years of age are most susceptible to viral meningitis. DIAGNOSTIC STRATEGIES The neurologic manifestations of viral meningitis are not diagnostically useful for differentiating among the causes. Therefore, systemic manifestations (see Table 3) combined with other clues (see Table 2) are useful in making the diagnosis. The differential diagnosis includes other viral infections (arbovirus, herpes simplex 2, mumps, varicella, LCM), Rocky Mountain spotted fever (RMSF), Lyme disease, bacterial meningitis, tuberculous meningitis, and fungal meningitis. DIAGNOSTIC TESTS Once viral meningitis is suspected, a number of tests can be performed to confirm the diagnosis, basically by ruling out other causes of meningitis. Computed tomography (CT), magnetic resonance (MR) imaging, and electroencephalography (EEG) are usually normal (Figure 1).

PATIENT RESOURCE
http://www.casg.uab.edu/: Collaborative Antiviral Study Group clinical trial of West Nile virus-specific high-titer intravenous immune globulin.

Enterovirus Infections
Burk Jubelt, M.D., and Stacie L. Ropka, Ph.D.

The human enterovirus (EV) genus, so called because the primary site of entry and replication is the gastrointestinal tract, includes the polioviruses (PVses), coxsackieviruses, echoviruses, and the unclassified EV-68 through EV-71. EVs are the etiologic agents of about a dozen neurologic syndromes, but from a practical standpoint, the important ones are meningitis, encephalitis, flaccid paralysis, and chronic infection. Although each of these syndromes can be caused by most of the different EVs, there are predominant species responsible for each syndrome (Table 1).

Epidemiologic Diagnostic Considerations


In tropical climates EVs are endemic. In temperate climates, however, most infections occur as epidemics from May through October. Because of this epidemic behavior, EVs are often referred to as summer viruses. People with EV infections shed virus for about a week in oral secretions and about a month in feces. Infection is spread primarily by the fecal-hand-oral route. EVs are spread horizontally in the community and are usually introduced into the household by young children. Therefore, transmission within a community depends on a number of factors, which are useful in diagnosing an enteroviral infection, especially host age, hygiene, crowded conditions, and overall sanitation (Table 2).
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TABLE 1 Common Enteroviral (EV) Neurologic Syndromes*


Syndrome Meningitis Encephalitis Predominant Etiology Echoviruses Coxsackieviruses EV-71 Echoviruses Coxsackieviruses EV-71 Polioviruses Polioviruses EV-70 EV-71 Echoviruses Polioviruses, vaccine like

Flaccid paralysis Chronic infection

*Syndromes that are rarely caused by or have been related to EV include cranial nerve palsies, opsoclonus-myoclonus, febrile convulsions, cerebellar ataxia, transverse myelitis, Guillain-Barr syndrome, and rhabdomyolysis.

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TABLE 2 Enteroviral Epidemiology


Variable Season Host characteristics Environment conducive to spread Factor(s) Epidemics, in the summer months in temperate climates Ageespecially young children Personal hygiene Overcrowding Poor sanitation Presence of young children Daycare centers Newborn nurseries

severe, fluid and electrolyte support may be needed. Infants in particular require fluid, electrolyte, and nutritional support. Although current treatment of viral meningitis is mostly supportive, specific agents are under study. Pleconaril, an antiviral agent specific for EVs, was developed by ViroPharma, Inc. Studies indicate that pleconaril is effective in treating enteroviral meningitis (38% to 50% improvement in drug group vs. placebo). It would appear to be particularly useful for stopping outbreaks of enteroviral meningitis in newborn nurseries. Pleconaril is still an investigational drug that was previously supplied on a compassionate use basis but currently is unavailable.

Occasionally the EEG may reveal diffuse slowing without clinical encephalitis. The cerebrospinal fluid (CSF) profile in viral meningitis usually consists of a mononuclear cell (lymphocytic) pleocytosis with a normal glucose level. However, virus has been recovered from the CSF with normal leukocyte counts. Occasionally during the first 24 to 48 hours of the infection, polymorphonuclear cells may be seen, mimicking bacterial meningitis. Rarely the CSF glucose level may be low, as in fungal and tuberculous meningitis. Echoviruses, coxsackieviruses, and EV-71, the predominant causes of viral meningitis (see Table 1), may be cultured from the CSF, usually from the stool, and occasionally from the throat. Polymerase chain reaction (PCR) analysis should also be ordered. Once virus is detected by culture or PCR, the specific species type can be determined by serology. TREATMENT Viral meningitis is usually a benign, self-limited illness. Many patients with viral meningitis are hospitalized to exclude bacterial meningitis and other treatable diseases. The headache may be intense, especially at onset, and may require narcotics for pain relief. If nausea is

Encephalitis and Rhombencephalitis


CLINICAL MANIFESTATIONS Encephalitis caused by echoviruses and coxsackieviruses resembles viral meningitis on initial presentation. Within 24 to 48 hours, however, signs of brain (parenchymal) involvement ensue, thus differentiating viral encephalitis from viral meningitis. The encephalitis is generally mild; however, neonates can develop a severe systemic group B coxsackievirus infection, including encephalitis, which can be fatal. Rhombencephalitis (brainstem encephalitis) has occurred with EV-71 epidemics of hand-foot-and-mouth disease (HFMD) in Taiwan and Malaysia over the last 6 to 7 years. This is a severe encephalitis, with a mortality rate of about 15%. Most cases occur in children younger than 5 years of age. The initial symptoms are tremor, myoclonic jerks, and ataxia. With progression, cranial nerve palsies (ocular and bulbar), respiratory failure, and coma occur. During these epidemics a few cases of aseptic meningitis and flaccid paralysis were also seen. Although PV-induced disease is now rare, when PV encephalitis did occur, it also frequently resulted in cranial nerve palsies and respiratory failure.

TABLE 3 Systemic Syndromes Caused by Enteroviruses (EVs)


Syndrome Rashes Hand-foot-and-mouth disease Herpangina Pleurodynia (epidemic myalgia, Bornholms disease) Myocarditis/pericarditis Conjunctivitis Associated Enterovirus Coxsackievirus Echovirus Coxsackievirus EV-71 Coxsackievirus Coxsackievirus groups A and B group A group A group B

TABLE 4 Typical Clinical Manifestations of Aseptic Meningitis


Age Group Older children and adults Presentation Severe headache Fever Photophobia Nausea Nuchal rigidity General irritability Kernig and/or Brudzinski signs (in 33%) Increased irritability Nonspecific rash Nuchal rigidity rare in infants Poor feeding Lethargy

Coxsackievirus group B EV-70 (acute hemorrhagic conjunctivitis) Coxsackievirus group A24

Infants and young children

Adapted from Ropka SL, Jubelt B: Enteroviruses. In Nata A, Berger JR, editors: Clinical neurovirology, New York, 2003, Marcel Dekker, 359-377.

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Symptoms and signs of acute meningitis Headache, fever, photophobia, nausea, nuchal rigidity, normal mental status

Normal

CT scan

Abnormal Focal lesion

LP

Collect serum and CSF samples for cultures, PCR, antibody testing, and cytology

Normal No CSF pleocytosis Normal glucose

Abnormal CSF pleocytosis Normal glucose

Abnormal CSF pleocytosis Low glucose

Not meningitis, evaluate for: Encephalitis Abscess Tumor Other

Not meningitis

Differential: Viral meningitis1 Lyme disease1 RMSF2 Mycoplasma2 Sarcoid1,4 Vasculitic meningitis1 Carcinomatous meningitis1

Non-viral meningitis: Bacterial3 Fungal1 TB1 Sarcoid1,4 Carcinomatous meningitis1

Culture or PCR positive for EV

Cultures and PCR negative for EV, Not EV meningitis: Other viral meningitis Other differential entity

Treat with pleconaril if in newborn nursery or immunocompromised

FIGURE 1. Algorithm for the diagnosis and treatment of enteroviral (EV) meningitis. CT, computed tomography; LP, Lumbar puncture; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; RMSF, Rocky Mountain spotted fever; TB, tuberculous meningitis. 1Mononuclear cells (lymphocytes) predominate, although it is not unusual to find polymorphonuclear cells within the first 24 hours of clinical symptoms. 2A variable combination of lymphocytes and polymorphonuclear (PMN) cells is seen. 3In bacterial meningitis, PMN cells usually predominate. 4In sarcoid meningitis, the glucose level is low about 20% of the time.

DIAGNOSTIC STRATEGIES The neurologic manifestations of coxsackievirus and echovirus encephalitis are nonspecific. As with meningitis, systemic manifestations, epidemic activity, and household disease may give clues to the diagnosis. The differential would include other causes of viral encephalitis including herpes simplex and the arboviruses. Nonviral infections to consider are Lyme disease, mycoplasmal infection, endocarditis, toxoplasmosis, and Rocky Mountain spotted fever. Noninfectious diseases in the differential include vasculitis, sarcoidosis, and gliomatosis cerebri. During the EV-71 HFMD-rhombencephalitis epidemics in Asia, several other EVs were circulating at the same time, some of which also caused HFMD. The differential would include other causes of brainstem or severe encephalitis, herpes simplex, herpes zoster,
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Japanese encephalitis virus, West Nile virus, and paraneoplastic syndrome. DIAGNOSTIC TESTS In coxsackievirus and echovirus encephalitis the CT scan and MR imaging are usually normal because focal parenchymal lesions are infrequently seen (Figure 2). In EV-71 rhombencephalitis, T2-weighted MR scans have revealed hyperintensities in the brainstem, most frequently in the pontine tegmentum. Occasionally, lesions extend to the thalamus and cervical cord (see Figure 2). In coxsackievirus and echovirus encephalitis the EEG usually reveals generalized slowing, but focal slowing or sharp waves may occur. In EV-71 rhombencephalitis there usually is severe, diffuse slowing.

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Symptoms and signs of acute encephalitis (or meningoencephalitis) Altered levels of consciousness, abnormal behavior, focal signs, seizure, fever, nuchal rigidity (plus headache, photophobia, nausea)

Normal Encephalitis Encephalopathy

CT scan

Abnormal Focal lesion(s) MRI for: Abscess Toxoplasmosis Endocarditis Vasculitis Tumor Other (mycoplasma3, sarcoid)

LP

Collect serum and CSF samples for culture, PCR and antibody testing

Normal No pleocytosis Normal glucose

Abnormal CSF pleocytosis Normal glucose

Abnormal CSF pleocytosis Low glucose

Encephalopathy

Viral encephalitis1 RMSF2 Mycoplasma2,3 Sarcoid1,4

Sarcoid1,4 Brucellosis Viral encephalitis5

MRI

MRI abnormal

MRI normal

Brainstem

Temporal lobe

Basal ganglia, thalamus > brainstem

Other: Mycoplasma Sarcoid

Culture or PCR

Culture or PCR positive for EV

EV-71 rhombencephalitis

Culture or PCR negative for EV: Other viral encephalitis Other differential entity

Probably HSV Probably arbovirus Start acyclovir

Positive for EV EV encephalitis Start pleconaril

Negative for EV Other encephalitides

Start pleconaril

FIGURE 2. Algorithm for the diagnosis and treatment of enteroviral (EV) encephalitis. CT, computed tomography; LP, Lumbar puncture; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; RMSF, Rocky Mountain spotted fever; HSV, herpes simplex virus; MRI, magnetic resonance imaging. 1 Mononuclear cells (lymphocytes) predominate, although it is not unusual to find polymorphonuclear (PMN) cells within the first 24 hours of clinical symptoms. 2 A variable combination of lymphocytes and PMNs is seen. 3 In mycoplasma encephalitis, the CT is abnormal about 50% of the time. 4 In sarcoid parenchymal disease, the CT reveals parenchymal lesions about 50% of the time and the glucose level is low about 20% of the time. 5Rarely, the glucose may be mild to moderately low in viral encephalitis.

In these infections the CSF profile resembles that of aseptic meningitis. Coxsackievirus, echovirus, and EV71 may be isolated from the CSF, stool, or throat. PV is not found in the CSF but in the stool and throat. TREATMENT Treatment of enteroviral encephalitis is primarily supportive. Pleconaril has been used in a small number

of cases of severe neonatal enteroviral systemic infections. The results have been promising in these uncontrolled compassionate use studies. Supportive care includes respiratory support, which may require tracheostomy during a prolonged period of recovery during severe encephalitis. Fluid and electrolyte balance is important to maintain. This can be followed by intravenous nutrition and eventually a feeding tube. Physical therapy is initially important for passive range
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Enterovirus Infections

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of motion to maintain joints and muscle tissue. Eventually with recovery, gait training and muscle strengthening will be required. Occupational therapy for activities of daily living (ADL) probably will be needed.

TREATMENT Treatment of paralytic disease, once it occurs, is supportive. Pleconaril has not been used for acute paralytic disease. It has decreased efficacy against PV as compared with other EVs. Supportive care includes physical therapy for paralysis and respiratory therapy for respiratory failure. Initially, treatment will include passive range of motion for paralysis, followed by strengthening exercises for mildly weak muscles. Respiratory therapy and artificial ventilation may be needed if respiratory failure occurs. Occupational therapy is also important during recovery for assistance with ADL. Eventually, braces and other assistive devices may be needed. Poliomyelitis (PV-induced paralysis) can be treated prophylactically with PV vaccine. In 2000 the recommended vaccine regimen for poliomyelitis was changed from live oral polio vaccine (OPV) to the inactivated poliomyelitis vaccine (IPV). This change was made because of the occurrence of about six cases yearly of vaccine-associated paralysis. IPV is given at 2, 4, and 6 to 18 months, and a booster is given at 4 to 6 years of age.

