The Encyclopedia of Neuropsychological Disorders 9780826198549, 9780826198556

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Neuropsychological Disorders

Noggle Dean Horton

The Encyclopedia of

Chad A. Noggle, PhD Raymond S. Dean, PhD, ABPP, ABPN Arthur MacNeill Horton Jr., EdD, ABPP, ABPN

his book serves as an A to Z reference that addresses the neuropsychological aspects of nearly 300 neurological disorders. Each entry contains 5 sections that cover (1) essential features of the disorder, (2) physiological basis of the disorder, (3) clinical presentation, (4) neuropsychological assessment and differential diagnosis, and (5) evidence-based treatments and interventions. This book is written for clinical professionals to help increase accurate diagnoses and successful interventions. This reference goes beyond the emotional and behavioral aspects of each disorder and views the broader impacts of the symptoms. This approach emphasizes the importance of looking at the other functional impacts of these manifestations, including cognitive deficits. The emphasis on neuropsychological assessment and treatment of disorders as well as the inclusion of conditions that occur across the lifespan makes this the most comprehensive resource available to clinical neuropsychologists, psychologists, neurologists, and other health professionals.

Key Features:

• Presents nearly 300 conveniently structured entries providing the description,



pathophysiology, neuropsychological presentation, diagnosis, and treatment of each disorder

• Covers neurological disorders across the lifespan (pediatric, adult, and geriatric



populations)

• Includes valuable, hard-to-find information on syndromes that most clinicians may

not frequently encounter, in addition to coverage of the most commonly occurring disorders

Chad A. Noggle, PhD, is a licensed psychologist in both Illinois and Indiana and is an Assistant Professor of Clinical Psychiatry at Southern Illinois University School of Medicine. Raymond S. Dean, PhD, ABPP, ABPN, is currently the George and Frances Ball Distinguished Professor of Neuropsychology and Director of the Neuropsychology Laboratory at Ball State University. Arthur MacNeill Horton Jr., EdD, ABPP, ABPN, is in independent practice as Director of the Neuropsychology Section at Psych Associates of Maryland. ISBN 978-0-8261-9854-9

The Encyclopedia of

T

Neuropsychological Disorders

Editors

The Encyclopedia of

Neuropsychological Disorders

Editors Chad A. Noggle Raymond S. Dean Arthur MacNeill Horton Jr.

11 W. 42nd Street New York, NY 10036-8002 www.springerpub.com

9 780826 198549

The Encyclopedia of

NEUROPSYCHOLOGICAL DISORDERS

CHAD A. NOGGLE, PHD, is Assistant Professor of Clinical Psychiatry and Chief of the Division of Behavioral and Psychosocial Oncology at Southern Illinois University-School of Medicine. He previously served as an Assistant Professor at both Ball State University and Middle Tennessee State University. Dr. Noggle holds a BA in Psychology from the University of Illinois at Springfield and completed his MA and PhD at Ball State University in School Psychology with specialization in Clinical Neuropsychology. He completed a 2-year post-doctoral residency at the Indiana Neuroscience Institute at St. Vincent’s Hospital with specialization in Pediatric and Adult/Geriatric Neuropsychology. To date, Dr. Noggle has published more than 250 articles, book chapters, encyclopedia entries, and research abstracts, and has made over 80 presentations at national and international conferences in neuropsychology. He currently serves as a reviewer for a number of neuropsychology journals. Dr. Noggle is a member of the American Psychological Association (Divisions 5, 16, 22, 38, 40), National Academy of Neuropsychology, and International Neuropsychological Society. He is a licensed Psychologist in both Illinois and Indiana. His research interests focus on both adult and pediatric populations, spanning psychiatric illnesses, dementia, PDDs, and neuromedical disorders. He has particular interest in the neuropsychological consequences of cancer and its treatment in both adults and children. RAYMOND S. DEAN, PHD, ABPP, ABPN, holds a BA degree in Psychology (Magna cum laude) and an MS degree in Research and Psychometrics from the State University of New York at Albany. As a Parachek-Frazier Research Fellow, he completed a PhD in School/Child Clinical Psychology at Arizona State University in 1978. Dr. Dean completed an internship focused on neuropsychology at the Arizona Neurophychiatric Hospital and post-doctoral work at the University of Wisconsin at Madison. From 1978–1980, Dr. Dean was Assistant Professor and Director of the Child Clinic at the University of Wisconsin at Madison. During this time he was awarded the Lightner Witmer Award by the School Psychology Division of the American Psychological Association. From 1980–1981, he served as Assistant Professor of Psychological Services at the University of North Carolina at Chapel Hill. From 1981–1984, Dr. Dean served as Assistant Professor of Medical Psychology and Director of the Neuropsychology Internship at Washington University School of Medicine in St. Louis. During this time, Dr. Dean received both the Outstanding Contribution Award from the National Academy of Neuropsychology and the Early Contribution Award by Division 15 of the APA. He was named the George and Frances Ball Distinguished Professor of Neuropsychology and Director of the Neuropsychology Laboratory at Ball State University and has served in this position since 1984. In addition, Dr. Dean served as Distinguished Visiting Faculty at the Staff College of the NIMH. Dr. Dean is a Diplomate of the American Board of Professional Psychology, the American Board of Professional Neuropsychology, and the American Board of Pediatric Neuropsychology. He is a Fellow of the American Psychological Association (Divisions Clinical, Educational, School and Clinical Neuropsyhology), the National Academy of Neuropsychology, and the American Psychopathological Association. Dr. Dean is a past president of the Clinical Neuropsychology Division of the American Psychological Association and the National Academy of Neuropsychology. He also served as editor of the Archives of Clinical Neuropsychology, Journal of School Psychology, and the Bulletin of the National Academy of Neuropsychology. Dr. Dean has published some 600 research articles, books, chapters, and tests. For his work he has been recognized by awards from the National Academy of Neuropsychology, the Journal of School Psychology, and the Clinical Neuropsychology Division of the American Psychological Association. ARTHUR MACNEILL HORTON JR., EDD, ABPP, ABPN, received his EdD degree in Counselor Education from the University of Virginia in 1976. He also holds Diplomates in Clinical Psychology and Behavioral Psychology from the American Board of Professional Psychology and in Neuropsychology from the American Board of Professional Neuropsychology. Dr. Horton is the author/editor of over 15 books, more than 30 book chapters, and over 150 journal articles. He also coauthored (with Cecil Reynolds, PhD) The Test of Verbal Conceptualization and Fluency, a measure of executive functioning in children, adults, and the elderly. He is past president of the American Board of Professional Neuropsychology, a doctoral-level certification board in neuropsychology, the Coalition of Clinical Practitioners in Neuropsychology, the National Academy of Neuropsychology, and the Maryland Psychological Association. In addition, Dr. Horton was a member of the State of Maryland Board of Examiners of Psychologists for two terms. Dr. Horton is a Fellow of the American Psychological Association (Divisions 6, 42, 50 and 56). Previously, Dr. Horton was a Program Officer with the National Institute of Drug Abuse and National Institutes of Health, with responsibilities for neuropsychology. He has taught at the University of Virginia, The Citadel, West Virginia University, Johns Hopkins University, The University of Baltimore, Loyola College in Maryland, the Department of Psychiatry of the University of Maryland School of Medicine, and the Fielding University Graduate Program in Neuropsychology. Currently, Dr. Horton is in independent practice as Director of the Neuropsychology Section at Psych Associates of Maryland and Editor-in-Chief of Applied Neuropsychology. Dr. Horton also consults on neuropsychology and drug abuse research issues.

The Encyclopedia of

NEUROPSYCHOLOGICAL DISORDERS Edited by

Chad A. Noggle, PhD Raymond S. Dean, PhD, ABPP, ABPN Arthur MacNeill Horton Jr., EdD, ABPP, ABPN

Copyright # 2012 Springer Publishing Company, LLC All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Springer Publishing Company, LLC, or authorization through payment of the appropriate fees to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400, fax 978-646-8600, [email protected] or on the Web at www.copyright.com. Springer Publishing Company, LLC 11 West 42nd Street New York, NY 10036 www.springerpub.com Acquisitions Editor: Nancy Hale Composition: S4Carlisle Publishing Services ISBN: 978-0-8261-9854-9 E-book ISBN: 9780826198556 11 12 13/ 5 4 3 2 1 The authors and the publisher of this Work have made every effort to use sources believed to be reliable to provide information that is accurate and compatible with the standards generally accepted at the time of publication. The authors and publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance on, the information contained in this book. The publisher has no responsibility for the persistence or accuracy of URLs for external or third-party Internet Web sites referred to in this publication and does not guarantee that any content on such Web sites is, or will remain, accurate or appropriate. Cataloging-in-Publication Data is available from the Library of Congress.

Special discounts on bulk quantities of our books are available to corporations, professional associations, pharmaceutical companies, health care organizations, and other qualifying groups. If you are interested in a custom book, including chapters from more than one of our titles, we can provide that service as well. For details, please contact: Special Sales Department, Springer Publishing Company, LLC 11 West 42nd Street, 15th Floor, New York, NY 10036-8002s Phone: 877-687-7476 or 212-431-4370; Fax: 212-941-7842 Email: [email protected] Printed in the United States of America by Bang Printing.

To my wife and children for your love and support: You are my everything. To my parents, for your encouragement and many life lessons, among them the importance of hard work. CAN

I dedicate this book to my three daughters, Sarah, Whitney, and Heather. RSD

To my wife Mary, with all of my love. AMH

EDITORIAL BOARD

Mark T. Barisa, PhD Shane Bush, PhD Valeria Drago, MD Paul Foster, PhD Charles Golden, PhD Gerald Goldstein, PhD Wm. Drew Gouvier, PhD Mary E. Haines, PhD Javan Horwitz, PsyD Teri McHale, PhD Michelle Pagoria, PsyD Antonio E. Puente, PhD Henry Soper, PhD Melissa M. Swanson, PhD Timothy F. Wynkoop, PhD

CONTENTS

Preface

ix

Contributors

xi

List of Entries

xix

Acknowledgments

xxv

Entries A–Z Index

1–778 779

PREFACE

The Encyclopedia of Neuropsychological Disorders was created as a reference manual of disorders that have a biological-psychological interaction. In many ways the title of this text can be seen as a misnomer. As professionals, we speak of neurological disorders and psychiatric disorders, but the concept of neuropsychological disorders is not readily used by the medical and psychological professions. The book makes this distinction in the discussion of the potential neuropsychological sequelae for an array of recognized neurological, psychiatric, as well as other medical disorders. As such, the book provides firm bases for numerous health care professionals to better understand and treat neurological, psychiatric, and neuromedical patients.While the book offers a wide array of disorders, the crux of the discussion is directed toward the fields of neuropsychology, neuropsychiatry, and behavioral neurology. Indeed, what we know of the functioning of normal and diseased brains has grown more in the last four decades than any other time in history. And, because there is an increased appreciation of the potential impact on the central nervous system by various unsuspected disorders, the variety of presentations now seen by

clinicians in the neurosciences is steadily expanding. Along with this knowledge comes vast improvements in the approaches to diagnosis and treatment by professionals across a wider band of specialties. As a consequence, there is need for a concise and synthesized discussion of the presenting features of recognized disorders. With this in mind specifically, we sought to create a reference work in which individual disorders are discussed with the fields of neuropsychology, neuropsychiatry, and neurology in mind, covering those domains of clinical relevance with emphasis placed on empirically based information. The internet can be a powerful tool, but in many ways it can be difficult to determine the reliability of that information. Thus, empirical backing of the information shared was of greatest importance. The product is designed to be useful to both veteran clinicians as well students in training. In all, the text includes a structured coverage of the clinical and neuropsychological features, neuropathological/pathophysiological correlates, diagnostic considerations, and methods of treatment for nearly 300 recognized disorders and diseases across the lifespan.

CONTRIBUTORS

J. Aaron Albritton, BA Research Assistant Functional Neurosurgery Laboratory Vanderbilt University Nashville, TN Ana Arenivas, MS Doctoral Student University of Texas Southwestern Dallas, TX Amanda Ballenger, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN Mark T. Barisa, PhD, ABPP-CN Clinical Neuropsychologist Department of Neuropsychology Baylor Institute for Rehabilitation Dallas, TX Alyse Barker, MA Doctoral Candidate Department of Psychology Louisiana State University Baton Rouge, LA Jeffrey T. Barth, PhD, ABPP-CN John Edward Fowler Professor Neurocognitive Assessment Laboratory Department of Psychiatry and Neurobehavioral Sciences University of Virginia School of Medicine Charlottesville, VA Audrey Baumeister, PhD Clinical Psychologist NeuroBehavioral Institute Weston, Florida

Melanie Blahnik, PsyD Clinical Psychologist Department of Physical Medicine and Rehabilitation Minneapolis Veterans Affairs Medical Center Minneapolis, MN Tonya M. Bennett, MS Graduate Student Department of Psychology Fielding Gradute University Santa Barbara, CA Ryan Boddy, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Josie Bolanos, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Justin J. Boseck, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN W. Howard Buddin Jr., MS Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL

xii & CONTRIBUTORS

Shane S. Bush, PhD, ABPP, ABN Clinical Neuropsychologist Long Island Neuropsychology, PC Lake Ronkonkoma, NY Department of Psychology VA New York Harbor Healthcare System St. Albans, NY Mei Chang, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN Sarah C. Connolly, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN Christine Corsun-Ascher, PsyD Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Nicole Cruz, PhD Instructor of Clinical Neurology Department of Neurology Washington University School of Medicine Department of Psychology St. Louis Children’s Hospital St. Louis, MO George M. Cuesta, PhD Supervisory Psychologist and Team Leader Department of Veterans Affairs Veterans Health Administration Readjustment Counseling Service New York, NY Clinical Assistant Professor of Neuropsychology Department of Neurology and Neuroscience Weill Medical College of Cornell University New York, NY Danielle S. Dance, MS Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Andrew S. Davis, PhD, HSPP Associate Professor of Psychology, Director of Doctoral Internships Department of Educational Psychology Ball State University Muncie, IN

Jeremy Davis, PsyD School of Psychological Sciences University of Indianapolis Indianapolis, IN Raymond S. Dean, PhD, ABPP, ABN, ABPdN George and Frances Ball Distinguished Professor of Neuropsychology Department of Educational Psychology Ball State University Muncie, IN Brenda Deliz-Rolda´n, MD Neurologist-Neuromuscular Specialist University of Puerto Rico Medical School San Juan, Puerto Rico Angela Dortch, BA, MA Graduate Student Department of Educational Psychology Ball State University Muncie, IN Maryellen C. Dougherty, MA Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Valeria Drago, MD, PhD Neurologist Services of Neurology and Rehabilitation ASP Siracusa Siracusa, Italy Adjunct Assistant Professor Department of Neurology University of Florida Gainesville, FL Rebecca Durkin, MD Department of Psychiatry Rush University Medical Center Chicago, IL Jennifer N. Fiebig, PhD Instructor Department of Psychology Loyola University Chicago, IL Glen R. Finney, MD Assistant Professor Department of Neurology University of Florida Gainesville, FL

CONTRIBUTORS & xiii

Jessica Foley, PhD Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Paul S. Foster, PhD Associate Professor Department of Psychology Middle Tennessee State University Murfreesboro, TN Adjunct Assistant Professor Department of Neurology University of Florida Gainesville, FL Jason R. Freeman, PhD Associate Professor Neurocognitive Assessment Laboratory Department of Psychiatry and Neurobehavioral Sciences University of Virginia School of Medicine Charlottesville, VA Daniel L. Frisch, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Jessica Garcia, PhD Paralegal Studies Coordinator Nova Southeastern University Fort Lauderdale, FL Jacob M. Goings, BA Doctoral Student Educational Psychology and Counseling Department University of Tennessee Knoxville, TN Charles Golden, PhD, ABPP, ABN Professor and Director Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Amy J. Goldman, PT, DPT Physical Therapist-Stroke Program Manager Department of Physical Therapy Madonna Rehabilitation Hospital Lincoln, NE

Gerald Goldstein, PhD Senior Research Career Scientist, Mental Illness Research, Education, and Clinical Center VA Pittsburgh Healthcare System Clinical Professor of Psychiatry Department of Psychiatry University of Pittsburgh Pittsburgh, PA Javier Gontier, MA Department of Psychology Universidad del Desarrollo Concepciœn, Chile William Drew Gouvier, PhD Professor Department of Psychology Louisiana State University Baton Rouge, LA Peyton Groff, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN Mary E. Haines, PhD, ABPP-CN Clinical Neuropsychologist Clinical Associate Professor Departments of Physical Medicine and Rehabilitation and Psychiatry University of Toledo Medical Center Toledo, OH Vishnumurthy S. Hedna, MD Resident Department of Neurology University of Florida Gainesville, FL Margie Hernandez, BA Graduate Student Department of Psychology University of North Carolina-Wilmington Wilmington, NC Jeremy Hertza, PsyD Director of Behavioral Medicine Clinical Neuropsychologist Walton Rehabilitation Hospital Assistant Clinical Professor of Psychiatry and Health Behavior Medical College of Georgia Augusta, GA

xiv & CONTRIBUTORS

Daniel J. Heyanka, MA Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL

Gaurav Jain, MD Resident Department of Psychiatry Southern Illinois University-School of Medicine Springfield, IL

Lindsay J. Hines, MS Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL

Christina Weyer Jamora, PhD San Francisco General Hospital/UCSF School of Medicine San Francisco, CA

James B. Hoelzle, PhD Assistant Professor Department of Psychology Marquette University Milwaukee, WI Matth Holcombe, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN Jessica Holster, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL

Nick P. Jenkins, MD Internal Medicine St.Vincent Hospital Indianapolis, IN Sarah C. Jenkins Counseling and Guidance Services Ball State University Muncie, IN Velisa M. Johnson, MA Graduate Student Department of Psychology Fielding Graduate University Santa Barbara, CA Evan Koehn, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN

Javan Horwitz, PsyD Clinical Neuropsychologist Department of Extended Care and Rehabilitation VA Northern Indiana Healthcare System Marion, IN

Abhay Kumar, MD Resident Department of Neurology University of Florida Gainesville, FL

Natalie Horwitz, MA Private Practice Indianapolis, IN

Darla J. Lawson, PhD Pediatric Neuropsychology Department Pediatric Neurobehavioral Diagnostics Idaho Falls, ID

Haojing Huang, MD, PHD Assistant Professor of Clinical Psychiatry Department of Psychiatry Southern Illinois University - School of Medicine Springfield, IL

Gershom T. Lazarus, MA University of North Carolina Wilmington, NC

Kelly N. Hutchins, MS Private Practice Bakersfield, CA

Hannah Lindsey, BA Graduate Student Department of Psychology University of North Carolina-Wilmington Wilmington, NC

J. T. Hutton, MD, PhD University of North Carolina Wilmington, NC

Raquel Vilar Lo´pez, PhD Universidad de Granada Granada, Spain

CONTRIBUTORS & xv

Shira Louria, PsyD Resident Neuroscience Institute Long Island Jewish Medical Center Long Island, NY Courtney Lund, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN Jacob T. Lutz, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN Jennifer Mariner, PsyD, HSPP Clinical Psychologist Geriatrics and Extended Care Department of Psychiatry Richard L. Roudebush VA Medical Center Assistant Professor of Clinical Psychology Department of Clinical Psychiatry Indiana University School of Medicine Indianapolis, IN

Katherine Meredith, MS Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Department of Neuropsychology Baylor Institute for Rehabilitation Dallas, TX Kynan Eugene Metoyer, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Liza San Miguel-Montes, PsyD Clinical Neuropsychologist Neurology Section-Medicine University of Puerto Rico Medical School San Juan, Puerto Rico Kathryn M. Lombardi Mirra, MA Doctoral Student Department of Psychology Suffolk University Boston, MA

Alyssa M. Maulucci, PhD VA Medical Center Washington, DC

Ashleigh R. Molz, BS Doctoral Student Temple University Department of Psychology Philadelphia, PA

Anya Mazur-Mosiewicz, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN

Jessie L. Morrow, MS Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL

Kathryn McGuire, PhD Clinical Psychologist Department of Physical Medicine and Rehabilitation Minneapolis Veterans Affairs Medical Center Assistant Professor Department of Psychiatry University of Minnesota Minneapolis, MN

Monica O. Murray, EdS Graduate Student School of Psychology Fielding Graduate University Santa Barbara, CA

Teri J. McHale, PhD Psychological Assistant Developmental Neuropsychology Laboratory Ventura, CA Bay Psychiatric Medical Group Torrance, CA

Mandi Musso, BS Doctoral Candidate Department of Psychology Louisiana State University Baton Rouge, LA Mo´nica Muzquiz, MA University of North Carolina Wilmington, NC

xvi & CONTRIBUTORS

Thomas E. Myers, MS Doctoral Student Department of Psychology The Graduate Center and Queens College City University of New York Flushing, NY

Antonio E. Puente, PhD Clinical Neuropsychologist Professor Department of Psychology University of North Carolina, Wilmington Wilmington, NC

Chad A. Noggle, PhD Assistant Professor of Clinical Psychiatry Chief, Division of Behavioral and Psychosocial Oncology Department of Psychiatry Southern Illinois University-School of Medicine Springfield, IL

Antonio N. Puente, BA Graduate Student Department of Psychology University of Georgia Athens, GA

Kyle Noll, MA Doctoral Student University of Texas Southwestern Dallas, TX Anthony P. Odland, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Carlos Ojeda, MA Graduate Student Department of Psychology University of Arkansas Fayetteville, AR Michelle R. Pagoria, PsyD Clinical Neuropsychologist Director of Neuropsychology Benchmark Psychiatric Services, Ltd Orland Park, IL Lisa A. Pass, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN Kelly R. Pless, MS Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL

Sandra Santiago Ramajo, PhD Universidad de Granada Granada, Spain Donna Rasin-Waters, PhD VA New York Harbor Healthcare System Brooklyn, NY Luz M. Restrepo, BA Graduate Student Center for Pscyhological Studies Nova Southeastern University Fort Lauderdale, FL Jamie Rice, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Ann M. Richardson Attorney at Law California State Government Sacramento, CA David Ritchie, MA Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Jessi H. Robbins, MS Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL

Lena M. F. Prinzi, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL

Stephen Robinson, MD Assistant Professor of Clinical Psychiatry Director, Adult Inpatient Services Assistant Chair, Department of Psychiatry Southern Illinois University–School of Medicine Springfield, IL

Stephen E. Prover, MD Diplomate-American Board of Psychiatry and Neurology Bay Psychiatric Medical Group Torrance, CA

Rachel Rock, MA Department of Psychology The University of Alabama Tuscaloosa, AL

CONTRIBUTORS & xvii

Miriam Jocelyn Rodriguez, BA, MS Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL

Eric Silk, MA, MS Visiting Professor of Psychology Farquhar College of Arts and Sciences Nova Southeastern University Fort Lauderdale, FL

Ronald Ruff, PhD, ABPP Clinical Neuropsychologist Clinical Professor Department of Psychiatry University of California-San Francisco San Francisco, CA

Anita H. Sim, PhD Clinical Neuropsychologist Physical Medicine and Rehabilitation Minneapolis VA Medical Center Minneapolis, MN

Saralyn Ruff, MEd Doctoral Student Department of Human Development and Family Studies Purdue University West Lafayette, IN Daniela Rusovici, MD Neurologist Private Practice Palm Beach, FL Mark A. Sandberg, PhD Clinical Neuropsychologist Independent Practice Smithtown, NY J. Forrest Sanders, PsyD Neurocognitive Assessment Laboratory Department of Psychiatry and Neurobehavioral Sciences University of Virginia Health System Charlottesville, VA Stephanie Lei Santiso, MS Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL David M. Scarisbrick, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL

Melissa Singh, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN Sarita Singhal, MD Resident Department of Pediatrics Southern Illinois University-School of Medicine Springfield, IL Henry V. Soper, PhD Professor School of Psychology Fielding Graduate University Santa Barbara, CA Tara V. Spevack, PhD, ABPP Pediatric Neuropsychologist St. Louis Children’s Hospital Washington University Medical Center St. Louis, MO Susan Spicer, MA Doctoral Student School of Psychology Fielding Graduate University Santa Barbara, CA Amanda R. W. Steiner, PhD University of Virginia Department of Psychology Charlottesville, VA

Mindy Scheithauer, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN

Amy R. Steiner, PsyD, LP Clinical Neuropsychologist HealthPartners Neurology Center for Dementia and Alzheimer’s Care Minneapolis, MN

Brian Schmitt, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN

Andrea Stephen, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN

xviii & CONTRIBUTORS

Carol Swann, MA Doctoral Student School of Psychology Fielding Graduate University Santa Barbara, CA Melissa Swanson, PhD Clinical Neuropsychology Postdoctoral Fellow Department of Physical Medicine and Rehabilitation University of Toledo Medical Center Toledo, OH Lori S. Terryberry, SPOHR, PhD, ABPP Clinical Neuropsychologist Manager, Brain Injury Program Department of Neuropsychology Madonna Rehabilitation Hospital Lincoln, NE Jon C. Thompson, PsyD, HSPP Department of Neuropsychology St.Vincent Hospital Indianapolis, IN Erin L. Tireman, MS Doctoral Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Jeffrey B. Titus, PhD Department of Psychology St. Louis Children’s Hospital Assistant Professor of Clinical Neurology Department of Neurology Washington University School of Medicine St. Louis, MO Issac Tourgeman, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Beth Trammell, MA Doctoral Student Department of Educational Psychology Ball State University Muncie, IN Krista Puente Trefz, PsyD Licensed Psychologist Circles of Care Melbourne, FL

Chriscelyn Tussey, PsyD Clinical Neuropsychologist Director of Psychological Assessment Bellevue Hospital Center New York University School of Medicine New York, NY Sarah M. Viamonte, PhD, MSPH Clinical Neuropsychology Post-doctoral Fellow Department of Psychology Nebraska Medical Center Omaha, NE O. J. Vidal, MA University of North Carolina, Wilmington Wilmington, NC Jacqueline Remondet Wall, PhD, HSPP, CRC Director, Undergraduate Programs in Psychology Associate Professor School of Psychological Sciences University of Indianapolis Ashley Ware, BA University of North Carolina, Wilmington Wilmington, NC Sarah E. West, BA Graduate Student Center for Psychological Studies Nova Southeastern University Fort Lauderdale, FL Timothy F. Wynkoop, PhD, ABPP-CN Clinical/Forensic Neuropsychologist Private Practice, Maumee, OH Clinical Assistant Professor Department of Psychiatry University of Toledo Medical Center Toledo, OH Maya Yutsis, PhD Clinical Neuropsychology Post-Doctoral Fellow Mayo Clinic, Rochester, MN Amy E. Zimmerman, MA Doctoral Student Department of Educational Psychology Ball State University, Muncie, IN Sophia Zavrou, PsyD Morrison Child and Family Services Center Portland, OR

LIST

Miriam Jocelyn

Acute Disseminated Encephalomyelitis Rodriguez and Charles Golden

J. Aaron Albritton and Chad

Adrenoleukodystrophy A. Noggle

Gerald Goldstein and Ashleigh

Melissa M. Swanson and Timothy Ashleigh R. Molz and Gerald

Adult Refsum Disease Charles Golden

Kynan Eugene Metoyer and

Agenesis of the Corpus Callosum Javan Horwitz

Chad A. Noggle and

Valeria Drago and Paul S. Foster

Aicardi’s Syndrome Evan Koehn, Beth Trammell, and Raymond S. Dean Alexander’s Disease Alexias

Justin J. Boseck and Andrew S. Davis

Valeria Drago and Paul S. Foster

Alien Hand Syndrome M. Lombardi Mirra Alper’s Disease

Maryellen C. Dougherty and Charles Golden Miriam Jocelyn

Alzheimer’s Disease Tiffany L. Cummings, Frank M. Webbe, and Antonio E. Puente Amyotrophic Lateral Sclerosis McGuire Aneurysms

Melanie Blahnik and Kathryn

Audrey L. Baumeister and William Drew Gouvier Jamie Rice and Charles Golden

Antiphospholipid Antibody Syndrome and Charles Golden Aphasias

Paul S. Foster and Valeria

Asperger’s Syndrome Javier Gontier and Antonio E. Puente Sophia Zavrou and Jon C. Thompson

Attention Deficit Hyperactivity Disorder Margie Hernandez, Hannah Lindsey, and Antonio E. Puente Autism

Henry V. Soper and Monica O. Murray

Batten’s Disease

Luz M. Restrepo and Charles Golden

Behçet’s Disease

Amy E. Zimmerman and Chad A. Noggle

Michelle R. Pagoria and Chad A. Noggle Nicole Cruz and Jeffrey B. Titus

Benign Rolandic Epilepsy

Bernhardt-Roth Syndrome Javan Horwitz, Natalie Horwitz, and Chad A. Noggle Binswanger’s Disease Shane S. Bush and Kathryn M. Lombardi Mirra Lena M. F. Prinzi and Charles Golden

Bloch-Sulzberger Syndrome Golden

Daniel L. Frisch and Charles

Brain Tumors Chad A. Noggle and Raymond S. Dean Brown-Se´quard Syndrome Chad A. Noggle and Michelle Pagoria Canavan’s Disease

J. Aaron Albritton and Chad A. Noggle

Capgras’s Syndrome Causalgia

Mark T. Barisa

Daniel L. Frisch and Charles Golden

Central Cord Syndrome Darla J. Lawson

J. Aaron Albritton and Chad A. Noggle

Angelman Syndrome

Courtney Lund and Raymond S. Dean

Arteriovenous Malformations Drago

Blepharospasm

Shane S. Bush and Kathryn

Alternating Hemiplegia in Childhood Rodriguez and Charles Golden

Anencephaly

Audrey L. Baumeister and William Drew

Arachnoid Cysts Gouvier

Bell’s Palsy

Paul S. Foster and Valeria Drago

Agraphias

Katherine Meredith and Mark T. Barisa

Apraxia

Ataxia Telangiectasia

Adult Mood Disorders Goldstein

Agnosias

ENTRIES

Arachnoiditis

Adult Anxiety Disorders R. Molz Adult Criminality F. Wynkoop

OF

W. Howard Buddin

Valeria Drago and Paul S. Foster

Central Pontine Myelinolysis and Extrapontine Myelinolysis Chad A. Noggle and Jon C. Thompson Cerebellar Hypoplasia

Justin Boseck and Raymond S. Dean

Cerebral Anoxia/Hypoxia M. Viamonte Cerebral Arteriosclerosis

Anita H. Sim and Sarah Jessi Robbins and Charles Golden

xx & LIST OF ENTRIES

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy M. Maulucci and Jon C. Thompson Cerebral Cavernous Malformations Henry V. Soper

Teri J. McHale and

Cerebral Palsy Tara V. Spevack Cerebro-Oculo-Facio-Skeletal Syndrome Charles Golden

Josie Bolanos and

Cerebrovascular Accidents Sandra Santiago Ramajo, Raquel Vilar Lo´pez, and Antonio E. Puente Charçot-Marie-Tooth Disease Charles Golden

Stephanie Lei Santiso and

Jeremy Hertza and Andrew S. Davis

Chiari Malformations

Sarah E. West and Charles Golden

Dejerine–Klumpke Palsy Alyssa

Delirium

Angela Dortch and Raymond S. Dean Shane S. Bush and Thomas E. Myers

Dementia Pugilistica

Christine Corsun-Ascher and Charles

Dermatomyositis Golden

Disorders of Written Language Tonya M. Bennett, Teri J. McHale, and Henry V. Soper Down’s Syndrome Matthew Holcombe, Raymond S. Dean, and Chad A. Noggle Chad A. Noggle and Javan Horwitz

Dravet’s Syndrome Dysautonomia A. Noggle

Javan Horwitz, Natalie Horwitz, and Chad

Childhood Absence Epilepsy

Nicole Cruz and Jeffrey B. Titus

Dyssynergia Cerebellaris Myoclonica Charles Golden

Childhood Anxiety Disorders and Chad A. Noggle

Melissa Singh, Beth Trammell,

Dystonias

Childhood Mood Disorders A. Noggle

Sarah Connolly and Chad

Cholesteryl Ester Storage Disease

Darla J. Lawson

Chronic Inflammatory Demyelinating Polyneuropathy Shira Louria and Chad A. Noggle Courtney Lund and Raymond

Chronic Pain Syndrome S. Dean

Darla J. Lawson

Churg–Strauss Syndrome

Paul S. Foster and Valeria Drago

Cluster Headaches

Coffin–Lowry Syndrome Maryellen C. Dougherty and Charles Golden Colpocephaly Chad A. Noggle and Javan Horwitz Coma and Persisting Vegetative State Glen R. Finney, Abhay Kumar, and Vishnumurthy S. Hedna Conduct Disorder and Oppositional Defiant Disorder Timothy F. Wynkoop, Mary E. Haines, and Melissa M. Swanson Congenital and Childhood Myasthenias and Javan Horwitz

Javan Horwitz, Natalie Horwitz, and

Congenital Myopathy Chad A. Noggle

Creutzfeldt–Jakob’s Disease A. Noggle Cytomegalovirus

Anita H. Sim and Sarah

Ryan Boddy and Charles Golden

Cushing’s Syndrome

Michelle R. Pagoria and Chad

Anita H. Sim and Maya Yutsis

Chad A. Noggle

Dandy-Walker Malformation/Syndrome and Andrew S. Davis Dawson’s Disease

Haojing Huang Beth Trammell and Raymond S. Dean

Eating Disorders

Empty Sella Syndrome Darla J. Lawson Encephalitis Gouvier

Mandi Musso, Alyse Barker, and William Drew

Encephalocele Teri J. McHale, Henry V. Soper, and Velisa M. Johnson Teri J. McHale, Henry V. Soper, and Carol

Encephalopathy Swann

Chad A. Noggle and Raymond S. Dean

Epilepsy and Seizures

Erb’s Palsy Eric Silk and Charles Golden Fabry’s Disease (Anderson-Fabry Disease) P. Odland and Charles Golden

Jeremy Hertza

Danielle S. Dance and Charles Golden

de Morsier’s Syndrome

Jessica Garcia and Charles Golden

Anthony

Lisa A. Pass and Andrew S. Davis

Factitious Disorder

O. J. Vidal, J. T. Hutton, and Antonio

Factor V Leiden E. Puente

Amy E. Zimmerman and Chad A. Noggle

Fahr’s Syndrome

Familial Periodic Paralyses V. Soper

Teri J. McHale and Henry

Familial Spastic Paraplegia

Eric Silk and Charles Golden

Jeremy Davis and Chad A. Noggle

Farber’s Disease

Fatal Familial Insomnia

Corticobasal Degeneration M. Viamonte Craniosynostosis

Chad A. Noggle

Erin L. Tireman and

Febrile Seizures

Chad A. Noggle

Darla J. Lawson

Fetal Alcohol Syndrome S. Dean

Justin J. Boseck and Raymond

Fibromuscular Dysplasia

Chad A. Noggle and Javan Horwitz

Fragile X Syndrome Mirra

Shane S. Bush and Kathryn M. Lombardi

Friedreich’s Ataxia Sarah C. Jenkins, Nick P. Jenkins, and Jon C. Thompson Frontotemporal Dementia Gaucher’s Disease

Antonio N. Puente

Lindsay J. Hines and Charles Golden

Gerstmann’s Syndrome

Beth Trammell and Chad A. Noggle

LIST OF ENTRIES & xxi

Gerstmann–Stra¨ussler–Scheinker Disease Ballenger and Raymond S. Dean

Amanda

Paul S. Foster and Valeria

Glossopharyngeal Neuralgia Drago

Guillain-Barre´ Syndrome Michelle R. Pagoria and Chad A. Noggle Michelle R. Pagoria and

Hallervorden–Spatz Disease Chad A. Noggle

Michelle R. Pagoria and Chad A. Noggle

Hemifacial Spasm

Hereditary Spastic Paraplegia Golden Herpes Zoster Oticus

Jessica Holster and Charles

Henry V. Soper and Teri J. McHale

HIV/AIDS Dementia Complex Chriscelyn Tussey and Jason R. Freeman Holmes–Adie Syndrome R. Pagoria

Chad A. Noggle and Michelle

Chad A. Noggle and Javan Horwitz

Homocystinuria

Stephanie Lei Santiso and Charles Golden

Hughes’ Syndrome

Huntington’s Disease Alyse Barker, Mandi Musso, and William Drew Gouvier Hydranencephaly

Chad A. Noggle and Javan Horwitz

Matt Holcombe, Raymond S. Dean, and Chad

Hydrocephalus A. Noggle

Hydromyelia and Syringomyelia Horwitz Hypersomnia

Chad A. Noggle and Javan

Mindy Scheithauer and Raymond S. Dean

Hypertonia

Jessica Holster and Charles Golden

Hypotonia

Christine Corsun-Ascher and Charles Golden

Increased Intracranial Pressure Yutsis Infantile Neuroaxonal Dystrophy Golden Infantile Refsum Disease Iniencephaly

Anita H. Sim and Maya

David Ritchie and Charles Golden

Infantile Hypotonia

Jessica Holster and Charles

Daniel L. Frisch and Charles Golden

Jacob M. Goings and Chad A. Noggle

Isaac’s Syndrome Golden

Maryellen C. Dougherty and Charles

Joubert’s Syndrome Javan Horwitz, Natalie Horwitz, and Chad A. Noggle Juvenile Delinquency Kawasaki’s Disease

Timothy F. Wynkoop Shane S. Bush and Thomas E. Myers

Kearns–Sayre’s Syndrome Chad A. Noggle Kennedy’s Disease

Gaurav Jain, Sarita Singhal, and

Jessica Holster and Charles Golden

Kinsbourne’s Syndrome

Klinefelter’s Syndrome Raymond S. Dean

Matthew Holcombe and

Klippel-Feil’s Syndrome Chad A. Noggle

Gaurav Jain, Sarita Singhal, and

Klippel-Trenaunay’s Syndrome

Jessie L. Morrow and Charles Golden

Chad A. Noggle

Antonio E. Puente

Krabbe’s Disease Chad A. Noggle and Javan Horwitz Kuru

Jeremy Davis and Chad A. Noggle

Lambert–Eaton Myasthenia Syndrome Golden Landau–Kleffner Syndrome M. Cuesta

Eric Silk and Charles

Shane S. Bush and George

Lead Intoxication

Jacob M. Goings and Chad A. Noggle

Leigh’s Syndrome

Danielle S. Dance and Charles Golden

Lennox–Gastaut’s Syndrome

J. Aaron Albritton and Chad A. Noggle

Holoprosencephaly

Kelly N. Hutchins and

Kluver-Bucy Syndrome

Chad A. Noggle and Javan Horwitz

Hemicrania Continua

Kleine-Levin Syndrome Jon C. Thompson

Chad A. Noggle

Lesch-Nyhan Syndrome Mandi Musso, Alyse Barker, and William Drew Gouvier Lewy Body Dementia Lipoid Proteinosis Lissencephaly

Glen R. Finney and Daniela Rusovici

Peyton Groff and Raymond S. Dean

Mei Chang and Andrew S. Davis Chad A. Noggle

Locked-In Syndrome

Lyme Disease Jeremy Davis and Chad A. Noggle Lindsay J. Hines and

Machado–Joseph’s Disease Charles Golden Macrencephaly

Chad A. Noggle

Maple Syrup Urine Disease A. Noggle Mathematics Disorders Drew Gouvier

Jacob M. Goings and Chad

Audrey L. Baumeister and William

Melkersson–Rosenthal’s Syndrome Issac Tourgeman and Charles Golden Meningitis Alyse Barker, Mandi Musso, and William Drew Gouvier Menkes’s Disease Mental Retardation

Isaac Tourgeman and Charles Golden Carlos Ojeda and Antonio E. Puente

Metachromatic Leukodystrophy Singhal, and Chad A. Noggle Microcephaly

Gaurav Jain, Sarita

J. Aaron Albritton and Chad A. Noggle

Migraines Amy R. Steiner, Chad A. Noggle, and Amanda R. W. Steiner Miller Fisher Syndromes

Eric Silk and Charles Golden

Mitochondrial Cardiomyopathy Drago Mitochondrial Myopathies S. Dean

Paul S. Foster and Valeria

Amanda Ballenger and Raymond

xxii & LIST OF ENTRIES

Chad A. Noggle and Amy R. Steiner

Moebius Syndrome

Michelle R. Pagoria and Chad

Monomelic Amyotrophy A. Noggle

Shane S. Bush and Thomas E. Myers

Moyamoya’s Disease

Mucopolysaccharidoses A. Noggle

Rebecca Durkin and Chad Stephen Robinson

Multi-Infarct Dementia Alyse Barker, Mandi Musso, and William Drew Gouvier Multiple Sclerosis Liza San Miguel-Montes, Brenda Deliz-Rolda´n, and Krista Trefz-Puente Javan Horwitz Natalie Horwitz, and Sarah C. Connolly and Chad A. Noggle

Muscular Dystrophy

Chad A. Noggle and Amy R. Steiner

Myasthenia Gravis

Angela Dortch and Raymond S. Dean

Paroxysmal Choreoathetosis R. Pagoria

Periventricular Leukomalacia R. Pagoria

Narcolepsy

Justin Boseck and Raymond S. Dean Lena M. F. Prinzi and Charles Golden

Neuroacanthocytosis

Neurodegeneration With Brain Iron Accumulation Michelle R. Pagoria and Chad A. Noggle Neurofibromatosis Chad A. Noggle Neuroleptic Malignant Syndrome Raymond S. Dean

Brian Schmitt and Rebecca Durkin and Chad

Neuronal Ceroid Lipofuscinoses A. Noggle

Neuropathy J. T. Hutton, R. Rock, O. J. Vidal, and Antonio E. Puente Neurosarcoidosis

Mark T. Barisa

Neurosyphilis Amy R. Steiner, Chad A. Noggle, and Amanda R.W. Steiner Neurotoxicity

Shane S. Bush and Mark A. Sandberg

Niemann–Pick Disease

Jacob T. Lutz and Raymond S. Dean

Nonverbal Learning Disability Mei Chang and Andrew S. Davis Normal Pressure Hydrocephalus Jeffrey T. Barth Occipital Neuralgia

J. Forrest Sanders and

Erin L. Tireman and Charles Golden

Ohtahara’s Syndrome

Jessi H. Robbins and Charles Golden

Olivopontocerebellar Atrophy Drago

Paul S. Foster and Valeria

Opsoclonus–Myoclonus Syndrome Chad A. Noggle Paraneoplastic Syndromes

Chad A. Noggle

Chad A. Noggle and Michelle

Beth Trammell and Raymond S. Dean

Personality Disorders Pick’s Disease N. Fiebig

Gaurav Jain, Sarita Singhal, and Chad

Ana Arenivas and Mark

Peripheral Neuropathy J. T. Hutton, Rachel Rock, O. J. Vidal, and Antonio E. Puente

Phenylketonuria

Myotonia Congenita A. Noggle

W. Howard Buddin Jr. and

Pelizaeus–Merzbacher’s Disease T. Barisa

Myopathy Matt Holcombe, Raymond S. Dean, and Chad A. Noggle Gaurav Jain, Sarita Singhal, and Chad A. Noggle

Chad A. Noggle and Michelle

Kyle Noll and Mark T. Barisa

Parry–Romberg’s Syndrome Charles Golden

Myoclonus Beth Trammel and Raymond S. Dean

Myotonia

Mindy Scheithauer and Raymond

Parkinson’s Disease S. Dean

Paroxysmal Hemicrania

Multifocal Motor Neuropathy

Multi-System Atrophy Chad A. Noggle

Paresthesias

Chad A. Noggle and Amy R. Steiner

Henry V. Soper, Susan Spicer, and Jennifer

Piriformis Syndrome Golden

David M. Scarisbrick and Charles

Polyarteritis Nodosa

Jacob M. Goings and Chad A. Noggle

Polymyositis

Chad A. Noggle and Michelle R. Pagoria

Pompe’s Disease Chad A. Noggle Porencephaly

Chad A. Noggle and Javan Horwitz

Postconcussion Disorder/Syndrome Chad A. Noggle

Matt Holcombe and

Postural Orthostatic Tachycardia Syndrome and Charles Golden

Josie Bolanos

Shane S. Bush and Mark A. Sandberg

Prader–Willi Syndrome

Primary Lateral Sclerosis Carlos Ojeda, Mo´nica Muzquiz, Javier Gontier, and Antonio E. Puente Primary Progressive Aphasia R. Pagoria

Chad A. Noggle and Michelle

Progressive Multifocal Leukoencephalopathy and Raymond S. Dean

Jacob T. Lutz

Progressive Supranuclear Palsy Anita H. Sim and James B. Hoelzle Pseudotumor Cerebri Psychotic Disorders

Chad A. Noggle and Amy R. Steiner Chad A. Noggle

Rasmussen’s Encephalitis Reading Disorders Gouvier

Ryan Boddy and Charles Golden

Audrey L. Baumeister and William Drew

Reduplicative Paramnesia Mark T. Barisa Repetitive Movement Disorders Horwitz, and Chad A. Noggle Restless Legs Syndrome S. Dean

Javan Horwitz, Natalie

Amy Zimmerman and Raymond

LIST OF ENTRIES & xxiii

Shane S. Bush and Donna Rasin-Waters

Rett’s Syndrome

Reye’s Syndrome Matthew Holcombe, Raymond S. Dean, and Chad A. Noggle Andrea Stephen and Raymond S. Dean

Rheumatoid Arthritis

Anya Mazur-Mosiewicz and Raymond

Sandhoff’s Disease S. Dean

Jamie Rice and Charles Golden

Schilder’s Disease

Teri J. McHale and Henry V. Soper

Schizencephaly Sclerodoma

Erin L. Tireman and Charles Golden

Semantic Dementia Amy R. Steiner, Chad A. Noggle, and Amanda R. W. Steiner Shaken Baby Syndrome Ronald Ruff, Saralyn Ruff, Christina Weyer Jamora, and Ann Richardson Shingles

Sarah E. West and Charles Golden

Sickle Cell Disease

Andrea Stephen and Raymond S. Dean

Sjo¨gren Syndrome

Jessie L. Morrow and Charles Golden

Sleep Apnea

Gershom T Lazarus and Antonio E. Puente

Somatoform and Conversion Disorders Melissa M. Swanson, Mary E. Haines, and Timothy F. Wynkoop Sotos’ Syndrome Spina Bifida

Kelly R. Pless and Charles Golden

Anya Mazur-Mosiewicz and Raymond S. Dean

Spinal Cord Injury Drew Gouvier

Alyse Barker, Mandi Musso, and William Chad A. Noggle and Michelle

Stiff-Person Syndrome Jennifer Mariner

Chad A. Noggle

Jacqueline Remondet Wall and

Striatonigral Degeneration Charles Golden

Christine Corsun-Ascher and

Sturge–Weber Syndrome Ashley L. Ware and Antonio E. Puente Subcortical Vascular Dementia SUNCT Headache Syndrome R. Pagoria

Glen Finney Chad A. Noggle and Michelle

Sarah E. West and Charles Golden

Syncope Teri J. McHale, Stephen E. Prover, and Henry V. Soper Javan Horwitz, Natalie Horwitz, and Chad

Javan Horwitz, Natalie

Thoracic Outlet Syndrome Rachel Rock and Antonio E. Puente Thyrotoxic Myopathy Kelly R. Pless and Charles Golden Todd’s Paralysis

Jessie L. Morrow and Charles Golden

Tourette’s Syndrome and Other Tic Disorders Mary E. Haines, Melissa M. Swanson, and Timothy F. Wynkoop Matthew Holcombe and Raymond

Transient Global Amnesia S. Dean Transient Ischemic Attacks Amy J. Goldman

Lori S. Terryberry-Spohr and

Chad A. Noggle and Michelle R. Pagoria

Transverse Myelitis

Christina Weyer Jamora and

Traumatic Brain Injury Ronald Ruff

Jennifer Mariner and Jacqueline

Trigeminal Neuralgia Remondet Wall

Tropical Spastic Paraparesis Amy R. Steiner, Chad A. Noggle, and Amanda R. W. Steiner Jacob M. Goings and Chad A. Noggle

Tuberous Sclerosis

Chad A. Noggle

Vasculitis Javan Horwitz, Natalie Horwitz, and Chad A. Noggle

Michelle R. Pagoria and

Amy Zimmerman and Raymond S. Dean

Anthony P. Odland and Charles

von Economo Disease Golden

von Hippel–Lindau Syndrome Charles Golden Wallenberg’s Syndrome

David M. Scarisbrick and

Jessica Foley and Charles Golden

Wegener’s Granulomatosis Charles Golden

Erin L. Tireman and

Wernicke–Korsakoff Syndrome Mandi Musso, Alyse Barker, and William Drew Gouvier West’s Syndrome

Chad A. Noggle

Whiplash Javan Horwitz, Natalie Horwitz, and Chad A. Noggle Kelly R. Pless and Charles Golden

Whipple’s Disease

Chad A. Noggle and Amy R. Steiner

Williams’ Syndrome

Systemic Lupus Erythematosis Chad A. Noggle Takayasu’s Disease

Chad A. Noggle

Tethered Spinal Cord Syndrome Horwitz, and Chad A. Noggle

Turner’s Syndrome

Spinocerebellar Degenerative Disorders and Michelle R. Pagoria

Syringomyelia A. Noggle

Tarlov Cysts Ryan Boddy and Charles Golden Tay–Sachs’ Disease

Troyer’s Syndrome Daniel J. Heyanka and Charles Golden

Spinal Muscular Atrophies R. Pagoria

Sydenham’s Chorea

Mandi Musso, Alyse Barker, and William

Tardive Dyskinesia Drew Gouvier

Wilson’s Disease Wolman’s Disease

Timothy F. Wynkoop Daniel J. Heyanka and Charles Golden

Zellweger’s Syndrome

Jessica Foley and Charles Golden

ACKNOWLEDGMENTS

Seeing this project through to publication has been very rewarding and has been made possible by the many authors and by the support of our colleagues and associated institutions (SIU School of Medicine, Middle Tennessee State University, Ball State University, Psych Associates of Maryland), as well as our editors (Nancy Hale and Phil Laughlin) at Springer Publishing Company, LLC.

The Encyclopedia of

NEUROPSYCHOLOGICAL DISORDERS

A ACUTE DISSEMINATED ENCEPHALOMYELITIS

site-restricted form that is characterized by pure encephalitis, myelitis, cerebellitis, and optic neuritis. Peripheral nervous system (PNS) involvement is suggested in 5–43% of cases (Marchioni et al., 2008).

DESCRIPTION

NEUROPATHOLOGY/PATHOPHYSIOLOGY

Acute disseminated encephalomyelitis (ADEM) is classified as a demyelinating disease of the central nervous system (CNS) and has onset in all age ranges, with more cases found in the pediatric population. Empirical studies suggest that ADEM is an immunemediated inflammatory process that predominately involves the white matter of the brain. Onset may manifest spontaneously, or, in most cases, it is triggered by a systemic viral infection such as mumps, rubella, varicella-zoster, herpes simplex virus, hepatitis A virus, and coxsackie virus. There are rare cases in which vaccinations have triggered this disease. Symptoms are characterized by rapid onset of encephalopathy with or without meningeal signs and focal/multifocal neurological signs (Alper, Heyman, & Wang, 2008; Marchioni et al., 2008; Sejvar, 2008; Tenembaum, 2007). Altered mental status, as minimal as lethargy or as severe as coma, may be present. Some focal neurologic deficits may be present, specifically extrapyramidal or pyramidal signs, which are shown in 60–90% of cases. Hemiplegia is present in 50–75% of cases, cranial nerve deficits in 7–45%, and concomitant spinal cord involvement in 25% (Sejvar, 2008). These symptoms are generally short lived with resolution over weeks or months. Complete recovery has been reported at 57–89% (Alper et al., 2008). Although ADEM shares similar characteristics to other CNS disorders, it can be distinguished because of its rapid onset, progression of the illness, rapid remission, and the characteristic pattern and distribution of brain lesions on a MRI. However, none of these differences are pathognomic of ADEM making diagnosis unclear. Furthermore, symptoms of ADEM are most similar to first episodes of multiple sclerosis (MS), which makes it difficult to distinguish (Marchioni et al., 2008; Sejvar, 2008). ADEM can be classified into two types. The classic form is characterized by brain and spinal cord involvement, and there is a

Neuroimaging studies have suggested that ADEM is a result of an inflammatory autoimmune response with resultant CNS inflammation and demyelination. A lack of biological markers make the pathophysiological basis of the condition unclear. Though the pathophysiological underpinnings of this response are unclear, one suggested explanation for ADEM, as well as other inflammatory CNS and PNS disorders, is that factors stimulate the immune system to produce antigen-specific humoral and/or cellular immunity (Sejvar, 2008; Tenembaum, 2007). A few mechanisms have been offered to explain the process of immune stimulation induced by an infection or vaccination. ‘‘Molecular mimicry’’ is a term used to describe the involvement of epitopes of a virus, vaccine, or other antigenic stimulus in developing immune antibodies and/or T cells that crossreact with epitopes on myelin or axonal glycoproteins of nerves. Another mechanism describes the initial event as the binding of cross-reactive antibodies and subsequent damage to oligodendrocytes. Also, the introduction of sequestered myelin antigens into the circulation could damage myelin cells and therefore incite autoimmunity (Sejvar, 2008). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

In most cases, the clinical course of ADEM involves a rapid onset and resolution of the disorder while resulting deficits develop within days. Predominately spontaneous recovery (of neurological deficits) occurs over a period of weeks to months. Some cases result in persistent motor deficits, cognitive impairment, and recurrent seizures. In general, outcome is favorable in adult ADEM (Sejvar, 2008). One study of adult ADEM followed patients diagnosed with ADEM over a period of 30 months and found some residual

2 & ACUTE DISSEMINATED ENCEPHALOMYELITIS

A

mild cognitive impairment, as shown by problems with memory and concentration, and speech (Hollinger, Sturzenegger, Mathis, Schroth, & Hess, 2002). Therefore, the literature supports that in adult cases of ADEM, long-lasting neuropsychological and behavioral deficits are minimal or nonexistent. Long-term neuropsychological or behavioral impairment in children with history of ADEM seems to be minimal or nonexistent as well. Although cognitive and motor deficits predominate in the initial stages of ADEM in adults, children may initially present with behavioral disturbances prior to diagnosis of ADEM. One study reported two cases where the child initially presented with symptoms of abnormal behavior such as irritability, violent tendencies, and behaviors mimicking delusions, suggestive of acute psychotic disorder. This suggests a different psychological manifestation of the disorder in some children. However, both these cases had positive outcomes and no residual cognitive, academic, or neuropsychological deficits were found (Krishnakumar, Jayakarishnan, Beegum, & Riyaz, 2008). This is consistent with the current literature that states serious complications are rare in childhood ADEM. However, some studies have found that the rate of relapse is considerable in this population (Anlar et al., 2003; Hollinger et al., 2002). DIAGNOSIS

The major differential diagnosis of ADEM is MS. Interestingly, it has been suggested that 10–30% of patients initially diagnosed with ADEM end up developing MS (Sejvar, 2008). Two more differential diagnoses are also important: that is, infectious meningoencephalitis of possibly treatable etiology and acute brain swelling (Hollinger et al., 2002; Schwarz, Mohr, Knauth, Wildemann, & Storch-Hagenlocher, 2001). MRIs generates similar results for MS. An MRI image of a case with ADEM would typically include widespread, bilateral, and asymmetric involvement of the white matter, deep gray nuclei, and spinal cord (Beleza et al., 2008). This is similar to MRI findings of 18% of children who are ultimately diagnosed with MS, making it indistinguishable (Alper et al., 2008; Callen et al., 2008). Several neuroimaging studies have made suggestions on how to distinguish between ADEM and first episodes of MS. Callen et al. (2008) proposed that the criteria for pediatric MS should include any two of the following:  2 periventricular legions, presence of black holes, or absence of diffuse bilateral legion distribution pattern. It has also been suggested that, in many cases, the presence of

encephalopathy is a strong indicator for the diagnosis of ADEM (Alper et al., 2008). Recently, four patterns of MRI results in ADEM have been identified. These include ADEM with small (30 ng/ mL), have a positive predictive value of 94.7% and a negative predictive value of 92.4% for the presence of a prion disease. False positives for first analysis may occur in patients with herpes simplex encephalitis, hypoxic brain damage, atypical encephalitis, intracerebral metastases of a bronchial carcinoma, metabolic encephalopathy, and idiopathic progressive dementia. If a second CSF analysis confirms the presence of elevated 14-3-3 protein and NSE levels, a prion protein gene analysis should be conducted as the final confirmatory step. GSS is distinct from CJD and FFI in the pace of disease progression, the order of clinical symptom presentation, and the morphology of the amyloid plaques that form in the patient’s cortex. GSS has a relatively long illness duration compared with CJD (49 months, compared with 4.5–8 months, respectively; Webb et al., 2008; WHO, 2003). In addition, motor symptoms present first in GSS, with cognitive symptoms appearing much later in the illness, whereas CJD first presents as cognitive impairments, followed by motor difficulties. GSS lacks the insomnia component required for a diagnosis of FFI (WHO, 2003). Finally, a histocytological examination of biopsied spongiform brain tissue can confirm the differential diagnosis (Sikorska, Liberski, Sobo´w, Budka, & Ironside, 2009). GSS amyloid plaques are multicentric, possessing several clusters of dense, interwoven fibrils, with fibrils radiating in a feathered pattern at the periphery. CJD plaques, on the other hand, are organized into thick, tongue-like processes and are often surrounded by vacuoles or vesicles. In comparison with the neuritic plaques and tangle that are hallmarks of Alzheimer’s disease, the fibrils in Alzheimer’s disease plaques are thinner (4–8 nm diameter) than GSS fibrils (7–9 nm) and organized similar to CJD. FFI lacks amyloid plaques altogether. TREATMENT

Because GSS is fatal in all cases (Irisawa et al., 2007; Patel et al., 2007), treatment should focus on the comfort and safety of the individual. The patient may

receive some benefit from exercise that focuses on balance and coordination. Although these exercises will not cure the motor symptoms, they may ameliorate some of the symptoms’ effects by maintaining or developing the patient’s proprioceptive ability. The individual’s environment should be kept free of clutter to minimize the number of potential hazards, and the individual should be encouraged to avoid stairs and escalators. Wherever possible, rails and ramps should be installed to maximize the individual’s safety while navigating the environment. As motor function impairment increases, a walker may become necessary. For ease and safety when sitting down or standing up, the patient should sit only in armchairs that are elevated slightly in the back. This will allow the patient to use his or her arms to aid in sitting and standing, while the tilt of the chair exploits gravity to facilitate the movement. Individuals with GSS should not drive because of the impairments to executive function. Driving requires concentration, planning, and the ability to shift attention between rapidly changing sets of stimuli — all of which may be impaired in individuals with GSS. Although planning and memory are often impaired, an individual with GSS may be able to maintain some degree of independent living. The patient may find it helpful to have a large whiteboard placed centrally in the home, with a daily to-do list written on it by a caregiver. A timer or alarm clock should be used to cue the individual with GSS to check the board for upcoming tasks. As cognitive impairments become more severe, the individual may require constant supervision, possibly in a hospice setting. Amanda Ballenger Raymond S. Dean Aksamit, A. J., Preissner, C. M., & Homburger, H. A. (2001). Quantitation of 14-3-3 and neuron-specific enolase in CSF in Creutzfeldt-Jakob disease. Neurology, 57, 728–730. Giovagnoli, A. R., Di Fede, G., Aresi, A., Reati, F., Rossi, G., & Tagliavini, F. (2008). Atypical frontotemporal dementia as a new clinical phenotype of GerstmannStraussler-Scheinker disease with the PrP-P102L mutation. Description of a previously unreported Italian family. Neurological Science, 29, 405–410. Irisawa, M., Amanuma, M., Kozawa, E., Kimura, F., & Araki, N. (2007). A case of Gerstmann-Stra¨ussler-Scheinker syndrome. Magnetic Resonance in Medical Sciences, 6(1), 533–557. Liberski, P. P. (2008). The tubulovesicular structures — the ultrastructural hallmark for all prion diseases. Acta Neurobiologiœ Experimentalis, 68, 113–121.

G

¨ USSLER–SCHEINKER DISEASE 332 & GERSTMANN–STRA

G

Patel, S. R., Thavaseelan, S., Handel, L. N., Wong, A., & Sigman, M. (2007). Bilateral manual externalization of testis with self-castration in patient with prion disease. Urology, 70, 15–16. Shevell, M. (2009). The tripartite origins of the tonic neck reflex. Neurology, 72, 850–853. Sikorska, B., Liberski, P. P., Sobo´w, T., Budka, H., & Ironside, J. W. (2009). Ultrastructural study of florid plaques in variant Creutzfeldt-Jakob disease: A comparison with amyloid plaques in kuru, sporadic Creutzfeldt-Jakob disease and Gerstmann-Stra¨ussler-Scheinker disease. Neuropathology and Applied Neurobiology, 35, 46–59. Tunnell, E., Wollman, R., Mallick, S., Cortes, C. J., DeArmond, S. J., & Mastrianni, J. A. (2008). A novel PRNP-P105S mutation associated with atypical prion disease and a rare PrPSc conformation. Neurology, 71, 1431–1438. Unverzagt, F. W., Farlow, M. R., Norton, J., Dlouhy, S. R., Young, K., & Ghetti, B. (1997). Neuropsychological function in patients with Gerstmann-Stra¨ussler-Scheinker disease from the Indiana Kindred (F198S). Journal of the International Neuropsychological Society, 3, 169–178. Webb, T. E. F., Poulter, M., Beck, J., Uphill, J., Adamson, G., Campbell, T., et al. (2008). Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series. Brain, 131, 2632–2646. World Health Organization. (2003). WHO manual for surveillance of human transmissible spongiform encephalopathies including variant Creutzfeldt-Jakob disease. Geneva, Switzerland: WHO. Yamamoto, S., Kinoshita, M., Furukawa, S., & Kajiyama, K. (2007). Early abnormality of diffusion-weighted magnetic resonance imaging followed by brain atrophy in a case of Gerstmann-Stra¨ussler-Scheinker disease. Archives of Neurology, 64, 450–451. Zerr, I., Bodemer, M., Gefeller, O., Otto, M., Poser, S., Wiltfang, J., et al. (2000). Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Annals of Neurology, 47(5), 683–684.

GLOSSOPHARYNGEAL NEURALGIA DESCRIPTION

Glossopharyngeal neuralgia (GN) is a relatively rare disorder affecting the ninth cranial nerve, with estimations of about 0.8 cases per 100,000 individuals (Katusic, Williams, Beard, Bergstralh, & Kurland, 1991). It shares many features with trigeminal neuralgia. GN is characterized by sharp, typically unilateral, paroxysmal pain in the tonsillar region, pharynx, posterior regions of the tongue, jaw, and/or ear. The painful

attacks can be triggered by swallowing, yawning, food contact on the pharynx, talking, chewing, and/ or coughing (Biller, 2002; Headache Classification Subcommittee of the International Headache Society, 2004), with some research suggesting that it more commonly affects the left side (Teixeira, de Siqueira, & Bor-Seng-Shu, 2008). The severe pain may last from seconds to minutes (Headache Classification Subcommittee of the International Headache Society, 2004; Rozen, 2004) and the course is usually episodic, with active phases of painful experiences lasting weeks or months, and periods of remission lasting variable lengths of time (De Simone, Ranieri, Bilo, Fiorillo, & Bonavita, 2008). NEUROPATHOLOGY/PATHOPHYSIOLOGY

GN often appears to be idiopathic in nature. However, vascular compression of the glossopharyngeal nerve has often been reported as a source for GN (Ferroli et al., 2009; Fischbach, Lehmann, Ricke, & Bruhn, 2003; Hiwatashi et al., 2008; Patel, Kassam, Horowitz, & Chang, 2002). A number of other disorders may also be secondary causes for GN. For instance, Eagle’s syndrome, which is associated with compression of the glossopharyngeal nerve due to an elongated styloid process, may result in GN (Montalbetti, Ferrandi, Pergami, & Savoldi, 1995; Soh, 1999). McCarron and Bone (1999) reported the case of a patient with ‘‘referred’’ GN arising from a left pontine lesion. A number of other disorders have been reported to cause GN including medullary infarction (Warren, Kotsenas, & Czervionke, 2006), cerebellopontine angle tumor (Phuong, Matsushima, Hisada, & Matsumoto, 2004), adhesive arachnoid (Fukuda, Ishikawa, & Yamazoe, 2002), nasopharyngeal carcinoma (Giorgi & Broggi, 1984), and posterior fossa arteriovenous malformation (Galetta, Raps, Hurst, & Flamm, 1993). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Regarding the effects of GN on neuropsychological functioning, there have been no published reports investigating the direct effects of GN on memory or cognitive functioning. However, GN may affect neuropsychological functioning from secondary sources, such as the treatment approach. Microvascular decompression is used to treat both GN and trigeminal neuralgia, and both procedures use a lateral suboccipital approach (Hitotsumatsu, Matsushima, & Inoue, 2003). Some investigators have reported the onset of peduncular hallucinosis following microvascular decompression for trigeminal neuralgia (Chen & Lui,

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1995; Tsukamoto, Matsushima, Fujiwara, & Fukui, 1993). However, more serious neuropsychological effects may result from the pharmacological treatment of GN. Anticonvulsant medications are often used to treat GN, and many of these medications may have negative influences on memory and cognitive functioning (Hessen, Lossius, & Gjerstad, 2009). Carbamazepine, in particular, has often been found to negatively affect neuropsychological functioning (Martin et al., 2001; Meador et al., 2007; Salinsky et al., 2002), including information processing speed and attention (Wesnes, Edgar, Dean, & Wroe, 2009) and motor functioning (Mecarelli et al., 2004). These adverse neuropsychological effects may arise partly due to the changes that accompany carbamazepine in neurophysiological functioning. Specifically, carbamazepine is known to increase delta-theta power and reduce alpha frequency rhythm (Mecarelli et al., 2004; Salinsky et al., 2002). Gabapentin has also been found to produce negative effects on neuropsychological functioning (Martin et al., 2001; Salinsky et al., 2002). However, the effects of lamotrigine on neuropsychological functioning are not as severe (Meador et al., 2001, 2005). Indeed, Smith et al. (2006) reported that although lamotrigine was associated with reduced EEG power it was not accompanied by impaired cognitive functioning. Similarly, pregabalin produces relatively minor changes in cognitive and psychomotor functioning (Hindmarch, Trick, & Ridout, 2005).

DIAGNOSIS

The diagnosis of GN is complicated by the fact that it closely resembles trigeminal neuralgia (Soh, 1999; Teixeira, de Siqueira, & Bor-Seng-Shu, 2008). Diagnosis is obtained from the patient’s history and by mapping the distribution of pain. The determination of trigger points for pain is important, as injecting the trigger point (often the pharynx) with topical anesthesia may aid in diagnosis if the pain is halted. Further, given the many secondary causes for GN, these additional sources should be evaluated and ruled out. This may involve an otolaryngology consultation and/or imaging of the head using CT or MRI to evaluate for the presence of cerebellopontine angle tumors (Biller, 2002; Rozen, 2004; Soh, 1999). In addition, recent research has supported the use of MRI in visualizing the source of vascular compression that gives rise to GN (Fischbach, Lehmann, Ricke, & Bruhn, 2003). Other investigators have used MRI to specifically evaluate the contribution of the posterior inferior cerebellar artery in causing GN (Boch, Oppenheim,

Biondi, Marsault, & Philippon, 1998; Hiwatashi et al., 2008).

G

TREATMENT

The treatment of GN may involve both pharmacological and surgical approaches. Regarding pharmacological treatment, anticonvulsants are the medications of choice (De Simone, Ranieri, Bilo, Fiorillo, & Bonavita, 2008; Rozen, 2004; Teixeira, de Siqueira, & BorSeng-Shu, 2008). Research has supported a wide range of anticonvulsant medications in effectively treating GN, with some viewing carbamazepine as the favored medication (Rushton, Stevens, & Miller, 1981). Indeed, a number of studies have supported the use of carbamazepine in treating GN (Giza, Kyriakou, Liasides, & Dimakopoulou, 2008; Johnston & Redding, 1990; Saviolo & Fiasconaro, 1987). Other anticonvulsants reported to effectively treat GN include gabapentin (Moretti, Torre, Antonello, Bava, & Cazzato, 2002) and lamotrigine (Titlic, Jukic, Tonkic, Grani, & Jukic, 2006). In addition, pregabalin (Kitchener, 2006) and baclofen (Ringel & Roy, 1987) are reported to be successful in treating GN. However, the benefit from anticonvulsant medication may dissipate with time (Soh, 1999). With reduced effectiveness of anticonvulsant medications or cases where patients experience medically intractable pain, surgical approaches may then be warranted. The surgical treatment of GN may involve intracranial sectioning of the glossopharyngeal nerve, a procedure resulting in good relief of pain (Ceylan, Karakus, Duru, Baykal, & Koca, 1997; Rushton et al., 1981). Microvascular decompression of the offending artery, however, has received considerable support as an effective treatment approach in appropriate cases. A number of investigators have reported reduced pain following microvascular decompression (Boch et al., 1998; Hitotsumatsu et al., 2003; Patel et al., 2002) as well as long-term benefits (Ferroli et al., 2009; Kondo, 1998; Resnick, Jannetta, Bissonnette, Jho, & Lanzino, 1995; Sampson, Grossi, Asaoka, & Fukushima, 2004). Recently, gamma knife surgery has also been reported to effectively treat GN (Yomo, Arkha, Donnet, & Regis, 2009). Paul S. Foster Valeria Drago

Biller, J. (2002). Practical neurology (2nd ed.). Philadelphia, PA: Lippincott, Williams, & Wilkins. Boch, A. L., Oppenheim, C., Biondi, A., Marsault, C., & Philippon, J. (1998). Glossopharyngeal neuralgia associated

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with vascular loop demonstrated by magnetic resonance imaging. Acta Neurochirurgica, 140, 813–818. Ceylan, S., Karakus, A., Duru, S., Baykal, S., & Koca, O. (1997). Glossopharyngeal neuralgia: A study of 6 cases. Neurosurgical Review, 20, 196–200. Chen, H. J., & Lui, C. C. (1995). Peduncular hallucinosis following microvascular decompression for trigeminal neuralgia: Report of a case. Journal of the Formosan Medical Association, 94, 503–505. De Simone, R., Ranieri, A., Bilo, L., Fiorillo, C., & Bonavita, V. (2008). Cranial neuralgias: From physiopathology to pharmacological treatment. Neurological Sciences, 29, S69–S78. Ferroli, P., Fioravanti, A., Schiariti, M., Tringali, G., Franzini, A., Calbucci, F., et al. (2009). Microvascular decompression for glossopharyngeal neuralgia: A long-term retrospective review of the Milan-Bologna experience in 31 consecutive cases. Acta Neurochirurgica, 151, 1245–1250. Fischbach, F., Lehmann, T. N., Ricke, J., & Bruhn, H. (2003). Vascular compression in glossopharyngeal neuralgia: Demonstration by high-resolution MRI at 3 tesla. Neuroradiology, 45, 810–811. Fukuda, H., Ishikawa, M., & Yamazoe, N. (2002). Glossopharyngeal neuralgia caused by adhesive arachnoid. Acta Neurochirurgica, 144, 1057–1058. Galetta, S. L., Raps, E. C., Hurst, R. W., & Flamm, E. S. (1993). Glossopharyngeal neuralgia from a posterior fossa arteriovenous malformation: Resolution following embolization. Neurology, 43, 1854–1855. Giorgi, C., & Broggi, G. (1984). Surgical treatment of glossopharyngeal neuralgia and pain from cancer of the nasopharynx. A 20-year experience. Journal of Neurosurgery, 61, 952–955. Giza, E., Kyriakou, P., Liasides, C., & Dimakopoulou, A. (2008). Glossopharyngeal neuralgia with cardiac syncope: An idiopathic case treated with carbamazepine and duloxetine. European Journal of Neurology, 15, e38–e39. Headache Classification Subcommittee of the International Headache Society. (2004). The international classification of headache disorders (2nd ed.). Cephalalgia, 24(Suppl. 1), 9–160. Hessen, E., Lossius, M. I., & Gjerstad, L. (2009). Antiepileptic monotherapy significantly impairs normative scores on common tests of executive functions. Acta Neurologica Scandinavica, 119, 194–198. Hindmarch, I., Trick, L., & Ridout, F. (2005). A double-blind, placebo- and positive-internal-controlled (alprazolam) investigation of the cognitive and psychomotor profile of pregabalin in healthy volunteers. Psychopharmacology, 183, 133–143. Hitotsumatsu, T., Matsushima, T., & Inoue, T. (2003). Microvascular decompression for treatment of trigeminal

neuralgia, hemifacial spasm, and glossopharyngeal neuralgia: Three surgical approach variations: Technical note. Neurosurgery, 53, 1436–1443. Hiwatashi, A., Matsushima, T., Yoshiura, T., Tanaka, A., Noguchi, T., Togao, O., et al. (2008). MRI of glossopharyngeal neuralgia caused by neurovascular compression. American Journal of Roentgenology, 191, 578–581. Johnston, R. T., & Redding, V. J. (1990). Glossopharyngeal neuralgia associated with cardiac syncope: Long term treatment with permanent pacing and carbamazepine. British Heart Journal, 64, 403–405. Katusic, S., Williams, D. B., Beard, C. M., Bergstralh, E. J., & Kurland, L. T. (1991). Epidemiology and clinical features of idiopathic trigeminal neuralgia and glossopharyngeal neuralgia: Similarities and differences, Rochester, Minnesota, 1945–1984. Neuroepidemiology, 10, 276–281. Kondo, A. (1998). Follow-up results of using microvascular decompression for treatment of glossopharyngeal neuralgia. Journal of Neurosurgery, 88, 221–225. Martin, R., Meador, K., Turrentine, L., Faught, E., Sinclair, K., Kuzniecky, R., et al. (2001). Comparative cognitive effects of carbamazepine and gabapentin in healthy senior adults. Epilepsia, 42, 764–771. McCarron, M. O., & Bone, I. (1999). Glossopharyngeal neuralgia referred from a pontine lesion. Cephalalgia, 19, 115–117. Meador, K. J., Gevins, A., Loring, D. W., McEvoy, L. K., Ray, P. G., Smith, M. E., et al. (2007). Neuropsychological and neurophysiologic effects of carbamazepine and levtiracetam. Neurology, 69, 2076–2084. Meador, K. J., Loring, D. W., Ray, P. G., Murro, A. M., King, D. W., Perrine, K. R., et al. (2001). Differential cognitive and behavioral effects of carbamazepine and lamotrigine. Neurology, 56, 1177–1182. Meador, K. J., Loring, D. W., Vahle, V. J., Ray, P. G., Werz, M. A., Fessler, A. J., et al. (2005). Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers. Neurology, 64, 2108–2114. Mecarelli, O., Vicenzini, E., Pulitano, P., Vanacore, N., Romolo, F. S., Di Piero, V., et al. (2004). Clinical, cognitive, and neurophysiologic correlates of short-term treatment with carbamazepine, oxcarbazepine, and levetiracetam in healthy volunteers. Annals of Pharmacotherapy, 38, 1816–1822. Montalbetti, L., Ferrandi, D., Pergami, P., & Savoldi, F. (1995). Elongated styloid process and Eagle’s syndrome. Cephalalgia, 15, 80–93. Moretti, R., Torre, P., Antonello, R. M., Bava, A., & Cazzato, G. (2002). Gabapentin treatment of glossopharyngeal neuralgia: A follow-up of four years of a single case. European Journal of Pain, 6, 403–407. Patel, A., Kassam, A., Horowitz, M., & Chang, Y. F. (2002). Microvascular decompression in the management of

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glossopharyngeal neuralgia: Analysis of 217 cases. Neurosurgery, 50, 705–710. Phuong, H. L., Matsushima, T., Hisada, K., & Matsumoto, K. (2004). Glossopharyngeal neuralgia due to an epidermoid tumour in the cerebellopontine angle. Journal of Clinical Neuroscience, 11, 758–760. Resnick, D. K., Jannetta, P. J., Bissonnette, D., Jho, H. D., & Lanzino, G. (1995). Microvascular decompression for glossopharyngeal neuralgia. Neurosurgery, 36, 64–68. Ringel, R. A., & Roy, E. P., III. (1987). Glossopharyngeal neuralgia: Successful treatment with baclofen. Annals of Neurology, 21, 514–515. Rozen, T. D. (2004). Trigeminal neuralgia and glossopharyngeal neuralgia. Neurologic Clinics, 22, 185–206. Rushton, J. G., Stevens, J. C., & Miller, R. H. (1981). Glossopharyngeal (vagoglossopharyngeal) neuralgia: A study of 217 cases. Archives of Neurology, 38, 201–205. Salinsky, M. C., Binder, L. M., Oken, B. S., Storzbach, D., Aron, C. R., & Dodrill, C. B. (2002). Effects of gabapentin and carbamazepine on the EEG and cognition in healthy volunteers. Epilepsia, 43, 482–490. Sampson, J. H., Grossi, P. M., Asaoka, K., & Fukushima, T. (2004). Microvascular decompression for glossopharyngeal neuralgia: Long-term effectiveness and complication avoidance. Neurosurgery, 54, 884–889. Saviolo, R., & Fiasconaro, G. (1987). Treatment of glossopharyngeal neuralgia by carbamazepine. British Heart Journal, 58, 291–292. Smith, M. E., Gevins, A., McEvoy, L. K., Meador, K. J., Ray, P. G., & Gilliam, F. (2006). Distinct cognitive neurophysiologic profiles for lamotrigine and topiramate. Epilepsia, 47, 695–703. Soh, K. B. K. (1999). The glossopharyngeal nerve, glossopharyngeal neuralgia and the Eagle’s syndrome — Current concepts and management. Singapore Medical Journal, 40, 659–665. Teixeira, M. J., de Siqueira, S. R. D. T., & Bor-Seng-Shu, E. (2008). Glossopharyngeal neuralgia: Neurosurgical treatment and differential diagnosis. Acta Neurochirurgica, 150, 471–475. Titlic, M., Jukic, I., Tonkic, A., Grani, P., & Jukic, J. (2006). Use of lamotrigine in glossopharyngeal neuralgia: A case report. Headache, 46, 167–169. Tsukamoto, H., Matsushima, T., Fujiwara, S., & Fukui, M. (1993). Peduncular hallucinosis following microvascular decompression for trigeminal neuralgia: Case report. Surgical Neurology, 40, 31–34. Warren, H. G., Kotsenas, A. L., & Czervionke, L. F. (2006). Trigeminal and concurrent glossopharyngeal neuralgia secondary to lateral medullary infarction. American Journal of Roentgenology, 27, 705–707. Wesnes, K. A., Edgar, C., Dean, A. D., & Wroe, S. J. (2009). The cognitive and psychomotor effects of remacemide and carbamazepine in newly diagnosed epilepsy. Epilepsy and Behavior, 14, 522–528.