Paralytic Disease
CLINICAL MANIFESTATIONS Acute flaccid paralysis usually begins with fever, flulike symptoms, and sometimes muscle cramps followed by muscle weakness in one or more limbs. Paralysis is usually asymmetrical, flaccid, more proximal than distal, and often patchy. The reflexes are lost as paralysis progresses. Over the next several days, paralysis may develop in other extremities, and bulbar involvement with impaired respiration may occur. Extension of paralysis is unlikely to occur after the 5th or 6th day. Paralysis caused by coxsackievirus and echoviruses is usually mild compared with that seen with PV, EV-70, and EV-71. Generally the weakened muscles regain some strength. DIAGNOSTIC STRATEGIES Again, systemic manifestations may provide a clue to the causative agent (see Table 3). EV-70 has caused flaccid paralysis during epidemics of acute hemorrhagic conjunctivitis in Africa and Asia. During the EV-71 epidemics of HFMD with rhombencephalitis, about 10% of cases developed acute flaccid paralysis. There are no characteristic systemic manifestations of PV infections. Several other viruses, such as rabies virus, flaviviruses, (especially West Nile virus) and herpes zoster virus, can occasionally cause acute lower motor neuron paralysis. Other entities in the differential include acute inflammatory polyradiculitis (Guillain-Barr syndrome), botulism, acute toxic neuropathies, acute intermittent porphyria, acute transverse myelitis, and acute spinal cord compression. DIAGNOSTIC TESTS Radiographic studies are usually normal, but there have been a few reports of MR T2-weighted hyperintensities in the anterior horns of the spinal cord. Ventral root and anterior horn cell involvement may be seen with contrast T1-weighted scans. Neurophysiologic studies during the first week of paralysis may reveal reduced to absent compound muscle action potential amplitudes, unobtainable F waves, and decreased to absent motor unit potentials. Fibrillation potentials may be seen toward the end of the first week. The CSF findings are similar to those in aseptic meningitis and encephalitis. PV, coxsackievirus, echovirus, and EV-71 can be isolated from the stool and throat but rarely from the CSF when the presentation is paralytic. EV-70 is not found in the stool or throat and is usually not isolated from the CSF. These viruses may be detected in the CSF by PCR amplification.
Johnson: Current Therapy in Neurologic Disease (7/E)

Persistent Infections
CLINICAL MANIFESTATIONS Persistent central nervous system infections caused by EVs primarily occur in children with agammaglobulinemia. The viruses that cause these infections are of low virulence. Most are caused by echovirus. Vaccine-like PVs have caused several dozen cases, and coxsackieviruses have caused several cases. Persistent echovirus infections primarily involve the brain, with alterations in behavioral and mental status, headaches, seizures, pyramidal tract signs, ataxia, and tremors. About one half of the patients with chronic echovirus infections develop a dermatomyositis-like syndrome, presumably from viral invasion of the muscle, although virus has been isolated from muscle in only two instances. In the PV cases, there is a prolonged incubation period of several months from the time of vaccination until the onset of neurologic disease. Some cases begin with lower motor neuron paralysis, but the persistent central nervous system infection continues, causing progressive intellectual and cerebral dysfunction. Other cases begin with these later manifestations, but ultimately paralysis occurs. DIAGNOSTIC STRATEGIES Other infections that occur in agammaglobulinemic children include bacterial infections that may result in meningitis. Other chronic infections to consider might include toxoplasmosis and infections from other viruses, especially nonenveloped viruses such as adenovirus, although increases in these have not been reported in these patients. DIAGNOSTIC TESTS The EEG and MR scan are usually normal. Examination of the CSF reveals a mononuclear pleocytosis, 6

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usually with an elevated protein and normal glucose. Echovirus but not PV is frequently isolated from the CSF. Both can be detected with PCR techniques. Occasionally virus can be isolated from the stool. TREATMENT Live OPV should not be given to these immunodeficient patients. Currently, this is not a problem in the United States, but it may be in other countries where OPV is still used. Intravenous immunoglobulin (IVIG) for the treatment of the agammaglobulinemia has decreased the occurrence of these infections. However, once infection is established, it is difficult to eradicate it with IVIG. Pleconaril has been used experimentally to treat some of these cases. In one report of 16 patients, 12 improved and 3 stabilized. SUGGESTED READING
Abzug MJ, Clous G, Bradley J, et al, and the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group: Double-blind, placebo-controlled trial of pleconaril in infants with enterovirus meningitis, Pediatr Infect Dis J 22:335-341, 2003. Johnson RT: Viral infections of the nervous system, ed 2, New York, 1998, Lippincott-Raven. Romero JR: Pleconaril: a novel antipicornaviral drug, Exp Opin Invest Drugs 10:369-379, 2001. Ropka SL, Jubelt B: Enteroviruses. In Nata A, Berger JR, editors: Clinical neurovirology, New York, 2003, Marcel Dekker, 359-377.

and by corneal transplantation. After inoculation of rabies virus into muscles or subcutaneous tissues, there may be amplification of the virus in muscle at the site of exposure, accounting for the long incubation period. Rabies virus binds to the muscarinic acetylcholine receptor and spreads within axons of peripheral nerves by retrograde fast axonal transport at a rate of about 50 to 100 mm per day and reaches the spinal cord and brain and disseminates throughout the CNS along neuroanatomic pathways. Rabies virus replicates in neurons and causes neuronal dysfunction by uncertain mechanisms, which is likely responsible for the clinical features and fatal outcome of the disease. Behavioral changes occur in rabies, which leads to transmission by biting in infected animals. There is centrifugal spread of the virus from the brain to the salivary glands, which is important for transmission of virus in rabies vectors. Rabies virus may be present in an animals saliva before the onset of symptoms or signs of rabies.

Clinical Manifestations
There is usually an incubation period after an exposure lasting between a few days to a year or more (usually 20 to 90 days). Early symptoms of rabies are nonspecific and include headache, malaise, anorexia, and nausea. The earliest neurologic symptoms are paresthesias, pain, or pruritus at the site of the wound, which may have healed. There are two clinical forms of rabies: a classic or encephalitic form in 80% and a paralytic form in 20% of patients. In classic rabies there are periods of hyperexcitability lasting minutes separated by lucid periods. Autonomic dysfunction, including hypersalivation, gooseflesh, cardiac arrhythmias, and priapism in males, is common. Fever is usually present. Up to half of patients have hydrophobia, with spasms of pharyngeal and inspiratory muscles, including the diaphragm, on attempts to drink. This becomes a conditioned reflex and even the sight of water may precipitate the spasms. The neurologic illness is progressive, and patients may become comatose and develop failure of multiple organ systems. In paralytic rabies patients develop flaccid weakness that often initially involves the bitten extremity and progresses to weakness of all limbs (quadriparesis) with impairment of bladder function. Paralytic rabies may be misdiagnosed as Guillain-Barr syndrome.

Rabies Virus Infection


Alan C. Jackson, M.D.

Rabies virus causes an acute infection of the central nervous system (CNS) in humans and animals. Worldwide, more than 50,000 people die of rabies every year, and most cases occur in developing countries with endemic dog rabies. Rabies is prevalent in wildlife in the United States, and the common vectors include bats, raccoons, skunks, and foxes. During the 1990s there was an increase in the number of human cases in the United States, and most cases were due to bat rabies virus variants, especially the silver-haired bat rabies virus. Many of these patients did not present with a history of a bat bite or even contact with bats. Silver-haired bats are small bats, and a bite may not be noticed or may be attributed to an insect.

Diagnosis
Rabies should be strongly suspected if there is a history of an animal bite that is followed by a typical neurologic illness, but patients may develop rabies without a history of an exposure, and in the United States these cases are usually due to transmission from bats. Electroencephalograms and imaging techniques (computed tomography, magnetic resonance) do not show specific findings in rabies. Cerebrospinal fluid may show a mononuclear pleocytosis. Diagnostic tests to confirm rabies include the demonstration of rabies virus antigen in small nerves around hair follicles in skin biopsies
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Pathogenesis
Rabies virus is usually transmitted in the saliva of a biting animal, although transmission has rarely been documented from aerosolized virus in caves and laboratories

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usually with an elevated protein and normal glucose. Echovirus but not PV is frequently isolated from the CSF. Both can be detected with PCR techniques. Occasionally virus can be isolated from the stool. TREATMENT Live OPV should not be given to these immunodeficient patients. Currently, this is not a problem in the United States, but it may be in other countries where OPV is still used. Intravenous immunoglobulin (IVIG) for the treatment of the agammaglobulinemia has decreased the occurrence of these infections. However, once infection is established, it is difficult to eradicate it with IVIG. Pleconaril has been used experimentally to treat some of these cases. In one report of 16 patients, 12 improved and 3 stabilized. SUGGESTED READING
Abzug MJ, Clous G, Bradley J, et al, and the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group: Double-blind, placebo-controlled trial of pleconaril in infants with enterovirus meningitis, Pediatr Infect Dis J 22:335-341, 2003. Johnson RT: Viral infections of the nervous system, ed 2, New York, 1998, Lippincott-Raven. Romero JR: Pleconaril: a novel antipicornaviral drug, Exp Opin Invest Drugs 10:369-379, 2001. Ropka SL, Jubelt B: Enteroviruses. In Nata A, Berger JR, editors: Clinical neurovirology, New York, 2003, Marcel Dekker, 359-377.

and by corneal transplantation. After inoculation of rabies virus into muscles or subcutaneous tissues, there may be amplification of the virus in muscle at the site of exposure, accounting for the long incubation period. Rabies virus binds to the muscarinic acetylcholine receptor and spreads within axons of peripheral nerves by retrograde fast axonal transport at a rate of about 50 to 100 mm per day and reaches the spinal cord and brain and disseminates throughout the CNS along neuroanatomic pathways. Rabies virus replicates in neurons and causes neuronal dysfunction by uncertain mechanisms, which is likely responsible for the clinical features and fatal outcome of the disease. Behavioral changes occur in rabies, which leads to transmission by biting in infected animals. There is centrifugal spread of the virus from the brain to the salivary glands, which is important for transmission of virus in rabies vectors. Rabies virus may be present in an animals saliva before the onset of symptoms or signs of rabies.

Clinical Manifestations
There is usually an incubation period after an exposure lasting between a few days to a year or more (usually 20 to 90 days). Early symptoms of rabies are nonspecific and include headache, malaise, anorexia, and nausea. The earliest neurologic symptoms are paresthesias, pain, or pruritus at the site of the wound, which may have healed. There are two clinical forms of rabies: a classic or encephalitic form in 80% and a paralytic form in 20% of patients. In classic rabies there are periods of hyperexcitability lasting minutes separated by lucid periods. Autonomic dysfunction, including hypersalivation, gooseflesh, cardiac arrhythmias, and priapism in males, is common. Fever is usually present. Up to half of patients have hydrophobia, with spasms of pharyngeal and inspiratory muscles, including the diaphragm, on attempts to drink. This becomes a conditioned reflex and even the sight of water may precipitate the spasms. The neurologic illness is progressive, and patients may become comatose and develop failure of multiple organ systems. In paralytic rabies patients develop flaccid weakness that often initially involves the bitten extremity and progresses to weakness of all limbs (quadriparesis) with impairment of bladder function. Paralytic rabies may be misdiagnosed as Guillain-Barr syndrome.

Rabies Virus Infection


Alan C. Jackson, M.D.

Rabies virus causes an acute infection of the central nervous system (CNS) in humans and animals. Worldwide, more than 50,000 people die of rabies every year, and most cases occur in developing countries with endemic dog rabies. Rabies is prevalent in wildlife in the United States, and the common vectors include bats, raccoons, skunks, and foxes. During the 1990s there was an increase in the number of human cases in the United States, and most cases were due to bat rabies virus variants, especially the silver-haired bat rabies virus. Many of these patients did not present with a history of a bat bite or even contact with bats. Silver-haired bats are small bats, and a bite may not be noticed or may be attributed to an insect.

Diagnosis
Rabies should be strongly suspected if there is a history of an animal bite that is followed by a typical neurologic illness, but patients may develop rabies without a history of an exposure, and in the United States these cases are usually due to transmission from bats. Electroencephalograms and imaging techniques (computed tomography, magnetic resonance) do not show specific findings in rabies. Cerebrospinal fluid may show a mononuclear pleocytosis. Diagnostic tests to confirm rabies include the demonstration of rabies virus antigen in small nerves around hair follicles in skin biopsies
Johnson: Current Therapy in Neurologic Disease (7/E)

Pathogenesis
Rabies virus is usually transmitted in the saliva of a biting animal, although transmission has rarely been documented from aerosolized virus in caves and laboratories

Rabies Virus Infection

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taken from the nape of the neck (rich in hair follicles) and in corneal impression smears. Rabies virus RNA may be detected in saliva, cerebrospinal fluid, brain tissue, or skin biopsies using polymerase chain reaction amplification. Brain biopsies are performed only infrequently, and brain tissue may show characteristic pathologic changes with cytoplasmic inclusions called Negri bodies, rabies virus antigen in neurons, and infectious rabies virus that can be cultured. Serum neutralizing antibodies do not usually appear until after the first week of clinical illness and are not useful in patients who have been immunized.

Did the animal bite the patient or did saliva contaminate a scratch, abrasion, open wound or mucous membrane? Yes Is rabies known or suspected to be present in the species and the geographic area? Yes

No

Rabies prophylaxis None

No None

No

Treatment
Treatment of rabies is supportive since no antiviral or immunotherapy therapy is effective. Survival has been reported in only six patients, and five received rabies vaccine prior to the onset of their neurologic disease. Intensive care has prolonged survival in patients with rabies. Barrier techniques, including the use of gowns, gloves, and masks, should be practiced when caring for patients with suspected rabies because of a theoretical risk of transmission. Health care workers may require postexposure prophylaxis (PEP) after high-risk contact with a patient with rabies.