Yomo, S., Arkha, Y., Donnet, A., & Regis, J. (2009). Gamma knife surgery for glossopharyngeal neuralgia. Journal of Neurosurgery, 110, 559–563.

G

GUILLAIN–BARRE´ SYNDROME DESCRIPTION

Guillain–Barre´ syndrome (GBS) is an acute demyelinating inflammatory syndrome involving acute peripheral neuropathy. GBS is a systemic disorder in which the immune system attacks the peripheral nervous system and is often triggered by an acute infectious process, including past surgical infection and vaccinations. Four GBS subtypes have been identified: (1) acute inflammatory demyelinating polyradiculoneuropathy being the most common, (2) acute motor axonal neuropathy, characterized by pure motor involvement, (3) acute motor and sensory axonal neuropathy, a subtype in which both motor and sensory fibers are affected, and (4) Fisher’s syndrome in which the hallmark feature is a triad of ophthalmoplegia, ataxia, and areflexia (Hughes & Cornblath, 2005). Worldwide estimates of GBS suggest an incidence of 1–2 per 100,000 (Pritchard & Hughes, 2004). Men are more often affected than women and the incidence of GBS increases with advancing age (Hughes & Cornblath, 2005). GBS can be debilitating and potentially fatal in 5% of cases, with considerable long-term disability implications. Recovery may take up to 1 or 2 years, though a number of patients continue to experience ongoing complaints (Forsberg, Press, Einarsson, Pedro-Cuesta, & Holmqvist, 2005; Pritchard & Hughes, 2004). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The pathophysiology of GBS is due to multifocal mononuclear cell infiltration in the peripheral nervous system via activated T lymphocytes and macrophages. Once activated, macrophages invade and denude the axons of the myelin sheaths (Haldeman & Zulkosky, 2005; Pritchard & Hughes, 2004). In particular, demyelination at the nodes of Ranvier has been a major finding. Increased protein is typically evident within the CSF, though it may not be evident during the first few days of illness. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Many GBS sufferers report acute infection prior to diagnosis of GBS. Often these manifest as flu-like

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symptoms, including malaise, progressive limb weakness, fatigue, and headache, which quickly progress to ascending paralysis, paresthesia, numbness, and pain (Hughes & Cornblath, 2005). Onset of symptoms usually occurs within 2 weeks, but may go up to 4. Autonomic involvement and respiratory failure requiring assistive ventilation occur in a number of patients, with the latter being associated with poorer prognosis and occasional mortality. Otherwise, neuropsychological data of GBS is sparse to nonexistent. DIAGNOSIS

Onset of GBS is often sudden and unexpected, but recent infections are present in the majority of cases. Key features include weakness, possible sensory disturbance, and diminished or absent tendon reflexes (hyporeflexia) typically associated with upper motor neuron pathology and the presence of raised protein concentration within the CSF in perhaps 80% of patients, although abnormal CSF findings may not be present initially (Bensa, Hadden, Hahn, Hughes, & Wilson; 2000; Hughes & Cornblath, 2005). Neurophysiological examination may include nerve conduction studies to identify demyelination and slowed conduction velocities (Pritchard & Hughes, 2004). Neurodiagnostic imaging might also be performed but is of limited utility in diagnosing GBS. Finally, GBS exclusion often requires diagnostic testing for the exclusion of other possible syndromes and etiologies.

TREATMENT

Intravenous immunoglobin therapies are the first-line course treatment for GBS. Plasmapheresis (plasma exchange) was the previous primary treatment

modality. Continued monitoring in an intensive care-type setting is warranted due to possible complications (e.g., respiratory failure and deep vein thrombosis in nonambulatory individuals). Due to the sudden onset of symptoms, depression and anxiety among patients and family members are to be expected and behavioral health interventions may be warranted. Finally, comprehensive rehabilitation, in addition to immunotherapy, is a primary treatment requirement in patients with GBS to restore premorbid physical and functional status (Hughes & Cornblath, 2005). GBS is potentially fatal, and a number of individuals experience residual effects of the illness lasting up to 2 years, though some reports suggest ongoing disability, including persisting fatigue (Forsberg et al., 2005; Hughes & Cornblath, 2005). Rate of recovery and prognosis are better for younger adults. Michelle R. Pagoria Chad A. Noggle Bensa, S., Hadden. R. D. M., Hahn, A., Hughes, R. A. C., & Wilson, H. J. (2000). Randomized controlled trial of brain-derived neurotrophic factor in Guillain-Barre´ syndrome: A pilot study. European Journal of Neurology, 7, 423–426. Forsberg, A., Press, R., Einarsson, U., de Pedro-Cuesta, J., Holmqvist, L. W. (2005). Disability and health-related quality of life in Guillain-Barre´ syndrome during the first two years after onset: A prospective study. Clinical Rehabilitation, 19, 900–909. Haldeman, D., & Zulkosky, K. (2005). Treatment and nursing care for a patient with Guillain-Barre´ syndrome. Dimensions of Critical Care Nursing, 24, 267–272. Hughes, R. A. C., & Cornblath, D. R. (2005). Guillain-Barre´ syndrome. The Lancet, 366, 1653–1666. Pritchard, J., & Hughes, R. A. C. (2004). Guillain-Barre´ syndrome. The Lancet, 363, 2186–2188.

H HALLERVORDEN–SPATZ DISEASE DESCRIPTION

Hallervorden–Spatz disease (HSD), more recently termed pantothenate kinase-associated neurodegeneration (PKAN), is a rare, progressive, and fatal autosomal recessive disease affecting both adults and children, though some sporadic cases have been cited within the literature. PKAN is characterized by excessive iron accumulation and discoloration of the medial globus pallidus and substantia nigra. Pathological and clinical features of PKAN include extrapyramidal signs (dystonia, rigidity, parkinsonism, and dysarthria), corticospinal tract involvement, pyramidal motor symptoms, optic atrophy, retinal pigmentation, psychiatric manifestations, cognitive deficits, dementia later in the course of the disease, and eventually death. PKAN was first identified in 1922 by Julius Hallervorden and Hugo Spatz. The pair witnessed pigmentation of the basal ganglia in five siblings with progressive dysarthria and dementia. The preferred name, PKAN, evolved from moral concerns raised regarding Hallervorden’s involvement in euthanasia during World War II (Hinkelbein, Kalenka, & Alb, 2006). One hallmark feature of PKAN is the ‘‘eye of the tiger’’ sign observed on T2-weighted MRI, due to bilateral low signal intensities within the globus pallidus and hyperintensity within the central or anteriomedial areas of the pallidum associated with iron accumulation (Hinkelbein et al., 2006). These high signal intensities have also been attributed to spongiosis and neuronal vacuolization (Bindu, Desai, Shehanaz, Nethravathy, & Pal, 2006; Hinkelbein et al., 2006). Worldwide, the incidence of PKAN is estimated to be between 1–3 per million (Freeman et al., 2007; Hinklebein et al., 2006). PKAN appears to affect both genders equally. Although PKAN has been reported in all ethnic groups, the frequency is unknown because it is quite rare (Hinkelbein et al., 2006). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Mutations in the pantothenate- kinase 2 gene (PANK2) on chromosome 20p13 have been identified (Bindu

et al., 2006; Matarin, Singleton & Houlden, 2006). Deficiency of pantothenate kinase may lead to accumulation of cysteine, which in the presence of iron leads to a cytotoxic event causing free radical production (Mendez & Cummings, 2003; Hinkelbein et al., 2006). Postmortem findings reveal cerebral atrophy, pigmentation, and iron accumulation in the globus pallidus and substantia nigra (Freeman et al., 2007). Iron-containing pigment granules, axonal swelling, neuronal loss, gliosis, and demyelination within affected tissues have also been reported (Mendez & Cummings, 2003; Hinkelbein et al., 2006). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Heterogeneity in clinical presentation has been well established, particularly within same-age subtypes. However, literature involving neuropsychological and clinical features of the disease has been limited as PKAN is extremely rare and small sample sizes and case studies predominate within the literature. Disease onset is typically during the first or second decade, though in rare cases it may occur up to the seventh decade (Freeman et al., 2006; Mendez & Cummings, 2003). Disease course is between 10 and 15 years. Although variations between classification systems exist, three variants of PKAN have been identified: (1) early onset childhood type with onset between 1 and 3 years of age (neuroaxonal dystrophy), (2) classic juvenile type with onset between ages 7 and 12, and (3) the more rare adult type (Mendez & Cummings, 2003). Among the early onset childhood type, a study discovered primary motor developmental delays among all participants (10) followed by cognitive decline. The juvenile type displayed more variability in presentation, including more behavioral features (e.g., verbal aggression and depression) in addition to extrapyramidal motor signs, but without developmental delay (Bindu et al., 2006). Neuropsychological assessment findings in PKAN are sparse and have revealed a great deal of variability, though age of onset appears to correlate with disease severity, degree of intellectual impairment, and adaptive functioning, with earlier onset having a poorer prognosis (Bindu et al., 2006; Freeman et al., 2007). Furthermore, diversity in symptom expression has

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made it difficult to capture a clear picture of neuropsychological presentation in patients with PKAN (Freeman et al., 2007). Slow processing speed is common with deficits in visuospatial abilities and memory reported; language may be affected later in the course of the disease (Loring, Sethi, Lee, & Meador, 1990). General intellectual functioning often varies between intact to markedly impaired and is often dependent upon disease progression (Freeman et al., 2007). Within the literature, the presence of dysarthria and neuro-ophthalmologic and motor signs almost universally impact formal neuropsychological assessment procedures making nonstandard administration imperative. Later in the course of the disease, psychiatric manifestations may develop, though one case study of prodromal behavioral symptoms (e.g., anxiety, depression, irritability, mood lability, and verbal aggression) has been identified. These psychiatric manifestations all occurred before the onset of extrapyramidal and pyramidal motor signs, and behavioral symptoms eventually progressed to paranoid delusions that responded well to antipsychotic medications. (Panas et al., 2007). DIAGNOSIS

Prior to the advancement of neuroradiologic imaging, confirmation of PKAN was typically given based on autopsy reports indicating aforementioned iron accumulation and discoloration within the brain or based on clinical presentation. Neurodiagnostic imaging with T2 weighted MRI scans may prove useful in the diagnosis of PKAN, although the hallmark ‘‘eye of the tiger’’ sign may be absent in a very small group of PKAN patients. Most recently, identifying the defect on the arm of chromosome 20 has led to positive diagnosis via genetic markers, and diagnosis based on the pathology results of an affected sibling are also possible. Based on prominent gait disturbance and extrapyramidal signs, differential diagnosis of PKAN includes dementia with Lewy bodies, Parkinson-plus syndromes, progressive supranuclear palsy, Wilson’s disease, normal pressure hydrocephalus, and Huntington’s disease. As such, clinical features including progressive course and neuro-ophthalmologic findings, molecular testing, and MRI findings all remain important in the diagnosis of PKAN, with genetic markers being the most recent advancement in differential diagnosis. TREATMENT

There is no cure for PKAN and no specific treatments exist. Current pharmacological treatments include

muscle relaxants, spasticity agents, and dopaminergic medications to control motor symptoms. Within the literature, stereotactic procedures of pallidotomy, thalamotomy, and bilateral pallidothalamotomy have been reported, but only in a very small number of patients and relief appears to be temporary in nature (Hinkelbein et al., 2006; Mendez & Cummings, 2003). Michelle R. Pagoria Chad A. Noggle Bindu, P. S., Desai, S., Shehanaz, K. E., Nethravathy, M., & Pal, P. K. (2006). Clinical heterogeneity of HallervordenSpatz syndrome: A clinicoradiological study in 13 patients from South India. Brain and Development, 28, 343–347. Freeman, K., Gregory, A., Turner, A., Blasco, P., Hogarth, P., & Hayflick, S. (2007). Intellectual and adaptive behaviour functioning in pantothenate kinase-associated neurodegeneration. Journal of Intellectual Disability Research, 51, 417–426. Hinkelbein, J., Kalenka, A., & Alb, M. (2006). Anesthesia for patients with pantothenate-kinase-associated neurodegeneration (Hallervorden-Spatz disease) — a literature review. Acta Neuropsychiatrica, 18, 168–172. Loring, D. W., Sethi, K. D., Lee, G. P., & Meador, K. J. (1990). Neuropsychological performance in HallervordenSpatz syndrome: A report of two cases. Neuropsychology, 4, 191–199. Matarin, M. M., Singleton, A. B., & Houlden, H. (2006). PANK2 gene analysis confirms genetic heterogeneity in neurodegeneration with brain iron accumulation (NBIA) but mutations are rare in other types of adult neurodegenerative disease. Neuroscience Letters, 407, 162–165. Mendez, M. F., & Cummings, J. L. (2003). Dementia: A clinical approach. (3rd ed.). Philadelphia: ButterworthHeinemann. Panas, M., Spengos, K., Koutsis, G., Tsivgoulis, G., Sfagos, K., Kalfakis, N., et al. (2007). Psychosis as presenting symptom in adult-onset Hallervorden-Spatz syndrome. Acta Neuropsychiatrica, 19, 122–124.

HEMICRANIA CONTINUA DESCRIPTION

Hemicrania continua, also known as chronic paroxysmal hemicrania, is a primary headache disorder that is characterized by continuous pain occurring on one side of the face and varying in severity. Relatively

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rare, the presentation is marked by a combination of autonomic and migraine-like features. Furthermore, it is categorized by whether the headaches are continuous or remitting. Although the clinical features of hemicrania continua are suggestive of diagnosis, complete response to indomethacin is considered definitive of the presentation in comparison with other primary headache disorders. Women are affected more often than men with a relative ratio of 7:1 (Silberstein & Young, 2007). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The pathological basis of hemicrania continua remains unknown. Autonomic dysfunction has been proposed as the most likely basis for the presentation (Russell & Vincent, 2000). It has not been associated with characteristic findings on structural imaging (e.g., MRI or CT) or functional techniques (e.g., functional magnetic resonance imaging or positron emission tomography). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Hemicrania continua is classified as a largely unremitting headache presenting on one side of the face and varying in severity. Although the pain is usually unremitting as patients will report a continuous dull ache between attacks, individuals will commonly have acute episodes of short, stabbing headaches that are in addition to that which is continuously experienced. Some individuals will demonstrate a period of remission in which no headaches are experienced for several weeks or months but upon relapse will manifest persistent headaches in upwards of 6 continuous months. The features of hemicrania continua are divided into two categories, autonomic and migrainous. In regard to the prior, individuals may develop nose bleeds and/or stuffiness, runny nose, increased perspiration and/or tearfulness, and eye irritation (Silberstein & Young, 2007). In terms of migrainous symptoms, individuals may manifest phonophobia or photophobia in addition to nausea. The symptoms may be exacerbated by, but not limited to, fatigue, physical exertion, stimulants such as caffeine, and/ or alcohol. Flexing, rotating, or applying pressure to the upper portion of the neck may serve as a trigger in 10% of patients (Russell & Vincent, 2000). DIAGNOSIS

Diagnosis is commonly made based on symptom description; however, given that there is considerable clinical overlap with other primary headache

syndromes, this is not considered definitive. Rather, full response to indomethacin is considered diagnostic. This helps differentiate hemicrania continua from shortlasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) headaches, which are relatively similar in presentation aside from being shorter in duration and occurring more frequently over the course of an hour (Silberstein & Young, 2007). As with other primary headache syndromes, diagnostic workup should include neuroimaging to evaluate for and rule out structural anomalies including tumors, aneurysms, or other arteriovenous malformations, as well as other neurological entities. TREATMENT

Indomethacin is the established treatment for hemicrania continua. In fact, as previously noted, complete response to the agent is itself considered diagnostic. Other commonly used NSAIs may provide some symptom relief but generally not to the same degree as indomethacin. In addition, some patients will demonstrate significant symptom response to tricyclic antidepressants. Beyond these intervention-based methods, preventive measures may also be employed. In particular, ‘‘triggers’’ of headaches should be avoided such as alcohol and particular forms of physical exertion. Chad A. Noggle Javan Horwitz Russell, D., & Vincent, M. (2000). Chronic paroxysmal hemicrania. In J. Olesen, P. Tfelt-Hansen, & K. M. A. Welch (Eds.), The headaches (2nd ed., pp. 741–750). Philadelphia, PA: Lippincott Williams & Wilkins. Silberstein, S. D., & Young, W. B. (2007). Headache and facial pain. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 1245–1266). Philadelphia, PA: Saunders Elsevier.

HEMIFACIAL SPASM DESCRIPTION

Hemifacial spasm (HFS) is a movement disorder arising from vascular compression of the seventh cranial facial nerve as it exits the brainstem. Primary HFS involves compression of the facial nerve by an adjacent artery (anterior inferior cerebellar artery, posterior inferior cerebellar artery, or vertebral artery), but in rare instances secondary causes include

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space-occupying lesion in the cerebellopontine angle, aneurysm, arteriovenous malformations (AVM), tumors within the posterior fossa, and inflammation owing to demyelinating conditions (Colosimo et al., 2006; Glocker, Krauss, Deuschl, Seeger, & Lu¨cking, 1998; Mauriello et al., 1996; Sato, Ezura, Takahashi, & Yoshimoto, 2001). As the name suggests, HFS presents as unilateral and involuntary tonic–clonic spasms and contractures of the facial nerve (Huh, Han, Moon, Chang, & Chang, 2008). HFS is a disorder affecting adults and is more common in women, with a prevalence of 14.5 per 100,000 American women and 7.4 per 100,000 American men. Asian populations also appear to have an increased incidence (Tan, Tan, & Khin, 2003). Familial cases of HFS are rare, but do exist (Wilkins, 1991). HFS generally occurs in the fourth or fifth decade with a mean age of onset of 45 years (Mauriello et al., 1996). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Chronic and focal compression of the facial nerve by an aberrant vessel further causes demyelination of nerve fibers. This causes hyperexcitability of adjacent nerve fibers via ephaptic (false) transmission. It remains controversial as to whether this represents an ephaptic transmission at the nuclear level or at the site of compression (Glocker et al., 1998). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Neuropsychological data of HFS was not available for review, though HFS is generally considered troubling to those affected due to social embarrassment. In some cases, binocular vision may be affected and interfere with routine tasks such as driving, reading, and writing (Wilkins, 1991). DIAGNOSIS

Diagnosis of HFS is made via observation of abnormal facial movements. It is important to rule out the following: blepharospasm, facial myokymia, facial tic, facial spasm of a psychogenic etiology, involvement due to lower motor neuron condition (Bell’s palsy), focal seizures, and tardive dyskinesia. Secondary causes of HSF, such as space occupying lesions, AVM, and aneurysm, should also be considered and warrant routine CT, MRI, and angiography studies in suspected cases (Wilkins, 1991), particularly when atypical features of facial numbness or weakness

are present. Electrophysiological studies are also recommended due to characteristic latency of response witnessed in HFS sufferers (Glocker et al., 1998).

TREATMENT

Spontaneous recovery of HFS is uncommon and surgical intervention via microvascular decompression (MVD) is the most widely accepted treatment. Primary risks include ipsilateral deafness and facial palsy that may be transient but in rare cases permanent (Wilkins, 1991). Recovery of symptoms following MVD may be incomplete with some experiencing a recurrence of symptoms. Recovery from auditory dysfunction appears to be somewhat slower than recovery from facial palsy. Finally, the more immediate and greater severity of facial nerve palsy and auditory dysfunction, the greater the likelihood for persistent and permanent damage. Other cranial nerve damage, including vocal cord paralysis, hoarseness, dysphagia, and surgical complications (e.g., intracranial bleed, wound infection, meningitis, vertebral artery injury) have also been reported (Huh et al., 2008). For patients who suffer postoperative complications of facial muscles, steroid medications and physical therapy may be introduced (Huh et al., 2008; Wilkins, 1991). Pharmacological treatments, such as haloperidol, carbamazepine, baclofen, and clonazepam, have been studied in HFS, but with limited efficacy (Wilkins, 1991). Another researcher also reported successful treatment of HFS owing to rare fusiform aneurysm via intravascular embolization and coiling procedure (Sato et al., 2001). Monitoring auditory evoked potentials during surgery is also suggested for improved outcomes and to minimize postoperative complications of ipsilateral hearing loss. Michelle R. Pagoria Chad A. Noggle Colosimo, C., Bologna, M., Lamberti, S., Avanzino, L., Marinelli, M., Fabbrini, G., et al. (2006). A comparative study of primary and secondary hemifacial spasm. Archives of Neurology, 63, 441–444. Glocker, F. X., Krauss, J. K., Deuschl, G., Seeger, W., & Lu¨cking, C. H. (1998). Hemifacial spasm due to posterior fossa tumors: The impact of tumor location on electrophysiological findings. Clinical Neurology and Neurosurgery, 100, 104–111. Huh, R., Han, I. B., Moon, J. Y., Chang, J. W., & Chung, S. S. (2008). Microvascular decompression for hemifacial spasm: Analysis of operative complications in 1582 consecutive patients. Surgical Neurology, 69, 153–157.

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Mauriello, J. A., Leonee, T., Dhillon, S., Pakeman, B., Mostafavi, R., & Yepez, M. C. (1996). Treatment choices for 119 patients with hemifacial spasm over 11 years. Clinical Neurology and Neurosurgery, 98, 213–216. Sato, K., Ezura, M., Takahashi, A., & Yoshimoto, T. (2001). Fusiform aneurysm of the vertebral artery presenting hemifacial spasm treated by intravascular embolization: Case report. Surgical Neurology, 56, 52–55. Tan, N. C., Tan, E. K., & Khin, L. W. (2003). Diagnosis and misdiagnosis of hemifacial spasm: A clinical and video study. Journal of Clinical Neuroscience, 11, 142–144. Wilkins, R. H. (1991). Hemifacial spasm: A review. Surgical Neurology, 36, 251–277.

HEREDITARY SPASTIC PARAPLEGIA DESCRIPTION

The hereditary spastic paraplegias (HSPs) encompass a group of neurodegenerative diseases characterized mainly by progressive spasticity and weakness of the lower limbs. The term HSP has been used interchangeably with ‘‘Strumpell–Lorrain disease’’ or ‘‘diplegia’’ in the literature, but these alternatives have become increasingly less common (Ropper & Brown, 2005). A relatively rare disease, its prevalence has been estimated to be between 2 and 9.6 cases per 100,000 individuals (Klebe et al., 2004). The HSPs have been classified into 24 genetically different types, among which there are autosomal-dominant, autosomalrecessive, and X-linked recessive types (Brust, 2006). HSPs are typically classified based on the absence (i.e., uncomplicated or pure HSP) or presence (i.e., complicated) of neurological or clinical features (Cimolin et al., 2007). Most patients with pure HSP are autosomal dominant, whereas complicated forms are autosomal recessive (Salinas, Proukakis, Crosby, & Warner, 2008). The first clear description of HSP was published by Strumpell in Germany in 1880, though Selligmuller had described a similar disorder 6 years prior (Harding, 1981; Ropper & Brown, 2005). Strumpell reported two brothers similarly affected with HSP at the ages of 37 and 56 years (Harding, 1981; McDermott, White, Bushby, & Shaw, 2000). The brothers’ father was suspected to have passed the disorder to his sons, indicating autosomal-dominant transmission (Harding, 1981; McDermott et al., 2000). Although the reflexes in the upper limbs were increased, the most observed abnormality was in their legs (Harding, 1981). Lorrain also made a significant contribution to the early understanding of HSP, documenting pure forms of

the disease much like Strumpell (McDermott et al., 2000). However, the definition of pure HSP varied from study to study with some including clinical features, such as pigmentary retinal degeneration and mental retardation, later associated with complicated HSP (Harding, 1981). It was not until 1981 that is was suggested that the HSPs be divided into complicated and uncomplicated forms (Harding, 1981). Type I was used to refer to those with an age of onset before age 35, exhibiting delays in walking and spasticity of the lower limbs, and Type II was used to describe those with later onset after age 35, who exhibited more marked muscle weakness, urinary difficulties, and sensory loss (Harding, 1981). Type I patients were found to exhibit a slower, more variable course in comparison to more rapidly symptomatic Type II patients (Harding, 1981). Harding’s initial classification did not uphold; with many families not meeting his criteria, patients began to be grouped based on presentation in his early work. Harding (1981) also suggested that more than one gene was attributable to HSP, with the core deficit identified as spasticity rather than weakness. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Although there are autosomal-dominant, autosomalrecessive, and X-linked recessive types of HSP, the most common is autosomal dominant, occurring in about 80% of HSP patients (Klebe et al., 2004). To date, at least 41 spastic paraplegia gene (SPG) loci have been found, with 17 genes associated with HSP (Salinas et al., 2008). The autosomal-dominant type has been linked to chromosomes 2q, 8q, 14q, and 15q, with 2q most common and frequently associated with dementia signs (Ropper & Brown, 2005). Mutations in 10 loci are associated with autosomal-dominant pure HSP: SPG3A, SPAST (formerly SPG4), SPG6, SPG8, SPG10, SPG12, SPG13, SPG19, SPG31, and SPG33 (Depienne, Stevanin, Brice, & Durr, 2007; Salinas et al., 2008). The SPAST gene is most frequently involved, accounting for 40% of cases (Depienne et al., 2007). In autosomal-dominant complicated HSP, alterations in SPG3A, SPAST, SPG9, SPG10, SPG17, and SPG29 have been found (Salinas et al., 2008). The recessive type is associated with chromosomes 8p, 15q, and 16q, 15q being most frequent (Ropper & Brown, 2005). In autosomal-recessive pure HSP, associated loci are SPG5A, SPG7, SPG11, SPG27, and SPG28 (Salinas et al., 2008). Mutation in SPG7, SPG11, SPG14, SPG15, SPG20, SPG21, SPG23, SPG24, SPG25, SPG26, SPG27, SPG28, and SPG30 have been reported relating to autosomal-recessive complicated HSP (Salinas et al., 2008). Loci associated with X-linked

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transmission include SPG1, SPG2, and SPG16 (Depienne et al., 2007). The main neurological correlate of HSP is progressive spasticity of the lower limbs attributed to pyramidal tract dysfunction (Depienne et al., 2007). Such dysfunction leads to retrograde degeneration of the corticospinal tracts and posterior columns (Depienne et al., 2007; Ropper & Brown, 2005; Salinas et al., 2008). Axonal degeneration of motor and sensory neurons is most noted at the distal ends of the longest axons within the central nervous system, which innervate the lower extremities (Depienne et al., 2007; McDermott et al., 2000). Patients with pure HSP typically evidence axonal degeneration of the distal portions of the corticospinal tracts, the fasciculus gracilis, and the spinocerebral tracts (Crosby & Proukakis, 2002). Thinning of the columns of Goll, most prominent in the lumbosacral regions and the spinocerebellar tracts, is found (Ropper & Brown, 2005). There is a reduction in the number of Betz and anterior horn cells (Ropper & Brown, 2005). Mitochondrial dysfunction is documented as the second most common cause of HSP (Depienne et al., 2007). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Presentation of HSP is always subtle but highly variable. The age of onset ranges from infancy to the eighth decade (Brust, 2006). There is gradual development of spastic leg stiffness or weakness, with patients evidencing increasing gait disturbances and trouble walking (Cimolin et al., 2007; Ropper & Brown, 2005). Those with more severe muscle tissue degeneration, particularly in the upper limbs, typically evidence symptoms for more than 15 years (Harding, 1981). Clinical features include hyperreflexia, extensor plantar reflexes, and weakness of pyramidal distribution in the lower limbs (Cimolin et al., 2007; Ropper & Brown, 2005). Children often exhibit delays in walking or ‘‘toe-walk,’’ attributed to underdeveloped legs, arched and shortened feet, and a shortening of the calf muscles (Cimolin et al., 2007; Ropper & Brown, 2005). The knees may appear slightly flexed, or adducted and fully extended (Ropper & Brown, 2005). Sensory loss in the feet has been reported (Salinas et al., 2008). Sphincteric function is usually normal but has been linked to HSP (i.e., vesicoureteric reflux, urinary frequency and urgency, bladder sacculation) and correlated with disease duration (Harding, 1981; Ropper & Brown, 2005). Other characteristics can include nystagmus, ocular palsies, optic atrophy, pigmentary macular degeneration, ataxia, sensorimotor

polyneuropathy, ichthyosis, patchy skin pigmentation, epilepsy, and dementia (Ropper & Brown, 2005). Pure versus complicated forms of HSP is distinguished based on presentation. Among patients who present with pure HSP, symptoms are usually confined to spastic paresis (Cimolin et al., 2007). Other features of pure HSP may include upper limb hyperreflexia, impaired lower limb vibratory sensation, Babinski signs, and urinary urgency and frequency (Brust, 2006; Cimolin et al., 2007). In pure HSP, nervous system and sensory functioning are normal (Ropper & Brown, 2005). Those with pure HSP initially present with upper motor neuron dysfunction, with later stages of the disorder associated with diminished vibration sense, sensory impairment, and urinary sphincter disturbance (Klebe et al., 2004). Complicated HSP has been associated with such co-occurring clinical features as peripheral neuropathy, ataxia, retinal pigmentary degeneration, deafness, optic atrophy, mental retardation, seizures, mental retardation, dementia, and extrapyramidal signs (Brust, 2006; Cimolin et al., 2007). DIAGNOSIS

A diagnosis of HSP is typically dependent upon family history, the presence or absence of clinical and neurological features, progression of symptoms, and the exclusion of other nongenetic causes of observed spasticity (Depienne et al., 2007). Cerebral and spinal MRI is necessary to rule out other conditions and to determine whether cerebellar or corpus callosum atrophy and/or white matter abnormalities exist, characteristic of HSP (Depienne et al., 2007). MRI of the lumbar or thoracic spinal cord may show thinning, and somatosensory evoked potentials may show delayed conduction when stimulating the legs (Brust, 2006). Magnetostimulation of the corticospinal tract usually shows reduced conduction velocities and evoked potentials in their legs (Brust, 2006). Genetic testing is possible to test in utero or among those suspected, but genetic markers have been found only in less than half of the genetic subtypes (Brust, 2006). Screening regarding SPAST and SPG3A can be used to detect over 50% of autosomal-dominant pure HSP cases (Salina et al., 2008). Diagnoses to disregard when HSP is suspected can be evaluated based on age of onset. Other diagnoses to consider with a childhood onset include cerebral palsy, Chiari malformation, leucodystrophy, arginase deficiency, abetalipoproteinemia, levadoparesponse dystonia, myelitis, and multiple sclerosis (Salinas et al., 2008). If during the 1st year of symptomatology delayed motor milestones present, cerebral

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palsy may be probable (Salinas et al., 2008). With an adult onset, diagnoses to consider are cervical spine degenerative disease, multiple sclerosis, motor neuron disease, neoplasm, myelitis, dural arteriovenous malformation, Chiari malformation, adrenoleucodystrophy, syphilis, copper deficiency, levadopa-response dystonia, lathyrism, spinocerebellar ataxia, and vitamin deficiency (i.e., B12 and E) (Salinas et al., 2008). If a sporadic case of spastic paraplegia is evidenced after the age of 20 without a family history, HSP should be considered only as a rule out (Salinas et al., 2008). If there is more of an acute onset rather than progressive, as with HSP, vascular or inflammatory causes should be suspected (Salinas et al., 2008). Tests for very long chain fatty acids, white cell enzymes, plasma amino acids, serum lipoprotein analysis, vitamins B12 and E, copper and ceruloplasmin, serum serology, human T-cell leukemia virus 1, and human immunodeficiency virus can be used to indicate causes other than HSP (Salinas et al., 2008). TREATMENT

No therapy has been found to reduce the progression of HSP (Klebe et al., 2004). However, Harding (1981) found that among HSP patients, only a few had to stop working due to the disorder. HSP did not appear to decrease life expectancy, but quality (Harding, 1981). Drugs suggested to reduce clonus and muscle tightness include benzodiazepines, baclofen, tizanidine, dantrolene, and botulinum toxin type A (Botox) injections (Fink, 2003). To reduce urinary urgency in patients, 5 mg oxybutynin, taken 2–3 times per day, or extended release oxybutynin, taken once per day in a dose varying from 5 to 30 mg, may be used (Brust, 2006). Regular physical therapy is recommended to reduce deconditioning, improve cardiovascular fitness, improve muscle strength and gain, and reduce spasticity. Physical therapy may also be suggested to prevent such complications as contractures and preserve the patient’s functioning (Brust, 2006; Klebe et al., 2004). Some patients may qualify for chemodenervation to reduce muscle overactivity (Fink, 2003). Occupational therapy may be necessary, particularly when walking becomes too difficult. Jessica Holster Charles Golden Brust, J. C. (2006). Current diagnosis and treatment in neurology. New York: McGraw-Hill. Cimolin, V., Piccinini, L., D’Angelo, M. G., Turconi, A. C., Berti, M., Crivellini, M., et al. (2007). Are patients with hereditary spastic paraplegia different from patients

with spastic diplegia during walking? Gait evaluation using 3D gain analysis. Functional Neurology, 22, 23–28. Crosby, A. H., & Proukakis, C. (2002). Is the transportation highway the right road for hereditary spastic paraplegia? Am J Hum Genet 71, 1009–1016. Depienne, C., Giovanni, S., Brice, A., & Durr, A. (2007). Hereditary spastic paraplegias: An update. Current Opinion in Neurology, 20, 674–680. Fink, J. K. (2003). Advances in the hereditary spastic paraplegias. Experimental Neurology, 184, 106–110. Harding, A. E. (1981). Hereditary pure spastic paraplegia: A clinical and genetic study of 22 families. Journal of Neurology, Neurosurgery & Psychiatry, 44, 871–883. Klebe, S., Stolze, H., Kopper, F., Lorenz, D., Wenzelburger, R., Volkmann, J., et al. (2004). Gain analysis of sporadic and hereditary spastic paraplegia. Journal of Neurology, 251, 571–578. McDermott, C. J., White, K., Bushby, K., & Shaw, P. J. (2000). Hereditary spastic paraparesis: A review of new development. Journal of Neurology, Neurosurgery & Psychiatry, 69, 150–160. Ropper, A. H., & Brown, R. H. (2005). Adams and Victor’s principles of neurology (8th ed.). New York: McGraw-Hill. Salinas, S., Proukakis, C., Crosby, A., & Warner, T. T. (2008). Hereditary spastic paraplegia: Clinical features and pathogenetic mechanisms. The Lancet Neurology, 7, 1127–1138.