Was the animal captured? Yes Was the animal a normally behaving dog, cat, or ferret? No Does laboratory examination of the brain by fluorescent antibody staining confirm rabies? Yes Yes

RIG and vaccine

Does the animal become ill under observation over the next 10 days? Yes

No None

None No RIG and vaccine

Prevention
Rabies can be prevented following an exposure if current guidelines, which are published in Morbidity and Mortality Weekly Report and available on the Internet at http://www.cdc.gov/mmwr, are carefully followed. A decision to initiate rabies PEP is based on details of the exposure, the species of animal, the animals availability for observation or laboratory testing, and the local epidemiological situation. Algorithms can be helpful in making management decisions concerning rabies PEP (Figure 1). Physicians may need to seek advice from local, state, or federal public health officials for assistance in making decisions about postexposure prophylaxis. Healthy dogs, cats, or ferrets may be closely observed, and if they remain healthy for 10 days, then rabies PEP is not necessary. If the dog, cat, or ferret is unwanted or if signs of rabies are present or develop during observation, the animal should be sacrificed immediately and the head transported under refrigeration for a laboratory examination. The brain should be examined for the presence of rabies virus antigen, which is usually performed with the fluorescent-antibody technique. Since the incubation period is uncertain in animals other than dogs, cats, and ferrets, they should be sacrificed immediately after an exposure, and the head should be submitted for a brain examination. In high-risk exposures, rabies prophylaxis should be initiated prior to obtaining results from a laboratory examination. If the brain examination is negative, then it can be safely concluded that the saliva of an animal did not contain rabies virus. If immunization has been initiated, it can be discontinued after a negative examination. If an
Johnson: Current Therapy in Neurologic Disease (7/E)

FIGURE 1. Algorithm for rabies postexposure prophylaxis. RIG, Rabies immune globulin. (Adapted from Corey L: Rabies virus and other rhabdoviruses. In Braunwald E, Fauci AS, Kasper DL, et al, editors: Harrisons principles of internal medicine, ed 15, New York, 2001, McGraw-Hill, 1149-1152.)

animal escapes after an exposure, it should be considered rabid unless information from public health officials indicates this is unlikely, and rabies prophylaxis should be initiated. Rodents (squirrels, chipmunks, hamsters, rats, and mice), rabbits, and hares rarely transmit rabies, and their bites do not normally require rabies prophylaxis. Abnormal behavior of animals suggests the possibility of rabies, and the risk is greater with an unprovoked attack than with a provoked attack. A provoked exposure may occur when a person attempts to feed or handle a healthy animal. Local wound cleansing is important to inactivate infectious rabies virus at the site of entry. Cleaning with soap and water is very useful, and the use of virucidal agents is important for deeper wounds. A combination of active and passive immunization should be used in previously unimmunized individuals with a rabies exposure. Five 1-mL doses of rabies vaccine (purified chick embryo cell vaccine, human diploid cell vaccine, or rabies vaccine adsorbed) should be given intramuscularly (IM) in the deltoid muscle (in infants in the anterolateral upper thigh) on days 0, 3, 7, 14, and 28. Pregnancy is not a contraindication for immunization. Live vaccines should not be given for 1 month after immunization. Local reactions (pain, swelling, and

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itching) and mild systemic reactions (fever, myalgias, headache, and nausea) are quite common. Antiinflammatory and antipyretics can be used, but immunization should not be discontinued. Systemic allergic reactions are uncommon (11 per 10,000 vaccinees). Anaphylactic reactions should be treated with epinephrine and antihistamines. Corticosteroids can interfere with the development of active immunity. The risk of developing rabies should be carefully considered before discontinuing immunization because of an adverse reaction. A serum neutralizing antibody determination is necessary after immunization only if a patient is immunocompromised. In developing countries, alternative rabies vaccines are commonly used that are less expensive. These vaccines, particularly ones derived from neural tissues, are associated with frequent systemic and neurologic reactions. Passive immunization includes administration of 20 IU/kg of human rabies immune globulin (HRIG) on day 0. As much HRIG as anatomically feasible should be infiltrated into and around the wounds, and any remaining volume should be given IM (in the gluteal area or lateral thigh muscles). In the case of an exposure involving a mucous membrane, the entire dose should be administered IM. HRIG should be administered at the same time as rabies vaccine and should not be given more than 8 days after vaccine. They should never be given at the same site or in the same syringe. Side effects of HRIG include local pain and low-grade fever. Persons at risk of acquiring rabies, such as veterinarians, animal handlers, rabies laboratory workers, and certain international travelers, can be protected by immunization with three 1-mL doses of rabies vaccine (preexposure prophylaxis) given on days 0, 7, and 21 or 28. An adequate serum-neutralizing titer should be demonstrated and repeated at intervals of 6 to 24 months, depending on the risk of exposure. Boosters should be given if the titer is inadequate. If a rabies exposure occurs in these individuals, local wound care and two doses of rabies vaccine should be given. The first should be given immediately, and the second should be given 3 days later. Passive immunization (HRIG) should not be given to these patients. SUGGESTED READING
Centers for Disease Control and Prevention: Human rabies preventionUnited States, 1999: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR 48 (No. RR-1):1-21, 1999. Jackson AC: Human disease. In Jackson AC, Wunner WH, editors: Rabies, San Diego, 2002, Academic Press, 219-244. Jackson AC, Warrell MJ, Rupprecht CE, et al: Management of rabies in humans, Clin Infect Dis 36:60-63, 2003. Jackson AC, Wunner WH, editors: Rabies, San Diego, 2002, Academic Press.

Human Immunodeficiency Virus Infections


Avindra Nath, M.D.

Human immunodeficiency virus (HIV) infection is the most common viral infection of the nervous system. It can affect the entire neuraxis. The nervous system is vulnerable to effects caused directly by invasion by the virus that may occur at any time during the course of the illness, though most commonly seen during the later stages of the disease. Several opportunistic infections can also invade the nervous system. In susceptible individuals early in the course of the illness, several autoimmune illnesses may also occur. Occasionally, patients may have more than one opportunistic infection simultaneously, which may be difficult to diagnose, and the clinician should also be alert to the occurrence of other common diseases that may occur independent of those seen in the setting of HIV infection.

HIV Meningitis
An acute viral meningitis may occur 3 to 6 weeks following primary HIV infection and thus prior to seroconversion. Cerebrospinal fluid (CSF) reveals an increased protein (>100 mg/dL), mononuclear pleocytosis (>200 cells/mm3), increased IgG, oligoclonal bands, and normal or mildly depressed glucose levels. HIV meningitis is typically a self-limited disease. However, when identified, early, aggressive antiretroviral therapy (ART) with central nervous system (CNS)-penetrant antiretrovirals may be warranted, as a window may exist for the substantial reduction of the virus from this compartment. At the least, early treatment may help limit trafficking of virus into the CNS.

HIV Dementia
Early recognition and treatment are key to the prevention of more severe forms of dementia, which may not respond well to treatment. The initial approach to a patient with HIV infection who has cognitive impairment should be to exclude other treatable causes of dementia (Figure 1). Hence investigations should include a careful history for depression, a neuroimaging study, preferably magnetic resonance (MR) imaging, to exclude opportunistic infections, thyroid function test, vitamin B12 levels, and a chemistry and hematology profile. CSF should be evaluated for opportunistic infections and for HIV viral load. A neuropsychological assessment is necessary to get a qualitative and quantitative baseline assessment. The Memorial Sloan-Kettering (MSK) Scale and HIV Dementia Scale (HDS) can be administered in the clinic. Assessment may be necessary for the patients ability to conduct his or her occupation and for
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itching) and mild systemic reactions (fever, myalgias, headache, and nausea) are quite common. Antiinflammatory and antipyretics can be used, but immunization should not be discontinued. Systemic allergic reactions are uncommon (11 per 10,000 vaccinees). Anaphylactic reactions should be treated with epinephrine and antihistamines. Corticosteroids can interfere with the development of active immunity. The risk of developing rabies should be carefully considered before discontinuing immunization because of an adverse reaction. A serum neutralizing antibody determination is necessary after immunization only if a patient is immunocompromised. In developing countries, alternative rabies vaccines are commonly used that are less expensive. These vaccines, particularly ones derived from neural tissues, are associated with frequent systemic and neurologic reactions. Passive immunization includes administration of 20 IU/kg of human rabies immune globulin (HRIG) on day 0. As much HRIG as anatomically feasible should be infiltrated into and around the wounds, and any remaining volume should be given IM (in the gluteal area or lateral thigh muscles). In the case of an exposure involving a mucous membrane, the entire dose should be administered IM. HRIG should be administered at the same time as rabies vaccine and should not be given more than 8 days after vaccine. They should never be given at the same site or in the same syringe. Side effects of HRIG include local pain and low-grade fever. Persons at risk of acquiring rabies, such as veterinarians, animal handlers, rabies laboratory workers, and certain international travelers, can be protected by immunization with three 1-mL doses of rabies vaccine (preexposure prophylaxis) given on days 0, 7, and 21 or 28. An adequate serum-neutralizing titer should be demonstrated and repeated at intervals of 6 to 24 months, depending on the risk of exposure. Boosters should be given if the titer is inadequate. If a rabies exposure occurs in these individuals, local wound care and two doses of rabies vaccine should be given. The first should be given immediately, and the second should be given 3 days later. Passive immunization (HRIG) should not be given to these patients. SUGGESTED READING
Centers for Disease Control and Prevention: Human rabies preventionUnited States, 1999: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR 48 (No. RR-1):1-21, 1999. Jackson AC: Human disease. In Jackson AC, Wunner WH, editors: Rabies, San Diego, 2002, Academic Press, 219-244. Jackson AC, Warrell MJ, Rupprecht CE, et al: Management of rabies in humans, Clin Infect Dis 36:60-63, 2003. Jackson AC, Wunner WH, editors: Rabies, San Diego, 2002, Academic Press.

Human Immunodeficiency Virus Infections


Avindra Nath, M.D.

Human immunodeficiency virus (HIV) infection is the most common viral infection of the nervous system. It can affect the entire neuraxis. The nervous system is vulnerable to effects caused directly by invasion by the virus that may occur at any time during the course of the illness, though most commonly seen during the later stages of the disease. Several opportunistic infections can also invade the nervous system. In susceptible individuals early in the course of the illness, several autoimmune illnesses may also occur. Occasionally, patients may have more than one opportunistic infection simultaneously, which may be difficult to diagnose, and the clinician should also be alert to the occurrence of other common diseases that may occur independent of those seen in the setting of HIV infection.

HIV Meningitis
An acute viral meningitis may occur 3 to 6 weeks following primary HIV infection and thus prior to seroconversion. Cerebrospinal fluid (CSF) reveals an increased protein (>100 mg/dL), mononuclear pleocytosis (>200 cells/mm3), increased IgG, oligoclonal bands, and normal or mildly depressed glucose levels. HIV meningitis is typically a self-limited disease. However, when identified, early, aggressive antiretroviral therapy (ART) with central nervous system (CNS)-penetrant antiretrovirals may be warranted, as a window may exist for the substantial reduction of the virus from this compartment. At the least, early treatment may help limit trafficking of virus into the CNS.

HIV Dementia
Early recognition and treatment are key to the prevention of more severe forms of dementia, which may not respond well to treatment. The initial approach to a patient with HIV infection who has cognitive impairment should be to exclude other treatable causes of dementia (Figure 1). Hence investigations should include a careful history for depression, a neuroimaging study, preferably magnetic resonance (MR) imaging, to exclude opportunistic infections, thyroid function test, vitamin B12 levels, and a chemistry and hematology profile. CSF should be evaluated for opportunistic infections and for HIV viral load. A neuropsychological assessment is necessary to get a qualitative and quantitative baseline assessment. The Memorial Sloan-Kettering (MSK) Scale and HIV Dementia Scale (HDS) can be administered in the clinic. Assessment may be necessary for the patients ability to conduct his or her occupation and for
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Human Immunodeficiency Virus Infections

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Viral Infections

Subacute cognitive impairment

MRI

Focal lesions

Diffuse white matter lesions/atrophy

Periventricular enhancement

Meningeal enhancement

Normal

See Figure 3

Likely HIV dementia

Likely CMV encephalitis

Likely cryptococcal or tubercular meningitis

CSF

CSF to rule out opportunistic infections

CSF PCR for CMV

CSF evaluation

Meningitis

Normal

Optimize ART with drugs that penetrate CNS

I.V. ganciclovir or foscarnet

Treat as shown in Table 4

Reinvestigate for other causes of dementia

Monitor plasma viral load and CD4+ cell count

Cognitive improvement

Continued cognitive impairment

Continue current therapy

Repeat MRI and CSF viral load

Normal viral load

Elevated viral load

Reinvestigate for other causes of dementia

Change ART regimen after HIV genotyping

FIGURE 1. Subacute cognitive impairment. CMV, Cytomegalovirus; HIV, human immunodeficiency virus; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; ART, antiretroviral therapy; CNS, central nervous system.

the ability to drive and other psychosocial issues. Occupational therapists and social workers may assist with these assessments. In patients with progressive dementia, medicolegal issues such as establishing a power of attorney, completing a living will, and arranging for the dispersal of assets should be discussed at any early stage before the dementia becomes too severe. Pharmacologic intervention is challenging in patients with HIV infection. Tight control of viral load is necessary to prevent drug resistance and for treatment of dementia. However, patients with cognitive abnormalities may not remember to take their medications or realize the importance of drug adherence. Hence a system needs to be in place for maintaining drug adherence and
Johnson: Current Therapy in Neurologic Disease (7/E)

for assisting patients to keep regular clinic appointments. Techniques for improving adherence include directly observed therapy, pill counts, intensive education, and electronic monitors. Periodic viral loads and neuropsychological assessments may be needed to determine the effect of treatment. Other factors that may affect compliance with medications include pill burden, side effects, frequency of administration, and cost of therapy. Usage of combination pills and once-daily therapy if and when possible would greatly improve compliance. Drug side effects may also affect compliance. Although aggressive ART is the current approach to treating HIV dementia, it is also realized that some additional neuroprotective

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therapy may be needed as well. Unfortunately, despite several clinical trials over the years, currently there is no single agent that has shown a clear benefit. In two small studies selegiline has showed some promise, and a larger phase II trial is currently under way using a transdermal form of the drug. The current approach is to hit early, hit hard. The wider availability of multiple, potent antiretroviral regimens can be combined in a variety of ways to provide effective suppression of HIV replication. Periodic follow-up should include monitoring the response to therapy through measurement of plasma HIV RNA levels and CD4+ cell counts. In addition, resistance to antiretrovirals can now be relatively easily measured with genotypic or phenotypic assays. In patients who fail to achieve HIV suppression with ART, it is often uncertain whether this reflects development of resistance, incomplete adherence, or inadequate delivery of antiretroviral agents to the target site. This is potentially of even greater importance for the treatment of CNS infection given the relatively limited penetrance of most of the available antiretroviral agents. Thus patients who progress neurologically despite good control of the virus peripherally should have repeat CSF evaluation with viral load in the CSF. Achieving control of the virus in CNS compartments is essential because patients who do not show CSF HIV RNA decreases may not have neuropsychological improvement. A typical antiretroviral regimen consists of at least three agents: one or two protease inhibitors or a nonnucleoside reverse transcriptase inhibitor (non-NRTI) combined with two nucleoside analogs. The goal of therapy is to reduce measurable plasma viral burden to below the level of detection. Viral load testing has made it possible to individualize therapy and to more accurately determine the best time to initiate or change therapy, long before declining CD4+ counts would have given evidence of active viral replication. The published pharmacokinetic data for CSF penetration for available agents are shown in Table 1. As a class, NRTIs can cause mitochondrial toxicity leading to lactic acidosis. Symptoms include fatigue, nausea, vomiting, abdominal pain, dyspnea, and weight loss. The NRTI should be discontinued if lactic acidosis is present with clinical symptoms. Peripheral neuropathies may occur. This is also likely due to mitochondrial toxicity, but the pathogenesis remains uncertain. Protease inhibitors can cause lipodystrophy that manifests as hyperlipidemia with risk of atherosclerosis; insulin resistance; fat redistribution with accumulation in abdomen, dorsal neck, and breasts; and fat atrophy in the face, extremities, and buttocks. Although fat redistribution is cosmetic, hyperlipidemia and diabetes should be managed as for that in non-HIV infected patients. Drug interactions involving antiretroviral agents have become increasingly important with the introduction of combination therapy involving protease inhibitors and non-NRTIs (http://aidsinfo.nih.gov/drugs) (Table 2). One of the most widely used protease inhibitor combinations uses this interaction to boost levels of lopinavir in combination with low-dose ritonavir. All protease

inhibitors are substrates and inhibitors of the hepatic cytochrome P-450 enzyme system. Ritonavir is the most powerful inhibitor, saquinavir the weakest, and indinavir and nelfinavir are intermediate. Examples of drug interactions arising from inhibition of cytochrome P-450 include the increases in rifampin and rifabutin levels with ritonavir and, to a lesser degree, with the other protease inhibitors. Some protease inhibitors are also inducers of cytochrome P-450. An example of this type of interaction is the lowering of ethinyl estradiol, triptans, (sildenafil), and zidovudine levels by nelfinavir and ritonavir. Dual protease inhibitor regimens make use of drug interactions to increase drug levels and/or prolong half-lives. Ritonavir increases saquinavir levels by more than 10-fold, allowing saquinavir to be given at a reduced dose twice daily. Nelfinavir also increases saquinavir levels, but the effect is less dramatic and does not allow dose reduction. Ritonavir also increases drug levels of nelfinavir and indinavir. The non-NRTIs are also metabolized through the CYP3A pathway, leading to significant drug interactions with protease inhibitors. Nevirapine induces cytochrome P-450 enzymes, leading to reductions in protease inhibitor levels. In contrast, delavirdine inhibits cytochrome P-450 and increases protease inhibitor levels. With both drugs, the effect is greatest with saquinavir, intermediate with indinavir, and negligible with ritonavir. There are conflicting data on drug interactions between nevirapine and nelfinavir. Efavirenz is both a modest inhibitor and a modest inducer of the cytochrome P-450 system. Although it decreases indinavir levels and reduces saquinavir levels by 61%, it increases the area under the plasma concentration-time curve (AUC) of nelfinavir by 20%. Of importance to neurologists are the anticonvulsants. Drugs such as phenytoin, carbamazepine, and phenobarbital should be used with caution and, if used, drug levels and viral loads should be closely monitored. Alternative anticonvulsants such as topiramate and gabapentin may be considered. Protease inhibitors may also induce withdrawal symptoms in patients on methadone. At this point, it is impossible to make definitive recommendations about the optimum ART for HIV dementia. Stavudine and abacavir appear to be useful alternatives to include in a combination regimen for patients with dementia, based on their pharmacokinetic properties, tolerability, and twice-daily dosing. Stavudine may have a role in treating neurologic disease based on favorable pharmacokinetic studies in CSF. The NRTI nevirapine and protease inhibitor indinavir achieve good CSF levels and may also be useful to include in ART regimens for patients with HIV dementia, based on accumulating clinical experience. Difficulties with ART of HIV dementia include the following: Drug resistance The role of resistance testing may become important in selection of ART combinations for demented patients, most of whom are heavily pretreated and are likely to have multiple resistance mutations (as in the abacavir trial where 90% of subjects had resistance mutations at baseline). There is no additional benefit of examining resistance patterns in
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TABLE 1 Antiretroviral Drugs: Generic and Trade Names, Characteristics


Generic Name Zidovudine Didanosine Trade Name Retrovir Videx Usual Dosage 300 mg bid 200 mg bid (125 mg bid if <60 kg) or 300-400 mg qd 0.75 mg tid 40 mg bid (30 mg bid if <60 kg) 150 mg bid 300 mg bid 60-120 mg qd 200 mg qd for 14 days, then 200 mg bid 400 mg tid 600 mg qd 1000 mg bid with ritonavir 100 mg bid 1200 mg tid 800 mg q 8 hr 600 mg bid 750 mg tid or 1250 mg bid 1200 mg bid 400 mg qd 1400 mg bid 90 mg SQ q12 hr Common Side Effects (Comments) Bone marrow suppression, GI upset, headache, myopathy Peripheral neuropathy, pancreatitis, diarrhea (take on empty stomach) Peripheral neuropathy, pancreatitis, oral ulcers Peripheral neuropathy Anemia, GI upset GI upset, hypersensitivity reaction GI upset, elevated transaminases, nephrotoxicity (must take with L-carnitine 500 mg/day Rash Rash Dizziness, nightmares, disconnectedness, rash (take with a fatty meal, or up to 2 hours after meal) CSF-toPlasma Ratio 0.3-1.3 0.2

Drug Class Nucleoside RT inhibitor Nucleoside RT inhibitor

Abbreviation AZT, ZDV ddI

Zalcitabine Stavudine Lamivudine Abacavir Adefovir Nevirapine Delavirdine Efavirenz Saquinavir

Nucleoside RT inhibitor Nucleoside RT inhibitor Nucleoside RT inhibitor Nucleoside RT inhibitor Nucleotide RT inhibitor Non-nucleoside RT inhibitor Non-nucleoside RT inhibitor Non-nucleoside RT inhibitor Protease inhibitor

ddC d4T 3TC ABC ADV NVP DLV EFV SQV

HIVID Zerit Epivir Ziagen Preveon Viramune Rescriptor Sustiva Invirase Fortovase Crixivan Norvir Viracept Agen erase Reyataz Lexiva Fuzeon

0.1-0.4 0.2 0.1 0.3

0.5 <0.05 <0.05 <0.05

Indinavir Ritonavir Nelfinavir Amprenavir Atazanovir Fosamprenavir Enfuvirtide

Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Fusion inhibitor

IDV RTV NFV APV ATV FPV ENF

Kidney stones, hyperbilirubinemia (take on an empty stomach) GI upset, circumoral paresthesias, diarrhea, fatigue Diarrhea (take with food) Rash, headache, GI upset GI upset, prolongation of QTc, no hyperlipidemia Rash, GI upset, headache, hepatitis Site reactions, bacterial pneumonia

0.14 <0.05 Undetectable <0.05 Unknown Unknown Unknown

RT, Reverse transcriptase; GI, gastrointestinal; CSF, cerebrospinal fluid.

CSF because there is generally concordance between the CSF and plasma with respect to major genotypic resistance mutations. Drug adherence Adherence is important in maintaining virologic suppression, particularly in patients with cognitive impairment. New techniques for improving adherence, including directly observed therapy, pill counts, intensive education, and electronic monitors, are being applied to this problem. Patients with HIV dementia are extremely susceptible to the adverse effects of psychoactive drugs, so
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hypnotics and anxiolytics should be avoided. Due to its selective action on D3 and D4 receptors, clozapine is the preferred neuroleptic. Small doses of neuroleptics such as haloperidol (Haldol), 0.5 mg, may be needed in the agitated or combative patient. In patients with HIV dementia and depression, tricyclic antidepressants or fluoxetine (Prozac) can be tried in doses 25% to 50% of the usual dose. Full doses of tricyclic antidepressants may precipitate delirium, and serum levels should be monitored frequently. If seizures are present, gabapentin and topiramate are the preferred anticonvulsants due to lack of drug-drug interactions.

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TABLE 2 Drugs That Should Be Avoided with Protease Inhibitors*


Drug Category Analgesics Antimycobacterial Indinavir None Rifampin Ritonavir Meperidine, piroxicam, propoxyphene Rifabutin Saquinavir None Rifampin, rifabutin Nelfinavir None rifampin Alternative(s) Acetylsalicylic acid, oxycodone, acetaminophen For rifabutin (as alternative for Mycobacterium aviumintercellulare treatment): clarithromycin, ethambutol (treatment, not prophylaxis), or azithromycin Loratadine Limited experience Fluoxetine, desipramine Limited experience Temazepam, lorazepam

Antihistamine Gastrointestinal agent Antidepressant Neuroleptic Psychotropic

Astemizole, terfenadine Cisapride None None Midazolam, triazolam

Astemizole, terfenadine Cisapride Bupropion Clozapine, pimozide Clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, zolpidem Dihydroergotamine ergotamine (various forms) Desipramine increased 145%: reduce dose Theophylline levels decreased: dose increase

Astemizole, terfenadine Cisapride None None None

Astemizole, terfenadine Cisapride None None Midazolam, triazolam

Ergot alkaloid Miscellaneous

Dihydroergotamine ergotamine (various forms) Grapefruit juice reduces indinavir levels by 26%

Dihydroergotamine ergotamine (various forms) Grapefruit juice increases saquinavir levels

Dihydroergotamine, ergotamine (various forms)

Limited experience

*The contraindicated drugs listed are based on theoretical considerations based on major metabolic contribution from cytochrome P450 3A, CYP2D6, or unknown pathways. Actual interactions may or may not occur in patients. Reduce rifabutin dose to one quarter of the standard dose (150 mg qod). This is likely a class effect.

Valproate should be particularly avoided because in vitro studies suggest that it can induce viral replication. Intractable vascular headaches may develop in some HIV-infected patients. Initial treatment should include migraine prophylaxis. Nonresponders may require treatment with opiates. Parkinsonism may be part of the symptom complex of HIV dementia. Dopamine agonists may be used for patients that manifest parkinsonism. However, the response is usually poor.

HIV Myelopathy
HIV myelopathy is also termed vacuolar myelopathy, and it an uncommon manifestation of HIV infection seen in terminal stages of the illness when it may be

accompanied by HIV dementia or neuropathy, which may make it difficult to diagnose. The presence of brisk reflexes, increased muscle tone of lower extremities, and symptoms of a spastic bladder may prompt the diagnosis, which may be confirmed by abnormal somatosensory evoked potentials. CSF is not diagnostic, and MR scanning is necessary to exclude other causes of a myelopathy. There is no definitive treatment for this condition. Supplementation with vitamin B12 is ineffective in improving the symptoms or delaying its progression. Nevertheless, it is commonly administered to patients with clinical evidence of HIV myelopathy. Corticosteroids and intravenous (IV) gamma globulin have also been ineffective in uncontrolled clinical experience. To date, there has been no controlled study describing the effect of highly active antiretroviral therapies (HAART) on the clinical manifestations or electrophysiologic
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measures of vacuolar myelopathy. The effect of combination antiretroviral drugs, HAART, in improving the symptoms or slowing the progression of HIV myelopathy is therefore not known. Recently there have been attempts to treat the possible underlying metabolic disorder. A pilot study using high doses of oral L-methionine led to improvement in clinical and electrophysiologic features of the disease in an open-label clinical trial. Symptomatic treatment is obviously indicated for patients with spasticity and urinary dysfunction.

several days to weeks before an adequate response is achieved. Desipramine and amitriptyline at doses of up to 150 mg/day can be used. In general, the dosages of the anticonvulsants used for pain control may be lower than those used for seizure control. Gabapentin is an attractive therapy for painful neuropathy due to its favorable pharmacokinetic profile and sparse drug-drug interactions, although it has not been studied in controlled trials in HIV neuropathy. Topical agents such as lidocaine patches are also effective adjuncts; adequate relief requires continuous use for several days.

Distal Sensory Polyneuropathy


Distal sensory polyneuropathy (DSP) can occur due to HIV infection alone or may be caused by the use of some NRTI drugs. The clinical features of DSP caused by HIV or the NRTIs are indistinguishable. Hence the need for NRTIs in a patient with DSP needs to be carefully evaluated. Often dose reduction can be achieved without compromising virologic control. The mainstay in the management of DSP is symptomatic treatment, with adequate pain control (Figure 2). Patients may initially be treated with nonopioid analgesics such as acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID); however, generally the response to these drugs is poor in this patient population. Although the use of opiates is appropriate in view of the severity of the pain, the use of these drugs poses unique challenges, since often HIV-infected patients have a history of drug abuse. Neuromodulatory drugs such tricyclic antidepressants (e.g., amitriptyline, nortriptyline) and anticonvulsants (e.g., lamotrigine, gabapentin, topiramate, diphenylhydantoin, carbamazepine) may be effective in controlling neuropathic pain (Table 3); however, dosage needs to titrated gradually to avoid side effects, and it may take
FIGURE 2. Management of distal symmetrical peripheral neuropathies with human immunodeficiency virus infection. NRTI, Nucleoside reverse transcriptase inhibitor; ART, antiretroviral therapy. (Modified from Bartlett JG, Gallant JE, editors: Medical management of HIV infection, 2003 edition, Baltimore, 2003, Johns Hopkins University Press.)

Mononeuritis Multiplex
Early mononeuritis multiplex may resolve spontaneously within several months. In cases of delayed or incomplete recovery, corticosteroids, plasmapheresis, or IV immunoglobulins may be indicated. Mononeuritis multiplex can also occur with hepatitis B and C due to associated cryoglobulinemia. Deposition of immune complexes or cryoglobulins in the vasa nervosa leads to focal infarcts of the nerves often manifesting as wristdrop or footdrop or cranial nerve involvement. In lateonset mononeuritis multiplex occurring in advanced HIV infection, empirical therapy for cytomegalovirus (CMV) should be considered.