HERPES ZOSTER OTICUS DESCRIPTION

Herpes zoster (HZ) is a reactivation of a latent chicken pox (varicella) virus. Zoster is a rash, blister, or lesion, usually painful, occurring in older adults (Harpaz, Ortega-Sanchez, & Seward, 2008.) As such, this disease may occur in anyone with a history of the chicken pox infection. HZ oticus is also usually called Ramsay Hunt syndrome. Some feel that only when facial paralysis is also present should the disorder be called Ramsay Hunt syndrome (Harpaz et al., 2008; Sweeney & Gilden, 2001). It develops when there is involvement of the facial and auditory nerves. One usually sees inflammation of the external ear and facial paralysis. These features are usually transitory. There is also involvement of the inner ear, the auditory nerve, the facial nerve, and at times the ninth and tenth cranial nerves. The symptoms can include hearing loss, vertigo, loss of taste, and tongue vesicles (Cunningham et al., 2008).

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The defining feature of HZ oticus is the reactivation of the varicella zoster virus (VZV) within the eighth facial nerve. The VZV will have lain dormant in the sensory or dorsal root ganglion since the initial outbreak of chicken pox, most often during childhood (Harpaz et al., 2008). When the geniculate ganglion is involved, facial paralysis develops (Crabtree, 1974). Hunt (1904) described the geniculate ganglion as comprised of the tympanic membrane, external auditory canal, tragus, antitragus, concha, parts of the helix, and parts of the lobule. The localization of the zoster eruption is dependent on which sensory afferent fibers flare up. Most often the seventh (facial) and eighth (auditoryvestibular) cranial nerves are involved. As a result, for example, among acute cases sensorineural hearing loss occurs in 10% of individuals and vestibular symptoms occur in 40% of individuals (Syal, Tyagi, & Goyal, 2004).

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The initial presenting symptom is usually otalgia and a burning sensation deep within the ear. In addition, within 1 to 4 days there will be an eruption of painful blisters in or around the external auditory canal. Eruptions can also occur on the face, neck, trunk, in the mouth, or on the tongue. Other reported symptoms include facial drooping, vertigo, decreased or loss of hearing, and tinnitus. At times, pain in the eye and lacrimation may also occur. Because the geniculate ganglion is affected there is also a decrease in taste sensation and decreased salivation.

DIAGNOSIS

Most often, the diagnosis relies on presenting clinical features such as varicelli form rash and otalgia, which must be present in order to make a diagnosis of HZ oticus. The history and neurological examination are of paramount importance. These along with the pain and other clinical features (facial drooping, sores on the tongue, hearing problems, vesicles on the pinna) contribute to the diagnosis. In addition it can be helpful to use the Tzanck preparation that requires a zoster to be scraped for cells. This method is difficult in that it is a struggle to obtain a valid specimen if the outbreak is located in the ear canal. When the preparation is positive the specimen contains multinucleated giant cells.

Also, vesicular fluid can be obtained and combined with human diploid fibroblasts, and after 3–5 days the presence of giant multinucleated cells also support a positive diagnosis. Several other medical conditions can mimic HZ oticus symptoms, and it is important to rule out the following possible conditions: Bell’s palsy, HZ, otitis externa, otitis media, hemorrhagic or ischemic stroke, and cluster, migraine, or tension headaches (Bloem, Doty, & Hirshon, 2008).

TREATMENT

The most common treatment for HZ oticus is the use of antiviral medications that often result in House– Brackmann Grade III recovery (Cunningham et al., 2008). The use of oral steroids has also proven to be effective in reducing posthepatic neuralgia and enhancing facial nerve recovery when combined with antiviral therapy (Murakami et al., 1997). Symptomrelated therapy (e.g., analgesic, antibiotics for secondary infection) is also recommended, but if the condition persists care to avoid addiction should be implemented. Henry V. Soper Teri J. McHale Bloem, C., Doty, C., & Hirshon, J. (2008, November 4). Herpes zoster oticus. Retrieved from http://emedicine.medscape.com/article/783332 Crabtree, J. (1974). Herpes zoster oticus and facial paralysis. Otolaryngol Clinics of North America, 7, 369–373. Cunningham, A., Breuer, J., Dwyer, D., Gronow, D., Helme, R., Myron, J., et al. (2008). The prevention and management of herpes zoster. The Medical Journal of Australia, 188(3), 171–176. Harpaz, R., Ortega-Sanchez, I., & Seward, J. (2008, June 06). Prevention of herpes zoster: Recommendations of the advisory committee on immunization practices (ACIP). Retrieved from http://www.cdc.gov/mmwr/preview/ mmwrhtml/rr57e0515al.htm Hunt, J. (1904). Herpetic inflammation of the geniculate ganglion. A new syndrome and its complication. Journal of Nervous and Mental Disorder, 34, 73–96. Murakami, S., Hato, N., Horiuchi, J., Honda, N., Gyo, K., & Yangihara, N. (1997). Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: Significance of early diagnosis and treatment. Annals of Neurology, 41, 353–357. Sweeney, C., & Gilden, D. (2001). Ramsay Hunt syndrome. Journal of Neurology, Neurosurgery and Psychiatry, 71, 149–154.

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Syal, R., Tyagi, I., & Goyal, A. (2004). Bilateral Ramsay Hunt syndrome in a diabetic patient. BMC Ear, Nose and Throat Disorders, 4, 3.

HIV/AIDS DEMENTIA COMPLEX DESCRIPTION

Numerous labels have been synonymously applied to the debilitating cognitive, motor, language, and behavioral impairments associated with HIV infection, such as AIDS dementia complex, HIV dementia, and HIV encephalopathy. Recently, the term HIVassociated dementia (HAD) has been employed to characterize the cluster of the most severe symptoms that are to be distinguished from mild cognitive motor disorder (MCMD) (Antinori et al., 2007). The development of highly active antiretroviral therapy (HAART) changed management of HIV and hence the progression of HAD. Prior to HAART, HAD was typically observed in the late stages of AIDS and was indicative of morbidity and mortality. In some instances, HAD was evidenced in 50% of AIDS patients prior to their death (Ances & Ellis, 2007). The annual incidence of HAD in Western countries prior to HAART was 7%, with a cumulative risk of 5% to 20% (McArthur, 2004). Although the incidence of HAD began declining after HAART, the prevalence rate of individuals with HAD and MCMD has been increasing in some samples, likely due to the increased life span of HIV-infected individuals. In some research, a prevalence rate of 37% for HAD and MCMD was found among individuals even with HAART (Sacktor, 2002; Schifitto et al., 2002). However, rapidly progressive dementia is less commonly observed in the post-HAART era. Instead, chronic and fluctuating forms of HAD are more widespread, and in 4% to 15% of patients, HAD is the presenting clinical manifestation of HIV (McArthur, 2004). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The development of dementia is typically delayed until severe immunodeficiency develops. After its onset, the progression of HAD is variable (Bouwman et al., 1998). HIV enters the central nervous system (CNS) early by infecting macrophages and monocytes and transporting the virus across the blood brain barrier. The overproduction of various proinflammatory cytokines and chemokines yields neurotoxic agents

that create an inflammatory environment by activating uninfected microglia that damage surrounding astrocytes and neurons (Brabers & Nottet, 2006). Although HIV does not directly infect the neuron, the proinflammatory neurotoxins ultimately impair cellular functioning and provoke change in neuronal functioning. Results from immunohistochemistry research have revealed that the virus is most densely located in the basal ganglia (and dopaminergic system), subcortical regions, and frontal cortex. Similarly, pathological changes at autopsy are predominantly subcortical, involving the deep gray and white matter regions. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Research indicates that the neuropsychological profile of HAD follows the neuropathology and is most consistent with a subcortical process that often involves psychomotor slowing, motor weakness, poor attention and working memory, reduced fluency, executive dysfunction, and decreased learning and memory functioning (Grant, 2008; Nath, Schiess, Rumbaugh, Sacktor, & McArthur, 2008). As such, the most comprehensive neuropsychological test battery for HAD identification would assess all areas of cognitive functioning, including current and premorbid intellectual ability, attention, verbal abilities, visuospatial functions, learning and memory, psychomotor and motor abilities, executive functioning, and personality. However, individual test-taker characteristics must be appreciated, such as sensory limitations, significant fatigue, and/or physical restrictions, any of which may render a lengthy battery impractical, and, thus, warrant modification. Also, as with any assessment, neuropsychological evaluation of HAD requires consideration of factors that can influence test performance, such as age, education, culture, gender, practice effects, and the individual’s motivation (Grant, 2008). Neuropsychological tests such as the Trail Making Test — Part B (a measure of speed, attention, and subcortical processing), the California Verbal Learning Test — II (a measure of learning and memory), and the Timed Gate Test are particularly relevant given the indication of preferential impairment of psychomotor speed and memory in HAD (Lopez et al., 1994; Nath et al., 2008; Roos, 2005). For an example of a comprehensive neuropsychological battery to evaluate HIV-related neurocognitive compromise, refer to van Gorp and Root (2008). Recognizing that early HAD may mimic a variety of psychiatric conditions, particularly major depressive disorder (MDD) (e.g., note the overlapping

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symptoms such as apathy, forgetfulness, impaired attention), prudent differential diagnostic skills are essential. However, if both HAD and MDD are suspected, an individual should be reevaluated for HAD when his/her depression has remitted. Despite the frequent comorbidity, there is little evidence that pseudodementia in HAD exists, and cognitive deficits generally do not improve with treatment of depression (Antinori et al., 2007). DIAGNOSIS

HAD is a diagnosis of exclusion that is further complicated by the fact that neurocognitive tests may be nonspecific, and deficits may or may not be present in neurologically asymptomatic patients with HIV. Thus, HAD is particularly difficult to diagnose. In 2007, Antinori et al. proposed that HAD required deficits in two or more cognitive domains, such as attention, memory, and/or abstract reasoning, causing impairment in activities of daily living and an abnormality in either motor or neurobehavioral function. Also, any other etiology of dementia should be ruled out, and there should be an absence of delirium. It is essential to differentiate, as soon as possible, between individuals with HAD and those with MCMD, the latter of whom have decreased function in two cognitive or behavioral domains but are not impaired severely enough to meet the criteria for HAD. Differentiation must also be made between the even less significantly impaired individuals with asymptomatic neurocognitive impairment (ANI). When evaluating for HAD, any other confounding and/or compounding etiology must be ruled out, such as metabolic and infectious etiologies, psychiatric conditions, substance abuse, opportunistic diseases such as progressive multifocal leukoencephalopathy (PML) or toxoplasmosis, systemic infections, toxicmetabolic states, and adverse medication effects. Although in the early stages of HAD, any or all of the available measures may result in unremarkable findings, there are a variety of methods to assist in the diagnosis of HAD. These include laboratory studies, neuroimaging, EEG, and/or neuropsychological testing. For example, EEG may be used to rule out subclinical seizures that are mimicking dementia. Cerebrospinal fluid (CSF) analyses may be used to exclude CNS infection and to provide useful data regarding potential immunological markers of HAD. Neuroimaging such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) may detect decreased metabolism in the thalamus and basal ganglia in the early stages of HAD. CT and MRI scans can reveal brain atrophy, ventricular

enlargement, and increased white matter signal in later stages of the dementia, or assist in identifying other pathology such as that caused by PML. Generally, the degree of cerebral atrophy correlates with the symptoms and progression of HAD. Neuropsychological testing is particularly valuable in the early screening of asymptomatic high-risk patients (e.g., those with high viral load and low CD4 count) as well as for follow-up evaluations of patients already diagnosed with HAD (Glass & Wesselingh, 1998). One of the most widely accepted and efficient screening tools for HAD is the HIV Dementia Scale, which can yield a total of 12 points — a score less than 6 points is considered abnormal (Power, Selnes, Grim, & McArthur, 1995). The Memorial Sloan–Kettering Rating Scale merges functional ability results with the findings from neuropsychological testing and is helpful for clinical staging of HAD from 0 (normal) to 4 (end stage) (Price & Brew, 1988).

TREATMENT

Several cohort studies have shown that treatment with multiple antiretroviral agents is superior to either no treatment or monotherapy in patients with HAD (McArthur, 2004). Targeting the pathophysiology by using antiretroviral agents with CNS penetration is essential. Some symptoms of HAD may be reversed, and symptom severity may be attenuated by HAART (Nath et al., 2008). Also, cognitive symptoms may be addressed through the use of psychostimulants, which may be particularly effective for early HAD symptoms such as psychomotor slowing and attention deficits (Hinkin et al., 2001). Neuroleptics may be more effective for later-stage HAD. Cognitive skills training and rehabilitation may be employed, and as with any condition, supportive caregivers are vital. Chriscelyn Tussey Jason R. Freeman Ances, B. M., & Ellis, R. J. (2007). Dementia and neurocognitive disorders due to HIV-1 infection. Seminars in Neurology, 27(1), 86–92. Antinori, A., Arendt, G., Becker, J. T., Brew, B. J., Byrd, D. A., & Cherner, M. (2007). Updated research nosology for HIV-associated neurocognitive disorders. Neurology, 69(18), 1789–1799. Bouwman, F. H., Skolasky, R., Hes, D., Selnes, O. A., Glass, J. D., Nance-Sproson, T. E., et al. (1998). Variable progression of HIV-associated dementia. Neurology, 50, 1814–1820.

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Brabers, N. A., & Nottet, H. S. (2006). Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIVassociated dementia. European Journal of Clinical Investigation, 36(7), 447–458. Glass, J. D., & Wesselingh, S. L. (1998). Viral load in HIVassociated dementia. Annals of Neurology, 44(1), 150–151. Grant, I. (2008). Neurocognitive disturbances in HIV. International Review of Psychiatry, 20(1), 33–47. Hinkin, C. H., Castellon, S. A., Hardy, D. J., Farinpour, R., Newton, T., & Singer, E. (2001). Methylphenidate improves HIV-1-associated cognitive slowing. Journal of Neuropsychiatry and Clinical Neuroscience, 13, 248–254. Lopez, O., Becker, J., Dew, M., Banks, G., Dorst, S., & McNeil, M. (1994). Speech motor control disorder after HIV infection. Neurology, 44, 2187–2189. McArthur, J. C. (2004). HIV dementia: An evolving disease. Journal of Neuroimmunology, 157(1–2), 3–10. Nath, A., Schiess, A. V., Rumbaugh, J., Sacktor, N., & McArthur, J. (2008). Evolution of HIV dementia with HIV infection. International Review of Psychiatry, 20(1), 25–31. Power, C., Selnes, O. A., Grim, J. A., & McArthur, J. C. (1995). The HIV dementia scale: A rapid screening test. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology: Official Publication of the International Retrovirology Association, 8(3), 273–278. Price, R. W., & Brew, B. J. (1988). The AIDS Dementia complex. The Journal of Infectious Diseases, 158, 1079–1083. Roos, K. (2005). Principles of neurologic infectious diseases. New York: McGraw Hill. Sacktor, N. (2002). The epidemiology of human immunodeficiency virus-associated neurological diseases in the era of highly active antiretroviral therapy. Journal of Neurovirology, 8(Suppl. 2), 115–121. Schifitto, G., McDermott, M. P., McArthur, J. C., Marder, K., Sacktor, N., Epstein, L., et al. (2002). Incidence of and risk factors for HIV-Associated distal sensory polyneuropathy. Neurology, 58, 1764–1768. van Gorp, W. G., & Root, J. (2008). CNS infection: HIV associated neurocognitive compromise. In J. Morgan & J. Ricker (Eds.), Textbook of clinical neuropsychology. New York: Taylor & Francis.

HOLMES–ADIE SYNDROME DESCRIPTION

First described in 1931 (Adie, 1931; Holmes, 1931), Holmes–Adie syndrome (HAS) is a benign condition characterized by tendon areflexia and unilateral pupil

dilation. In some instances, the presentation expands bilaterally, affecting both pupils. Delayed responsiveness to near vision effort with delayed redilation is commonly observed (Martinelli et al., 1999). HAS is most commonly spontaneous, although familial or symptomatic forms have been noted (Lowenfield, 1993; Martinelli et al., 1999). Regarding the latter, HAS may present in conjunction with various diseases/disorders affecting the central nervous system, including polyneuropathies (e.g., hereditary, inflammatory, paraneoplastic, diabetic, amyloidotic, and alcoholrelated neuropathies), Sjo¨gren syndrome, and both rheumatoid and temporal arthritis (Martinelli et al., 1999). Epidemiological studies suggest an annual incidence rate of 4–7 per 100,000, with greater prevalence in women compared with men, and a peak incidence rate in the third decade of life, although it is noted across the life span. Onset is gradual in nature, and with time, symptoms often partially recover. In 10% of cases, there is permanent failure of the pupil to react either to light or to near vision (Martinelli et al., 1999). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The neuropathological literature on HAS is quite sparse, although generally agreeable in that the presentation arises from a partial or total loss of neurons of the ciliary ganglion on the same side as the tonic pupil while peripheral glial cell accumulations are also noted. The basis of this neuronal loss is unknown. Microscopic evaluation has largely ruled-out an infectious process. This has been concluded based on findings demonstrating absence of scarring or inflammatory cells in combination with myelinated fibers passing through the ganglion (Ulrich, 1980). Decreased numbers of nerve cells have been noted in lumbar and thoracic ganglia. Within the posterior roots and medial part of the posterior funiculi of the spinal cord there is nerve-cell destruction with loss of the myelin sheath (Ulrich, 1980). The areflexia that occurs in addition to papillary dilation is associated with impaired spinal monosynaptic connections, particularly afferent projections to motor neuron in their proximal tracts. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATIONS

HAS is characterized by unilateral pupil dilation and tendon areflexia. Although the pupil dilation starts unilaterally, progression to a bilateral presentation has been noted. This pupil dilation is noted on a continuous basis whereas slit lamp examination

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demonstrates dysfunction of the papillary sphincter muscle. Consequently, constriction and dilation of the affected pupil is significantly slowed. Beyond unilateral pupil dilation, the absence of deep tendon reflexes is also characteristic of HAS. Multiple tendon reflexes can be affected, although the loss of the Achilles tendon reflex is the most commonly seen. Similar to pupil dilation, though areflexia starts unilaterally, it can become bilateral although at low frequency (i.e., 50 33 30 25–35 20–30 15–20 12–15 4–29

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DIAGNOSIS

Routine radiographs, computed CT scans, and MRI assessments may be useful in the evaluation of KFS. High-quality radiographs of the cervical spine are often the first step to evaluate the nature and extent of fusion (Dietz, 2001). All patients should also have radiographs of thoracic and lumbar spine done to look for any other deformity and to monitor for development of scoliosis (Dietz, 2001). MRI, including flexion and extension MRI, is indicated when preliminary studies suggest instability or stenosis. MRI scans are also helpful in the detection of associated abnormalities like syrinx (i.e., a fluid-filled cavity that develops in either the spinal cord or brainstem) tethered cord (i.e., the presence of an abnormal attachment of the spinal cord to its surrounding tissue), or diastomyelia. CT is helpful in defining bony pathoanatomy but is associated with radiation exposure to the child. Detailed evaluation of all patients is required to rule out other associated anomalies of the cardiovascular, renal, auditory, gastrointestinal, respiratory, and dermatologic systems. Periodic neurologic examination is also necessary to rule out cranial nerve abnormalities, cervical radiculopathy, or myelopathy. TREATMENT

Traction, cervical collar, and analgesics are useful for mechanical symptoms caused by degenerative joints. Neurological symptoms should be evaluated carefully to locate the exact pathological condition. Three specific patterns of cervical fusion create a high risk for symptomatic instability (Beaty, 2007): C2–C3 fusion with occipitocervical synostosis, extensive fusion over several cervical vertebrae with an abnormal occipitocervical junction, and two fused segments separated by an open joint space. With clinical evidence for compression of the cervical cord, laminectomy is indicated (Sarnat, 2006). Prophylactic fusion of a hypermobile segment remains a doubtful treatment. The risk of neurological compromise must be weighed against further reduction in the neck motion. Cosmetic surgery is quite helpful for Sprengel deformity. Gaurav Jain Sarita Singhal Chad A. Noggle Beaty, J. H. (2007). Klippel-Feil syndrome. In S. T. Canale & J. H. Beaty (Eds.), Campbell’s operative orthopaedics (11th ed.). Mosby, MO: Imprint of Elsevier.

Chi, N., & Epstein, J. A. (2002). Getting your Pax straight: Pax proteins in development and disease. Trends in Genetics, 18, 41–47. Clarke, R. A., Kovacic, A., Yip, M. Y., & Diwan, A. (1997). Genetic basis of the Klippel-Feil syndrome. Journal of Bone and Joint Surgery, 79-B(4S), 406. Dietz, F. (2001). Congenital abnormalities of the cervical spine. In S. L. Weinstein (Ed.), The pediatric spine — principles and practice (2nd ed., pp. 239–251). Philadelphia: Lippincott Williams & Wilkins. Golden, J. A., & Bonnemann, C. G. (2007). Developmental structural disorders. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 561–591). Philadelphia: Saunders Elsevier. Gunderson, C. H., & Solitare, G. B. (1968). Mirror movements in patients with Klippel-Feil syndrome. Archives of Neurology, 18, 675–679. Hensiger, R. N., & MacEwen, G. D. (1982). Congenital anomalies of the spine. In R. H. Rothman & F. A. Simeone (Eds.), The spine (pp. 188–315). Philadelphia: WB Saunders. Krumlauf, R. (1994). Hox genes in vertebrate development. Cell, 78, 191–201. Sarnat, H. B. (2006). Neuroembryology, genetic programming, and malformations of the nervous system. In J. H. Menkes, H. B. Sarnat, & B. L. Maria (Eds.), Child neurology (7th ed., p. 307). Philadelphia: Lippincott Williams & Wilkins. Thomsen, M. N., Schneider, U., Weber, M., Johannisson, R., & Niethard, F. U. (1997). Scoliosis and congenital anomalies associated with Klippel-Feil syndrome types I-III. Spine, 22, 396–401. Tracy, M. R., Dormans, J. P., & Kusumi, K. (2004). KlippelFeil syndrome: Clinical features and current understanding of etiology. Clinical Orthopedics and Related Research, 424, 183–190. Van Kerckhoven, M. F., & Fabry, G. (1989). The Klippel-Feil syndrome: A constellation of deformities. Acta Orthopaedica Belgica, 55, 107–118. Warner, W. C. (1998). Pediatric cervical spine. In S. T. Canale (Ed.), Campbell’s operative orthopaedics (9th ed., pp. 2815– 2847). St Louis, MO: Mosby.

KLIPPEL–TRENAUNAY’S SYNDROME DESCRIPTION

Klippel–Trenaunay’s syndrome (KTS) is a rare, congenital disorder that disrupts the normal development of blood and lymph vessels leading to the development of hemangiomas, including port-wine stains

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(PWS), and arteriovenous abscesses (Albertini et al., 2008). In addition, asymmetrical hypertrophy of the limbs are often noted, in which one extremity (usually a leg) is significantly larger than its opposite (i.e., the left leg is significantly larger than the right) (Hai & Shrivastava, 2003). Again, the presentation is related to abnormal blood and lymph vessel development; however, the basis for these developmental mishaps remains unknown although some theories have been more favored than others. KTS is sometimes also referred to as angioosteohypertrophy syndrome, congenital dysplastic angiectasia, and hemangiectatic hypertrophy. The term Klippel–Trenaunay–Weber’s syndrome is also commonly used and has even been adopted as the recognized name by the International Classification of Diseases-10. NEUROPATHOLOGY/PATHOPHYSIOLOGY

The underlying pathophysiology of KTS corresponds with a disruption of the normal development of the peripheral lymph and blood vessels. Although a definitive basis for this disruption has not been agreed upon, dysregulation of angiogenic cells’ proliferation and maturation, vasoconstrictor paralysis (ParkesWeber, 1907), loss of sympathetic tone and resulting dilation of arteriovenous shunting (Bliznak & Staple, 1974), and chronic venous hypertension and venous compression and its resulting alteration of venous pressure have been suggested as contributing factors (Servelle, 1985). Klippel and Trenaunay (1900) actually thought that spinal cord abnormalities may serve as the basis of the presentation. The presentation is defined by the development of hemangiomas and arteriovenous abscesses. Hemangiomas represent areas on the dermis made up of masses of blood vessels. Port wine stains (PWS) represent specific types of hemangiomas, are most commonly seen on the hypertrophied extremity, and are often the first symptom observed (Jacob et al., 1998; Lambrechts & Carmeliet, 2004). Although the PWS may be relatively shallow in depth and only present slightly above the dermal surface, cases have been noted in which they may have infiltrated the deeper muscle and even bone. The hypertrophied limb presents as significantly larger than its opposite. Although the presentation is traditionally isolated to one limb, multiple extremity, unilateral, and even whole body involvement have been reported (Gloviczki et al., 1983; Samuel & Spitz, 1995). Although most patients with KTS present with no neurological sequelae or underlying neuropathological features, hemangiomas may develop within the brain.

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The clinical features of KTS largely correspond with the morphological characteristics of the presentation: the development of hemangiomas includingPWS and arteriovenous abscesses. In addition, individuals commonly present with a hypertrophied limb. This is more commonly noted to involve the legs although in some instances two limbs present with hypertrophy. This can also be noted in the trunk of the body. Additional morphological anomalies can include syndactyly, polydactyly, or oligodactyly, more commonly noted in the hypertrophied limb. Varicose veins present at higher rates (i.e., >75%) and are often quite obvious (Gloviczki et al., 1991; Samuel & Spitz, 1995; Servelle, 1985). This also contributes to issues with cellulitis, hemorrhage, paresthesias, and pulmonary emboli (Mikula, Gupta, Miller, & Felder, 1991; Phillips, Gordon, Martin, Haller, & Casarella, 1978). Visual defects related to glaucoma and/or cataracts may develop. More often than not, neurocognitive functioning is unimpaired in KTS unless hemangiomas develop within the brain raising the potential for focal deficits and seizures. In comparison, Sturge–Weber’s syndrome, which demonstrates significant clinical overlap with KTS, is far more commonly linked with seizures and neuropsychological dysfunction due to the neurological involvement noted in association with this presentation. DIAGNOSIS

Diagnosis is based on the clinical and morphological features of the presentation. It is differentiated from two clinically similar presentations. Sturge–Weber’s syndrome is similar to KTS in that it too is a PWS disorder, presents with vascular anomalies, and limb hypertrophy. In comparison, Sturge–Weber’s syndrome is far more commonly linked with seizures, neurocognitive dysfunction, and an increased risk of other neurological residuals. Parkes-Weber’s syndrome is diagnosed when the individual also develops numerous arteriovenous fistulas in addition to the features commonly noted in KTS. Imaging is crucial to diagnosis and evaluation of KTS as hemangiomas must be differentiated from vascular malformations, with Doppler ultrasound representing the starting point (Dubois & Garel, 1999; Dubois et al., 1998; Laor & Burrows, 1998). MRI and CT are also useful tools. They can offer refined images of the extent of lesions, including their exact locality and depth of infiltration; however, they cannot

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differentiate between hemangiomas and vascular malformations like the Doppler can (Kern et al., 2000). Electroencephalogram should be utilized in cases where seizures occur. TREATMENT

There is no cure for KTS. Treatment is symptom based with focus on relief (Enjolras & Mulliken, 1993). Laser surgery can diminish or erase some skin lesions. Surgery may also be attempted to correct discrepancies in limb size through a method known as debulking, but orthopedic devices may be more appropriate. If seizures present, antiepileptic drugs can be effective in reducing or eliminating symptoms. These coincide with hemangiomas in the brain that may require neurosurgical intervention. Physical therapy is often needed to aid in ambulation issues. KTS is a progressive disorder and complications may be lifethreatening, thus continual follow-up and management is required. Chad A. Noggle Albertini, G., Onorati, P., De Pandis, F., Giulittle, E., Calcarl, L., & Sara, M. (2008). Cognitive level and adaptive behaviour in the Klippel-Trenaunay-Weber syndrome. An example of the potentials of an early intervention model applied to a complex pathology. Disability and Rehabilitation, 30, 26, 1999–2000. Bliznak, J., & Staple, T. W. (1974). Radiology of angiodysplasias of the limb. Radiology, 110, 35–44. Dubois, J., & Garel, L. (1999). Imaging and therapeutic approach of hemangiomas and vascular malformations in the pediatric age group. Pediatric Radiology, 29, 879–893. Dubois, J., Garel, L., Grignon, A., David, M., Laberge, L., Filiatrault, D., et al. (1998). Imaging of hemangiomas and vascular malformations in children. Academic Radiology, 5, 390–400. Enjolras, O., & Mulliken, J. B. (1993). The current management of vascular birthmarks. Pediatric Dermatology, 10, 311–313. Gloviczki, P., Hollier, L. H., Telander, R. L., Kaufman, B., Bianco, A. J., & Stickler, G. B. (1983). Surgical implications of Klippel–Tre´naunay syndrome. Annals of Surgery, 197, 353–362. Gloviczki, P., Stanson, A. W., Stickler, G. B., Johnson, C. M., Toomey, B. J., Meland, N. B., et al. (1991). Klippel– Trenaunay syndrome: The risks and benefits of vascular interventions. Surgery, 110, 469–479. Hai, A. A., & Shrivastava, R. B. (2003). The Association of Surgeons of India: Textbook of surgery (1st ed.). New Delhi, India: Tata McGraw-Hill.

Jacob, A. G., Driscoll, D. J., Shaughnessy, W. J., Stanson, A. W., Clay, R. P., & Gloviczki, P. (1998). Klippel– Trenaunay syndrome: Spectrum and management. Mayo Clinic Proceedings, 73, 28–36. Kern, S., Niemeyer, C., Darge, K., Merz, C., Laubenberger, J., & Uhl, M. (2000). Differentiation of vascular birthmarks by MR imaging. An investigation of hemangiomas, venous and lymphatic malformations. Acta Radiologica, 41, 453–457. Klippel, M., & Trenaunay, P. (1990). Du naevus variqueux osteohypertrophique. Archives of General Medicine (Paris), 185, 641–672. Lambrechts, D., & Carmeliet, P. (2004). Genetic spotlight on a blood defect. Nature, 427, 592–594. Laor, T., & Burrows, P. E. (1998). Congenital anomalies and vascular birthmarks of the lower extremities. Magnetic Resonance Imaging Clinics of North America, 6, 497–495. Mikula, N., Jr., Gupta, S. M., Miller, M., & Felder, S. (1991). Klippel–Trenaunay syndrome with recurrent pulmonary embolism. Clinical Nuclear Medicine, 16, 253–255. Parkes-Weber, F. (1907). Angioma formation in connection with hypertrophy of limbs and hemi-hypertrophy. British Journal of Dermatology and Syphilis, 19, 231–235. Phillips, G. M., Gordon, D. H., Martin, E. C., Haller, J. O, & Casarella, W. (1978). The Klippel and Tre´naunay syndrome: Clinical and radiological aspects. Radiology, 128, 429–434. Samuel, M., & Spitz, L. (1995). Klippel–Trenaunay syndrome: Clinical features, complications and management in children. British Journal of Surgery, 82, 757–761. Servelle, M. (1985). Klippel and Trenaunay’s syndrome. 768 operated cases. Annals of Surgery, 201, 365–373.

KLUVER–BUCY SYNDROME DESCRIPTION

Kluver–Bucy syndrome, an extraordinarily rare neurological disorder, was first documented in primates a little more than a century ago. Research by Brown and Shafer (1888) noted unusual behaviors following bilateral damage or removal of large sections of the temporal lobes in primates. The animals no longer expressed fear or aggression, developed voracious appetites for meat, experienced sensory deficits, and would identify all foreign objects orally. Beginning in the 1930s with Kluver and Bucy, this syndrome resurfaced under the name of temporal lobe syndrome. Although unaware of Brown and Shafer’s work, Kluver and Bucy recorded the same behavioral

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changes in primates after severe bilateral temporal lobe damage or removal. Kluver and Bucy did acknowledge they were never interested in deciphering the neural or cortical mechanisms responsible for this syndrome, but instead the general role of the temporal lobe in emotional and sensory functioning. Why this syndrome has been renamed after Kluver and Bucy remains unclear. Nahm (1997) offers the explanation that Brown and Shafer were ahead of their time and Kluver and Bucy’s research happens to coincide with a time period where new and exciting advances were being made in brain research. This timing, in turn, permitted their findings to complement the work of others and be more easily accepted and subsequently frequently cited. Although human examples of Kluver–Bucy syndrome likely existed throughout history, the first human case was not documented until 1955. An epileptic patient following surgery developed an incomplete case of Kluver–Bucy syndrome, which requires the appearance of only three core symptoms. The first definitive human case came 20 years later in 1975. A 22-year-old man exhibited all six core symptoms following a meningoencephalitis infection, likely herpes simplex encephalitis. Since that time, few cases have been documented, attesting to the unusual nature of the syndrome.

explain the syndrome’s associated sensory deficits. Further disruption in the connecting fibers with the frontal cortex and limbic areas can also be used to explain the associated memory, emotional, and sexual behavior problems as well. Specific damage to the temporal lobe or its connections may be the underlying cause of human Kluver–Bucy syndrome, but a host of medical maladies serve as catalysts for this process. They can be grouped into three categories: pathogen, neurological, or other. The pathogenic causes are bacterial or viral and include herpes simplex encephalitis, mycoplasma bronchitis, anoxic-ischemic encephalopathy, tuberculosis meningitis, and methotrexate leukoencephalopathy. Regarding the neurological causes and deficits, human Kluver–Bucy syndrome is viewed, instead, as comorbid or resulting from a primary neurological disorder. Some of the more common neurological disorders are epilepsy, Pick’s disease, Reye’s syndrome, Alzheimer’s disease, Huntington’s chorea, and Parkinson’s disease. The last category or ‘‘other’’ is unusual since there seems to be no unifying theme. Among this list, there is head trauma, hypoglycemia, arachnoid cysts, carbon monoxide intoxication, postirradiation, and heat stroke.