Inflammatory Demyelinating Neuropathy


Two major forms of inflammatory demyelinating polyneuropathy (IDP) may occur. The acute type, with rapidly progressive ascending weakness, minor sensory

Pain, paresthesia or numbness in feet, hyperesthesia, decreased pain or vibration and diminished ankle jerk

Diagnosis established

Nerve conduction velocities and electromyography to detect axonal neuropathy

NRTI therapy (ddC, ddI, d4T)

Skin biopsy for quantification of nerve endings

Evaluate for; Other neurotoxic drugs (INH, B6, metronidazole, dapsone) Alcoholism Diabetes B12 deficiency

Alter ART regimen

Symptoms resolve

Symptoms persist

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No diagnosis and CD4+ count <300/mm3

Avoid tight footware, soak feet in ice water + symptomatic pharmacological therapy (Table 4)

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TABLE 3 Common Drugs Used in the Treatment of Distal Sensory Polyneuropathy


Class/Drug Nonprescription analgesics Nonsteroidal anti-inflammatory drugs Acetaminophen Tricyclic antidepressants Amitriptyline Nortriptyline Anticonvulsants Gabapentin Lamotrigine Topical analgesics Lidocaine patch Capsaicin 0.075% Narcotic analgesics Oxycodone Morphine Fentanyl patch Dosage Variable, depending on the agent 500-1000 mg q 4-6 hr 25-150 mg qhs 10-100 mg qhs 300-1200 mg tid 200-250 mg bid (after slow escalation) 1-3 patches to affected areas bid Apply on affected areas bid 1 or 2 tablets q 4-6 hr Variable depending on the pain intensity Variable, usually start at 25 g/hr q 72 hr

symptoms, and generalized areflexia, is referred to as acute IDP (also called Guillain-Barr syndrome). The chronic, more slowly progressive, monophasic, or relapsing form is chronic IDP. A lymphocytic pleocytosis (10 to 50 cells/mm3) in the CSF in HIV-infected patients with IDP helps distinguish HIV-infected from seronegative individuals. In fact, the presence of CSF lymphocytes greater than 5/mm3 in this setting should raise suspicion of undiagnosed HIV infection. Electrophysiologic findings in HIV-related IDP are similar to those in HIV-uninfected patients. Case series have shown a positive response of HIV-related IDP to immunomodulating therapy, such as corticosteroids, high-dose IV immunoglobulins (0.5 to 1 gm/kg for 2 days), and plasmapheresis (four or five exchanges). In advanced HIV infection, therapy against CMV may be indicated.

light-headedness, syncope, diarrhea, impotence, or urinary disturbance. Management of autonomic neuropathy is mainly supportive. It includes recognition and discontinuation of offending medications, correction of fluid and electrolyte imbalance, use of compressive stockings and abdominal binders, liberal salt intake, and reconditioning exercises, as well as maneuvers such as squatting and standing with crossed legs. In severe cases, pharmacologic agents such as fludrocortisone, midodrine, and antiarrhythmic agents may be needed. Treatment of impotence may require pharmacologic intervention with sildenafil or tadalafil. In some cases, surgical intervention may be needed. In these patients, safe sex practices should be advocated.

Progressive Polyradiculopathy
Progressive polyradiculopathy (PP) occurs most commonly in advanced HIV infection, with CD4+ cell counts less than 50 cells/mm3 but is rarely seen in the HAART era. PP is characterized clinically by the rapid onset of radicular pain and paresthesias in a cauda equina distribution, followed by signs of progressive involvement of multiple nerve roots, usually lumbar and sacral. Clinical signs include flaccid paraparesis, sphincter dysfunction, and lower extremity areflexia. CMV is the major cause of PP in patients with acquired immunodeficiency syndrome (AIDS), although less common causes include neurosyphilis and lymphomatous meningitis. Case series have reported improvement of CMV-associated PP with antiviral therapy, including ganciclovir, valganciclovir, foscarnet, and cidofovir.

Diffuse Infiltrative Lymphocytosis Syndrome


Infiltration of CD8+ lymphocytes in nerves may occur as part of a more systemic involvement involving multiple organs. Often there is associated involvement of the parotid glands resulting in sicca syndrome. Involvement of the nerves can clinically resemble mononeuritis multiplex, distal sensory neuropathy, or an inflammatory demyelinating neuropathy.

HIV Myopathy
A proximal myopathy may occur in some patients with HIV infection owing to polymyositis or toxicity of zidovudine. Muscle biopsy may be needed to differentiate the two. Recently another severe, rapidly progressive neuromuscular weakness syndrome has been described likely secondary to stavudine. Withdrawal of the offending agent may be useful in some. In patients with polymyositis, corticosteroids may provide benefit, but they should be used with caution because of the immunosuppressant effects. Although IV immunoglobulins may be an alternative option without risk of
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Autonomic Neuropathy
Although frequently found by formal testing, autonomic neuropathy is an uncommon symptomatic manifestation of HIV infection. Patients may complain of

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immunosuppression, there is only limited reported experience in HIV myopathy.

Other Autoimmune Diseases


Several autoimmune diseases such myasthenia gravis, polymyositis, multiple sclerosis, and acute inflammatory demyelinating neuropathy may occur in susceptible individuals that get unmasked early in the course of the illness, when a polyclonal gammopathy is present. As immunosuppression occurs, the diseases go into spontaneous remission. However, these manifestations may require disease-specific treatment, in which case the treatment strategy should be similar to that used in HIV-seronegative patients.

Toxoplasma Encephalitis
Toxoplasma encephalitis is the most common cause of cerebral brain abscess in patients with HIV infection, often occurring in patients with CD4+ cell counts of less than 100 cells/mm3; hence, patients who have multiple brain abscesses and are seropositive for Toxoplasma can be empirically treated for toxoplasmosis (Table 4). Patients with single brain lesions or who are seronegative for Toxoplasma gondii should undergo brain biopsy for confirmation of the diagnosis (Figure 3). Initial therapy includes sulfadiazine with pyrimethamine for 3 to 6 weeks with a repeat MR scan at 2 weeks post-therapy to monitor regression in size of abscesses, since a radiologic response may predate a change in clinical status. Sulfadiazine is the sulfonamide of choice. It is highly protein bound with good penetration into the CSF and other tissues. Unfortunately, hypersensitivity is a common side effect with prolonged treatment that is more frequently observed in HIV-infected patients than in other populations. Pyrimethamine is well absorbed and has a variable half-life from 1 to 4 days. The CSF levels of the drug are about one fifth of the serum levels. A small

starting dose for toxoplasmosis is recommended in patients with convulsive disorders to avoid the potential nervous system toxicity of pyrimethamine. This drug should always be used in conjunction with folinic acid to counterbalance the antifolate effects of the drug. In patients allergic to sulfonamides, clindamycin with pyrimethamine may be used. Clindamycin is less effective than sulfadiazine but better tolerated. Clindamycin is highly lipid soluble and highly protein bound. It has good penetration into the eye and dense tissues, such as bone. Its penetration into the CSF is poor; hence, it is used as a drug of second choice. Although less well studied, several other alternative regimens have been used that include either sulfadiazine or pyrimethamine in conjunction with one of the following: azithromycin, 900 to 1200 mg/day; atovaquone, 1500 mg twice daily; minocycline, 150 to 200 mg twice daily; or doxycycline, 300 to 400 mg/day. Clarithromycin 500 mg twice daily can be used as an add-on drug to these regimens if needed. A fundamental problem in the treatment of Toxoplasma infection is that chemotherapy targets the actively growing tachyzoite but has limited effects on the slow-growing bradyzoite. As a consequence, even prophylactic treatment in immunocompromised individuals is aimed at arresting tachyzoites should reactivation occur. Maintenance therapy should be continued indefinitely or until CD4+ counts are greater than 200 cells/mm3 for 6 months. In pregnant women, because of the low incidence of cerebral toxoplasmosis during pregnancy and the possible teratogenicity associated with pyrimethamine treatment, chemoprophylaxis with pyrimethamine-containing regimens can reasonably be deferred until after pregnancy.

Cryptococcus Meningitis
Cryptococcus is the most common cause of meningitis in HIV-infected populations in Western Europe and North America. Patients typically present with headache, fever, seizures, or altered sensorium. Symptoms may be

TABLE 4 Treatment of Cerebral Toxoplasmosis


Drug Sulfadiazine Mechanism of Action Inhibits de novo synthesis in microorganisms that are obliged to make their own folic acid Inhibits the microbial dihydrofolate reductase Inhibits protein synthesis in parasite ribosomes Dosage 1000-1500 mg q 6 hr Major Side Effect(s) Hypersensitivity, lupus, polyarteritis nodosa, myocarditis Bone marrow suppression Diarrhea due to suppression of normal flora Drug Interactions Increase levels of warfarin, barbiturates, hydantoins, sulfonylureas, tolbutamide, and uricosuric agents Increase in sulfadiazine levels with thiazides, indomethacin, probenecid, and salicylates Synergizes with sulfadiazine on Toxoplasma, with 10-fold greater activity than that expected with the drugs together Enhances the action of neuromuscular blocking agents

Pyrimethamine

Clindamycin

200 mg loading dose, 50-75 mg/ day + folinic acid 10-20 mg/day 600 mg q 6 hr

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Subacute onset of neurologic symptoms with focal lesion on MRI

Single lesion

Multiple lesions

FIGURE 3. Subacute onset of neurologic symptoms with focal lesion on MR imaging. SPECT, Single-photon emission computed tomography; PCNSL, primary central nervous system lymphoma; XRT, radiation therapy; CSF, cerebrospinal fluid; JCV, JC virus; PCR, polymerase chain reaction; ART, antiretroviral therapy.

SPECT scan

Enhancing

Non-enhancing

uptake

uptake

Toxoplasma titer in serum

Edema

No edema

Likely tumor

Abscess or necrotic lymphoma

Negative

Positive

Biopsy

CSF for JCV PCR

Biopsy center of lesion

Biopsy edge of lesion

Biopsy

Treat for toxoplasmosis

Negative

Positive

If PCNSL, treat with XRT

Repeat MRI in 10 days

Aggressive ART

No improvement

Improvement

Biopsy

Continue maintenance therapy

mild; hence a high level of suspicion is necessary. Since the infection occurs in the setting of advanced immunosuppression, meningeal signs may be absent and CSF may show only a mild mononuclear pleocytosis (5 to 100 cells/mL) with mild elevation in protein (50 to 150 mg/dL). However, the organism can be seen by India ink staining in 60% to 80% patients, and cryptococcal antigen and cultures are positive in nearly all patients. MR imaging of the brain may be normal or may show some meningeal enhancement. Management of intracranial pressure is critical in these patients and may require daily spinal punctures for drainage or the placement of a CSF drain or even a ventriculoperitoneal shunt. The aim is to maintain CSF pressures below 200 mm H2O. Pharmacologic therapy includes an induction phase of amphotericin B (0.7 mg/ kg/day IV; i.e., nearly twice the dosage used for non-HIV patients) in combination with flucytosine (Table 5). The duration of treatment may be for as little as 2 weeks if (1) a lumbar puncture is performed documenting negative CSF fungal cultures and (2) if followed by at least 10 weeks of high-dose fluconazole (400 to 800 mg daily orally) maintenance therapy. This is followed by a

prolonged maintenance course of fluconazole 200 mg daily orally for 6 months and then may be discontinued if CD4+ cell counts are greater than 200 cells/mm3. Patients with significant renal insufficiency or who are receiving other nephrotoxic agents should likely be treated with a liposomal preparation of amphotericin B (3 to 5 mg/kg daily IV). This formulation of amphotericin B is much more expensive than the conventional formulation. Premedication with acetaminophen or meperidine may decrease infusion-related untoward effect. Flucytosine should also be used with caution in patients with renal impairment. Dosage should be adjusted for renal insufficiency, and drug levels should be monitored to ensure appropriate dosing. Owing to the rapid development of resistance when used as monotherapy, this drug should not be used as the sole agent to treat cryptococcal disease. Hydrocephalus is a well-documented late sequela of cryptococcal meningitis, even after lasting sterilization of the CNS. New or progressive neurologic signs after successful treatment of cryptococcal meningitis should be evaluated with brain imaging to monitor for the development of hydrocephalus. If hydrocephalus is present, permanent shunt placement may be required.
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TABLE 5 Drugs Used for Management of Neurologic Cryptococcus Meningitis in HIV-Infected Patients
Drug Amphotericin B Dosage 0.7 mg/kg/day IV for 2 wk Monitor electrolytes Major Side Effects Infusion-related erythema (red man syndrome), rigors, fever, decreased renal function, hypokalemia, hypomagnesemia Rarely, renal tubular acidosis, hypotension Bone marrow suppression, azotemia Rarely, causes severe hepatitis/ hepatic failure Hair loss with prolonged therapy Rarely, severe hepatic toxicity or severe exfoliative dermatitis Drug Interactions Use with caution with other nephrotoxic drugs

Flucytosine Fluconazole

100 mg/kg/day PO in four divided doses for 2 wk Initially 400-800 mg/day PO for 10 wk followed by 200 mg/day for at least 6 mo

Itraconazole

200-400 mg/day Oral absorption requires gastric acidity, so must be taken with meal or acidic beverages

Nausea, vomiting, rash, edema, headache Uncommonly, severe hepatic dysfunction, neuropathy, hypertriglyceridemia

Drugs that decrease glomerular filtration may increase serum concentration of flucytosine With warfarin, results in increased prothrombin time Increases half-life of phenytoin, cyclosporine, zidovudine, theophylline, and sulfonylureas Rifampin results in decreased fluconazole levels Contraindicated with terfenadine or astemizole Increases serum levels of cyclosporine and digoxin Level of itraconazole is decreased by phenytoin, rifampin, isoniazid, histamine H2 antagonists, proton pump inhibitors With oral hypoglycemics, may result in severe hypoglycemia

HIV, Human immunodeficiency virus.

Progressive Multifocal Leukoencephalopathy


Progressive multifocal leukoencephalopathy usually manifests as focal neurologic deficits over days or weeks in the setting of advanced immunosuppression. MR imaging typically shows multifocal white matter changes without surrounding edema and only rarely does contrast enhancement occur. Pathologic studies show infection by JC virus of oligodendrocytes causing demyelination, and the infected astrocytes assume a characteristic large shape. The prognosis of the illness remains poor and the treatment remains frustrating. To date there are no unequivocally successful therapeutic modalities. Restoration of immune function is likely critical to recovery. ART may be associated with prolonged survival and recovery; hence aggressive HAART therapy is advocated even though the benefit of HAART is not seen universally. Despite anecdotal reports of success, clinical trials with cytarabine (ara-C), vidarabine (araA), camptothecin, cidofovir, and interferons have been disappointing.

Primary CNS Lymphoma


Primary CNS lymphoma occurs in patients with advanced immunodeficiency with CD4+ counts less than 100 cells/mm3. It usually presents as a focal mass but can be multicentric. It is a B cell lymphoma, and the cells are nearly always positive for Epstein-Barr virus. Prominent cerebral edema is seen on MR imaging; hence, the mass effects can be controlled temporarily with dexamethasone 4 mg every 6 hours. The prognosis for survival is poor, but aggressive treatment with whole-brain radiation and optimization of HAART therapy can improve outcome. Use of chemotherapy remains controversial, but if malignant cells are found in the CSF, intrathecal cytosine arabinoside is recommended.

Cytomegalovirus Encephalitis and Radiculitis


Neurologic complications with CMV are uncommon, but due to the rapidity of progression and the poor prognosis untreated, early recognition and intervention are critical. CMV encephalitis presents in the setting of CD4+ counts <50 cells/mm3 with progressive severe dementia and can be confused with HIV dementia. MR imaging may be normal or may show evidence of ventriculitis. CMV radiculopathy presents initially with pain and paresthesias in the saddle distribution because of involvement of the sacral nerves. This may then spread

Cerebellar Atrophy
Cerebellar atrophy is a rare manifestation of HIV infection. Recently, it was demonstrated that there is infection of cerebellar granule cells with JC virus. No specific treatment is available for this entity.
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to involve both lower limbs and be accompanied by flaccid weakness and loss of sphincter tone. MR imaging shows swollen nerve roots with clumping and contrast enhancement in the lumbosacral region. CMV retinitis often accompanies or predates these syndromes; hence a careful ophthalmoscopic evaluation is needed. The clinical picture of a cauda equina syndrome can also be caused by syphilis or metastatic lymphoma. Demonstration of CMV by polymerase chain reaction (PCR) in CSF is diagnostic. However, this is the only viral infection that results in elevated neutrophils in the CSF (>100 cells/mm3). Owing to the poor prognosis for survival of CMV encephalitis and rapid progression of CMV radiculitis, treatment should be initiated while awaiting the CSF results. Combination therapy with ganciclovir (5 mg/kg IV twice a day) and foscarnet (90 mg/kg IV twice a day) for 3 to 6 weeks is recommended. In severe cases, induction therapy may need to be continued for several months, but tolerability is poor. This should be followed by lifelong maintenance therapy with valganciclovir (900 mg/day orally) plus foscarnet. Oral ganciclovir (1000 mg orally three times a day) can also be used, but serum levels are better with valganciclovir. Cidofovir maybe used as an alternate therapy, but there is minimal experience with the use of this drug for neurologic complications of CMV infection. The most important factor is the immune reconstitution with HAART. Electromyography and nerve conduction velocities may be useful in monitoring the response to treatment. They show widespread demyelination and denervation in the lower limbs. Decreased distal latencies suggest axonal involvement. Repeated CSF and MR imaging evaluations may also be needed for monitoring response to therapy. In CMV radiculopathy, clinical improvement is noticed within 2 to 3 weeks of treatment. If relapse occurs after 6 months, the possibility of ganciclovir resistance should be considered.

Neurosyphilis
Neurosyphilis may be a more common and more aggressive complication of syphilis in those infected with HIV. However, the diagnosis and treatment of neurosyphilis in persons infected with HIV are challenging. It may be more difficult to diagnose because, as with neurosyphilis, HIV infection itself may cause CSF pleocytosis or an elevated CSF protein concentration. In addition, retrospective studies suggest that for 23% to 60% of HIV-infected patients, currently recommended neurosyphilis therapy with penicillin G fails. PCR for Treponema pallidum in CSF is inconsistent and may be negative even when CSF VDRL is positive; hence, it is of

limited value as a diagnostic tool. Curiously, despite the associated immunosuppression, serum non-treponemal (VIDRL) titers in HIV-infected individuals with neurosyphilis are typically high, averaging 1:128. In the absence of visible blood contamination in the CSF, a positive CSF VDRL result is specific and establishes the diagnosis of neurosyphilis; however, the sensitivity of CSF VDRL against clinical diagnosis is only 30% to 70%. In contrast, treponemal tests are sensitive, but nonspecific; a negative CSF FTA-abs result virtually excludes the diagnosis of neurosyphilis. It has been suggested that asymptomatic HIV-infected patients be treated for neurosyphilis if they have a positive CSF FTA-abs result and a CSF pleocytosis (>5 white blood cells per cubic millimeter). Whether secondary prophylaxis in the AIDS patient with syphilis needs to be administered, as with Toxoplasma encephalitis and cryptococcal meningitis, remains uncertain. The Centers for Disease Control and Prevention has recommended that the initial therapy of IV aqueous penicillin be followed in HIV-infected individuals by weekly intramuscular injections of 2.4 million units of benzathine penicillin for 3 weeks. The latter component of this regimen fails to achieve treponemicidal levels of penicillin in the CSF. Furthermore, highdose penicillin regimens are not consistently effective in patients infected with HIV. A more logical course may be the administration of a 30-day course of doxycycline 200 mg twice daily, following the completion of IV therapy. Although secondary prophylaxis has been extensively employed, further studies are required before secondary prophylaxis can be widely recommended. It is prudent to carefully monitor HIV-seropositive patients for relapse of neurosyphilis for 2 or more years following initial treatment. Ceftriaxone (2 gm IV once daily for 10 days) may be an alternative to penicillin for treatment of HIV-infected patients with neurosyphilis. Reversion of a reactive CSF VDRL, the decline in a CSF pleocytosis, is probably of greatest diagnostic value in monitoring the success of therapy. The potential for relapse of neurosyphilis following a course of recommended therapy in HIV infection has been largely supported by anecdote but relapse occurs more than 12 months after initial therapy. Lumbar punctures may be repeated at weeks 14 and 26 and at 6-month intervals thereafter for 2 years. As with other opportunistic infections, immune reconstitution should be achieved if possible. SUGGESTED READING
Bartlett JG, Gallant JE, editors: Medical management of HIV infection, 2003 edition, Baltimore, 2003, Johns Hopkins University Press. NeuroAIDS clinical trials http://www.neuro.wistl.edu/narc

Johnson: Current Therapy in Neurologic Disease (7/E)

SECTION 7

Nonviral Infectious Disease


Acute Bacterial Meningitis
Allen J. Aksamit, Jr., M.D.
Haemophilus influenzae was the most frequent cause in children who are 3 months to 6 years of age. However, since the advent of the H. influenzae vaccine, incidence has declined. It can also occur in adults, especially if debilitated or with upper respiratory infection. Staphylococcus is especially associated with surgery or trauma. Its presence without that history should suggest a break in the blood-brain barrier or bacteremia. Gram-negative bacteria usually are associated with systemic bacteremia causing the meningitis. Group B Streptococcus is the most common cause of meningitis in newborn infants. Anthrax (Bacillus anthracis) causes hemorrhagic meningitis.

Bacterial meningitis is an acute to subacute purulent infection of the subarachnoid space and spinal fluid pathways, incited by bacterial seeding and growth. Inflammation of the leptomeninges produces the clinical syndrome of headache, fever, and nuchal irritation.

Clinical Aspects
Bacterial meningitis incidence approximates 5 to 10 per 100,000 population per year. Untreated, it is universally fatal. Headache is the usual heralding symptom. Seizures and altered consciousness are also common. Malaise, fever, and chills as a prodrome are followed in 12 to 24 hours by Brudzinskis and Kernigs signs of neck stiffness. Meningeal signs can be absent in elderly, comatose, and immunosuppressed patients. Focal signs are secondary to cerebritis, venous or arterial infarction, subdural empyema, or subdural effusion. Meningitis can manifest with cranial neuropathies, the syndrome of inappropriate antidiuretic hormone or hydrocephalus, as part of the primary inflammatory process.

Diagnosis
Blood cultures (positive in 70%) should be done, as well as cerebrospinal fluid (CSF) cultures. Early treatment determines outcome, so antibiotics should be started after blood cultures are performed, while other diagnostic studies are being undertaken. Computed tomographic or magnetic resonance head scanning is advisable in any patient suspected of having meningitis with focal neurologic signs, to look for brain abscess, subdural empyema, or subdural effusion, which could make lumbar puncture hazardous. The diagnosis of bacterial meningitis rests on spinal fluid bacterial culture or identification of bacterial antigen by latex agglutination. Rapid antigen detection assays for pneumococcus, Haemophilus, meningococcus, and Streptococcus group B are routinely available for spinal fluid. Grams stain should be done in all cases to help guide initial therapy. Spinal fluid abnormalities in bacterial meningitis usually include a protein value greater than 100 mg/dL, spinal fluid glucose level less than 40% of the serum glucose, and nucleated cell count greater than 500/L with a predominance of polymorphonuclear cells. When collecting CSF from the ventricles, some principles need be kept in mind. CSF glucose is always higher in the ventricles than in the lumbar sac (even when infection is present). CSF protein is normally lower in the ventricles than in the lumbar sac. Imaging helps identify patients with acute hydrocephalus, increased intracranial pressure, cerebritis, venous or arterial infarction, subdural empyema, or subdural effusion. 155

Infectious Agents
Pneumococcus (Streptococcus pneumoniae) is the most common cause in adults. Splenectomy and humoral defects are predisposing factors. Penicillin-resistant strains are becoming more common, which influences empirical treatment choices. With meningococcus (Neisseria meningitidis), 50% to 75% of the patients have skin petechiae or purpura, though rarely this sign can be seen with pneumococcus as well. This agent is responsible for 20% to 30% of all cases of meningitis. Peak age of incidence is in the teenage years and young adulthood. It is acquired by respiratory transmission.
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Acute Bacterial Meningitis

Pathophysiology
Bacteria may enter the subarachnoid space by a number of different routes. In most cases the bacteria enter the body from the respiratory tract, sometimes infecting only the nasopharynx. The bacteria spread to the meninges by bacteremia. Once in the bloodstream the bacteria probably settle along the walls of the venous sinuses as the result of slow flow. The organisms then penetrate the dura or arachnoid granulations and enter the subarachnoid space. Bacteria may spread to the subarachnoid space from parameningeal infections of the sinuses, mastoids, middle ear, or nasopharynx. Spread from these foci is probably along connecting veins. Bacteria may also be directly implanted into the subarachnoid space in cases of broken barriers. Examples are craniospinal surgery, penetrating injuries, and skull fractures, especially with CSF rhinorrhea or otorrhea. Other predispositions include persistent sinus tracts in the sacrococcygeal or occipital area and foreign bodies such as CSF shunts, Ommaya reservoirs, or ventricular pressure monitors or drains. Once bacteria enter the subarachnoid space, they undergo unrestricted logarithmic growth because of an absence of complement and opsonization in CSF. The presence of bacteria in the subarachnoid space causes surrounding neural tissue damage by endotoxins from the bacteria as well as cytokines released from inflammatory cells. The blood-brain barrier and the blood-CSF barrier are disrupted as cells are recruited from the bloodstream to ingest the bacteria. The inflammatory response may partially block CSF flow and resorption. Cerebral edema occurs as a result of these processes. The limited natural defense against invading bacterial organisms of the leptomeninges and the damage produced by the organisms has led to two rules of treatment. Antibiotics used to treat bacterial meningitis must be bactericidal (capable of destroying bacteria) rather than bacteriostatic (limiting the proliferation of bacteria). The most effective antibiotics penetrate the blood-brain barrier. The levels of antibiotics in the CSF should be 10 times greater than the minimal inhibitory concentration.

the brain, they must pass through the endothelial cell, and such passage is limited by the lipid bilayer of the cell membrane, effects of cytoplasmic enzymes of the endothelial cell, and limited pinocytosis of endothelial cells. Astrocytic foot processes surround the capillaries. Brain endothelial formation of tight junctions is dependent on contact with the astrocyte foot processes. As implied earlier, there is also a barrier between the blood and CSF, the so-called blood-CSF barrier. The choroid plexus and the capillaries of the brain form the CSF. The capillaries of the choroid plexus do not have tight junctions, but the epithelial cells of the surface of the choroid plexus do have tight junctions constituting the blood-CSF barrier. The choroid plexus also actively removes some material from the CSF including the penicillins and aminoglycosides. Fortunately, in meningitis the removal of antibiotics from the CSF is slowed, resulting in higher levels of antibiotics for longer periods. The blood-brain CSF barrier restricts the entry of antibiotics into the brain and CSF. Some drugs pass the barrier better than others do. Most antibiotics permeate the barrier partially broken by meningitis much better than the normal barrier. However, as the meningitis remits and the bloodbrain barrier is repaired, the amount of antibiotic in the CSF will decrease. Also, steroids may partially repair the broken barrier and thus limit the concentration of antibiotics in the CSF (Table 1).

Treatment
To compensate for the limited defenses of the leptomeninges and CSF against bacterial infections, it is preferable to use a bactericidal antibiotic whenever possible. Bactericidal antibiotics include penicillins, cephalosporins, aminoglycosides, and metronidazole. Bacteriostatic antibiotics include chloramphenicol, tetracyclines, erythromycin, and sulfonamides. In selecting an antibiotic to use for the treatment of bacterial meningitis, several factors should be considered, including the concentration of the antibiotic that can be achieved in the CSF in the presence of inflamed meninges. The minimal concentration in micrograms per milliliter necessary to inhibit 90% of bacterial isolates is the minimal inhibitory concentration (MIC). The MIC is used by most experts despite the fact that the minimal bactericidal concentration would theoretically be a better measurement. Most important is the relationship between the obtainable CSF concentration and the MIC, referred to as the inhibitory quotient. The inhibitory quotient should probably exceed 10 to 30 for the treatment of meningitis. In summary, Inhibitory quotient = CSF concentration MIC where CSF concentration and MIC are measured in micrograms per milliliters. The interactions between various drugs must also be kept in mind. Examples of synergism of antibiotics include penicillins and aminoglycosides against enterococci, and carbenicillin or ticarcillin and aminoglycosides against Pseudomonas. Examples of antagonism of
Johnson: Current Therapy in Neurologic Disease (7/E)

Blood-Brain Barrier
To understand the changes in the CSF and brain in meningitis as well as the complexities of the treatment, one has to understand the blood-brain barrier. This term developed when it was noted that the injection of dyes into the bloodstream would result in the staining of all the organs of the body except the brain. It was reasoned that there had to be some special barrier between the brain and the blood that was not present in other organs. The blood-brain barrier consists of several components. Gap junctions that allow the passage of molecules separate the endothelial cells of the capillaries of other organs besides the brain. The endothelial cells of the capillaries in the brain are joined together by tight junctions. For materials to pass from the blood into