NEUROPATHOLOGY/PATHOPHYSIOLOGY

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

In humans, the precise lesion locations required for Kluver–Bucy syndrome remain unknown, but disruption in several brain areas, including the limbic system, do result in it. Bilateral temporal ablation, as demonstrated by primate research, remains the principle cause of this syndrome. One case in the literature, however, noted Kluver–Bucy syndrome symptoms after just a left temporal lobe resection (Anson & Kuhlman, 1993). Temporal lobe damage as the main cause of human Kluver–Bucy syndrome has gained support from autopsy studies. These studies report significant lesions in the medial, inferior, and anterior temporal cortex along with amygdalae and hippocampi impairment, specifically the rhinencephalon regions (Lilly, Cummings, Benson, & Frankel, 1983). Overall, human Kluver–Bucy syndrome may require dual hippocampi damage before it can occur. An alternative explanation of origin proposes that the connecting fibers leading to and from the temporal lobes are disrupted, essentially isolating them from the rest of the brain. Geschwind (1965) used this to define human Kluver–Bucy syndrome as a disconnection between the visual and limbic system. This may

Kluver–Bucy syndrome has six core symptoms. These are visual agnosia, excessive oral tendencies, hypermetamorphosis, placidity, altered sexual behavior, and changes in dietary habits. Although humans and primates will display these symptoms, there may be some differences between species as well as minor variations between subjects. During visual agnosia or psychic blindness, both humans and primates seem to lose their ability to recognize objects visually despite an intact and functioning system. There is some speculation in the literature that sensory agnosias also appear during auditory and olfactory processing, but research in this area is limited. In humans, the visual agnosia usually becomes prosopagnosia where patients experience difficulty distinguishing among the faces of family, friends, hospital staff, and strangers. Primates suffering from excessive oral tendencies will attempt to identify all objects (e.g., nonfood and food) by licking, biting, and chewing. Once identified, nonfood items are spit out, whereas the food is eaten. Furthermore, nonhuman primates will not typically use their hands to pick up the items but try to use their mouths in a scooping motion.

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The excessive oral tendencies in humans are expressed as hyperphagia and bulimia. Humans will lick, bite, and even engage in self-biting. Caution must be exercised with such patients because they will attempt to taste urine (e.g., urophagia) and fecal matter (e.g., coprophagia). Hypermetamorphosis, the third core symptom, refers to a compulsive need for humans and primates to examine the minute details of every object they encounter while placid. The fourth symptom is a lack of fear, aggression, or interests. Kluver described hypermetamorphosis in primates as appearing as though they were intoxicated from hallucinogenic drugs. Kluver–Bucy syndrome in humans is unique because some patients will be very aggressive whereas others will not, but almost all will be apathetic. Altered sexual behavior can be extreme in both primates and humans, but it is reported to be one of the least common core symptoms in humans. Primates will excessively masturbate as well as pursue both hetero- and homosexual relations. Some humans will masturbate compulsively though generally only crude remarks and gestures are made. Their attempts for sexual contact are usually unsuccessful. A few humans have reported changing their sexual preference. The last core Kluver–Bucy syndrome is a remarkable change in dietary habits. Primates, normally vegetarian, will develop an insatiable hunger for meat. Humans will decrease their intake of meat and vegetables for sweets and nonhealthy foods. Although human Kluver–Bucy syndrome appears more common in teenagers and adults judging by the literature, it can occur in children. Children are capable of having any of the six core symptoms but will exhibit them in somewhat different ways. For example, instead of making crude sexual remarks, they will thrusts their pelvises or rub their genitals against other objects. Children do seem to recognize their parents and other family members, but direct no attention or attraction toward them. Furthermore, children will not respond to any type of behavioral manipulations from family and hospital staff. As of yet, a complete Kluver–Bucy syndrome case has not been documented in a child.

with CSF analysis may be utilized to determine the presence of an infectious process.

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TREATMENT

Treatment options, other than those that are pharmacological, for human Kluver–Bucy syndrome are extremely limited. The most effective pharmacological agents appear to be the antipsychotics followed by the selective serotonin reuptake inhibitors (SSRIs). The literature regarding the effectiveness of such agents is mixed, and there appears to be no real cure for Kluver–Bucy syndrome. The antipsychotic, haloperidol, given frequently (e.g., three times a day) does seem helpful in reducing the altered sexual and excessive oral behaviors while reestablishing normal dietary behaviors. During situations when haloperidol is ineffective, it may be combined with other agents such as risperidone, carbamazepine, and propranolol. The best combinations of these agent types and dosages are usually determined through a trial and error basis with each patient. For nontraumatic Kluver–Bucy syndrome examples, a combination of carbamazepine and leuproline is recommended. Recently, sertraline and fluoxetine, the SSRIs, have been found to be useful in reducing the altered sexual behaviors in Kluver–Bucy syndrome. In one case, risperidone and carbamazepine were ineffective until fluoxetine was added. Once the patient stopped taking just the fluoxetine, the previous Kluver–Bucy syndrome symptoms returned (Slaughter, Bobo, & Childers, 1999). Recovery from human Kluver–Bucy syndrome can occur, thus indicating an overall positive prognosis. This is unusual because primate examples rarely improve, even after 2-year follow-ups. Generally, anywhere from 1 month to 1 year after symptoms first appear, patients may experience a return to normal eating, sexual, and emotional behaviors. Hyperorality is often considered the slowest to recover from and may only be partial at best. Human Kluver–Bucy syndrome caused by trauma is generally temporary ranging from 7 days to 1 year after the injury. Antonio E. Puente

DIAGNOSIS

Given that Kluver–Bucy is a syndrome, recognition and identification of its symptoms constitutes the primary diagnostic practice. It occurs in relation to infection, trauma, or other acute neurological event; thus, diagnostic workup should also seek to elucidate the pathological correlates. MRI and CT are preferred. Depending on imaging results, lumbar puncture

Anson, J. A., & Kuhlman, D. T. (1993). Post-ictal Kluver-Bucy syndrome after temporal lobectomy. Journal of Neurology, Neurosurgery, and Psychiatry, 56, 311–313. Brown, S., & Schafer, E. A. (1888). An investigation into the functions of the occipital and temporal lobes of the monkey’s brain. Philosophical Transactions of the Royal Society of London: Biological Sciences, 179, 303–327.

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Geschwind, N. (1965). Disconnection syndromes in animals and man. Brain, 88, 237–294. Lilly, R., Cummings, J. L., Benson, F., & Frankel, M. (1983). The human Kluver-Bucy syndrome. Neurology, 33, 1141–1145. Nahm, F. K. D. (1997). Heinrich Kluver and the temporal lobe syndrome. Journal of the History of the Neurosciences, 6, 193–208. Slaughter, J., Bobo, W., & Childers, M. K. (1999). Selective serotonin reuptake inhibitor treatment of post-traumatic Kluver-Bucy syndrome. Brain Injury, 13, 59–62.

KRABBE’S DISEASE DESCRIPTION

Krabbe’s disease is an inherited disease that leads to degeneration of the white matter within the central and peripheral nervous systems due to a deficiency of galactocerebrosidase. Classified as a leukodystrophy, the enzyme deficient in the disease is necessary for myelin development and integrity; thus, its deficiency leads to white matter degeneration. Rare in nature, Krabbe’s disease occurs in approximately 1 in 100,000 births. Krabbe’s disease is most often diagnosed in infancy, although later-onset cases have been noted, and is terminal in nature. Symptom onset usually occurs at approximately 4–6 months of age, first presenting as a distinct change in temperament in which the infant will cry uncontrollably and exhibit general irritability. As the disease progresses, development halts and eventually reverses, particularly in the realm of motor functioning causing permanent opisthotonic posturing with hypertonic flexion in the extremities. Tonic spasms ensue, particularly in response to sensory stimulation, either visual or auditory (Graham & Lantos, 1997). In the final stages, infants become blind, decerebrate, and die (Graham & Lantos, 1997). There is no cure for Krabbe’s disease. Given the presentation is terminal in nature, treatment is supportive, particularly for parents and family. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Krabbe’s disease is defined by widespread white matter degeneration as a result of the system’s inability to metabolize galactocerebroside. This is related to deficient activity of lysosomal galactocerebroside -galactosidase in the gray and white matter, liver, spleen, serum, leucocytes and fibroblasts (Kolodny,

Raghavan, & Krivit, 1991; Suzuki & Suzuki, 1971). Consequently, brain-lipid analysis demonstrates a sever loss of myelin lipids with a significantly elevated concentration of galactocerebroside compared with sulfatide in globoid cells (Austin, 1963a,b). Neurologically, brains are undersized with smaller gyri and wider sulci and cerebellar folia. There is some loss of differentiation of white matter from gray matter beyond the central white matter pathways (Krabbe, 1916) with occasional segmental demyelination of peripheral nerves (Baram, Goldman, & Percy, 1986). The white matter is decreased in mass and is gliotic, firm, and rubbery to palpation (Maertens & Dyken, 2007). Globoid cells increase in the initial stages of the disease. They are even commonly noted in the pontine tegmentum, medulla, and spinal cords of affected fetuses (Harzer, 1982; Ida, Rennert, Watabe, Eto, & Maekawa, 1994; Martin et al., 1981; Suchlandt, Schlote, & Harzer, 1982). Neuronal degeneration of the thalamus, pons, and dentate nuclei is commonly noted. By the end-stages of the presentation, microscopic review demonstrates few if any globoid cells (Dunn, 1976) and almost total loss of axons (D’ Agostino et al., 1963). Neuronal loss in focal areas including the dentate nucleus and inferior olives have also been noted (Norman et al., 1961; Crome et al., 1973; Shaw et al, 1970). In comparison, when onset is later, the neurological changes are not as prominent. MRI findings may be nearly normal (Graham & Lantos, 1997). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Irritability and excessive crying are commonly reported as the first symptoms of Krabbe’s disease when presenting in infants. Most commonly, onset occurs at 4–6 months of age. Prior to symptom emergence, infants demonstrate a normal developmental period in terms of eye and head control. Soon after these features present, development comes to a halt. Around this same time, infants develop tonic spasms in response to visual or auditory stimulation. Simultaneously, a gradual decline in motor functioning may be noted and feeding difficulties may develop. This motor deterioration leads to a permanent opisthotonic posturing with hypertonic flexion of the extremities (Graham & Lantos, 1997). In the later stages, myoclonic jerking and seizures eventually ensue and blindness develops secondary to optic atrophy. In the final stages, infants become decerebrate (Graham & Lantos, 1997). Infants commonly die between 12 and 18 months of age. Although the disease most commonly presents in infancy, when onset is later the presentation is more

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commonly characterized by sensorimotor deficits including gait disturbance, spasticity, neuropathy, and loss of visual acuity. Seizures are not as common and death is not imminent. DIAGNOSIS

Diagnosis commonly begins with the identification of the clinical symptoms that define Krabbe’s disease once development halting is noted. Neuroimaging may be utilized to reveal white matter loss within the cerebrum and cerebellum (Baram et al., 1986). Laboratory diagnosis may be the most accurate; diagnosis is made by enzyme assay of leucocytes or cultured fibroblasts (Graham & Lantos, 1997). Similar capabilities are possible prenatally by assay of chorionic villus samples (Harzer, Hager, & Tariverdian, 1989; Harzer, & Schuster, 1987). TREATMENT

There is no cure for Krabbe’s disease. Given that most infants die prior to 2 years of age, treatment is largely support based. There are some initial findings that suggest benefit of umbilical cord blood stem cells prior to symptom onset in regard to improving neurological outcomes. Bone marrow transplantation has also demonstrated a positive impact in milder cases when used early in the disease process. Nevertheless, treatment remains symptom based. Chad A. Noggle Javan Horwitz Austin, J. H. (1963a). Studies in globoid (Krabbe) leukodystrophy. II. Controlled thin-layer chromatographic studies of globoid body fractions in 7 patients. Journal of Neurochemistry, 10, 921–930. Austin, J. H. (1963b). Studies in globoid (Krabbe) leukodystrophy. I. The significance of lipid abnormalities in white matter in 8 globoid and 13 control patients. Archives of Neurology, 9, 207–231. Baram, T. Z., Goldman, A. M., & Percy, A. K. (1986). Krabbe disease: Specific MRI and CT findings. Neurology, 36, 111–115. Crome, L., Hanefield, F., Patrick, D., & Wilson, J. (1973). Late onset of globoid cell leucodystrophy. Brain, 96, 841–848. D’Agostino, A. N., Sayre, G. P., & Hayles, A. B. (1963). Krabbe’s disease. Archives of Neurology, 8, 82–96. Dunn, H. G., Dolman, C. L., Farrell, D. F., Tischler, B., Hasinoff, C., & Woolf, L. I. (1976). Krabbes leukodystrophy without globoid cells. Neurology, 26, 1035–1041. Graham, D. I., & Lantos, P. L. (Eds). (1997). Greenfield’s neuropathology (6th ed.). New York: Oxford University Press.

Harzer, K. (1982). Prenatal enzymic diagnosis in 24 pregnancies with risk of Krabbe disease. Clinica Chimica Acta; International Journal of Clinical Chemistry, 122, 21–28. Harzer, K., Hager, H. D., & Tariverdian, G. (1987). Prenatal enzymatic diagnosis and exclusion of Krabbe’s disease (globoid-cell leukodystrophy) using chorionic villi in five risk pregnancies. Human Genetics, 77, 342–344. Harzer, K., & Schuster, I. (1989). Prenatal enzymatic diagnosis of Krabbe’s disease (globoid-cell leukodystrophy) using chorionic villi. Pittfalls in the use of uncultured villi. Human Genetics, 84, 83–85. Ida, H., Rennert, O. M., Watabe, K., Eto, Y., & Maekawa, K. (1994). Pathological and biochemical studies of fetal Krabbe disease. Brain & Development, 16, 480–484. Kolodny, E. H., Raghavan, S., & Krivit, W. (1991). Late-onset Krabbe disease (globoid cell leukodstrophy): Clinical and biochemical features of 15 cases. Developmental Neuroscience, 13, 232–239. Krabbe, K. (1916). A new familial, infantile form of diffuse brain sclerosis. Brain, 39, 74–1141. Maertens, P., & Dyken, R. (2007). Storage diseases: Neuronal ceroid-lipofuscinoses, lipidoses, glycogenoses, and leukodystrophies. In C. Goetz (Ed.), Textbook of clinical neurology (pp. 612–639). Philadelphia, PA: Saunders Elsevier. Martin, J. J., Leroy, J. C., Ceuterick, C., Libert, J., Dodinval, P., & Martin, L. (1981). Fetal Krabbe leukodystrophy. A morphological study of two cases. Actas Neuropathologica (Berl), 53, 87–91. Norman, R. M., Oppenheimer, D. R., & Tingey, A. H. (1961). Histological and chemical findings in Krabbe’s leucodystrophy. Journal of Neurology, Neurosurgery, and Psychiatry, 24, 223–232. Shaw, C. M., & Carlson, C. G. (1970). Crystalline structures in globoid-epithelioid cells: An electron microscopic study of globoid leukodystrophy (Krabbe’s disease). Journal of Neuropathology and Experimental Neurology, 29, 306–319. Suchlandt, G., Schlote, W., & Harzer, K. (1982). Ultrastrukturelle Befunde bei 9 Feten nach pranataler Diagnose von Neurolipidosen. Arch Psychiat Nervenkr, 232, 407–426. Suzuki, Y., & Suzuki, K. (1971). Krabbe’s globoid cell leukodystrophy: Deficiency of glactocerebrosidase in serum, leukocytes and fibroblasts. Science, 171, 73–75.

KURU DESCRIPTION

Kuru is a form of transmissible spongiform encephalopathy (TSE) or prion disease that was identified in the 1950s among the Fore people living in the

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highlands of Papua New Guinea (Gajdusek & Zigas, 1957). Like other TSEs (e.g., Creutzfeldt–Jakob’s disease), kuru is a fatal neurodegenerative disorder thought to be caused by structurally abnormal neuronal proteins (i.e., proteinaceous infectious particles or prions) that have the capability of propagating structural anomalies in neighboring proteins. Kuru was endemic to the Fore people and a few neighboring tribes and was a leading cause of death among Fore women and children in the 1950s. Ingestion of infected brain tissue through the practice of ritual cannibalism of deceased family members was identified as the primary mode of transmission, and the incidence of the disease decreased dramatically after the institution of government prohibitions against cannibalism.

continued to progress throughout this stage. The transition to the terminal stage was signaled by the inability to sit without assistance, and the patient became bedridden, mute, and incontinent. Death typically occurred 6–9 months following onset of the disease; common causes of death were starvation, infection from decubitus ulcers, or bronchopneumonia (Gajdusek & Zigas, 1959). Cognitive abilities remain preserved apart from reduced processing speed, but progression to dementia (as in Creutzfeldt–Jakob’s disease) was not part of the clinical picture. Mood lability including outbursts of laughter and persistent smiling were often present during the sedentary stage and led to a description of the disease as the laughing death (Liberski & Brown, 2009).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

DIAGNOSIS

Early reports of neuropathologic findings in kuru noted neuronal degeneration, demyelination of motor tracts, gliosis, and distinctive round or ovoid amyloid plaques that were observed to have a dark center surrounded by a lighter halo (Fowler & Robertson, 1959; Klatzo, Gajdusek, & Zigas, 1958; Neumann, Gajdusek, & Zigas, 1964). These plaques consequently came to be labeled ‘‘kuru plaques’’ and were noted in approximately 75% of cases (Collins, McLean, & Masters, 2001; Liberski & Brown, 2009). Concentrations were noted in the cerebellum, basal ganglia, thalamus, and cortex; they have been found to contain structurally abnormal prion protein. Subsequent investigations also identified extensive vacuolation or spongiform changes in areas of the cortex, basal ganglia, and cerebellum (Brandner et al., 2008).

Given the gradual disappearance of kuru following government prohibitions against ritual cannibalism among the Fore people, diagnosis of the disease is more a matter of historical interest rather than an issue of contemporary clinical relevance (Collins, Lawson, & Masters, 2004; Liberski & Brown, 2009). Diagnosis of kuru was based primarily on clinical features of the disease (Gajdusek & Zigas, 1959). Despite its insidious onset, the progression of kuru was well known among the Fore people and was described in uniform terms across different villages in the endemic area. It came to be readily identified by the physicians who first described it. The initial locomotor ataxia was so subtle that it was often only noticed by the patient, but the rapid progression over the course of several months to severe ataxia and tremor, and the eventual inability to sit upright without assistance were diagnostic.

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The term kuru means shaking or shivering in the Fore language and accurately suggests the predominance of movement disorders in the disease (Liberski & Brown, 2009). The progression of the disease was classified into three stages: ambulatory, sedentary, and terminal (Gajdusek & Zigas, 1959; Kompoliti, Goetz, Gajdusek, & Cubo, 1999). Following a prodromal period involving headache, limb and abdominal pain, and weight loss in the absence of fever, the ambulatory stage was identified by the initial sign of mild locomotor ataxia. Over a period of about 1 month, this progressed to severe astasia, ataxia, and titubation; the patient eventually became unable to walk without a crutch. Horizontal convergent strabismus was observed in some patients during the ambulatory stage. Onset of the sedentary stage was demarcated by the inability to walk without assistance; ataxia, tremor, and postural unsteadiness

TREATMENT

No treatment for kuru was identified (Liberski & Brown, 2009). The incidence of the disease declined rapidly once the Fore people stopped practicing ritual cannibalism. The few reported cases in the 21st century have resulted from exceptionally long incubation periods (Collinge et al., 2006). Jeremy Davis Chad A. Noggle Brandner, S., Whitfield, J., Boone, K., Puwa, A., O’Malley, C., Linehan, J. M., et al. (2008). Central and peripheral pathology of Kuru: Pathological analysis of a recent case and comparison with other forms of human prion disease. Philosophical Transactions of the Royal Society B, 363, 3755–3763.

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Collinge, J., Whitfield, J., McKintosh, E., Beck, J., Mead, S., Thomas, D. J., et al. (2006). Kuru in the 21st century — An acquired human prion disease with very long incubation periods. Lancet, 367, 2068–2074. Collins, S. J., Lawson, V. A., & Masters, C. L. (2004). Transmissible spongiform encephalopathies. Lancet, 363, 51–61. Collins, C., McLean, C. A., & Masters, C. L. (2001). Gerstmann-Stra¨ussler-Scheinker syndrome, fatal familial insomnia, and kuru: A review of these less common human transmissible spongioform encephalopathies. Journal of Clinical Neuroscience, 8, 387–397. Fowler, M., & Robertson, E. G. (1959). Observations on kuru, III: Pathological features in five cases. Australasian Annals of Medicine, 8, 16–26. Gajdusek, D. C., & Zigas, V. (1957). Degenerative disease of the central nervous system in New Guinea: The endemic occurrence of ‘‘kuru’’ in the native population. The New England Journal of Medicine, 257, 974–978.

Gajdusek, D. C., & Zigas, V. (1959). Kuru: Clinical, pathological and epidemiological study of an acute progressive degenerative disease of the central nervous system among natives of the eastern highlands of New Guinea. The American Journal of Medicine, 26, 442–469. Klatzo, I., Gajdusek, D. C., & Zigas, V. (1959). Pathology of kuru. Laboratory Investigation, 8, 799–847. Kompoliti, K., Goetz, C. G., Gajdusek, D. C., & Cubo, E. (1999). Movement disorders in kuru. Movement Disorders, 14, 800–804. Liberski, P. P., & Brown, P. (2009). Kuru: Its ramifications after fifty years. Experimental Gerontology, 44, 63–69. Neumann, M. A., Gajdusek, D. C., & Zigas, V. (1964). Neuropathologic findings in exotic neurologic disorders among natives of the highlands of New Guinea. Journal of Neuropathology and Experimental Neurology, 23, 486–507.

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L LAMBERT–EATON MYASTHENIA SYNDROME DESCRIPTION

Lambert–Eaton syndrome, also called myasthenic syndrome or Lambert–Eaton myasthenic syndrome, is a rare autoimmune disorder of neuromuscular transmission. Lambert–Eaton syndrome has symptoms that are very similar to myasthenia gravis. Like myasthenia gravis, Lambert–Eaton syndrome involves muscle weakness associated with a disruption in the communication at the neuromuscular junction, but there are clear differences between the disorders (Lang, Newsom-Davis, Wray, Vincent, & Murray, 1981). Lambert–Eaton syndrome affects the presynaptic neuron inhibiting the release of acetylcholine causing muscle weakness, depressed tendon reflexes, posttetanic potentiation, and autonomic changes. It is estimated that 50–70% of patients with Lambert–Eaton syndrome have an identifiable cancer (Chalk, Murray, Newsom-Davis, O’Neill, & Spiro, 1990; Elmqvist & Lambert, 1968). The disorder was first described by Anderson in 1953 in a patient with lung cancer. However, Lambert, Eaton, and Rooke further published electrophysiological data on six patients with the disorder. Although children, adolescents, and young adults may have Lambert–Eaton syndrome, the disease is usually observed in adults. The incidence of Lambert– Eaton syndrome is difficult to determine due to its low frequency (Sanders, 1995). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Lambert–Eaton syndrome is an autoimmune disorder of neuromuscular transmission in which the immune system, which normally protects the body, mistakenly attacks the body’s voltage-gated calcium channels on the presynaptic motor nerve terminal of sympathetic, parasympathetic, and enteric neurons (Lang, et al., 1981; Lang, Johnston, Leys, Elrington, Marqueze, & Leveque, 1993; Lang, Newsom-Davis, 1995). The disruption of electrical impulses at the voltage-gated calcium channels is a consequence of this autoimmunity

and reduces nerve impulses. The reduction in nerve impulses inhibits the release of acetylcholine from the presynaptic neuron. Symptoms from the inhibition of activity at the presynaptic neuron include muscle weakness, a tingling sensation in the affected areas, fatigue, and dry mouth (Waterman, Lang, & Newsom-Davis, 1996). The stores of acetylcholine in the presynaptic neuron are normal, so if the neuromuscular transmission can be artificially stimulated, a temporary increase in muscle strength will occur (Sanders, 1995). Lambert– Eaton syndrome is closely associated with cancer, specifically small cell lung cancer. More than half the individuals diagnosed with Lambert–Eaton syndrome eventually develop small cell lung cancer. Lambert– Eaton syndrome may appear up to 3 years before cancer is diagnosed (Chalk et al., 1990). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The major clinical finding in Lambert–Eaton syndrome is a progressive weakness that does not usually involve the respiratory muscles or the muscles of the face. Typically, the proximal muscles in the lower extremities are affected, although the arms may be affected in some cases. Patients may report difficulty with standing from a sitting position, walking upstairs, or even walking in general. The symptoms may be present for several years before diagnosis is made. Cancer is present or subsequently diagnosed in 50–70% of patients with Lambert–Eaton syndrome (Chalk et al., 1990). Only 25% of patients have ocular or oropharyngeal muscles affected and exhibit symptoms of ptosis, diplopia, and dysarthria. In patients with affected ocular and oropharyngeal muscles, the involvement is not as severe as myasthenia gravis, but it may be difficult to differentiate between the disorders. Research has demonstrated that if a patient’s first symptom is ocular weakness, Lambert–Eaton syndrome can be virtually excluded. The respiratory muscles may also be affected, but not as severe as myasthenia gravis. Many patients initially present with autonomic symptoms, specifically dry mouth, but impotence may also be reported. In Lambert– Eaton syndrome reflexes are typically reduced or

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absent (O’Neil, Murray, & Newsom-Davis, 1988; Sanders, 1995).

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DIAGNOSIS

The evaluation and diagnosis of Lambert–Eaton syndrome will typically include a thorough physical examination and medical history. Initially patients may present with autonomic symptoms, specifically dry mouth. Physical examination will typically show muscle atrophy and weakness or even paralysis, but the muscle weakness symptoms will improve with physical activity. The patients may also have decreased or absent reflexes. A Tensilon test, an injection of edrophonium chloride used to block the action of acetylcholinesterase that increases levels of acetylcholine, can be positive in which the patient’s muscle strength evaluation is noticeably improved. EMG or nerve conduction velocity tests can also measure nerve conductivity to the muscles by inserting an electrode into the muscle that appears to be affected by the nerve damage (Wirtz et al., 2002). The above diagnostic measures may not differentiate between myasthenia gravis and Lambert–Eaton syndrome, so the diagnosis of underlying cancer or the detection of acetylcholine antibodies may differentiate between the disorders (Sanders, 1995). Another differentiation between the disorders is that in myasthenia gravis muscle weakness tends to develop in a craniocaudal direction, and in Lambert–Eaton syndrome muscle weakness tends to develop in the opposite direction (Wirtz, Sotodeh, Nijnuis, Van Engelen, Hintzen, de Kort, et al., 2002). The arms may be affected in both disorders, but research has shown that limb weakness specifically confined to the arms is found only in generalized myasthenia gravis and not in Lambert–Eaton syndrome (Sanders, 1995). TREATMENT

In Lambert–Eaton syndrome, the primary goal of treatment is to treat any tumors or other underlying disorders that are diagnosed during examination. Although rare, respiratory distress or failure is a primary concern in treatment. Plasmapheresis, where blood plasma is removed and replaced with fluid, has been reported to improve symptoms. Pharmacotherapy for Lambert–Eaton syndrome can be initiated only after myasthenia gravis has been excluded. Typical pharmacotherapeutic interventions include the use of cholinesterase inhibitors, immunosuppressants, and/or immunomodulating agents. Physical therapy and exercise are an important component to the treatment of Lambert–Eaton syndrome. Physical therapy

and exercise on an outpatient basis are helpful in maintaining muscle tone and strength (Maddison & Newsom-Davis, 2005; Sanders, 1994, 1995; Verschuuren, Wirtz, Titulaer, Willems, & van Gerven, 2006). Psychosocial interventions may also be utilized to help the patient overcome any psychological or social ramifications of the disorder or an underlying cancer. Eric Silk Charles Golden Chalk, C. H., Murray, N. M., Newsom-Davis, J., O’Neill, J. H., & Spiro, S. G. (1990). Response of the Lambert– Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma. Neurology, 40, 1552–1556. Elmqvist, D., & Lambert, E. H. (1968). Detailed analysis of neuromuscular transmission in a patient with the myasthenic syndrome sometimes associated with bronchogenic carcinoma. Mayo Clinic Proceedings, 43, 689–713. Lambert, E. H., Eaton, L. M., & Rooke, E. D. (1956). Defect of neuromuscular conduction associated with malignant neoplasma. American Journal of Physiology, 187, 612–613. Lang, B., Newsom-Davis, J., Wray, D., Vincent, A., & Murray, N. M. F. (1981). Autoimmune aetiology for myasthenic (Eaton–Lambert) syndrome. Lancet, 318(8240), 224–226. Lang, B., Johnston, I., Leys, K., Elrington, G., Marqueze, B., & Leveque, C. (1993). Autoantibody specificities in Lambert–Eaton myasthenic syndrome. Annals of the New York Academy of Science, 681, 382–393. Lang, B., & Newsom-Davis, J. (1995). Immunopathology of the Lambert-Eaton myasthenic syndrome. Springer Seminars in Immunopathology, 17(1), 3–15. Maddison, P., & Newsom-Davis, J. (2005). Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database of Systematic Reviews, CD003279. Sanders, D. B. (1994). Lambert-Eaton myasthenic syndrome: Pathogenesis and treatment. Seminars in Neurology, 14(2), 111–117. Sanders, D. B. (1995). Lambert-Eaton myasthenic syndrome: Clinical diagnosis, immune-mediated mechanisms, and update on therapies. Annals of Neurology, 37(1), 63–73. Verschuuren, J. J., Wirtz, P. W., Titulaer, M. J., Willems, L. N., & van Gerven, J. (2006). Available treatment options for the management of Lambert-Eaton myasthenic syndrome. Expert Opin Pharmacother, 7(10), 1323–1336. Waterman, S. A., Lang, B., & Newsom-Davis, J. (1996). Lambert–Eaton myasthenic syndrome autoantibodies inhibit neurotransmission from postganglionic sympathetic neurons by blocking voltage-gated calcium channels. Neurology, 46, 223–224.

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Wirtz, P. W., Sotodeh, M., Nijnuis, M., Van Doorn, P. A., Van Engelen, B. G., Hintzen, R. Q., et al. (2002). Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. Journal of Neurology, Neurosurgery & Psychiatry, 73(6), 766–768.

LANDAU–KLEFFNER SYNDROME DESCRIPTION

Landau–Kleffner syndrome (LKS) is a rare, childhood neurological disorder characterized by the sudden or gradual development of aphasia (i.e., the inability to understand or express language) and an abnormal EEG. It is also known as acquired epileptiform aphasia, infantile acquired aphasia, acquired epileptic aphasia, or aphasia with convulsive disorder. The syndrome was first described in 1957 by Dr. William M. Landau and Dr. Frank R. Kleffner, who identified six children with the disorder (Landau & Kleffner, 1957). LKS usually occurs in children between the ages of 3 and 7 years. Typically, children with LKS develop normally but then lose their language skills for no apparent reason. Many affected individuals have seizures but some do not. More than 200 cases have been described in the global literature. A slight predominance in boys has been reported (Sotero de Menezes, 2007). The cause(s) of LKS remain unknown, and the disorder is not likely to be inherited. Furthermore, the prognosis varies; some affected children have a permanent severe language disorder whereas others regain much of their language abilities over the course of months to years. Remission and relapse may also occur; however, in general, seizures disappear by adulthood (Sotero de Menezes, 2007). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The pathophysiology of LKS remains poorly understood. Cerebral spinal fluid (CSF), CT, and MRI findings are typically normal (Feekery, Parry-Fielder, & Hopkins, 1993). There may be mild elevations of CSF protein (Pascual-Castroviejo, Lopez-Martı´n, Martinez-Bermejo, & Perez-Hinojosa, 1992), white matter changes on CT/MRI, or a structural lesion (Otero, Cordova, Diaz, Garcia-Terul, & Del Brutto, 1989). All children with LKS have abnormal electrical brain waves that can be documented by an EEG. Paroxysmal EEG abnormalities involving the temporal or temporalparietal-occipital regions are present bilaterally. EEG

results usually return to normal by age 15 (Pearl, Carrazana, & Holmes, 2001). Several single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies on small numbers of patients have shown temporal lobe abnormalities in brain perfusion and glucose metabolism, respectively (Guerreiro et al., 1996; O’Tuama et al., 1992). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

With LKS, normally developing children between the ages of 3 and 7 begin having trouble understanding what is said to them. Doctors often refer to this problem as auditory agnosia or ‘‘word deafness.’’ Parents often think that their child is developing a hearing problem or has suddenly become deaf. These children may also appear to be developmentally delayed. The inability to understand language eventually affects spoken language and may progress to a complete loss of the ability to speak. Children who have learned to read and write before the onset of auditory agnosia can often continue communicating through written language. Nonverbal functions are relatively preserved, and some children develop a type of gestural communication or sign-like language. Intelligence is frequently unaffected. Behavioral disorders such as hyperactivity, aggressiveness, and depression can also accompany this disorder. DIAGNOSIS

The differential diagnosis of LKS is challenging because of the nonspecific nature of the symptoms. LKS may be misdiagnosed as autism, pervasive developmental disorder, hearing impairment, learning disability, auditory/verbal processing disorder, attention deficit disorder, mental retardation, childhood schizophrenia, or emotional/behavioral problems. Acquired aphasia in children may be secondary to head trauma, brain tumors, stroke, or neurocysticercosis. Like LKS, head injury, brain neoplasms, and cerebrovascular thromboembolism may be associated with an epileptiform EEG and seizures. Other neurologic deficits, such as hemiparesis or signs of increased intracranial pressure, may be a clue of an underlying structural lesion. MRIs, which are typically negative, can clarify the diagnosis. Deaf children may have many of the symptoms of LKS. When in doubt, a sleep EEG is required to rule out LKS (Sotero de Menezes, 2007). TREATMENT

Pharmacologic treatment includes anticonvulsants and corticosteroids to control seizure activity

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(Marescaux et al., 1990; McKinney & McGreal, 1974). Speech and language therapy is indispensable. Surgical therapy including temporal lobectomy has been associated with improvement in both language functioning and seizure control (Cole et al., 1988; Solomon, Parson, Pavlakis, Fraser, & Labar, 1993). Another treatment option is intravenous gamma-globulin (Fayad, Choveiri, & Mikati, 1997). Sign language construction has benefited others. Initiating treatment early improves outcome, although the variable nature of the syndrome renders controlled outcome studies quite difficult. Some children with long-standing verbal auditory agnosia may successfully be integrated into schools for the deaf, although others continue to have marked deficits in social adaptation, communication, and functioning. Listening can be assisted by increasing speech volume over the ambient noise. Classrooms can be acoustically modified and sound amplification technology can be utilized (Pearl et al., 2001). Introduction of an effective communication system can help alleviate problematic behavior. Shane S. Bush George M. Cuesta Cole, A. J., Andermann, F., Taylor, L., Olivier, A., Rasmussen, T., Robitaille, Y., et al. (1988). The Landau-Kleffner syndrome of acquired epileptic aphasia: Unusual clinical outcome, surgical experience, and absence of encephalitis. Neurology, 38, 31–38. Fayad, M., Choveiri, R., & Mikati, M. (1997). Landau Kleffner syndrome: Consistent response to repeated intravenous gamma-globulin doses: A case report. Epilepsia, 38, 489–494. Feekery, C. J., Parry-Fielder, B., & Hopkins, J. J. (1993). Landau Kleffner syndrome: Six patients including discordant monozygotic twins. Pediatric Neurology, 9, 49–53. Guerreiro, M. M., Camargo, E. E., Kato, M., Menezes Netto, J. R., Silva, E. A., Scotoni, A. E., et al. (1996). Brain single photon emission computed tomography imaging in Landau-Kleffner syndrome. Epilepsia, 37, 60–67. Landau, W. M., & Kleffner, F. R. (1957). Syndrome of acquired aphasia with convulsive disorder in children. Neurology, 7, 523–530. Marescaux, C., Hirsch, E., Finck, P., Maquet, P., Schlumberger, E., Sellal, F., et al. (1990). Landau Kleffner syndrome: A pharmacologic study of five cases. Epilepsia, 31, 768–777. McKinney, W., & McGreal, D. (1974). An aphasic syndrome in children. Canadian Medical Association Journal, 110, 637–639. Otero, E., Cordova, S., Diaz, F., Garcia-Terul, I., & Del Brutto, O. H. (1989). Acquired epileptic aphasia due to neurocysticercosis. Epilepsia, 30, 569–572.

O’Tuama, L. A., Urion, D. K., Janicek, M. J., Treves, S. T., Bjornson, B., & Moriarity, J. M. (1992). Regional cerebral perfusion in Landau-Kleffner syndrome and related childhood aphasias. Journal of Nuclear Medicine, 33, 1758–1765. Pascual-Castroviejo, I., Lopez-Martı´n, V., Martinez-Bermejo, A., & Perez-Hinojosa, A. (1992). Is cerebral arteritis the cause of the Landau Kleffner syndrome? Four cases in childhood with angiographic study. Canadian Journal of Neurological Science, 19, 46–52. Pearl, P. L., Carrazana, E. J., & Holmes, G. L. (2001). The Landau-Kleffner syndrome. Epilepsy Currents, 1, 39–45. Solomon, G. E., Parson, D., Pavlakis, S., Fraser, R., & Labar, D. (1993). Intracranial EEG monitoring in Landau-Kleffner syndrome associated with a left temporal lobe astrocytoma. Epilepsia, 34, 557–560. Sotero de Menezes, M. (2007). Landau-Kleffner syndrome. Retrieved November 25, 2008, from www.emedicine.com/neuro/topic182.htm

LEAD INTOXICATION DESCRIPTION

Lead intoxication, also called plumbism, describes the process by which excessive amounts of lead accumulate within the body, potentially causing harm to multiple organs and systems, including the central nervous system. Although rates of intoxication have dropped as awareness of lead toxicity has increased, including the elimination of known risk factors (e.g., lead-based paint), new cases continue to be documented as routes of exposure vary. Children remain the most vulnerable to lead intoxication, yet it can be experienced across the life span. Susceptibility in children is due to them absorbing a higher fraction of bioavailable lead in combination with the fact that their system is still developing through growth and cell differentiation and are more vulnerable to inhibition and damage (Holtzman, DeVries, Nguyen, Olson, & Bensch, 1984; Krigman, 1978). Nevertheless, relative consistency is seen in symptoms. Irritability, inattention, memory loss, headaches, impulsivity, lethargy, and general cognitive deterioration may all be seen as a consequence in children and adults (Papanikolaou, Hatzidaki, Belivanis, Tzanakakis, & Tsatsakis, 2005). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Lead intoxication has various routes but most commonly occurs through respiratory and gastrointestinal (GI) tracts. Phillip and Gerson (1994) noted that

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approximately 30% to 40% of inhaled lead is absorbed into the bloodstream. In both instances, lead-based paint in homes has been most commonly reported when discussing lead intoxication. For example, children with pica have historically been reported as those with the greatest risk of lead intoxication due to a tendency to eat paint chips among other inedible substances. This risk has dissipated with the reduction of lead-based paint. In terms of respiratory infiltration, this was historically noted in homes that had leadbased paint, poor ventilation, and no air conditioning. In summer months, if the interior became too hot, the lead-based paint could heat to the point that it would give off a vapor that could be inhaled. Toxicity encephalopathy was traditionally reported to occur when levels exceeded a ‘‘clinical’’ level of 80–100 mg/dL, although milder symptoms have been consistently observed with lesser amounts leading to a reduction of this ‘‘clinical’’ level to 10 mg/dL. Once in the system, the physiological basis of lead’s impact is multidimensional. It demonstrates a strong binding capacity for particular proteins in the system that interferes with the production and synthesis of various enzymes and structural protein (Phillip & Gerson, 1994). Because of its dependence upon these various proteins and enzymes, the developing nervous system is particularly vulnerable. Lead is particularly toxic to immature astrocytes and interferes with myelin formation, which may result secondarily in compromise of the blood–brain barrier increasing risk of increased intracranial pressure and encephalopathy (Holtzman et al., 1984). The aforementioned encephalopathy can contribute to global cerebral edema with obliteration of sulci and the lateral ventricles associated with congestion of the meningeal vasculature (Pentshschew, 1965). Synaptogenesis, cell migration, and glial cell growth can also be impeded by lead toxicity (Holtzman et al., 1984). Myelinated axons within white matter are separated by microspongiosis with gliosis and may show variable degeneration (Ohnishi et al., 1977) with variable axonal degeneration. The cerebellum may be particularly vulnerable due to lead’s tendency to compete for binding sites in this region for phosphokinase C, affecting calcium entry into cells, mitochondrial structure, and neuronal function (Bressler & Goldstein, 1991). Consistent with this, petechial hemorrhages are reported at high rates throughout the molecular and Purkinje cell layers of the cerebellum (Verity, 1997). In rodent models, reduction in the thickness of the cerebellar molecular layer and stunted Purkinje cell dendrite arborization have been reported in addition to reduced cortical synaptogenesis and complexity (McCauley et al., 1979).

Aside from the cerebellum, the hippocampus has also demonstrated relative susceptibility to lead intoxication. In their studies, Valpey et al. (1978) found cortical and cerebellar atrophy with selective neuronal loss in the hippocampus and cerebellum and neuronal chromatolysis in the reticular formation (Verity, 1997). Extensive neuronalnecrosis of hippocampal neurons as well as neurons of the fascia dentate has been reportedly observed (81–84-GL). Additional studies of the hippocampus revealed a decrease in the density of mossy fiber boutons in combination with hypertrophy of granule cells (Slomianka et al., 1989). Finally, neurotransmitter disruption has been commonly associated with lead intoxication. Spontaneous neurotransmitter release and an inhibition of what would otherwise be controlled stimulated release of neurotransmitters have been reported. Dopaminergic, cholinergic, and glutamatergic systems have all been found to be affected by lead intoxication (Cory-Slechta, 1997; Davis, 1990). Inhibition of GABA uptake has also been reported (Seidman et al., 1987) NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Variability is seen clinically from person to person when it comes to lead intoxication. Mediating factors include age and toxicity levels. Although greater levels are associated with greater toxicity, as suggested, residuals can be seen even with small amounts of lead. In a meta-analysis by Davis (1990) of four key studies on lead and behavior, they found that lead can cause impaired neurobehavioral activity at a level of 10–15 mg/dL. Initial or early symptomology in both adults and children include headache, potentially photophobia, irritability, inattention and feeling cognitively ‘‘foggy’’ or ‘‘sluggish,’’ memory loss (mainly retrieval based), and low-level cognitive impairment (Papanikolaou et al., 2005). In children, as elevated levels persist or increase, behavioral symptoms of impulsiveness, inability to follow sequences or directions, decreased play activity, lowered IQ, learning deficits, and increased inattentiveness are commonly seen (Papanikolaou et al., 2005). Infants and toddlers may demonstrate delays in normal physical and mental development. Adults commonly report peripheral neuropathy of extensor muscle groups and mild sensory loss. Wrist drop and foot drop have been commonly documented. In regard to neurocognitive functioning, no unitary profile exists, with diverse domains being indicted (Bellinger, 2011). Executive functions have demonstrated greatest susceptibility in children

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(Bellinger, Hu, Titlebaum, & Needleman, 1994) but also have been reported in adults (Schwartz & Otto, 2000). In this latter study, Schwartz and Otto (2000) also noted deficits in verbal memory, learning, and visuoconstructional abilities in a sample of 535 adult patients with lead intoxication compared with controls. Similar findings have been noted in pediatric populations. Drops in verbal IQ of roughly five points have been noted in children with lead burdens between 25 and 55 mg/dL (Needleman et al., 1990). Fine motor dysfunction has been reported (Ris et al., 2004) as have visuoconstructional abilities (Baghurst et al., 1995). DIAGNOSIS

Diagnosis of lead intoxication is laboratory based. Both blood lead level and zinc protoporphyria should be obtained through diagnostic chelation following infusion of 1 g of calcium ethylenediaminetetra-acetic acid (EDTA) with more than 600 grams of lead over a 72-hour period indicating elevation (Bolla & Cadet, 2007). Excessive levels are determined through blood analysis with comparisons made based on age and gender as children have lower tolerance than adults and thus toxicity is reached at lower levels. Furthermore, unborn fetuses of pregnant women are also vulnerable; thus, the limits for women of childbearing age are set in accordance with accepted pediatric levels. Currently, greater than 10 mg/dL is considered excessive for infants, children, and women of childbearing age. In adults, levels greater than 30 mg/dL are considered elevated. However, as noted by Papanikolaou et al. (2005), there is no measurable level of lead in the body below which no harm occurs, so the less the better. Research has consistently demonstrated deficits in children and adults below these thresholds. Beyond the aforementioned analyses, MRI and CT are beneficial given the potential for neurological deterioration. White matter tracts should be carefully evaluated, thus also potentially suggesting the role of diffusion tensor imaging in diagnostic workup. Hippocampal and cerebellar regions should be closely evaluated. Neuropsychological assessment should be comprehensive in its approach. Although particular attention should be placed on executive functions, domains of attention, verbal learning and memory, and visuoconstructional and visuospatial skills, other domains may still be impacted on a case-by-case basis. TREATMENT

Treatment of lead intoxication understandably is directed at reducing levels of lead in the system.

Chelation therapy is the standard method of removing lead from the system and is also a key tool in diagnosis. Calcium disodium EDTA and dimercaptosuccinic acid (DMSA) have both been used in chelation therapy to remove lead from the system as part of treatment as well as for diagnostic purposes (Lee et al., 2000; Wedeen, 1992). Dietary supplementation has also been effective. Increased dietary calcium has been found to reduce the absorption of lead in infants and children (Bogden et al., 1992; Mahaffey, Gartside, & Glueck, 1986). Increased intakes of magnesium, phosphate, alcohol, and dietary fat have demonstrated similar benefits in terms of their reduction of gastrointestinal absorption of lead (Barltrop & Meek, 1979). Although chelation therapy controls further toxicity secondary to increased lead levels, in many ways the consequences of the initial level elevations are irreversible. This is particularly true when it comes to neuropsychological outcomes. Although chelation therapy has been shown to decrease blood lead levels appropriately in children with concentrations as high as 20–45 mg/dL, the cognitive impairments presenting at that point in time cannot be reversed (Lee et al., 2000; Wedeen, 1992). Given this, appropriate services should be initiated based on findings of neuropsychological assessment such as special education services, cognitive rehabilitation, and training. If mood or behavioral issues remain prevalent, therapy, behavioral modification, and, if need be, pharmacological intervention may be utilized as deemed appropriate. Jacob M. Goings Chad A. Noggle Baghurst, P. A., McMichael, A. J., Tong, S., Wigg, N. R., Vimpani, G. V., & Robertson, E. F. (1995). Exposure to environmental lead and visual-motor integration at age 7 years: The Port Pirie Cohort Study. Epidemiology, 6, 2, 104–109. Barltrop, D., & Meek F. (1979). Effect of particle size on lead absorption from the gut. Archives of Environmental Health, 34, 280–285. Bellinger, D. (2011). Toxic Effects. In: Davis, A. Handbook of Pediatric Neuropsychology (955–962). New York, NY: Springer Publishing. Bellinger, D., Hu, H., Titlebaum, L., & Needleman, H. (1994). Attentional correlates of dentin and bone lead levels in adolescents. Archives of Environmental Health, 49, 98–105. Bogden, J. D., Gertner, S. B., Christakos, S., Kemp, F. W., Yang, Z., Katz, S. R., et al. (1992). Dietary calcium modifies concentrations of lead and other metals and renal calbindin in rats. The Journal of Nutrition, 122, 1351–1360.

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Bolla, A., & Cadet, J. (2007). Exogenous Acquired Metabolic Disorders of the Nervous System: Toxins and Illicit Drugs. In: Goetz C. Textbook of Clinical Neurology. Philadelphia: Saunders. Bressler, J. P., & Goldstein, G. W. (1991). Mechanisms of lead neurotoxicity. Biochemical Pharmacology, 41, 4, 479–484. Cory-Slechta, D. A. (1997). Relationships between Pb-induced changes in neurotransmitter system function and behavioral toxicity. Neurotoxicology, 18, 3, 673–688. Davis, J. M. (1990). Risk assessment of the developmental neurotoxicity of lead. Neurotoxicology, 11, 2, 285–291. Holtzman, D., DeVries, C., Nguyen, H., Olson, J., & Bensch, K. (1984, Fall). Maturation of resistance to lead encephalopathy: Cellular and subcellular mechanisms. Neurotoxicology, 5, 3, 97–124. Krigman, M. R. (1978, October). Neuropathology of heavy metal intoxication. Environmental Health Perspectives, 26, 117–120. Lee, B., Ahn, K. D., Lee, S. S., Lee, G. S., Kim, Y. B., & Schwartz, B. S. (2000). A comparison of different lead biomarkers in their associations with lead-related symptoms. International Archives of Occupational and Environmental Health, 73, 5, 298–304. Mahaffey, K. R., Gartside, P. S., & Glueck, C. J. (1986). Blood lead levels and dietary calcium intake in 1- to 11-yearold children: The Second National Health and Nutrition Examination Survey, 1976 to 1980. Pediatrics, 78, 2, 257–262. Needleman, H.L, Schell, A., Bellinger, D., et al. (1990). The long-term effects of exposure to low dose of lead in childhood: An 11 year follow-up report. The New England Journal of Medicine, 322, 83–88. Ohnishi, A., Schilling, W.S., Brimijoin, W.S. et al. (1997). Lead neuropathy. 1. Morphometry, nerve conduction ad choline acetyltransferase transport: New finding of endoneurial oedema associated with segmental demyelination. Journal of Neuropathology & Experimental Neurology, 36, 499–518. Papanikolaou, N. C., Hatzidaki, E. G., Belivanis, S., Tzanakakis, G. N., & Tsatsakis, A. M. (2005). Lead toxicity update. A brief review. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 11, 10, RA329–RA336. Pentschew A. (1965). Morphology and morphogenesis of lead encephalopathy. Acta Neuropathol (Berl), 5, 133–160. Phillip, A. T., & Gerson, B. (1994). Lead poisoning — Part I. Incidence, etiology, and toxicokinetics. Clinics in Laboratory Medicine, 14, 2, 423–444. Ris, M. D., Dietrich, K. N., Succop, P.A., & Berger, O.G (2004). Early exposure to lead and neuropsychological outcome in adolescence. Journal of International Neuropsychological Society, 10 (2), 261–270. Schwartz, B. S., Stewart, W. F., Bolla, K. I., et al. (2000). Past adult lead exposure is associated with longitudinal decline in cognitive function. Neurology, 55, 1144–1150.

Seidman, B.C., Olsen, A. W., Verity, M. A. (1987). Triethyl lead inhibits Y-aminobutyric acid binding to uptake sites in synaptosomal membranes. Journal of Neurochemistry, 49, 415–420. Slomianka, L., Rungby, J., West, M. J. et al. (1989). Dosedependent bimodel effect of low-level lead exposure on the developing hippocampal region of the rat: A volumetric study. Neurotoxicology, 10, 177–190. Valpey, R., Sumi, M., Copss, MK, Goble, G.J. (1978). Acute and chronic progressive encephalopathy due to gasoline sniffing. Neurology, 28, 507–510. Verity, M.A. (1997). Toxic disorders. In D.I. Graham & P.L. Lantos (Eds.) Greenfield’s Pathology (6th Ed.). London: Arnold (pp. 755–811). Wedeen, R. (1992). Removing lead from bone: Clinical implications of bone lead stores. Neurotoxicology, 13, 4, 843–852.

LEIGH’S SYNDROME DESCRIPTION

Leigh’s syndrome, also called subacute necrotizing encephalomyelopathy, is a rare neurometabolic disorder that is characterized by an acute degeneration of the brain, spinal cord, and optic nerve. It was first described in 1951 in a 7-month-old infant who showed severe nerve damage that resulted in lesions in the brainstem. The disorder is characterized by a rapid degeneration of the central nervous system and the development of symmetrical patches of demyelinated nerves. Leigh’s syndrome is most commonly diagnosed in infancy or early childhood; however, there are a limited number of adult cases reported. Research pertaining to adult onset Leigh’s syndrome does not currently exist and the cause is unknown. Characteristically the individual will develop normally until approximately 1 year of age, at which time a gradual reduction of development may be seen; previously learned skills such as walking, sucking, and crawling show a significant regression. Throughout the progression of the disease, these developmental changes will continue to regress to previous states. Prognosis for the disease is poor and death usually occurs within 1–2 years after symptoms first appear. In some rare cases, individuals have reportedly lived to early adolescence. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Leigh’s syndrome has been shown to be associated with a thiamine deficiency. This deficiency appears

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to result from an inhibitor that is present in body fluids that prevents the formation of the thiamine (Pincus et al., 1973). Due to the disturbance of thiamine metabolism, paralysis of the motor nerves in the eye (ophthalmoplegia), rapid involuntary movement of the eye (nystagmus), and disordered gaze, Leigh’s syndrome is said to resemble Wernicke’s disease; however, the hypothalamus and mammillary bodies are not affected in Leigh (Dale & Federman, 2008; De Vivo & Hirano, 2005; Murphy, 1973; Murphy, Isohashi, Weinberg, & Utter, 1981; Ropper & Brown, 2005). Lesions are noted to be quite extensive and very distinctive and consist of a combination of cell necrosis, demyelination, and vascular proliferation that can be found in the midbrain, pons, medulla, spinal cord, thalamus, basal ganglia, and cerebellum, and in the optic nerve and tracts. Cranial nerve abnormalities have also been observed. (Dale & Federman, 2005; De Vivo & Hirano, 2005; De Vivo & Hirano, 2008; Ropper & Brown, 2005; Williams et al., 1977). In the majority of cases the cerebral spinal fluid is normal; however, the levels of protein may be increased. Pyruvate and lactate levels have been found to be elevated in the blood and urine and indicate a potential disorder of mitochondrial oxidation (Atalar, Egilmez, Bulut, & Icagasioglu, 2005; Williams et al., 1977). The most commonly identified biochemical abnormalities that lead to Leigh’s syndrome have been found to exist in pyruvate dehydrogenase metabolism and oxidative phosphorylation (OXPHOS) defects (Complexes 1 and IV) (Murphy et al., 1981). All gene mutations are said to be transmitted in an autosomal recessive fashion. In the event that the deficiency occurs in the enzyme pyruvate dehydrogenase, the variation of the disease is said to be X-linked and for this reason shows a greater occurrence in boys, where girls are likely to be the carriers (De Vivo & Hirano, 2005; Macnair, 2006). There are four types of mutations in the nuclearencoded respiratory chain subunits that have been identified in Leigh’s syndrome patients. One mutation exists in the gene coding for the flavoprotein subunit of Complex II (Shoffner, 2003). The other three mutations exist in Complex I subunits, specifically 18-KDa that maps to chromosome 5, NDUSF9, and 51-kDa. However, it is noted that these deficits do not produce the metabolic abnormalities that are known to occur in Leigh’s syndrome. Complex IV deficits are frequently observed and may be the result of a mutation in the SURF1 gene, which causes poor assembly of cytochrome-c-oxidase. When both parents carry the mutated gene, their children have a 25% chance of having a child that is

affected (Macnair, 2006; Shoffner, 2003). A final defect that can lead to Leigh’s syndrome may be the result of a mutation of the mitochondrial DNA that may also lead to the deficiency of cytochrome-c-oxidase. Oxygen respiration is essential to the functioning of the mitochondria. Thus, when cellular respiration is dysfunctional, a deficit of supply to the mitochondria occurs, ultimately preventing the mitochondria from operating properly. This type of defect is one of the rarest causes of Leigh’s syndrome (Pecina, Gnaiger, Zeman, Pronicka, & Houstek, 2004). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Infants with this disease develop normally for up to 2 years prior to developing the first symptoms. In infants, the first symptoms include poor sucking, loss of head control, poor appetite, vomiting, irritability, and weight loss. If the onset occurs within the second year, a delay in walking, ataxia, psychomotor regression, respiration disturbance, and abnormal movement of limbs can be seen. Disorders of gaze may also occur when the degeneration begins to affect the optic nerve. Cognitive and intellectual deterioration may also begin to develop, specifically loss of previous ability for speech. The onset is very swift as is the deterioration. In some cases, heart difficulties have been noted. In the case of adult onset, the regression of previously developed skills, ataxia, respiration disturbance, vision difficulties, limb weakness, and hearing difficulties can also be seen; however, the progression of the disease is slower. The course of Leigh’s syndrome is characterized by remissions and exacerbations. The frequency and intensity is varied among individuals depending on the acuteness of the disease. Exacerbations may be associated with a high fever, or a high carbohydrate diet. The prognosis is poor for individuals diagnosed with Leigh’s syndrome — most do not live more than 2 years — although there have been a couple of cases reported of individuals who live into adolescence and adulthood. DIAGNOSIS

Leigh’s syndrome is difficult to diagnose due to the broad variability in symptoms and the many genetic causes of the disease. Characteristically the individual will develop normally until approximately 1 year of age, at which time a gradual reduction of development may be seen; previously learned skills such as walking, sucking, and crawling show a significant regression. Throughout the progression of the disease,

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there will be continued degeneration. This marked decline in function is the first clinical sign for diagnosis. Thereafter, Leigh’s syndrome is typically detected through blood and urine screening followed by genetic tests that are performed to confirm the presence or absence of the abnormal gene. In addition, evidence of brain lesions may be seen in CT scans and in MRIs. Electron microscopy may also show an increase of mitochondria in rare cases. As these symptoms overlap with many other degenerative diseases of childhood, modern diagnosis depends on genetic analysis.

TREATMENT

There are little to no successful treatments for Leigh’s syndrome. In some cases, thiamine and vitamin B1 supplements are given as an attempt to decrease the rate of deterioration (Rocco, Lamba, Minniti, Caruso, & Naito, 2000). Over time, however, the effectiveness of these treatments plateau and deterioration continues. In some cases, a high fat, low carbohydrate diet may be prescribed. Similar to thiamine treatment, the benefits of this type of treatment are short-lived and degeneration continues. Danielle S. Dance Charles Golden Altalar, M. H., Egilmez, H., Bulut, S., & Icagasioglu, D. (2005). Magnetic resonance spectroscopy and diffusion-weighted imaging findings in a child with Leigh’s disease. Pediatrics International, 47, 601–603. Dale, D. C., & Federman, D. D. (2008). ACP Medicine. New York: Web MD.. De Vivo, D. C., & Hirano, M. (2005). Mitochondrial diseases with mutations of nuclear DNA. In L. P. Rowland (Ed.), Merritt’s neurology. Philadelphia: Lippincott Williams & Wilkins. McCandless, D. W., & Hodgkin, W. E. (1977). Subacute necrotizing Encephalomyelopathy (Leigh’s disease). Pediatrics, 60(6), 935–937. Mcnair, T. (2006). Leigh’s disease. BBC health. Retrieved January 7, 2009. Murphy, J. V. (1973). Subacute necrotizing encephalomyelopathy (Leigh’s disease): Detection on the heterozygous carrier state. Pediatrics, 51(4), 710–715. Murphy, J. V., Isohashi, F., Weinberg, M. B., & Utter, M. F. (1981). Pyruvate carboxylase deficiency: An alleged biochemical cause of Leigh’s disease. Pediatrics, 68(3), 401– 404. Pecina, P., Gnaiger, E., Zeman, J., Pronicka, E., & Houstek, J. (2004). Decreased affinity for oxygen of cytochrome-c

oxidase in Leigh syndrome caused by SURF1 mutations. American Journal of Physiology, 287, 1384–1388. Pincus, J. H., Cooper, J. R., Murphy, J. V., Rabe, E. F., Lonsdale, D., & Dun, H. G. (1973). Thiamine derivatives in sub acute necrotizing encephalomyelopathy. Pediatrics, 51(4), 716–721. Rocco, M. D., Lamba, L. D., Minniti, G., Caruso, U., & Naito, E. (2000). Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive pyruvate dehydrogenase deficiency. European Journal of Paediatric Neurology, 4(3), 115–117. Ropper AH, Brown RJ: Adams and Victor’s principles of neurology, 8th edn.. New York, McGraw-Hill, 2005. Shoffner, J. M. (2003). Oxidative phosphorylation diseases and disorders of pyruvate oxidation. In C. D. Rudolph, A. M. Rudolph, M. K. Hostetter, G. Lister, & N. J. Siegel (Eds.), Rudolph’s pediatrics. McGraw-Hill. Williams, J. L., Monnens, L. A. H., Trijbels, J. M. F., Veerkamp, J. H., Meyer, A. E. F. H., Van Dam, K., et al. (1977). Leigh’s encephalomyelopahty in a patient with cytochrome c oxidase deficiency in muscle tissue. Pediatrics, 60(6), 850–857.

LENNOX–GASTAUT’S SYNDROME DESCRIPTION

Lennox–Gastaut’s syndrome (LGS) is a form of childhood epilepsy primarily characterized by tonic seizures during sleep or at times of awakening. Symptoms onset fairly early and may have been preceded historically by infantile spasms/West’s syndrome. Atonic, atypical absence, myoclonic seizures, and/or status epilepticus are also common manifestations (Foldvary-Schaefer & Wyllie, 2007). Clinical manifestations may vary. Mental retardation of moderate to severe degrees is seen. In fact, the latter is noted in a majority of cases and may be noted even prior to seizure activity. LGS accounts for approximately 2% to 3% of all cases of childhood epilepsy (Farrell & Tatum, 2006). Symptoms most commonly onset between 1 and 8 years of age. The presentation is often noted in relation to other central nervous system (CNS) manifestations. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Generalized cerebral atrophy is often observed. The etiological basis is often determined in approximately 70% of cases (Arzimanoglou, Guerrini, & Aicardi, 2004). As suggested, LGS is usually seen in

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conjunction with other CNS malformations of either a genetic or acquired basis. CNS infections, tuberous sclerosis, and other noncutaneous disorders, CNS development disorders, and hypoxic events have been associated with LGS. LGS is preceded by West’s syndrome in approximately 20% to 30% of children and is related to poorer outcomes (Gastaut et al., 1966; Genton, Guerrini, & Dravet, 2000). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

As suggested, LGS is a seizure disorder characterized by a mixture of seizure types, with an onset in childhood, usually between 1 and 8 years of age, and potentially preceded historically by infantile spasms. Atypical absence seizures can present, which are longer in duration or more complicated than traditional or typical absence seizures. Generalized tonic–clonic seizures are also associated with the presentation as are atonic seizures. Regarding the latter, this leads to an acute loss of muscle tone, leading to these sometimes being referred to as drop seizures. This constitutes a risk for children, as they may hit their head when falling. As a result, children often wear protective helmets to reduce risk of serious injury. From a neuropsychological standpoint, a unitary profile isnot really seen. Rather, individuals demonstrate generalized and global deficits in cognition (Besag, 2006). More than half of all children demonstrate severe mental retardation, with 20% to 60% arising even prior to seizure onset (Foldvary-Schaefer & Wyllie, 2007). Mild to moderate mental retardation is noted in the remaining children. Normal functioning is rarely ever noted and, again, the pattern is fairly generalized without sparing or more prominent dysfunctions noted in particular areas. Coinciding with this general dysfunction, learning deficits are prominent. Behaviorally, children exhibit tendencies toward irritability, increased anger, and impulsivity. They can demonstrate tendencies toward explosiveness and destructive behavior at times of agitation. DIAGNOSIS

Diagnosis is made through a combination of clinical features and electroencephalogram, which is essential to diagnosis. The pattern commonly reveals diffuse slow spike-wave complexes or polyspike-wave discharges during wakefulness and bursts of diffuse fast rhythms at 10–20 Hz during sleep (Beaumanoir & Blume, 2005; Dulac & N’Guyen, 1993; Gastaut et al., 1966). This pattern is noted in conjunction with the clinical features of mental deterioration, behavioral

disturbance, and drug-resistant epilepsy marked by atonic and atypical absence seizures during the day and largely nocturnal tonic seizures. TREATMENT

LGS responds poorly to standard anticonvulsant treatment. Polytherapy is often needed. Rufinamide, lamotrigine, and topiramate have all been approved by the U.S. FDA for the treatment of LGS. However, empirical reviews have still suggested that these are not highly effective (Hancock & Cross, 2003). Clonazepam and valproic acid have also demonstrated utility (Foldvary-Schaefer & Wyllie, 2007). Phenytoin and rectal diazepam are useful in the treatment of serial tonic seizures and status epilepticus with refractory cases potentially benefitting from felbamate or a ketogenic diet (Foldvary-Schaefer & Wyllie, 2007). In highly refractory cases, particularly a lack of response of atonic seizures, neurosurgical intervention may be required in the form of a corpus callosotomy. Implantation of vagus nerve stimulators have also shown some efficacy. As previously suggested, children should wear protective helmets to avoid secondary injury resulting from atonic (a.k.a. drop) seizures. For children who can function in a school setting, multiple services are often required by way of individualized education programs and special education services. Chad A. Noggle Arzimanoglou, A., Guerrini, R., & Aicardi, J. (2004). LennoxGastaut syndrome. In Aicardi’s epilepsy in children (3rd ed., pp. 38–50). Philadelphia: Lippincott Williams and Wilkins. Beaumanoir, A., & Blume, W. (2005). The Lennox-Gastaut syndrome. In J. Roger, M. Bureau, C. Dravet, P. Genton, C. A. Tassinari, & P. Wolf (Eds.), Epileptic syndromes in infancy, childhood and adolescence (4th ed., pp. 125–148). Paris: John Libbey Eurotext. Besag, F.M. (2006). Cognitive and behavioral outcomes of epileptic syndromes: Implications for education and clinical practice. Epilepsia, 47 (Suppl. 2), 119–125. Dulac, O., & N’Guyen, T. (1993). The Lennox-Gastaut syndrome. Epilepsia, 34 (Suppl. 7), 7–17. Farrell, K., Tatum, W.O. IV (2006). Encephalopathic generalized epilepsy and Lennox-Gastaut syndrome. In E. Wyllie, A. Gupta, D.K. Lachhwani (Eds.) The treatment of epilepsy: Principles and practice (4th ed., pp. 429–440). Philadelphia: Lippincott, Williams, & Wilkins. Foldvary-Schaefer, N., & Wyllie, E. (2007). Epilepsy. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 1213–1244). Philadelphia: Saunders Elsevier.

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Gastaut, H., Roger, J., Soulayrol, R., Tassinari, C.A., Regis, H., Dravet, C. (1966). Childhood epileptic encephalopathy with diffuse slow spikes and waves (otherwise known as ‘‘petit mal variant’’) or Lennox syndrome. Epilepsia, 7, 139–179. Genton, P., Guerrini, R., & Dravet, C. (2000). The LennoxGastaut syndrome. In H. Meinardi (Ed.), Handbook of clinical neurology: The epilepsies, part II (pp. 211–222). Amsterdam: Elsevier. Hancock, E., & Cross, H. (2003). Treatment of LennoxGastaut syndrome. Cochrane Database of Systematic Reviews, (3), CD0P3277.

LESCH–NYHAN SYNDROME DESCRIPTION

Medical student Michael Lesch and Dr. William Nyhan published a 1964 paper in which they described two brothers presenting with delayed motor development, increased muscle tone, positive Babinski signs, involuntary movements, self-injurious behavior (SIB), mental retardation, and crystals of uric acid in the urine. Now known as Lesch–Nyhan syndrome (LNS), it results from a recessive X-linked chromosomal abnormality that leads to a deficiency of the hypoguanine phosphoribosyltransferase (HPRT) enzyme that leads to increased purine production. LNS occurs in approximately 1:100,000–1:380,000 births and most frequently occurs in boys (Sikora et al., 2006). A milder variant (Lesch–Nyhan variant, LNV) is also known, defined by increased HPRT activity 1.5% to 50% of normal levels and hyperuricemia, but milder cognitive and motor symptoms and the absence of SIB characteristic of LNS. NEUROPATHOLOGY/PATHOPHYSIOLOGY

LNS is caused by a mutation on the X chromosome, HPRT1 gene, located at q26-q27 causing a deficiency in the HPRT enzyme that is part of the purine salvage pathway. Hypoguanine phosphoribosyltransferase catalyzes the conversion of purine bases to nucleic acids (hypoxanthine to inosinic acid guanidine to guanylic acid). Hypoxanthine is converted to uric acid by xanthine oxidase, and increased levels of hypoxanthine due to defects in the HPRT enzyme result in increased uric acid production and hyperuricemia. In infants, uric acid crystals can sometimes be seen in the diaper and patients may present with renal stones, neuropathy, manifestation of gout, and if

untreated, renal failure (Nyhan, 1976). No specific locations on the HPRT gene have been implicated in LNS; however, several sites have been deemed ‘‘mutational hotspots,’’ and it is suggested that less severe LNVs may result from mutations that allow partial HPRT enzyme activity (Jinnah et al., 2000). Mutations of HPRT can affect intracellular concentrations of the HPRT enzyme, most likely due to enzyme instability, or can impair catalytic activity of HPRT (Eads et al., 1994). It is likely that many features of LNS may be attributed to dysfunction of dopamine and the basal ganglia, including motor abnormalities and SIB (Visser, Bar, & Jinnah, 2000). Reduction in size and volume of the caudate have been noted in LNS patients compared to controls (Harris et al., 1998; Wong et al., 1996). A positron emission tomography study found a reduction in dopamine binding in the caudate and putamen in LNS patients compared to controls and patients with Rett’s syndrome. In addition, reduced total brain volume, atrophy of the brainstem, thickening of the skull marrow, and pneumatization of the sinuses were found in five of the seven patients with LNS (Harris et al., 1998). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Motor impairments are severe in classic is brainderived neurotrophic growth factor LNS, and most patients never achieve independence in unsupported sitting or walking. Hypotonia develops at approximately 3–6 months of age. At 6–12 months, infants demonstrate an inability to sit up and involuntary movements which progress in severity through the fourth year or life. Then motor abnormalities become static, neither worsening nor improving in most cases. Dystonia is the most prominent motor feature of LNS and is present in the upper body, mandible, and lower body causing difficulty or inability in grasping, speaking, and walking, respectively. Choreoathetosis (spastic movements of the limbs and face), dysarthia (slurred speech), difficulty swallowing and frequent vomiting, and ballism (abnormal swinging, hurling, or jerking movements) were also reported in patients with LNS (Jinnah et al., 2006; Olson & Houlihan, 2000). The first descriptions of LNS included mental retardation with IQ scores less than 50. However, it has been recognized that motor and speech deficits may limit testing and individuals with LNS may have intellectual functioning higher than suggested by their measured IQ scores. There are published case reports of LNS patients with average intelligence; however, in these patients sustained attention remained impaired

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(Scherzer & Ilson, 1969). In a survey designed specifically to assess cognitive ability in LNS patients, caretakers reported that all subjects over 5 years of age were alert and oriented to date, location, and identity of caregivers; 97% of the patients reportedly showed appropriate affect and an understanding of events and environment. In that same study, anecdotes provided by caretakers alluded to memory abilities. Parents also indicated that LNS patients over the age of 5 were capable of inductive and deductive reasoning, as they were able to understand the plots of movies and keep up with sports programs. Though speech is difficult for LNS patients, parents report the ability to improve communication skills with training. In most children, academic ability was impaired and found to be below grade level and cognitive ability (Anderson, Ernst, & Davis, 1992). Research using standardized measures has shown that over 70% of LNS patients obtain IQ scores in the ranges associated with mental retardation (Jinnah, DeGregorio, Harris, Nyhan, & O’Neill, 2000; Matthews, Solan, & Barabas, 1995). Individuals with LNV typically obtain scores lower than normals, but higher than typical LNS patients (Schretlen, Harris, Park, Jinnah, & Del Pozo, 2001). The hallmark of LNS is SIB that begins at approximately 2 years of age; however, the range of age at onset varies from 5 months to 10 years. Self-injury is related to stressful situations and worsens in aversive situations. Patients’ sensory modalities are intact and they are capable of feeling pain; however, they are compulsively driven to injure themselves, and though they are conscious of their behavior, it is apparently beyond their volitional control. In a survey of 40 parents of patients with LNS, approximately 50% reported that their children were able to predict activities that precipitate SIB (Anderson & Ernst, 1994). Patients often show remorse afterwards. Biting is the most prevalent form of self-injury often causing loss of tissue around the mouth and amputation of fingers. Other forms of SIB include head banging, arching of the spine, throwing limbs or head out when passing by a doorway when in wheelchair, and snapping the head back. After approximately 5 years of age, new forms of SIB rapidly evolve (Anderson & Ernst, 1994; Robey, Reck, Giacomini, Barabas, & Eddey, 2003). Aggression toward others has also been reported in patients with LNS and, like self-injury, appears to be beyond the patient’s control. Individuals with LNV typically do not self-injure, but often have difficulty with attention (Schretlen et al., 2005). DIAGNOSIS

Developmental delay, motor abnormalities, and uric acid crystals may be seen in infancy. Definitive

diagnoses may be made by examining erythrocyte HPRT enzyme concentrations (less than 1.5% of normal concentrations in classic LNS) and alternatively, screening for the HPRT gene mutation. Levart (2007) presented a case report in which diagnosis of LNS was not straightforward and was made only through examination of serum uric acid and subsequent mutation screening of the HPRT1 gene. He concluded that a diagnosis of LNS must be ruled out in every boy with supposed cerebral palsy with no history of perinatal illness by carefully examining the patient for hyperuricosuria. Nyhan (1976) defined a spectrum of HPRT deficiency. He defined full-blown LNS as showing virtually no HPRT enzyme activity under any conditions, whereas those with partial variant LNV showed some HPRT activity, but still less than 50% of the normal values. Alternatively, Levart (2007) suggests that patients be diagnosed with LNS if HPRT enzyme activity is less than 1.5% under all conditions, and those with levels between 1.5% and 10% may be diagnosed as ‘‘neurologic variants.’’ TREATMENT

Presently, there is no remedy for HPRT deficiency; however, patients with LNS are treated with medication to lessen uric acid production, motor abnormalities, and SIB. Allopurinol is an inhibitor of xanthine oxidase and may be used to lower blood levels of uric acid, preventing kidney stones and gout manifestations; however, doses should be carefully monitored as too much allopurinol may cause increased excretions of uric acid. In addition, a potassium citrate mixture may be used to increase the solubility of uric acid. Baclofen and diazepam are used to lessen muscle spasms. Diazepam has the additional benefit of reducing anxiety but also presents a risk for developing dependency. Tetrabenzine and L-dopa have proven successful in ameliorating some movement disabilities (McCarthy, 2004). Pharmacologic treatments of SIB with agents such as benzodiazepines, neuroleptics, chloral hydrates, anticonvulsives, and antidepressants have shown variable success with parental reports indicating that anticonvulsives and benzodiazepines being the most effective (Anderson & Ernst, 1994). Behavior therapy is pallative, but not curative, and in many cases of LNS, individuals must be restrained in order to prevent injury. Most patients are at ease in restraints and may show terror when they are not restrained (Anderson & Ernst, 1994; Nyhan, 1976). Affected individuals often participate in decisions regarding restraints. Another technique used in the management of SIB is dental extraction. In Anderson and Ernst’s (1994) survey, 60% of patients with LNS

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had teeth extracted to prevent injurious side effects of biting, and all of the parents reported no regrets. Some researchers suggest that there may be a gene by environment interaction involved in SIB. Such as changes in the brain resulting from for example, HPRT deficiency may cause changes in the brain lead to the expression of certain behaviors which are subsequently reinforced by parents’ actions. In Anderson and Ernst’s (1994) survey, over 42% of parents indicated that their child occasionally used SIB to obtain a desired goal. Psychosocial therapy has variable success in the LNS population. Behavior modification alleviated SIB to some degree in 70% of patients surveyed (Anderson & Ernst, 1994). Reports indicate variable success with combinations of play therapy, extinction, desensitization, and reinforcement (Olson & Houligan, 2000). LNS is a recessive, X-linked, genetic disorder resulting in disruption of the purine salvage pathway via the HPRT enzyme. The disorder manifests in hyperuricemia, and disorders in motor, neurological, cognitive, and behavioral functions — the hallmark of LNS being the severity of self-injury that individuals are compulsively driven to engage in. Although there is no remedy for HPRT deficiency, treatments of hyperuricemia and motor disorders have proven highly successful. The efficacy of treatments of SIB has been variable and entirely pallative. Mandi Musso Alyse Barker William Drew Gouvier Anderson, L. T., & Ernst, M. (1994). Self-injury in LeschNyhan disease. Journal of Autism and Developmental Disorders, 24(1), 67–81. Anderson, L. T., Ernst, M., & Davis, S. V. (1992). Cognitive abilities of patients with Lesch-Nyhan disease. Journal of Autism and Developmental Disorders, 22(2), 189–203. Eads, J. C., Scapin, G., Xu, Y., Grubmeyer, C., & Sacchettini, J. C. (1994). The crystal structure of human hypoxanthine-guanine phosphoribosyltransferase with bound GMP. Cell, 78, 325–334. Harris, J. C., Lee, R. R., Jinnah, H. A., Wong, D. F., Yaster, M., & Bryan, R. N. (1998). Craniocerebral magnetic resonance imaging measurement and findings in LeschNyhan syndrome. Archives or Neurology, 55, 547–553. Jinnah, H. A., De Gregorio, L., Harris, J. C., Nyhan, W. L., & O’Neill., J. P. (2000). The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutation Research, 463, 309–326. Jinnah, H. A., Visser, J. E., Harris, J. C., Verdu, A., Larovere, L., Ceballos-Picot, I., et al.; Lesch-Nyhan Disease Internation Study Group. (2006). Delineation of the motor disorder of Lesch-Nyhan disease. Brain, 12(9, Pt. 5), 1201–1217.