Acute Bacterial Meningitis

157
Nonviral Infectious Disease

TABLE 1 Antibiotic Concentrations in the CSF


Good Concentrations in CSF with and without Meningitis Chloramphenicol Sulfonamides Cephalosporins Cefotaxime Ceftriaxone Ceftazidime Moxalactam Metronidazole Trimethoprim-sulfamethoxazole Isoniazid Adequate Concentrations in CSF in Meningitis Penicillin Ampicillin Methicillin Oxacillin Nafcillin Carbenicillin Ticarcillin Tetracycline Erythromycin Ethambutol Rifampin Vancomycin Meropenem Fair to Poor Concentrations in Meningitis First-generation cephalosporins Cephalothin Cefoxitin Aminoglycosides Gentamicin Tobramycin Amikacin Clindamycin Benzathine penicillin

CSF, Cerebrospinal fluid.

antibiotics are coincident use of ampicillin and tetracyclines, and of penicillin and chloramphenicol. Other drug interactions need to be kept in mind. Phenobarbital reduces the peak serum concentration of chloramphenicol by 35%. Phenytoin causes a 60% increase in peak serum concentrations of chloramphenicol. Treatment needs to be a minimum of 14 days of intravenous (IV) therapy. The need for repeat CSF examination at 2 to 7 days of treatment to prove sterilization of CSF in every case is controversial. Corticosteroids in children have been shown to reduce the incidence of late complications, hearing loss in particular. They are used routinely as dexamethasone, 0.6 mg/kg/day in four divided doses for 4 days. The duration remains controversial. Use of steroids routinely in adults is more controversial. A recent prospective study in adults suggested a reduction in mortality, fever, and unfavorable outcomes. Dexamethasone can be used, and should probably be used for all patients with CSF obstruction, coma, significant cerebral edema, or parenchyma invasion (cerebritis). Caution needs to be observed because of the previously mentioned reduction of CSF penetration by some antibiotics potentiated by steroids. The dose of dexamethasone is 10 mg four times a day in adults for 4 days. Empirical therapy should usually consist of a third-generation cephalosporin (e.g., ceftriaxone) and vancomycin (because of penicillin-resistant streptococci and staphylococci). Additionally, metronidazole can be added if dirty or anaerobic contamination is suspected. Once identification and sensitivity of the organism are known, antibiotics can be simplified. Vancomycin resistance has been reported, but staphylococci or penicillinresistant streptococci justify its use in the circumstance of bacterial meningitis (Table 2). Pneumococcus (S. pneumoniae) meningitis is still in some circumstances sensitive to penicillin, but penicillin-resistant strains are becoming more common, which influences empirical treatment choices. Usually the initial ceftriaxone (2 gm every 12 hours IV) or cefotaxime (3 gm every 6 hours IV) treatment will be completed if the organism is sensitive, rather than
Johnson: Current Therapy in Neurologic Disease (7/E)

switching to penicillin. If penicillin is used, the dose is 20 to 24 million units per day IV, in a divided every4-hour infusion schedule. If the organism is cephalosporin resistant, vancomycin, 1 gm every 12 hours IV, should be continued for a minimum of 14 days, with dose adjustment based on monitoring of levels in the blood. Meningococcus (N. meningitidis) meningitis is treated with penicillin, although ampicillin, ceftriaxone, or cefotaxime can be used. If penicillin is used, the dose is 20 to 24 million units per day, in a divided every-4-hour infusion schedule for 14 days. The organism is acquired by
TABLE 2 Empirical Antibiotic Therapy of Bacterial Meningitis
Age, Disability Children Drug, Dosage Ceftriaxone 50 mg/kg q 12 hr IV or Cefotaxime 150 mg/kg q 8 hr IV and Vancomycin 15 mg/kg q 6 hr IV plus Dexamethasone 0.15 mg/kg q 6 hr for 4 days Vancomycin 1 gm q 12 hr IV (until sensitivities of organism are known) and Ceftriaxone 2 gm q 12 hr IV or Cefotaxime 3 gm q 6 hr IV and Dexamethasone 10 mg q 6 hr for 4 days above, plus Ampicillin 2 gm q 4 hr IV (for Listeria) Cefepime 2 mg q 8 hr

Adults Community acquired

Alcoholism Neurosurgical procedure or head trauma

plus Vancomycin (above doses) plus Metronidazole 500 mg q 6 hr IV (if contaminated wound is suspected)

158

Tuberculous Meningitis

respiratory transmission, so contacts need prophylaxis of rifampin 10 mg/kg every 12 hours for four doses. H. influenzae meningitis is treated with ceftriaxone, 2 gm every 12 hours IV, or cefotaxime, 3 gm every 6 hours IV. Alternatively, ampicillin plus chloramphenicol, 12.5 mg/kg every 8 hours IV) can be considered, depending on sensitivities of the organism. Staphylococcus meningitis is treated with vancomycin, 1 gm every 12 hours IV, until sensitivities are known. Dose adjustment is based on monitoring of levels in the blood. If methicillin susceptible, nafcillin, 2 gm every 4 hours IV, can be used. Gram-negative bacteria (Klebsiella, Escherichia coli, Proteus sp.) usually are associated with systemic bacteremia causing the meningitis. Treatment is guided by sensitivities and is somewhat organism dependent. Usual initial treatment is cefepime 2 gm every 8 hours. Meropenem, 2 gm every 8 hours IV; or aminoglycosides, 6 mg/kg every 8 hours IV, can be considered. For Pseudomonas sp., cefepime, 2 gm every 8 hours IV, should be the initial therapy. Ceftazidime, 2 gm every 8 hours IV, with an aminoglycoside (gentamicin, 6 mg/kg every 8 hours IV) can be considered as an alternative. For anaerobic bacteria (e.g., Bacteroides fragilis), metronidazole, 500 mg every 6 hours IV, should be used. Clindamycin has poor spinal fluid penetration with an intact blood-brain barrier. Listeria monocytogenes meningitis is treated with ampicillin, 2 gm every 4 hours IV, with or without an aminoglycoside for 14 to 21 days. IV sulfamethoxazoletrimethoprim is used for those who are penicillin allergic. L. monocytogenes meningitis often occurs in the elderly, in transplant patients, and in those with liver disease or alcoholism. Brainstem encephalitis has also been described associated with Listeria meningitis.

Diagnosis
Identification of cases is the first challenge because early-stage TM is protean in its manifestations and lacks pathognomonic physical examination and laboratory findings (Figure 1). Depending on the stage of disease, the most common signs and symptoms include fever, headache, changes in mentation, and meningismus in most patients. Other signs include focal neurologic deficits such as cranial nerve palsies, paresis, seizures, and diminished cognition. Symptoms indistinguishable from acute pyogenic meningitis have also been described, although most patients with TM have a prolonged prodromal period (>7 days). The diagnosis of TM should be considered in any patient with subacute meningitis. Even when antituberculous medications are administered, morbidity and mortality are very high, especially with late-stage disease, so after reasonable efforts to make a diagnosis are made, empirical treatment may be warranted. Epidemiologic links to a case of active TB may be helpful but are absent in most cases. High-risk groups include the human immunodeficiency virus (HIV)-infected, injection drug users, alcoholics, and some racial groups (African American and Native American). Patients are divided into three stages based on the examination at presentation. Stage I disease is characterized by lucid patients with fever, malaise, headache, and possibly meningismus. Stage II patients often have single cranial nerve impairment due to basilar disease, paresis, and focal seizures. Hyperactive deep tendon reflexes, worsening headache, and impaired cognitive capacity are often seen. Stage III patients are comatose or stuporous and have marked neurologic impairment, including multiple cranial nerve palsies, hemiparesis, or paraplegia. Hydrocephalus is common. This stage of disease has a high rate of neurologic sequelae (30%) or death (30%) despite antibiotic therapy. Tuberculin skin testing (PPD) is positive in only 31% to 64% of patients with known TM. Chest radiography and chest computed tomographic (CT) scan may provide adjunctive clues, with 30% to 74% of patients having an abnormal study with evidence of miliary or focal tuberculous disease. Nonspecific laboratory tests, such as elevated sedimentation rate, peripheral leukocytosis, anemia, and thrombocytosis, occur as a result of subacute or chronic inflammation and are common in all granulomatous diseases. Mild to moderate hyponatremia may be seen in some patients as a result of the syndrome of inappropriate antidiuretic hormone secretion. Examination of the cerebrospinal fluid (CSF) is the most helpful diagnostic procedure, with larger volumes of CSF (>5 mL) often leading to higher microbiologic yields for smear and culture. The possibility of high opening pressures and noncommunicating hydrocephalus should be highlighted because herniation is a distinct danger in these settings. The CSF may be turbid with more chronic infections and is more likely to be smear positive with acid-fast bacilli. A lymphocyte-predominant pleocytosis in the CSF occurs in most patients except early in disease when polymorphonuclear cells may be predominant. Elevated protein in the range of 100 to
Johnson: Current Therapy in Neurologic Disease (7/E)

Tuberculous Meningitis
Yukari Manabe, M.D.

Tuberculosis (TB) is a global infectious disease problem with an estimated 8 million new cases yearly and 2 million deaths. Coinfection with human immunodeficiency virus (HIV) has compounded the problem, causing increasing incidence rates in areas where rates were previously decreasing due to better treatment control strategies. Tuberculous meningitis (TM) remains a dreaded manifestation of TB infection because it is often difficult to diagnose, requires a long course of therapy, and is associated with significant morbidity and mortality despite antituberculous chemotherapy.

158

Tuberculous Meningitis

respiratory transmission, so contacts need prophylaxis of rifampin 10 mg/kg every 12 hours for four doses. H. influenzae meningitis is treated with ceftriaxone, 2 gm every 12 hours IV, or cefotaxime, 3 gm every 6 hours IV. Alternatively, ampicillin plus chloramphenicol, 12.5 mg/kg every 8 hours IV) can be considered, depending on sensitivities of the organism. Staphylococcus meningitis is treated with vancomycin, 1 gm every 12 hours IV, until sensitivities are known. Dose adjustment is based on monitoring of levels in the blood. If methicillin susceptible, nafcillin, 2 gm every 4 hours IV, can be used. Gram-negative bacteria (Klebsiella, Escherichia coli, Proteus sp.) usually are associated with systemic bacteremia causing the meningitis. Treatment is guided by sensitivities and is somewhat organism dependent. Usual initial treatment is cefepime 2 gm every 8 hours. Meropenem, 2 gm every 8 hours IV; or aminoglycosides, 6 mg/kg every 8 hours IV, can be considered. For Pseudomonas sp., cefepime, 2 gm every 8 hours IV, should be the initial therapy. Ceftazidime, 2 gm every 8 hours IV, with an aminoglycoside (gentamicin, 6 mg/kg every 8 hours IV) can be considered as an alternative. For anaerobic bacteria (e.g., Bacteroides fragilis), metronidazole, 500 mg every 6 hours IV, should be used. Clindamycin has poor spinal fluid penetration with an intact blood-brain barrier. Listeria monocytogenes meningitis is treated with ampicillin, 2 gm every 4 hours IV, with or without an aminoglycoside for 14 to 21 days. IV sulfamethoxazoletrimethoprim is used for those who are penicillin allergic. L. monocytogenes meningitis often occurs in the elderly, in transplant patients, and in those with liver disease or alcoholism. Brainstem encephalitis has also been described associated with Listeria meningitis.

Diagnosis
Identification of cases is the first challenge because early-stage TM is protean in its manifestations and lacks pathognomonic physical examination and laboratory findings (Figure 1). Depending on the stage of disease, the most common signs and symptoms include fever, headache, changes in mentation, and meningismus in most patients. Other signs include focal neurologic deficits such as cranial nerve palsies, paresis, seizures, and diminished cognition. Symptoms indistinguishable from acute pyogenic meningitis have also been described, although most patients with TM have a prolonged prodromal period (>7 days). The diagnosis of TM should be considered in any patient with subacute meningitis. Even when antituberculous medications are administered, morbidity and mortality are very high, especially with late-stage disease, so after reasonable efforts to make a diagnosis are made, empirical treatment may be warranted. Epidemiologic links to a case of active TB may be helpful but are absent in most cases. High-risk groups include the human immunodeficiency virus (HIV)-infected, injection drug users, alcoholics, and some racial groups (African American and Native American). Patients are divided into three stages based on the examination at presentation. Stage I disease is characterized by lucid patients with fever, malaise, headache, and possibly meningismus. Stage II patients often have single cranial nerve impairment due to basilar disease, paresis, and focal seizures. Hyperactive deep tendon reflexes, worsening headache, and impaired cognitive capacity are often seen. Stage III patients are comatose or stuporous and have marked neurologic impairment, including multiple cranial nerve palsies, hemiparesis, or paraplegia. Hydrocephalus is common. This stage of disease has a high rate of neurologic sequelae (30%) or death (30%) despite antibiotic therapy. Tuberculin skin testing (PPD) is positive in only 31% to 64% of patients with known TM. Chest radiography and chest computed tomographic (CT) scan may provide adjunctive clues, with 30% to 74% of patients having an abnormal study with evidence of miliary or focal tuberculous disease. Nonspecific laboratory tests, such as elevated sedimentation rate, peripheral leukocytosis, anemia, and thrombocytosis, occur as a result of subacute or chronic inflammation and are common in all granulomatous diseases. Mild to moderate hyponatremia may be seen in some patients as a result of the syndrome of inappropriate antidiuretic hormone secretion. Examination of the cerebrospinal fluid (CSF) is the most helpful diagnostic procedure, with larger volumes of CSF (>5 mL) often leading to higher microbiologic yields for smear and culture. The possibility of high opening pressures and noncommunicating hydrocephalus should be highlighted because herniation is a distinct danger in these settings. The CSF may be turbid with more chronic infections and is more likely to be smear positive with acid-fast bacilli. A lymphocyte-predominant pleocytosis in the CSF occurs in most patients except early in disease when polymorphonuclear cells may be predominant. Elevated protein in the range of 100 to
Johnson: Current Therapy in Neurologic Disease (7/E)

Tuberculous Meningitis
Yukari Manabe, M.D.

Tuberculosis (TB) is a global infectious disease problem with an estimated 8 million new cases yearly and 2 million deaths. Coinfection with human immunodeficiency virus (HIV) has compounded the problem, causing increasing incidence rates in areas where rates were previously decreasing due to better treatment control strategies. Tuberculous meningitis (TM) remains a dreaded manifestation of TB infection because it is often difficult to diagnose, requires a long course of therapy, and is associated with significant morbidity and mortality despite antituberculous chemotherapy.