Levart, T. K. (2007). Rare variant of Lesch-Nyhan syndrome without self-mutilation or nephrolithiasis. Pediatric Nephrology, 22, 1975–1978. Matthews, W. S., Solan, A., & Barabas, G. (1995). Cognitive functioning in Lesch-Nyhan syndrome. Developmental Medicine and Child Neurology, 37, 715–722. McCarthy, G. (2004). Medical diagnosis, management, and treatment of Lesch-Nyhan disease. Nucleosides, Nucleotides, & Nucleic Acids, 23(8 & 9), 1147–1152. Nyhan, W. L. (1976). Behavior in the Lesch-Nyhan syndrome. Journal of Autism and Childhood Schizophrenia, 6(3), 235–252. Olson, L., & Houlihan, D. (2000). A review of behavioral treatments used for Lesch-Nyhan syndrome. Behavior Modification, 24(2), 202–222. Robey, K. L., Reck, J. F., Giacomini, K. D., Barabas, G., & Eddey, G. E. (2003). Modes and patterns of self-mutilation in person with Lesch-Nyhan disease. Developmental Medicine and Child Neurology, 45(3), 167–171. Schretlen, D. J., Harris, J. C., Park, K. S., Jinnah, H. A., & Del Pozo, N. O. (2001). Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthineguanine phosphoribosyltransferase deficiency. Journal of the International Neuropsychological Society, 7, 805–812. Schretlen, D. J., Ward, J., Meyer, S. M., Yun, J., Puig, J. G., Nyhan, W. L., et al. (2005). Behavioral aspects of LeschNyhan disease and its variants. Developmental Medicine and Child Neurology, 47(10), 673–677. Sherzer, A. L., & Ilson, J. B. (1969). Normal intelligence in the Lesch-Nyhan syndrome. Pediatrics, 44(1), 116–120. Sikora, P., Pijanowska, M., Majewski, M., Bienias, B., Borzecka, H., & Zajaczkowska, M. (2006). Acute renal failure due to bilateral xanthine urolithiasis in a boy with LeschNyhan syndrome. Pediatric Nephrology, 21, 1045–1047. Visser, J. E., Bar, P. R., & Jinnah, H. A. (2000). Lesch-Nyhan disease and the basal ganglia. Brain Research Reviews, 32, 449–475. Wong, D. F., Harris, J. C., Naidu, S., Yokoi, F., Marenco, S., Dannals, R. F., et al. (1996). Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo. Proceedings of the National Academy of Sciences, 93, 5539–5543.

LEWY BODY DEMENTIA DESCRIPTION

Lewy body dementia (LBD) and its underlying pathology of Lewy bodies with diffuse cortical distribution was first described by Friedrich Heinrich Lewy in 1923 (Holdorff, 2002). However, the inclusionary bodies named after him were first identified and described in 1913. Since then, neuropathological and

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clinical criteria have been outlined — and currently, it is well accepted that the main clinical symptoms essential for diagnosis involve a progressive cognitive decline, with pronounced cognitive fluctuations, especially related to alertness and attention, such as frequent drowsiness, lethargy, lengthy periods of time spent staring into space, or disorganized speech, and is frequently associated with recurrent visual hallucinations, visuospatial dysfunction, and early parkinsonian motor symptoms, such as rigidity and the loss of spontaneous movement. The constellation of symptoms is such that LBD has been conceptualized as bridging the gap between Alzheimer’s disease and Parkinson’s disease. Onset generally occurs toward the end of an individual’s fifth decade of life and progresses until death, which often comes after 10–15 years (Louis, Gaoldman, Powers, & Fahn, 1995). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The defining neuropathology of this disease is a cortical accumulation of Lewy bodies — an eosinophilic (hematoxylin and eosin staining), round inclusion found in the cytoplasm. Cortical amyloid plaques similar to those seen in Alzheimer’s disease can also co-occur with the cortical Lewy bodies. If the Lewy bodies are noted in cortical regions, they are also commonly seen in brainstem regions. Also implicated in LBD is alpha-synuclein protein — a presynaptic protein. Multiple neurotransmitters, including acetylcholine and dopamine, are diminished. The apolipoprotein E subtype four (ApoE4) genotype is overrepresented in LBD but only when it occurs with concomitant Alzheimer’s disease. Pathologically, the brain appears largely to slightly atrophic. The cingulate gyrus, insular cortex, and parahippocampal gyrus often demonstrate the greatest proliferation of cortical Lewy bodies (Caselli & Boeve, 2007). Unlike other primary neurodegenerative diseases, LBD pathology spreads relatively early to the occipital lobes. Degeneration of basal ganglion regions including substantia nigra decay eventually occur and correspond with the parkinsonian features that present clinically. Likewise, atrophy of the nucleus basalis similar to that which is seen in Alzheimer’s disease is commonly noted. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Clinically, patients present with a chronic complaint of dementia in combination with the proposed core features of cognitive fluctuation, visual hallucinations,

and parkinsonism (McKeith et al., 2005). Fluctuations in cognitive function occur with varying levels of alertness and attention. Visual hallucinations are seen and very commonly are in the shape of animals, insects, and persons. Parkinsonian motor features appear relatively early in LBD with dementia preceding or occurring simultaneously with the features of parkinsonism and add to the severity (Lopez et al., 2000). Executive function deficits and visuospatial impairment may be more prominent in persons with LBD than in those with Alzheimer’s disease (e.g., outcomes on the Stroop, digit span backwards). In addition, in comparison to patients with Alzheimer’s disease, LBD has been associated with significantly worse processing speed, sequencing, and letter fluency but significantly better performance in naming and verbal memory (Ferman et al., 1999). Memory dysfunction may not be present at the initial evaluation, but it certainly will develop later in the course of the disease. Suggestive and supportive features can include nonvisual hallucinations, delusions, syncope, rapid eye movement (REM) sleep disorder, neuroleptic sensitivity, depression, apathy, autonomic impairment, and brief episodes of loss of consciousness. On neurological examination, patients may show some parkinsonian motor signs and gait impairment. Myoclonus may precede severe dementia. Resting tremor occurs less frequently than in Parkinson’s disease. DIAGNOSIS

A diagnosis of probable LBD requires the presence of dementia and at least two of the three core features of fluctuating level of attention, recurrent visual hallucinations, or parkinsonism. Additional suggestive features include REM sleep disorder, neuroleptic sensitivity, low dopamine transporter uptake in basal ganglia on SPECT or PET. One of these suggestive features can be substituted for a core feature. Possible LBD is diagnosed when only one core or suggestive feature accompanies the dementia. Primary diagnosis remains clinical and is based on the clinical presentation as listed above. Diagnoses with overlapping symptomatology include Parkinson’s disease dementia, Alzheimer’s disease, cortical basal ganglionic degeneration, progressive supranuclear palsy, and frontotemporal lobar degeneration. Reversible causes of dementia should be ruled out by laboratory studies. Structural neuroimaging is required to rule out other etiologies. MRI findings in LBD typically show less hippocampal atrophy than patients with Alzheimer’s disease. SPECT scanning or PET scanning may show decreased occipital lobe

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blood flow or metabolism in LBD but not in Alzheimer’s disease. Reduced dopamine transporter activity in the basal ganglia is seen with PET scanning or SPECT scanning. If there is concern that the fluctuating mentation and hallucinations may represent temporal lobe epilepsy, an electroencephalogram should be considered.

TREATMENT

There are no curative or disease-modifying treatments available for LBD. Symptomatic treatment consists of controlling the cognitive, psychiatric, and motor symptoms of the disorder. Acetylcholinesterase inhibitors can be tried to treat the cognitive symptoms of LBD, and they may also be of some benefit in reducing the psychiatric and motor symptoms (McKeith, 2002). A trial of treatment with levodopa/carbidopa can be considered as it may improve motor function in some patients; however, this can serve to exacerbate the neuropsychiatric features. Hallucinations are not always bothersome to this patient group and should only be treated if they are disturbing or dangerous to the patient. Consequently, medicinal treatment of neuropsychiatric features, based on the type of agent used, can promote an exacerbation of parkinsonian symptoms. As a result, standard neuroleptics such as Haldol and so forth due to neuroleptic sensitivity that could worsen the motor symptoms should be avoided. Rather, agitation could be treated with atypical neuroleptics such as clozapine, quetiapine, or aripiprazole when cholinesterase inhibitors are ineffective (Miyasaki et al., 2006). Glen R. Finney Daniela Rusovici Caselli, R. J., & Boeve, B. F. (2007). The degenerative dementias. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 699–733). Philadelphia: Saunders Elsevier. Ferman, T. J., Boeve, B. G., Smith, G. E., Silber, M. H., Kokmen, E., Petersen, R. C., et al. (1999). REM sleep behavior disorder and dementia: Cognitive differences when compared with AD. Neurology, 52, 951–957. Holdorff, B. (2002). Friedrich Heinrich Lewy (1885–1950) and his work. Journal of the History of the Neurosciences, 11, 1, 19–28. Lopez, O. L., Wisniewski, S., Hamilton, R. L., Becker, J. T., Kaufer, D. I., & DeKosky, S. T. (2000). Predictors of progression in patients with AD and Lewy bodies. Neurology, 54, 1774–1779. Louis, E. D., Goldman, J. E., Powers, J. M., & Fahn, S. (1995). Parkinsonian features of eight pathologically diagnosed

cases of diffuse Lewy body disease. Movement Disorders, 10, 188–194. McKeith, I.G. (2002). Dementia with Lewy bodies. The British Journal of Psychiatry, 180, 144–147. McKeith, I. G., Dickson, D. W., Lowe, J., Emre, M., O’Brien, J. T., Feldman, H., et al., (2005). Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium. Neurology, 65, 12, 1863–1872. Miyasaki, J. M., Shannon, K., Voon, V., Ravina, B., KleinerFisman, G., Anderson, K., et al. (2006). Practice parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 66, 7, 996–1002.

LIPOID PROTEINOSIS DESCRIPTION

Lipoid proteinosis, also known as Urbach–Wiethe’s disease or hyalinosis cutis et mucosae, is a very rare hereditary disorder transmitted by an autosomal recessive gene. The most striking and common features are hoarseness in speech and pox-like acneiform and thickening of the skin and mucous membrane of the pharynx and larynx. This often leads to restricted movement of the tongue and visible skin thickening around the eyes and areas of mechanical friction (e.g., elbows, hands, knees). The disorder usually manifests with vocal symptoms soon after birth to within the first year, whereas skin complications usually develops in the first few years of life. Damage to the medial temporal lobe of the brain has also been documented in a larger percent of cases, with incidents of epilepsy also common in such cases. Difficulties in emotional regulation and memory, executive processing, and comorbidity with certain Axis I disorders have also been documented. The disorder was first described by a Viennese dermatologist and an otorhinolaryngologist, Urbach and Wiethe, in 1929 with 300 plus cases reported since such time. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Lipoid proteinosis is a recessive inherited gene disorder that has been linked to the mutation of the extracellular protein 1 gene classified as ECM1, with over 20 pathogenic mutations classified (Hamada et al., 2002). ECM1 in humans encodes glycoprotein that is

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believed to have key roles in bone mineralization and epidermal differentiation. It has been hypothesized as a ‘‘biological glue’’ that acts as a homeostasis for the skin, used in roles such as regulation of basement membrane and growth factor binding (Chan, 2004). The disease is characterized by rings of excessive basement membrane surrounding blood vessels and irregular reduplication of lamina densa at the dermalepidermal junction. These mutations most often lead to invasion of the mucosa of the pharynx, tongue, soft palate, and lips. Hoarseness in vocal projection is the most common result from such development following birth, though more severe cases can lead to a restricted tongue and respiratory difficulty. Often the most visible symptom is beaded eye papules. There are often noticeable, waxy yellow papules and nodules with skin thickening in other areas. This often occurs in areas such as the hands, elbows, buttocks, and knees where friction is encountered (Nanda, Alsaleh, & AlSabah, 2001). Beyond dermatological symptoms, a significant number of documented cases (approximately 50% to 75%) also have shown bilateral, circumscribed, and symmetrical damage to the medial temporal region of the brain. This is an area containing both the amygdala and hippocampus. In this region calcium minerals find their way to the tissue and harden (i.e., calcification). The disorder has been documented to show strong and prevalent calcification in the amygdaloid complex. However, case studies suggest that the age of onset, severity of calcification, and the spreading to surrounding areas such as the uncinate and parahippocampal gyri can vary greatly (Emsley & Paster, 1985; Siebert, Hans, & Bartel, 2003). It is also common for epilepsy (specifically in the temporal lobe) to occur when such calcification is noted. These seizures can often be visual or olfactory in nature, and often have loss of consciousness with or without automatisms and behavioral disturbances (Claeys et al., 2007). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The main body of research concerning neuropsychological issues with lipoid proteinosis is based on the study of the amygdala. This is due to the disorders unique feature of often having calcification damage specific to this location. General research on the amygdala has been shown to be involved in the regulation of emotions, specifically fear, as well as aspects of episodic memory, and executive functioning (Tranel & Hyman, 1990). The body of studies on lipoid proteinosis patients with medial temporal lobe damage varies greatly in their supportive findings of the functions

of the amygdala. There is also a wide range of case studies that document varying levels of intelligence and comorbid Axis I disorders associated with the disorder. In the largest known sample study of patients with lipoid proteinosis (Thornton et al., 2008) a statistically significant number of comorbid disorders were found including anxiety disorders (33%), mood disorders (33%), psychosis (22%), and schizophrenia (15%). Furthermore, the study found that these patients were significantly less likely to identify both positive and negative emotions, showed impairment in memory, and lowered executive functioning. The study also showed that these patients performed significantly worse on assessments that dealt with identity of emotional expressions such as the Ekman facial emotional recognition test. They also performed worse on assessments testing the memory and executive functioning — specifically tests of visual organization, design initiative, dual sequencing, and abstract thinking (Thornton et al., 2008). These results have also been supported by other studies that showed poor performance with measure of executive functioning, implying symptoms of reduced decision making under both conditions of ambiguity and risk (Brand, Grabenhorst, Starcke, Vandekerckhove, & Markowitsch, 2007). Other studies have not found such strong results for emotional regulation, executive functioning, and memory problems. Various subject groups have shown different ranges of intelligence from the above average to borderline range or lower. In one study of nine lipoid proteinosis patients (Sibert et al., 2003), they found that patients were able to identify different emotional faces despite amygdala damage. They did find, however, that differentiation of emotional expression does appear to suffer with damage to the amygdala as well as emotional memory, though there was no specific preference to negative emotions or fear. A majority of these cases also had a high school or college education and showed far less cognitive problems in comparison to other studies (Sibert et al., 2003). Although there is no clear understanding for such variation, both timing of symptom onset and rate of degeneration play a role in terms of cognitive functioning and emotional regulation. There is also a difference in what specific areas of the brain beyond the amygdala are affected in each case, which may also factor into the severity of symptoms (Papps, Calder, Young, & O’Carroll, 2003). DIAGNOSIS

The disorder usually manifests its first symptom within a year or so after birth. This is most often the hoarseness in voice quality due to infiltration of the

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lungs and vocal cords. In more severe cases the infiltration may cause respiratory problems or a stiffening of the tongue. Visible papules and nodules along with generalized skin thickening usually occur within the next several years. Most noticeably these can be found around the eyes, elbows, hands, and buttocks (Nanda, Alsaleh, & Al-Sabah, 2001). CT scans or MRIs often show degeneration and calcification in the medial temporal lobes, often in the amygdale region (Siebert et al., 2003). Such brain degeneration has been linked to seizures and migraines also specific to this area. There is also evidence that with more severe degeneration and early onset, paranoia and psychotic features may manifest (Claeys et al., 2007). It may also be a biological root for anxiety disorders and mental retardation (Thornton et al., 2008) In the past, the disorder was also believed to have features similar to porphyria and cutaneous amyloidosis. There was also some former similarities found with diabetic microangiopathy. Today, however, the most definitive way to diagnose lipoid proteinosis is through gene analysis for mutations in gene ECM1. To date, there are over 20 different mutations documented for the gene. The gene is recessive and there are believed to be several identified families, most notably in the Northern Cape Province of South Africa (Hamada et al., 2002). TREATMENT

There is no known cure for lipoid proteinosis to date, though discovery of the ECM1 gene does provide hope. In the past oral steroids and oral dimethyl sulphoxides have been used with lackluster results. Carbon dioxide laser surgery to the vocal cords and eyelids of thickened skin regions has been shown to have some success with dermatological issues (Hamada, 2005). Peyton Groff Raymond S. Dean Brand, M., Grabenhorst, F., Starcke, K., Vandekerckhove, M., & Markowitsch, H. J. (2007). Role of the amygdale in decisions under ambiguity and decisions under risk: Evidence from patients with Urbach-Wiethe disease. Neuropsychologia, 45(9), 1305–1317. Claeys, K. G., Claes, L. R., Van Goethem, J. W., Sercu, S., Merregaert, J., Lambert, J., et al. (2007). Epilepsy and migraine in patient with Urbach-Wiethe disease. Seizure, 16(4), 465–468. Chan, I. (2004). The role of extracellular matrix protein 1 in human skin. Clinical Experimental Dermatology, 29(1), 52–56.

Emsley, R. A., & Paster, L. (1985). Lipoid proteinosis presenting with neuropsychiatric manifestations. Journal of Neurology, Neurosurgery, and Psychiatry, 48(12), 1290–1292. Hamada, T. (2005). Lipoid Proteinosis. Retrieved March 10, 2009, from Orphanet Encyclopedia. Web site: http:// www.orpha.net/data/patho/GB/uk-lipoidproteinosis. pdf Hamada, T., McLean, W. H., Ramsay, M., Ashton, G. H., Nanda, A., Jenkins, T., et al. (2002). Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1). Human Molecular Genetics, 11(7), 833–840. Nanda, A., Alsaleh, Q. A., & Al-Sabah, H. (2001). Lipoid proteinosis: Report of four siblings and brief review of the literature. Pediatric Dermatology, 18(1), 21–26. Papps, B. P., Calder, A. J., Young, A. W., & O’Carroll, R. E. (2003). Dissociation of affective modulation of recollective and perceptual experience following amygdale damage. Journal of Neurology, Neurosurgery, and Psychiatry, 74, 253–254. Siebert, M., Hans, J. M., & Bartel, P. (2003). Amygdala, affect and cognition: Evidence from 10 patients with UrbachWiethe disease. Brain, 126(12), 2627–2637. Thorton, H. B., Nel, D., Thorton, D., Honk, J. V., Baker, G. A., & Stein, D. J. (2008). The neuropsychiatry and neuropsychology of Lipoid Proteinosis. Journal of Neuropsychiatry Clinical Neuroscience, 20(1), 86–92. Tranel, D., & Hyman, B. T. (1990). Neuropsychological correlates of bilateral amygdale damage. Neurology, 47(3), 349–355.

LISSENCEPHALY DESCRIPTION

Lissencephaly is a cerebral developmental disorder characterized by a smooth cortical surface following defective neuronal migration during the first trimester of pregnancy (Cardoso et al., 2000; Dobyns, 1987; Verloes, Elmaleh, Gonzales, Laquerrie`re, & Gressens, 2007). Neuronal migration is a brain development process in which nerve cells move from their place of origin to their ultimate location during fetal development. Lissencephaly is a type of neural migration disorder; it occurs because the process of developing neurons proceeding to their permanent place is disrupted, leading to an arrest of the ordered migration of neurons to the cortex (Dobyns, 1987; Verrotti et al., 2009). The surface of a normally developed brain is formed by a complex series of folds (also called gyri or convolutions) and grooves (also called sulci).

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In individuals with lissencephaly, the normal convolutions are absent or only partly formed, making the surface of the brain appear smooth (Verloes et al., 2007); thus, the term ‘‘lissencephaly,’’ from the Greek words ‘‘lissos’’ (smooth) and ‘‘encephalus’’ (brain), was used to describe the broad feature of an agyric or pachygyric brain (Walker, 1942). In addition, a normally developed cerebral cortex has six distinct cellular layers, but the brains of individuals with lissencephaly have only four. With such disturbances of brain maturation, individuals with lissencephaly are often profoundly retarded from birth and often develop seizure disorders (Reiner & Lombroso, 1998; Reiner & Sapir, 1998; Wynshaw-Boris, 2007). The range of disorders associated with lissencephaly has become more defined as neuroimaging and knowledge of genetics has provided more insights into the causes of migration disorders. Possible causes of lissencephaly include inherited genetic conditions, new random genetic mutations, intrauterine viral infections, viral infections of the fetus during pregnancy, or interruptions of the blood supply to the fetus’s brain during the first trimester of pregnancy (Dobyns & Truwit, 1995; Dorovini-Zis & Dolman, 1977). Communities with a high rate of parental consanguinity have much greater incidence of individuals with lissencephaly than other forms of noninherited neuronal migration disorders (Al-Qudah, 1998). Lissencephaly may occur as an isolated birth defect or may be associated with other birth abnormalities occurring together in a specific inherited syndrome. Some cases of lissencephaly result from deletions of certain identified genes involving neuronal migration (Pilz et al., 1998; Wynshaw-Boris, 2007). NEUROPATHOLOGY/PATHOPHYSIOLOGY

To date, mutations of five different genes have been known to cause different types of lissencephaly in humans. Each of these genes has been shown to play a role in normal cell migration (Forman, Squier, Dobyns, & Golden, 2005; Koul, Jain, & Chacko, 2005). Subtypes of lissencephaly are generally divided into two distinct pathologic forms based on differences in the physical structure of the brain — Type I (classical) lissencephaly and Type II lissencephaly (cobblestone dysplasia) (Verloes et al., 2007; Verrotti et al., 2009). Type I lissencephaly results in four, rather than six, layers in the cortex and shows a smooth brain surface with relatively few broad gyri. The cortex is markedly thicker with larger than normal posterior ventricles. The corpus callosum is often small and sometimes absent (Forman et al., 2005; Koul et al., 2005).

Type I lissencephaly can be seen in a number of genetic syndromes or can occur by itself in a condition called isolated lissencephaly sequence (ILS). The majority of ILS is a result of mutations or deletions in one of two identified genes involved in brain development, namely LIS1 and XLIS (or Doublecortin/ DCX). LIS1 is a gene located on the short arm of chromosome 17, identified as the first lissencephaly gene, and the first gene recognized to be part of an intracellular signaling pathway involved in neuronal migration (Reiner & Sapir, 1998; Wynshaw-Boris, 2007). Most deletions and mutations in the LIS1 gene are sporadic and are not present in other family members. XLIS (or DCX) is a gene located on the long arm of the X chromosome. Mutations in XLIS cause X-linked lissencephaly in males; mothers who carry the mutation may or may not display the symptoms. Subcortical band heterotopia (SBH) is a milder form of lissencephaly, often seen in female carriers of XLIS. Studies show that LIS1 mutations affect mainly the parietal and occipital regions, whereas the frontal cortex is more affected in individuals with mutated XLIS (Pilz et al., 1998; Reiner & Sapir, 1998). Miller–Dieker syndrome (MDS) is a commonly seen genetic syndrome involving Type I lissencephaly. In MDS, the effect of the deletions of the LIS1 gene extends to nearby genes required for normal development of other organ systems. Thus, individuals with MDS often produce more severe disorders than individuals with ILS, in which the mutations are constrained within single genes (Cardoso et al., 2000; Reiner & Lombroso, 1998). As a result, in addition to the features associated with lissencephaly, children with MDS also have distinct facial features, including a high forehead, a small jaw, a short upturned nose, thin lips, and narrowing at the temples. Calcium deposits in the midline of the brain are common in MDS, but not in ILS or other syndromes. Type II lissencephaly is also called cobblestone dysplasia because of the pebbled appearance of the surface of the cerebral cortex. Unlike Type I lissencephaly, in which the abnormally thick cortex has a smooth interface with the underlying white matter, brains of individuals with cobblestone dysplasia often show abnormalities of the white matter, enlarged ventricles, underdeveloped brainstem and cerebellum, and absence of the corpus callosum. Examples of disorders associated with Type II lissencephaly include cobblestone lissencephaly without other birth defects, Fukuyama congenital muscular dystrophy, muscleeye-brain disease, and Walker–Warburg syndrome (Dobyns, Kirkpatrick, Hittner, Roberts, & Kretzer, 1985).

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NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Individuals with lissencephaly often experience seizures/infantile spasms, mental retardation, psychomotor developmental delay, failure to thrive, muscle spasticity (hypotonia), microcephaly (a smaller than normal head), dysmorphism, and poor scholastic performance. Other symptoms may include craniofacial anomalies, difficulty swallowing and eating, and anomalies of the hands, fingers, or toes (Gu¨no¨r et al., 2007; Verloes et al., 2007). Epilepsy is associated with lissencephaly and is often resistant to conventional treatment (Koul et al., 2005). Respiratory illnesses and recurrent aspiration are common. In particular, individuals with Type I lissencephaly usually have severe mental retardation. Babies with ILS often have small jaws and hollowing at the temporal region (Koul et al., 2005). Many infants with lissencephaly appear normal at birth, although some may have immediate respiratory problems. Head size is usually within normal limits at birth; however, as the baby grows, the growth slows down, resulting in a small head (microcephaly) (Gu¨no¨r et al., 2007). Following the initial few months after birth, parents may begin to notice lessened activity, inability to visually track objects, and feeding problems in the baby. Feeding difficulty may include choking, gagging, or regurgitating food or liquid. Apnea and muscle weakness are also common. Over time, muscle weakness may change to excessive muscle tension (spasticity). Seizures occur in most children with lissencephaly and frequently begin within the first year of life. These are usually severe and difficult to control with medication. Repeated bouts of pneumonia from swallowing food down an airway and into the lungs also are common.

of the ventricles (Ghai et al., 2006). Individuals with MDS have more severe MRI findings than individuals with ILS. The smooth brain appearance is more striking in the back portion of the brain in individuals with chromosome 17 LIS1 deletions and mutations, whereas it is more obvious in the front part of the brain in individuals with XLIS mutations. In addition, underdevelopment of a part of the cerebellum on MRI also helps identify individuals with XLIS mutations (Dorovini-Zis & Dolman, 1977). A CT scan can be done to look for calcium deposits in the midline of the brain in individuals with MDS, which is not seen in other lissencephaly syndromes (Cibis & Fitzgerald, 1995). Individuals with SBH often have minor changes in the gyri, shallow sulci, and ribbons of white and gray matter beneath the cortex that show up on MRI. Likewise, signs of Type II lissencephaly also can be detected through MRI, including a cobblestone appearance of the cortex, enlarged ventricles, abnormalities of the white matter, and changes in the cerebellum, corpus callosum, and brainstem (Kojima et al., 2002). To confirm the diagnosis of MDS or ILS, high resolution chromosome testing and other specialized genetic tests are often helpful in determining whether a deletion is sporadic or due to an inherited chromosome rearrangement. If necessary, mutation analysis can be performed to look for specific errors in the sequence of LIS1 and XLIS genes (Cibis & Fitzgerald, 1995). In addition to MRI and CT testing, a careful clinical evaluation and examination by a medical geneticist is necessary to confirm the diagnosis and evaluate the child for the presence of a syndrome. After a precise diagnosis is made, genetic counselors should be able to give the family accurate information about the inheritance pattern and describe the likelihood of the condition recurring in future births (Cibis & Fitzgerald, 1995).

DIAGNOSIS

The diagnosis of lissencephaly is usually made through neuroimaging at or soon after birth with the help of CT and/or MRI. Diagnosis by ultrasound cannot be reliably made until 26–28 weeks’ gestation when the normal gyri and sulci become well defined (Dorovini-Zis & Dolman, 1977; Kojima et al., 2002). When lissencephaly is suspected, chorionic villus sampling, a screening technique for genetic defects, can test for some lissencephaly with a known genetic mutation (Miny, Wolfgang, & Ju¨rgen, 1993). MRI findings can be used to help diagnose Type I lissencephaly through detecting the absence of, or very shallow, convolutions on the surface of a markedly thick cerebral cortex and sometimes enlargement

TREATMENT

There are no cures to reverse the effects of lissencephaly; treatment for those with lissencephaly is symptomatic and depends on the severity and locations of the brain malformations. Although medical management of seizures is available, most seizures associated with lissencephaly are resistant to conventional treatment (Gurrrini, Sicca, & Parmeggiani, 2003). Infantile spasms may be treated with adrenocorticotropic hormones, though they are not always effective. Shunting can be required for hydrocephalus. For children who continue to have serious feeding difficulty, a gastrostomy feeding tube placement can be considered to ensure adequate nutrition.

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Liquids and thin foods can be thickened to make swallowing easier and avoid aspiration problems. Reflux can be managed with medications. Physical and occupational therapy can help prevent or reduce tightening of the joints and help normalize muscle tone; however, the improvements are often limited and temporal. Medical management is available for recurrent infections. However, the progress and average life expectancy for individuals with lissencephaly vary depending on the type of lissencephaly, the particular syndromes involved, and the degree of brain malformation. Many individuals with lissencephaly show no significant development beyond a 3–5month-old level (Dobyns & Truwit, 1995). Life span can be significantly shortened by recurrent aspiration and pneumonia (Reiner & Lombroso, 1998). Individuals with Type I lissencephaly usually need lifelong care for all basic needs. Infants and toddlers with MDS usually die by 2 years of age, but the majority of babies with ILS live into childhood. Many infants with Type II lissencephaly die in infancy, whereas individuals with SBH may have near-normal or normal development and life span. As such, supportive care is likely needed to help with comfort and nursing needs for children affected and their family. Mei Chang Andrew S. Davis Al-Qudah, A. A. (1998). Clinical patterns of neuronal migrational disorders and parental consanguinity. Journal of Tropical Pediatrics, 44, 351–354. Cardoso, C., Leventer, R. J., Matsumoto, N., Kuc, J. A., Ramocki, M. B., Mewborn, S. K., et al. (2000). The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene. Human Molecular Genetics, 9(20), 3019–3028. Cibis, G. W., & Fitzgerald, K. M. (1995). Abnormal electroretinogram associated with developmental brain anomalies. Transactions of the American Ophthalmological Society, 93, 147–158. Dobyns, W. B. (1987). Developmental aspects of lissencephaly and the lissencephaly syndromes. Birth Defects Original Article Series, 23(1), 225–241. Dobyns, W. B., Kirkpatrick, J. B., Hittner, H. M., Roberts, R. M., & Kretzer, F. L. (1985). Syndromes with lissencephaly. II. Walker-Warburg and Cerebro-oculo-muscular syndromes and a new syndrome with Type II lissencephaly. American Journal of Medical Genetics, 22, 157–195. Dobyns, W. B., Stratton, R. F., & Greenberg, F. (1984). Syndromes with lissencephaly. I. Miller-Dieker and Norman-Roberts syndromes and isolated lissencephaly. American Journal of Medical Genetics, 18, 509–526.

Dobyns, W. B., & Truwit, C. L. (1995). Lissencephaly and other malformations of cortical development: 1995 update. Neuropediatrics, 26, 132–147. Dorovini-Zis, K., & Dolman, C. L. (1977). Gestational development of brain. Archives of Pathologic Laboratory Medicine, 101(4), 192–195. Forman, M. S., Squier, W., Dobyns, W. B., & Golden, J. A. (2005). Genotypically defined lissencephalies show distinct pathologies. Journal of Neuropathology and Experimental Neurology, 64(10), 847–857. Ghai, S., Fong, K. W., Toi, A., Chitayat, D., Pantazi, S., & Blaser, S. (2006). Prenatal US and MR imaging findings of lissencephaly: Review of fetal cerebral sulcal development. RadioGraphics, 26, 389–405. Guerrini, R., Sicca, F., & Parmeggiani, L. (2003). Epilepsy and malformations of the cerebral cortex. Epileptic Disorders, 5, 9–26. Gu¨no¨r, S., Yalnizog˘lu, D., Turanli, G., Saatçi, I., ErdoganBakar, E., & Topcu, M. (2007). Malformations of cortical development: Clinical spectrum in a series of 101 patients and review of the literature. The Turkish Journal of Pediatrics, 49, 120–130. Kojima, K., Suzuki, Y., Seki, K., Yamamoto, T., Sato, T., Tanaka, T., et al. (2002). Prenatal diagnosis of lissencephaly (Type II) by ultrasound and fast magnetic resonance imaging. Fetal Diagnosis and Therapy, 17, 34–36. Koul, R., Jain, R., & Chacko, A. (2005). Pattern of childhood epilepsies with neuronal migrational disorders in Oman. Journal of Child Neurology, 21(11), 945–949. Miny, P., Wolfgang, H., & Ju¨rgen, H. (1993). Genetic factors in lissencephaly syndromes: A review. Child’s Nervous System, 9(7), 413–417. Pilz, D. T., Matsumoto, N., Minnerath, S., Mills, P., Gleeson, J. G., Allen, K. M., et al. (1998). LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Human Molecular Genetics, 7(13), 2029–2037. Reiner, O., & Lombroso, P. J. (1998). Development of the cerebral cortex: II. Lissencephaly. Journal of the American Academy of Child and Adolescent Psychiatry, 37(2), 231–232. Reiner, O., & Sapir, T. (1998). Abnormal cortical development; towards elucidation of the LIS1 gene product function. International Journal of Molecular Medicine, 1(5), 849–853. Verloes, A., Elmaleh, M., Gonzales, M., Laquerrie`re, A., & Gressens, P. (2007). Genetic and clinical aspects of lissencephaly. Revue Neurologique, 163(5), 533–547. Verrotti, A., Spalice, A., Ursitti, F., Papetti, L., Mariani, R., Castronovo, A., et al. (2009, March 3). New trends in neuronal migration disorders. European Journal of Pediatric Neurology, Mar 3. Walker, A. E. (1942). Lissencephaly. Archives of Neurological Psychology, 48, 13–29.

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Wynshaw-Boris, A. (2007). Lissencephaly and LIS1: Insights into the molecular mechanisms of neuronal migration and development. Clinical Genetics, 72(4), 296–304.

ocular motor pathways are spared (Hammerstad, 2007; Love & Biller, 2007). Consciousness and awareness remain unimpaired.