Tuberculous Meningitis

159
Nonviral Infectious Disease

FIGURE 1. Diagnostic work-up for tuberculous meningitis. PE, Physical examination; HA, headache; CN, cranial nerve; ESR, erythrocyte sedimentation rate; SIADH, syndrome of inappropriate antidiuretic hormone; CXR, chest radiograph; PPD, purified protein derivative; CSF, cerebrospinal fluid; Cx, culture; PCR, polymerase chain reaction; M. tb., Mycobacterium tuberculosis; AFB, acid-fast bacillus.

Suspect tuberculous meningitis

Diagnostic work-up: 1) History prodrome > 7 days, fever, HA, meningismus 2) PE focal neurologic deficits (CN palsies, paresis, seizures, diminished cognition) 3) Labs leukocytosis, anemia, ESR, hyponatremia 2 SIADH, albumin, plts 4) CXR/chest CT abnormal 3074% of time 5) Sputum smear and Cx (or gastric aspirate) 6) PPD skin test

Consider screening head CT to rule out hydrocephalus prior to lumbar puncture

Lumbar puncture: CSF acid-fast bacilli smear and Cx protein (100500 mg/dL), glucose, lymphocyte-predominant pleocytosis (>50% lymphs)

Negative/ low suspicion

Positive/ high suspicion

7
Consider brain MRIsuperior to brain CT for examining basilar area for meningeal enhancement, tuberculoma CSF PCR for M. tb suffers from poor sensitivity, but has high specificity; result is likely to be positive Multiple high-volume (5 mL) CSF samples may increase yield for organism Treat (see Figure 2)

Await cultures

Adjust treatment based on sensitivities

In enigmatic patients consider meningeal biopsy in inflamed areas for culture and histology, AFB stain.

500 mg/dL is most common, although up to one fourth of patients may have a CSF protein concentration of less than 100 mg/dL. Rare cases of protein levels higher than 1000 mg/dL have been reported, especially in those with a noncommunicating hydrocephalus or longstanding inflammatory disease. Low CSF glucose level is seen in 43% to 88% of patients. The gold standard for diagnosing TM remains CSF acid-fast bacilli smear and subsequent culture. Multiple high-volume samples may increase the yield, but treatment should not be withheld if large volumes cannot be obtained. CT and magnetic resonance imaging of the brain may provide important adjunctive information about hydrocephalus, tuberculomas, and basilar meningeal enhancement and can help rule out other differential diagnostic possibilities. CSF polymerase chain reaction (PCR) may be helpful especially in smear-positive disease. In general, however, CSF PCR assay is specific, and positive results are likely to be real cases. False-negative results occur even in true cases of TM secondary to low bacillary numbers and PCR inhibitors in the CSF. Therefore, sensitivity varies widely and PCR assay cannot be used as a screening tool.
Johnson: Current Therapy in Neurologic Disease (7/E)

For particularly enigmatic patients, meningeal biopsy may be helpful in diagnosing TM. Specimens should be sent for culture and histopathology to look for caseating granulomas and acid-fast bacilli.

Treatment
Treatment for TM should be initiated with four antituberculous drugs because the drug levels achieved in CSF may be marginally adequate (Figure 2). Unlike the treatment of pulmonary TB, daily dosing for the duration of the course is recommended. The only drug with documented CSF penetration and clinical efficacy is isoniazid; it should be the cornerstone of any regimen for TM. A dose of 5 mg/kg daily with a 300 mg maximum daily dose is recommended, although rapid acetylators may benefit from increased doses of 10 to 15 mg/ kg/day with TM. The risk for liver toxicity increases with increasing dose and therefore high-dose therapy is not recommended for patients with underlying liver disease. Rifampin has poor CSF penetration but is an

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Tuberculous meningitis

FIGURE 2. Treatment of tuberculous meningitis (TM). ICP, Intracranial pressure; CSF, cerebrospinal fluid; LFT, liver function test; TB, tuberculosis; MDR-TB, multidrug-resistant tuberculosis; h/o, history of. Stage III: comatose, multiple cranial nerve palsies, hemiplegia, hydrocephalus, ICP

Stage I: fever, headache, meningismus, malaise, prodrome > 3 weeks, conscious, rational

Stage II: single cranial nerve impairment, paresis, focal seizures, impaired cognition, fever

Culture and susceptibilitiesCSF and sputum (if possible)

If PANSENSITIVE: 4 drug therapy INH mainstay of Rx 510 mg/kg/day 300 mg/day Rifampin poor penetration, 10 mg/kg/day 600 mg/day Pyrazinamide 25 mg/kg/day for 2 months (max 2 gm), 15 mg/kg/day (max 1.5 gm) + Ethambutol 1525 mg/kg/day (standard) OR Streptomycin IM 2535 mg/kg 3x/wk max 1.5 gm (alternative) OR Ethionamide 1015 mg/kg/day (alternative in pediatric patients) If DRUG-RESISTANT: INH 10 mg/kg/day + 3 other drugs Tailor treatment based on sensitivities; if limited choices, consider increasing dose of INH to 20 mg/kg/day; monitor LFTs closely; consider addition of a fluoroquinolone such as moxifloxacin Daily directly observed therapy is standard for 12 month minimum goal (can decrease to 9 months if toxicity is an issue and patient improved). May need to extend for as long as 1824 months.

Stage II and Stage III disease: Add corticosteroids to decrease IC pressure and as adjunctive therapy. Dexamethasone 812 mg/day OR prednisone 1 mg/kg/day for 48 weeks, then taper over 34 weeks. If clinical worsening, go back up to lowest asymptomatic dose. If h/o treatment for TB (inadequate), at high risk for MDR-TB, or documented MDR-TB with no clinical improvement on oral medications, considering broadening coverage. Anecdotal reports of intrathecal amikacin/ levofloxacin in MDR-TB case with progression of TM, despite improvement in other areas.

important sterilizing drug in pulmonary TB and is recommended as part of the regimen. A dose of 10 mg/kg with a maximum daily dose of 600 mg is recommended although up to 750 mg daily may be used for TM. Liver function tests should be monitored closely because the risk for jaundice increases at the higher doses. Pyrazinamide is recommended in TM because it has good CSF penetration even in the absence of inflammation and is also an important sterilizing drug in pulmonary TB. Doses of 25 mg/kg/day are recommended for the first 2 months of therapy to a maximum dose of 2 gm, then 15 mg/kg/day for the duration of therapy. Ethambutol 25 mg/kg/day has some CSF penetration and is the least toxic fourth drug to add to the regimen but is static and has no proven efficacy with TM. Optic neuritis is its most worrisome side effect, and ethionamide 10 to 15 mg/kg/day may be a better choice in children, in whom it is difficult to monitor for the presence of color discrimination. Streptomycin is also a reasonable alternative for a fourth drug because it has

been used successfully in the past as monotherapy. Intramuscular streptomycin given three times per week at 22 mg/kg appears to be associated with less frequent cranial nerve VIII nerve toxicity. If a patient has a history of inadequate treatment for TB, epidemiologic links to a multidrug-resistant (MDR) TB case, or hails from an area with high rates of MDR-TB, consider broadening coverage to include a fluoroquinolone. If microbiologic failure is evident or progression of TM occurs in the face of treatment, intrathecal amikacin and levofloxacin have been used. For patients with MDR-TB, therapy must be tailored to the susceptibilities of the organism. The addition of other active drugs to an isoniazid-based regimen may not be unreasonable because the population may not be clonal, and isoniazid has the most documented clinical efficacy. Treatment should be continued for at least 12 months. For patients who are unable to take medications orally or by nasogastric tube, isoniazid, rifampin, and streptomycin are available parenterally, as is moxifloxacin.
Johnson: Current Therapy in Neurologic Disease (7/E)

Fungal Infections

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Nonviral Infectious Disease

In patients with stage II or III disease, dexamethasone 8 to 12 mg/day or prednisone 1 mg/kg/day should be given for 4 to 8 weeks followed by a slow taper over 3 to 4 weeks. If symptomatic worsening occurs, the steroid dose should be increased to the lowest dose used before worsening, with treatment for an additional 3 to 4 weeks before attempting to taper the steroid dose again. SUGGESTED READING
Dooley DP, Carpenter JL, Rademacher S: Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature, Clin Infect Dis 25:872-887, 1997. Iseman M: A clinicians guide to tuberculosis, Philadelphia, 2000, Lippincott Williams & Wilkins. Manabe YC, Chaisson RE: Tuberculosis. In Asbury AK, McDonald WI, McArthur JC, et al, editors: Diseases of the nervous system, New York, 2001, Cambridge University Press.

Fungal Infections
Larry E. Davis, M.D., and Beth S. Porter, M.D., Ph.D.

Aspergillus sp., and Candida sp., can invade cerebral blood vessels, causing an arteritis that can thrombose or rarely, rupture. Most pathogenic fungi are dimorphic. Depending on growth conditions, they may be in the yeast phase (unicellular and round with reproduction by budding or fission) or in a filamentous or mold phase (hyphae that grow by extension and produce spores). In general, fungi found in the meninges and CSF are in the yeast phase, whereas those found in the brain parenchyma are in the filamentous phase. Fungi that cause CNS infections can be classified as primary or secondary pathogens. Primary pathogens are fungi that occasionally cause disease in healthy individuals. The most common primary pathogen, Cryptococcus neoformans, accounts for more than half of all CNS fungal infections. Other important primary pathogens include Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis. In the setting of immunosuppression, the incidence of primary CNS fungal pathogens is markedly increased. Secondary fungal pathogens are opportunistic fungi that cause CNS infection in the setting of obvious immune dysfunction or anatomic abnormalities. Major secondary pathogens include Aspergillus sp., Zygomycetes sp. (mucormycosis), and Candida sp., but numerous other species rarely cause CNS infections, such as Fusarium and Scedosporium.

Although fungal infections of the central nervous system (CNS) remain uncommon, their incidence has increased primarily due to increased prevalence of immunosuppression (from acquired immunodeficiency syndrome [AIDS], transplants, corticosteroids, and chemotherapy). Accordingly, a fungal infection should be in the differential diagnosis for all patients with subacute or chronic meningitis, particularly the immunocompromised patient (Table 1). Of the more than 100,000 species of fungi, most are nonpathogenic for healthy humans or cause only a short-lived infection. Only a handful regularly cause CNS infections. Fungal spores enter the body mainly from inhalation and are small enough in particle size to reach the lungs to create a localized infection. The infection usually is asymptomatic or causes vague, brief pulmonary symptoms. Less common routes of initial fungal infection are from a skin puncture wound, chronic sinusitis, wounds, indwelling catheters, and fungal overgrowth from prolonged administration of systemic antibiotics. CNS fungal infections usually result from a systemic fungal infection elsewhere in the body leading to a fungemia that successfully invades the meninges or brain parenchyma. Most pathogenic fungi cause meningitis, but some fungi cause meningoencephalitis (meningitis with microabscesses) or localized brain abscesses. Fungi that invade the brain can produce an abscess with a necrotic center surrounded by a fibrous capsule or an intense inflammatory reaction that forms a granuloma. The organisms of Zygomycetes sp.,
Johnson: Current Therapy in Neurologic Disease (7/E)

Clinical Presentations
SUBACUTE MENINGITIS Meningitis is the most common presentation of CNS fungal disease but lacks specific characteristics that distinguish it from other types of subacute meningitis, such as tuberculous meningitis. Individuals typically present with a 1- to 3-week history of meningeal signs (low-grade fever and progressive lethargy, malaise, nausea, headache, stiff neck, and mental status changes). If the patient has AIDS or another form of immunosuppression, presenting signs may be only confusion and fever without headache or nuchal rigidity. As the fungal meningitis progresses, meningoencephalitis often develops with additional signs and symptoms that may include (1) stupor, nausea and vomiting, dizziness, diplopia, and papilledema from increased intracranial pressure; (2) diplopia, facial numbness or weakness, dysarthria, dysphagia, and hearing loss from trapping of cranial nerves by the basilar meningitis; and (3) hemiparesis, aphasia, visual loss, and cerebellar ataxia from cerebral infarctions due to meningeal vessel thrombosis or from localized brain damage from a fungal abscess/granuloma. BRAIN PARENCHYMAL INFECTION Patients with brain parenchymal infection develop an invasive fungal infection of the brain that manifests as an abscess, granuloma, or angioinvasion leading to vessel thrombosis or rarely rupture. CNS symptoms are based on the location of the involved brain. Common presenting

Fungal Infections

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Nonviral Infectious Disease

In patients with stage II or III disease, dexamethasone 8 to 12 mg/day or prednisone 1 mg/kg/day should be given for 4 to 8 weeks followed by a slow taper over 3 to 4 weeks. If symptomatic worsening occurs, the steroid dose should be increased to the lowest dose used before worsening, with treatment for an additional 3 to 4 weeks before attempting to taper the steroid dose again. SUGGESTED READING
Dooley DP, Carpenter JL, Rademacher S: Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature, Clin Infect Dis 25:872-887, 1997. Iseman M: A clinicians guide to tuberculosis, Philadelphia, 2000, Lippincott Williams & Wilkins. Manabe YC, Chaisson RE: Tuberculosis. In Asbury AK, McDonald WI, McArthur JC, et al, editors: Diseases of the nervous system, New York, 2001, Cambridge University Press.

Fungal Infections
Larry E. Davis, M.D., and Beth S. Porter, M.D., Ph.D.

Aspergillus sp., and Candida sp., can invade cerebral blood vessels, causing an arteritis that can thrombose or rarely, rupture. Most pathogenic fungi are dimorphic. Depending on growth conditions, they may be in the yeast phase (unicellular and round with reproduction by budding or fission) or in a filamentous or mold phase (hyphae that grow by extension and produce spores). In general, fungi found in the meninges and CSF are in the yeast phase, whereas those found in the brain parenchyma are in the filamentous phase. Fungi that cause CNS infections can be classified as primary or secondary pathogens. Primary pathogens are fungi that occasionally cause disease in healthy individuals. The most common primary pathogen, Cryptococcus neoformans, accounts for more than half of all CNS fungal infections. Other important primary pathogens include Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis. In the setting of immunosuppression, the incidence of primary CNS fungal pathogens is markedly increased. Secondary fungal pathogens are opportunistic fungi that cause CNS infection in the setting of obvious immune dysfunction or anatomic abnormalities. Major secondary pathogens include Aspergillus sp., Zygomycetes sp. (mucormycosis), and Candida sp., but numerous other species rarely cause CNS infections, such as Fusarium and Scedosporium.

Although fungal