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LOCKED-IN SYNDROME DESCRIPTION

Locked-in syndrome is a rare neurological presentation in which individuals present with complete paralysis of all the voluntary muscles of the body leading to quadriplegia and mutism. In essence, the only voluntary movements that remain possible are eye movements and eye blinking. The presentation is acquired, most commonly occurring as a result of a cerebrovascular accident although traumatic brain injury, degenerative processes, and neurotoxicity can serve as causes. Regardless of the underlying etiology, the pathological basis of the presentation corresponds with lesioning of the ventral pons. The presentation has also been called cerebromedullospinal disconnection, de-efferented state, pseudocoma, and ventral pontine syndrome. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Locked-in syndrome is most commonly associated with a lesion of the ventral pons. Although this lesion impairs global motor functioning by way of corticospinal and corticobulbar pathway disruption, somatosensory pathways and the ascending systems essential to arousal and wakefulness remain spared (Ropper & Brown, 2005). Eyelid control remains intact as well due to sparing of particular midbrain areas (Ropper & Brown, 2005). The most prevalent etiology of locked-in syndrome is an occlusion of the basilar artery leading to the aforementioned ventral pons. This more often than not is related to cerebrovascular trauma due to a thrombus. Infarction, traumatic brain injury, and medicinal overdose have also all been associated with the presentation by way of lesioning the ventral pons. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Locked-in syndrome presents as quadriplegia and mutism in conjunction with preserved neurocognitive functioning. In some instances, when symptoms first present they manifest as hemiparesis, but within a few hours symptoms progress to bilateral hemiplegia and finally classic features of locked-in syndrome (Fisher, 1988). Communication remains possible via eye movements and blinking as the supranuclear

Locked-in syndrome is diagnosed based on a combination of the clinical presentation and neuroimaging findings. Initial workup is commonly undertaken with CT as is standard practice in the acute phase following a potential cerebrovascular or traumatic event. Eventually, if not contraindicated, MRI is utilized to offer a more detailed view of the anatomical area of interest. Differential diagnosis must rule out severe motor neuropathy (e.g., Guillain-Barre´ syndrome), pontine myelinolysis, and/or periodic paralysis as they may all have a similar effect (Ropper & Brown, 2005). Differentiation from a state of coma is made by bedside examination to determine whether the patient is conscious and alert. To make this determination efficiently, evaluation over a longer period of time is often required (Ropper & Brown, 2005). TREATMENT

The lesion(s) associated with locked-in syndrome is permanent and incurable although a very small portion of patients will regain minimal and specific functions. In many respects, treatment is simply supportive and educational. A substantially high percentage of patients with locked-in syndrome die within approximately 6 months following the trauma. Chad A. Noggle Fisher, C. M. (1988). ‘‘The herald hemiparesis’’ of basilar artery occlusion. Archives of Neurology, 45, 1301–1303. Hammerstad, J. P. (2007). Strength and reflexes. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 243–288). Philadelphia, PA: Saunders Elsevier. Love, B. B., & Biller, J. (2007). Neurovascular system. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 405–434). Philadelphia, PA: Saunders Elsevier. Ropper, A. H., & Brown, R. J. (2005). Adams and Victor’s principles of neurology (8th ed.). New York: McGraw-Hill.

LYME DISEASE DESCRIPTION

Lyme disease is a tick-borne disease caused by a spirochete transmitted to humans through bites of

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blacklegged (or deer) ticks. The disease was identified after a number of children living near Lyme, Connecticut, presented with a unique symptom cluster in the 1970s. Although the disease has been reported in all 50 states, the incidence is highest in New England and Mid-Atlantic states, Minnesota, Wisconsin, and northwestern California. Initial symptoms often include a rash at the site of the bite, malaise, and fatigue; later manifestations may include neurologic, cardiovascular, and musculoskeletal symptoms (Bratton, Whiteside, Hovan, Engle, & Edwards, 2008; Centers for Disease Control and Prevention, 2008). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Lyme disease is transmitted to humans by blacklegged ticks (Ixodes scapularis) in New England and the Great Lakes regions, and western blacklegged ticks (Ixodes pacificus) in the West (Bratton et al., 2008). In larval and nymphal stages of the life cycle, Ixodes ticks feed on the white-footed mouse, which is the primary host for the spirochete (Borrelia burgdorferi) responsible for Lyme disease. Adult Ixodes ticks feed on deer, which do not carry B. burgdorferi. Infection with B. burgdorferi initially occurs at the site of the tick bite, and the most common initial symptom is a distinctive rash (erythema migrans) that gradually expands over the course of several days. Transmission occurs only after prolonged attachment and feeding (greater than 24 hours). Histologic examination of erythema migrans lesions reveals immune response to the infectious spirochete including increased lymphocytes, macrophages, proinflammatory cytokines, and antibody production (Steere, Coburn, & Glickstein, 2004). After an interval (ranging from 3 to 30 days), the organism may spread through the lymph system and bloodstream with a propensity for the central nervous system (CNS), joints, heart, and eyes. In many ways it mimics syphilis in that after inoculation, spirochetemia transpires with widespread dissemination, which when involving the CNS, presents as meningitis (Roos, 2007). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The course of Lyme disease has been classified into three stages (Steere et al., 2004). During the first stage, the most common sign of infection is the development of a spreading skin lesion (erythema migrans) at the site of the tick bite within 1–2 weeks. The characteristic presentation of erythema migrans is a bull’s-eye or target-shaped rash that is not painful

but may itch. Additional symptoms of fatigue, malaise, elevated temperature, and joint pain are also found in one-third of cases or fewer. After the initial localized infection, the second stage is generalized infection in which B. burgdorferi is found in the cerebrospinal fluid (CSF) and blood as well as spread through organs including the heart, retina, liver, spleen, meninges, and brain. During the second stage, additional erythema migrans lesions may develop, joint or muscle pain may be present, and neurological signs may occur. Neurologic symptoms of disseminated infection can include meningitis, neuropathy (especially, facial nerve palsy), radiculopathy, and subtle encephalopathy with memory and concentration difficulties and changes in mood and sleep. Elevated protein levels in CSF differentiate disseminated infection from viral infection. In children, the primary neurologic symptom is acute facial paralysis. If left untreated, transition to a third stage will occur 6 months to several years after infection and includes primarily rheumatologic (chronic arthritis, especially in the knees) or neurologic symptoms. Third-stage neurologic manifestations may include chronic meningitis resulting in narrowing of leptomeningeal arteries and subsequent infarction (Miklossy, Kuntzer, Bogousslavsky, Regli, & Janzer, 1990). A minority of patients who have been treated for Lyme disease continue to report neurocognitive and musculoskeletal symptoms in a syndrome referred to as posttreatment chronic Lyme disease (PCLD; Radolf, 2005). PCLD is controversial due to differences of opinion on whether it represents persistent infection or a noninfectious condition akin to chronic fatigue syndrome (Halperin et al., 2007; Radolf, 2005). The neurocognitive features of Lyme encephalopathy may include difficulty with verbal memory, naming, and attention in addition to changes in mood and sleep patterns (Bratton et al., 2008). Although these symptoms persist in a number of patients, studies have failed to consistently evidence objective neurocognitive deficits despite lowered positive affect (Elkins, Pollina, Scheffer, & Krupp, 1999) and subjective memory complaints (Kaplan et al., 2003). In a comparison of patients with PCLD and patients with abnormal findings in CSF, patients with CSF abnormalities demonstrated objective memory deficits, and both groups of patients reported greater memory complaints than controls (Kaplan et al., 1999). At long-term follow-up, patients previously diagnosed with Lyme disease scored within normal limits on measures of attention, processing speed, verbal memory, and verbal fluency (Kalish et al., 2001). Neuropsychological outcomes in children treated for Lyme disease consistently demonstrate a good prognosis with no neurocognitive

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differences found between children treated for Lyme disease and controls at 2- and 4-year follow-up (Adams, Rose, Eppes, & Klein, 1994, 1999) and across a range of follow-up intervals from 7 to 161 months (Va´zquez, Sparrow, & Shapiro, 2003). DIAGNOSIS

Diagnosis of Lyme disease relies heavily on clinical features and is supported when the presentation includes an erythema migrans lesion and history of living or traveling in an endemic region (Bratton et al., 2008; Wormser et al., 2006). History of a tick bite can be helpful to ascertain, but patients frequently do not recall a tick bite. Typical laboratory tests (e.g., blood counts) are nonspecific for Lyme disease, and serologic tests (e.g., antibody titers) are often inconclusive as seroconversion may occur late, be absent, or indicate prior exposure rather than recent infection. TREATMENT

Treatment of Lyme disease may include oral or parenteral antimicrobial regimens (for medications and dosages see Halperin et al., 2007). Adjustments in the pharmacotherapeutic regimen are made when neurologic symptoms are present. Treatment guidelines for PCLD are variable, and there is no strong evidence for continued antimicrobial therapy in those patients. Oral doxycycline (100 mg twice daily for 2 weeks) is useful in addressing the facial palsy that may occur in the absence of CSF abnormalities whereas intravenous ceftriaxone for 4 weeks is preferred for other neurological features related to Lyme disease (Roos, 2007). As suggested, transmission is usually dependent upon prolonged attachment and feeding over a 24-hour period. Consequently, prevention becomes an essential intervention. When going into areas that are more likely to have ticks, individuals may use repellants. In addition, clothing that reduces the chances of ticks getting on the person or into hidden areas is recommended. Carefully checking one self for ticks after leaving such higher-risk areas is recommended. Jeremy Davis Chad A. Noggle Adams, W. V., Rose, C. D., Eppes, S. C., & Klein, J. D. (1994). Cognitive effects of Lyme disease in children. Pediatrics, 94, 185–189. Adams, W. V., Rose, C. D., Eppes, S. C., & Klein, J. D. (1999). Long-term cognitive effects of Lyme disease in children. Applied Neuropsychology, 6, 39–45.

Bratton, R. L., Whiteside, J. W., Hovan, M. J., Engle, R. L., & Edwards, F. D. (2008). Diagnosis and treatment of Lyme disease. Mayo Clinic Proceedings, 83, 566–571. Centers for Disease Control and Prevention. (2008). Surveillance for Lyme disease — United States, 1992–1996 (Surveillance Summaries, Morbidity and Mortality Weekly Report, Vol. 57, SS-10). Atlanta, GA: Author. Elkins, L. E., Pollina, D. A., Scheffer, S. R., & Krupp, L. B. (1999). Psychological states and neuropsychological performances in chronic Lyme disease. Applied Neuropsychology, 6, 19–26. Halperin, J. J., Shapiro, E. D., Logigian, E., Belman, A. L., Dotevall, L., Wormser, G. P., et al. (2007). Practice parameter: Treatment of nervous system Lyme disease (an evidence-based review). Neurology, 69, 91–102. Kalish, R. A., Kaplan, R. F., Taylor, E., Jones-Woodward, L., Workman, K., & Steere, A. C. (2001). Evaluation of study patients with Lyme disease, 10–20 year followup. The Journal of Infectious Diseases, 183, 453–460. Kaplan, R. F., Jones-Woodward, L., Workman, K., Steere, A. C., Logigian, E. L., & Meadows, M. E. (1999). Neuropsychological deficits in Lyme disease patients with and without other evidence of central nervous system pathology. Applied Neuropsychology, 6, 3–11. Kaplan, R. F., Trevino, R. P., Johnson, G. M., Levy, L., Dornbush, R., Hu, L. T., et al. (2003). Cognitive function in post-treatment Lyme disease: Do additional antibiotics help? Neurology, 60, 1916–1922. Miklossy, J., Kuntzer, T., Bogousslavsky, J., Regli, F., & Janzer, R. C. (1990). Meningovascular form of neuroborreliosis: Similarities between neuropathological findings in a case of Lyme disease and those occurring in tertiary neurosyphilis. Acta Neuropathologica, 80, 568–572. Radolf, J. (2005). Posttreatment chronic Lyme disease — What it is not. The Journal of Infectious Diseases, 192, 948–949. Roos, K. L. (2007). Viral infections. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 919–968). Philadelphia, PA: Saunders Elsevier. Steere, A. C., Coburn, J., & Glickstein, L. (2004). The emergence of Lyme disease. The Journal of Clinical Investigation, 113, 1093–1101. Va´zquez, M., Sparrow, S. S., & Shapiro, E. D. (2003). Longterm neuropsychologic and health outcomes of children with facial nerve palsy attributable to Lyme disease. Pediatrics, 112, e93–e97. Wormser, G. P., Dattwyler, R. J., Shapiro, E. D., Halperin, J. J., Steere, A. C., Klempner, M. S., et al. (2006). The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases, 43, 1089–1134.

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M MACHADO–JOSEPH’S DISEASE DESCRIPTION

Machado–Joseph’s disease (MJD) is a slow, progressive neurodegenerative disease. It is one of 28 spinocerebellar ataxias (SCA type 3) that are dominantly inherited. It is caused by an unstable and expanded CAG trinucleotide repeat in the MJD1 gene on chromosome 14q32.1 (Onodera et al., 1998). First reported in North American families of Portuguese-Azorean ancestry, and now found throughout the world, MJD is the most prevalent autosomal-dominant cerebellar ataxia in North America, Europe, and much of Asia. As a result of the significant familial patterns, there have been a number of studies examining the disease in specific ethnic groups (Burk, 2007). NEUROPATHOLOGY/PATHOPHYSIOLOGY

MJD belongs to a class of genetic disorders called triplet repeat diseases. These disorders are characterized by the frequent and abnormal repetition of the ‘‘CAG’’ sequence on a gene located on chromosome 14q32.1. This results in the production of a mutated protein that is called ataxin-3. Ataxin-3 accumulates in the cells of the body producing inclusion bodies that interfere with the normal operation of the nucleus. This in turn causes the cell to die, as the nucleus is unable to maintain the health of the cell. Disorders like MJD generally show more severe symptoms in children of parents with MJD disease, with the disease starting earlier and progressing faster in the children. The disease causes central nervous degeneration, producing a widespread pattern of lesions in the brain. The progression is suggested to primarily involve the cerebellar dentate nucleus, pallidum, substantia nigra, subthalamic, red and pontine nuclei, select cranial nerve nuclei, and the anterior horn and Clarke’s column of the spinal cord. Central nervous white matter lesions are confined to the medial lemniscus, spinocerebellar tracts, and dorsal columns. Involvement of the cerebellar Purkinje cell layer and the inferior olive is disputed (for a review, see Rub, Brunt, & Deller, 2008). MRI findings have suggested

severe atrophy of the pons, globus pallidus, and middle and superior cerebellar peduncles as well as a degree of atrophy of the frontal and temporal lobes (Murata et al., 1998). This pattern affects many functional systems, resulting in an array of clinical presentations.

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The pattern of central nervous neurodegeneration includes the visual, auditory, vestibular, somatosensory, ingestion-related, dopaminergic, and cholinergic systems (Rub et al., 2008). The earliest and most common symptom is gait ataxia (Spinella & Sheridan, 1992). Additional symptoms include dysarthria, dysphagia, dystonia, bradykinesia, intentional tremor, oculomotor disorders, exophthalmos, sensory deficits (peripheral neuropathy), pyramidal, and extrapyramidal dysfunctions, autonomic dysfunctions, sleep disturbances, and muscle wasting (Sudarsky, Corwin, & Dawson, 1992). Individuals with the disease have been found to have a number of functional difficulties as a result of central nervous system dysfunction. Performance on neuropsychological assessment most commonly indicates deficits in memory and executive functioning, specifically attention, verbal fluency, and cognitive flexibility (Burk et al., 2003; Garrard, Martin, Giunti, & Cipolotti, 2008; Kawai et al., 2004; Radvany, Camargo, Costa, Fonseca, & Nascimento, 1993). Poor performance on Theory of Mind tasks has also been found (Garrard et al., 2008). Many studies suggest slowed processing on visual measures, as well as visuospatial and constructional deficits (Maruff et al., 1996; Zawacki, Grace, Friedman, & Sudarsky, 2002). The presence of depression and anxiety is also common in individuals with the disease (Kawai et al., 2004; Zawacki et al., 2002). A number of studies have also emphasized an absence of cognitive impairment (Burk, 2007), including studies focused on executive dysfunction (Sequeiros & Coutinho, 1993; Spinella & Sheridan, 1992). Some studies have suggested the cognitive profile is unrelated to age of onset, age at time of evaluation, and/or education (Maruff et al., 1996). However, symptoms of dementia

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and delirium have been found in late stages of patients with history of a relatively young onset age and long clinical course (Ishikawa et al., 2002).

M DIAGNOSIS

MJD is clinically diagnosed and genetically confirmed (Maciel et al., 2001). Early diagnosis can be made by recognizing symptoms or by presymptomatic genetic testing. Family history is important in prognosis and defining symptomatology. Prenatal diagnosis of MJD has been found to be successful (Sequeiros et al., 1998; Tsai et al., 2003). TREATMENT

An effective treatment has not yet been established, and thus treatment is focused on symptom management and support. Patients usually become wheelchair bound approximately 15 years after symptom onset; thus, environmental manipulations eventually become warranted to aid in home living and mobility (e.g., ramps, chair lifts, etc.). With a median survival of 20–30 years (Klockgether, 2007), patients and family members may benefit from supportive services to aid in adjustment to continued deterioration and eventually end-of-life issues. Lindsay J. Hines Charles Golden Burk, K. (2007). Cognition in hereditary ataxia. Cerebellum, 6(3), 280–286. Burk, K., Globas, C., Bosch, S., Klockgether, T., Zuhlke, C., Daum, I., et al. (2003). Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3. Journal of Neurology, 250(2), 207–211. Garrard, P., Martin, N. H., Giunti, P., & Cipolotti, L. (2008). Cognitive and social cognitive functioning in spinocerebellar ataxia: A preliminary characterization. Journal of Neurology, 255(3), 398–405. Ishikawa, A., Yamada, M., Makino, K., Aida, I., Idezuka, J., Ikeuchi, T., et al. (2002). Dementia and delirium in 4 patients with Machado-Joseph disease. Archives of Neurology, 59(11), 1804–1808. Kawai, Y., Takeda, A., Abe, Y., Washimi, Y., Tanaka, F., & Sobue, G. (2004). Cognitive impairments in MachadoJoseph disease. Archives of Neurology, 61(11), 1757–1760. Klockgether, T. (2007). Ataxias. In C. G. Goetz (Ed.), Textbook of clinical neurology. Philadelphia: Saunders, Elsevier. Maciel, P., Costa, M. C., Ferro, A., Rousseau, M., Santos, C. S., Gaspar, C., et al. (2001). Improvement in the molecular diagnosis of Machado-Joseph disease. Archives of Neurology, 58(11), 1821–1827.

Maruff, P., Tyler, P., Burt, T., Currie, B., Burns, C., & Currie, J. (1996). Cognitive deficits in Machado-Joseph disease. Annals of Neurology, 40(3), 421–427. Murata, Y., Yamaguchi, S., Kawakami, H., Imon, Y., Maruyama, H., Sakai, T., et al. (1998). Characteristic magnetic resonance imaging findings in MachadoJoseph disease. Archives of Neurology, 55(1), 33–37. Onodera, O., Idezuka, J., Igarashi, S., Takiyama, Y., Endo, K., Takano, H., et al. (1998). Progressive atrophy of cerebellum and brainstem as a function of age and the size of the expanded CAG repeats in the MJD1 gene in MachadoJoseph disease. Annals of Neurology, 43(3), 288–296. Radvany, J., Camargo, C. H., Costa, Z. M., Fonseca, N. C., & Nascimento, E. D. (1993). Machado-Joseph disease of Azorean ancestry in Brazil: The Catarina kindred. Neurological, neuroimaging, psychiatric and neuropsychological findings in the largest known family, the ‘‘Catarina’’ kindred. Arq Neuropsiquiatr, 51(1), 21–30. Rub, U., Brunt, E. R., & Deller, T. (2008). New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease). Current Opinion Neurology, 21(2), 111–116. Sequeiros, J., & Coutinho, P. (1993). Epidemiology and clinical aspects of Machado-Joseph disease. Advances in Neurology, 61, 139–153. Sequeiros, J., Maciel, P., Taborda, F., Ledo, S., Rocha, J. C., Lopes, A., et al. (1998). Prenatal diagnosis of MachadoJoseph disease by direct mutation analysis. Prenatal Diagnosis, 18(6), 611–617. Spinella, G. M., & Sheridan, P. H. (1992). Research initiatives on Machado-Joseph disease: National Institute of Neurological Disorders and Stroke Workshop summary. Neurology, 42(10), 2048–2051. Sudarsky, L., Corwin, L., & Dawson, D. M. (1992). MachadoJoseph disease in New England: Clinical description and distinction from the olivopontocerebellar atrophies. Movement Disorders, 7(3), 204–208. Tsai, H. F., Liu, C. S., Chen, G. D., Lin, M. L., Li, C., Chen, Y. Y., et al. (2003). Prenatal diagnosis of MachadoJoseph disease/spinocerebellar ataxia type 3 in Taiwan: Early detection of expanded ataxin-3. Journal of Clinical Laboratory Analysis, 17(5), 195–200. Zawacki, T. M., Grace, J., Friedman, J. H., & Sudarsky, L. (2002). Executive and emotional dysfunction in Machado-Joseph disease. Movement Disorders, 17(5), 1004–1010.

MACRENCEPHALY DESCRIPTION

Macrencephaly, also called megalencephaly, refers to the presentation of an abnormally large brain for an

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infant or child’s age and gender. It is the third most common central nervous system malformation behind micrencephaly and hydrocephalus. The term is often used interchangeably with macrocephaly but this is inaccurate. Although macrencephaly refers to an abnormally large brain, macrocephaly simply refers to an abnormally large head. This categorical error originates from the fact that brain and skull growth usually present in parallel with one another thus both terms are often accepted as describing the same morphological feature (Harding & Copp, 1997). Deviations from this principle are more often seen on the micrencephalic side, whereby the skull plates fuse prematurely while the brain attempts to grow normally. Macrencephaly is classified by a brain size that is two or more standard deviations above the average and originates from an overactivity in the process of neuron proliferation. Although the process ceases once the appropriate number of cells are produced within a layer or area, in macrencephaly an overabundance of cells are produced causing a general disruption and disorganization of the system. Similar to microcephaly, macrencephaly’s morphological opposite, the term is purely descriptive and not suggestive of an underlying etiology. As such, it can occur developmentally or secondary to another primary presentation such as Alexander’s disease and neurofibromatosis. The overproduction of cells in various areas and layers most prominently disrupts the electrical and neuronal integrity of the system, increasing risk of seizures, sensorimotor deficits, and diffuse neurocognitive deficits including mental retardation. It is differentiated from hemimegalencephaly in which only one hemisphere is enlarged. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Macrencephaly arises from excessive brain growth. As previously suggested, it often represents a feature of another primary manifestation. Alexander’s disease, Canavan’s disease, and Tay–Sachs’s disease are the most common causes of macrencephaly. The mechanism by which the presentations cause macrencephaly varies yet can be linked to their advancing metabolic dysfunctions. The interested reader is recommended to review these individual entries within this text. Anatomically, it presents with diffuse increase in brain volume in the presence of normal or only slightly enlarged ventricles. The cortex is often disorganized owning to part of the volumetric increase. Cellular and neuronal swelling and effacement of cortex lamination also serve as root causes (Ropper & Brown, 2005). This disruption occurs at the point of

neuroblast formation during embryogenesis (Ropper & Brown, 2005). When this is isolated to only one of the hemispheres, it is termed hemimegalencephaly.

M NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Few empirical studies have sought to outline the neuropsychological consequences of macrencephaly itself given it is often a manifestation of another underlying etiology. Again, the reader is referred to the articles on the most common underlying causes and their specific sequelae (e.g., Alexander’s Disease, Canavan’s Disease, Tay-Sachs’ Disease, Neurofibromatosis). In general, individuals often present with mental retardation. Furthermore, increased prevalence of seizures and epilepsy is also reported. DIAGNOSIS

Fetal ultrasound can often first identify the presentation within the womb. MRI and/or CT scan are recommended in the neonatal period and are most accurate. Electroencephalogram best identifies seizure activity and should always be done when macrencephaly is noted. Neuropsychological testing should be undertaken to identify neurocognitive functioning. Beyond this, standard diagnostic practices recommended for those entities most likely to serve as the underlying basis of macrencephaly should be employed and are discussed elsewhere. TREATMENT

Given macrencephaly constitutes a structural abnormality and is often associated with another primary presentation, there is no cure. Treatment is focused on symptom resolution or treatment of the primary etiology. In regard to the latter, readers are encouraged to see these specific diseases/disorders in regard to their method of treatment. Consequently, prognosis is directly related to the underlying etiology. Therapeutic support should be with a multidimensional focus. Given that a variety of symptoms may be observed in relation to macrencephaly, interventional services ranging from physical and occupational therapy, speech therapy, and special education may all be relevant depending upon the functional profile. In some instances where the presentation is related to a terminal primary diagnosis (e.g., Tay–Sachs’ disease), supportive therapy for the family is warranted. Chad A. Noggle

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Harding, B., & Copp, A. J. (1997). Malformations. In D. L. Graham & P. L. Lantos (Eds.), Greenfield’s neuropathology (6th ed., pp. 397–533). New York: Oxford. Ropper, A. H., & Brown, R. H. (2005). Adams and Victor’s principles of neurology. Developmental diseases of the nervous system (8th ed., pp. 850–894). New York: McGraw-Hill.

MAPLE SYRUP URINE DISEASE DESCRIPTION

Maple syrup urine disease (MSUD) is an inherited metabolic dysfunction that leads to an accumulation of the branched-chain amino acids (BCAAs) and the corresponding branched-chain 2-keto acids (BCKAs) (Chuang & Shih, 2001). This occurs due to a deficiency of branched-chain l-2-keto acid dehydrogenase complex (BCKD) activity. To a lesser extent, specific hydroxyl derivatives also accumulate (Treacy et al., 1992). The buildup of these compounds within the central nervous system (CNS) results in pronounced neurological dysfunction that may include manifestation of convulsions, seizures, ataxia, psychomotor delay, mental retardation, and, in some instances, coma. Rare in prevalence, MSUD has an occurrence of 1 in 185,000 worldwide (Chuang & Shih, 2001). However, higher incidence rates of roughly 1 in 200 births have been noted in Mennonite settlements throughout the Midwest purportedly due to a founder effect (Mitsubuchi et al., 1992). There is no cure for the disorder. Treatment is commonly focused on dietary/nutritional management in combination with more targeted interventions to further regulate the accumulative compounds. To this end, peritoneal dialysis, exchange transfusion, hemodialysis, hemofiltration, hemodiafiltration, and/or administration of a large dose of thiamine are all options for treatment. Beyond this, treatment is focused on addressing the residuals of neurological dysfunction. NEUROPATHOLOGY/PATHOPHYSIOLOGY

MSUD is an inherited disorder. It represents a metabolic flaw that results from a severe deficiency of BCKD activity (Bridi, 2003). The by-product of this dysfunction is system-based accumulation of the BCAAs leucine, isoleucine, and valine, and the corresponding BCKAs l-2-ketoisocaproic, l-2-ketoisovaleric, and l-2-keto-3-methylvaleric acids (Chuang &

Shih, 2001; Yeman, 1986). The hydroxyl derivatives l-2-hydroxyisocaproic, l-2-hydroxyisovaleric, and l-2-hydroxy-3 methylvaleric acids, produced by the reduction of their respective l-2-keto acids, also accumulate but to a lesser degree (Treacy et al., 1992). Ketoacidosis manifests and represents a clinical feature of MSUD (Nyhan, 1984). From a neuropathological standpoint, MSUD impact is multifaceted and generally diffuse. In the initial stages, the cerebral peduncles and the dorsal part of the brainstem are primarily involved. The discussed accumulation contributes to demyelination, edema, reduced brain uptake of essential amino acids, brain energy deficiency, and neuronal apoptosis (Ara´ujo et al., 2001; Jouvet et al., 2000; Pilla et al., 2003). In patients who die, generalized spongy CNS degeneration is noted (Gascon, Ozand, & Cohen, 2007). Neurotransmitter disturbance is also a common outcome of the presentation (Tavares et al., 2000). In animal models, specific disturbances are in the form of reduced brain tissue concentrations of glutamate, aspartate, and GABA (Dodd et al., 1992). Cerebral edema is also commonly noted with preferential targeting of the pyramidal tracts of the spinal cord and the white matter of the cerebral hemispheres, corpus callosum, and dentate nuclei (Chuang & Shih, 2001). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Beyond aforementioned metabolic features, MSUD is manifested as heterogeneous clinical phenotypes, ranging from classical to mild variants (Schadewaldt & Wendel, 1997). Although the features may vary from person to person, the salient features that have been most commonly noted in classical MSUD include ketoacidosis, failure to thrive, poor feeding, apnea, ataxia, seizures, coma, psychomotor delay, and mental retardation presenting in the neonatal period (Nyhan, 1984). Variability across other forms has been proposed as being possibly due to the distinct residual enzyme activity that itself may vary. In fact, MSUD patients can be divided into five different clinical and biochemical phenotypes (Chuang & Shih, 2001). Acutely sick children or adults with MSUD first present with muscle fatigue, epigastric pain, vomiting, and increased confusion (Korein, Sansaricq, Kalmijn, Honig, & Lange, 1994; Riviello, Rezvani, DiGeorge, & Foley, 1991). Neurological sequelae are present in most patients having been linked to both white matter demyelination and diffuse subcortical gray matter edema (Korein et al., 1994; Riviello et al., 1991). Dystonia, stupor, hallucination, and sleep disturbances

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may present. There is a high prevalence of ataxia and psychomotor delay (Nyhan, 1984). Cognitively, mental retardation is commonly seen over the long term. Even in those who have milder neurological involvement, learning disabilities are seen at higher rates of incidence (Chuang & Shih, 2001). Death during acute metabolic decompensation results from central transtentorial herniation. DIAGNOSIS

MSUD must be ruled out in any case of neonatal lethargy progressing to coma; with altering tone changes; in the absence of changes in blood pH, glucose, and ammonia; and regardless of the presence of an infection (Gascon et al., 2007). Definitive diagnosis is accomplished through urinalysis or evaluation of the plasma. Diagnostic findings are that of elevated L-leucine, isoleucine, and valine. Electroencephalogram (EEG) and neuroimaging can also have a role in diagnostics in terms of identifying CNS involvement as opposed to confirming MSUD. EEG often presents with a characteristic sharp wave pattern described as comb-like. It is an essential tool given the relative prevalence of seizures in this population, even when the disorder is controlled. On MRI, white matter attenuation may be seen fairly early on. Edema may be observed in the deep cerebellum, the dorsal part of the brainstem, the cerebral peduncles, and the dorsal limb of the internal capsule initially and then spreads to include the central white matter, particularly of the frontal lobes (Gascon et al., 2007). Neuropsychological assessment is essential once children come of age to determine the nature and extent of any presenting neurocognitive deficits. Domains of impairment may vary. Assessment should also seek to evaluate academic domains as children would naturally be at greater risk for learning disabilities. TREATMENT

Treatment begins with identification of the presentation. Given classical MSUD presents in the neonatal period with metabolic decompensation that may prove fatal or contribute to various neurological sequelae and psychomotor retardation, management of this decompensation as early as possible is essential. This is attempted by suppressing catabolism and facilitating the incorporation of free amino acids in body protein by drip infusion of balanced electrolytes and hypertonic glucose solution in combination with nutritional management and nasogastric feeding

with or without insulin administration (Berry et al., 1991; Parini et al., 1991; Townsend & Kerr, 1982; Wendel, Langenbeck, Lombeck, & Bremer, 1982). Peritoneal dialysis, hemodialysis, exchange transfusion, hemodiafiltration, and/or administration of a large dose of thiamine to enhance the residual activity of branched-chain ketoacid dehydrogenase complex may be utilized in an attempt to remove the accumulating toxic metabolites (Rutledge et al., 1990; Thompson, Butt, Shann et al., 1991; Thompson, Francis, & Halliday, 1991). Beyond management of the biochemical components of the presentation, treatment is symptom based and related to standard practices of addressing those residuals. For example, learning disabilities may be addressed through special education services or other classroom or educational adaptations. Jacob M. Goings Chad A. Noggle Arau´jo, P., Wassermann, G. F., Tallini, K., Furlanetto, V., Vargas, C. R., Wannmacher, C. M. D., et al. (2001). Reduction of large neutral amino acid levels in plasma and brain of hyperleucinemic rats. Neurochemistry International, 38, 529–537. Berry, G. T., Heidenreich, R., Kaplan, P., Levine, F., Mazur, A., Palmieri, M. J., et al. (1991). Branched-chain amino acid free parenteral nutrition in the treatment of acute metabolic decompensation in patients with maple syrup urine disease. The New England Journal of Medicine, 324, 175–179. Bridi, R., Araldi, J., Sgarbi, M. B., Testa, C. G., Durigon, K., Wajner, M., et al. (2003). Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease. International Journal of Developmental Neuroscience: The Official Journal of the International Society for Developmental Neuroscience, 21(6), 327–332. Chuang, D. T., & Shih, V. E. (2001). Maple syrup urine disease (branched-chain ketoaciduria). In C. R. Scriver, A. L. Beaudet, W. L. Sly, & D. Valle (Eds.), The metabolic and molecular bases of inherited disease (8th ed., pp. 1971– 2005). New York: McGraw-Hill. Dodd, P. R., Williams, A. L., Gundlach, A. L., Harper, P. A. W., Healy, P. J., Dennis, J. A., et al. (1992). Glutamate and gamma-aminobutyric acid neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves. Journal of Neurochemistry, 59, 582–590. Gascon, G. G., Ozand, P. T., & Cohen, B. (2007). Aminoacidopathies and organic acidopathies, mitochondrial enzyme defects, and other metabolic errors. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 641–681). Philadelphia, PA: Saunders Elsevier.

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Jouvet, P., Rustin, P., Taylor, D. L., Pocock, J. M., FelderhoffMueser, U., Mazarakis, N. D., et al. (2000). Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane despolarization or cytochrome c release: Implications for neurological impairment associated with maple syrup urine disease. Molecular Biology of the Cell, 11, 1919–1932. Korein, J., Sansaricq, C., Kalmijn, M., Honig, J., & Lange, B. (1994). Maple syrup urine disease: Clinical, EEG, and plasma amino acid correlations with a theoretical mechanism of acute neurotoxicity. International Journal of Neuroscience, 79, 21–45. Mitsubuchi, H., Matsuda, I., Nobukuni, Y., Heidenreich, R., Indo, Y., Endo, F., et al. (1992). Gene analysis of Mennonite maple syrup urine disease kindred using primer-specified restriction map modification. Journal of Inherited Metabolic Disease, 15, 181–187. Nyhan, W. L. (1984). Abnormalities in amino acid metabolism in clinical medicine (pp. 21–35). Norwalk, CT: AppletonCentury-Crofts. Parini, R., Sereni, L. P., Bagozzi, D. C., Corbetta, C., Rabier, D., Narcy, C., et al. (1991). Nasogastric drip feeding as the only treatment of neonatal maple syrup urine disease. Pediatrics, 92(2), 280–283. Pilla, C., Cardozo, R. F. D., Dutra, C. S., Wyze, A. T. S., Wajner, M., & Wannmacher, C. M. D. (2003). Effect of leucine administration on creatine kinase activity in rat brain. Metabolic Brain Disease, 18, 17–25. Riviello, J. J. Jr., Rezvani, I., DiGeorge, A. M., & Foley, C. M. (1991). Cerebral edema causing death in children with maple syrup urine disease. Journal of Pediatrics, 119, 42–45. Rutledge, S. L., Havens, P. L., Haymond, M. W., McLean, R. H., Kan, J. S., & Brusilow, S. W. (1990). Neonatal hemodialysis: Effective therapy for the encephalopathy of inborn errors of metabolism. Journal of Pediatrics, 116, 125–180. Schadewaldt, P., & Wendel, U. (1997). Metabolism of branched-chain amino acids in maple syrup urine disease. European Journal of Pediatrics, 156(Suppl. 1), S62–S66. Tavares, R. G., Santos, C. E. S., Tasca, C., Wajner, M., Souza, D. O., & Dutra-Filho, C. S. (2000). Inhibition of glutamate uptake into synaptic vesicles of rat brain by the metabolites accumulating in maple syrup urine disease. Journal of Neurological Science, 181, 44–49. Thompson, G. N., Butt, W. W., Shann, F. A., Kirby, D. M., Henning, R. D., Howells, D. W., et al. (1991). Continuous venovenous hemofiltration in the management of acute decompensation in inborn errors of metabolism. Journal of Pediatrics, 118, 879–884. Thompson, G. N., Francis, D. E., & Halliday, D. (1991). Acute illness in maple syrup urine disease: Dynamics of

protein metabolism and implications for management. Journal of Pediatrics, 119, 35–41. Townsend, I., & Kerr, D. S. (1982). Total parenteral nutrition therapy of toxic maple syrup urine disease. The American Journal of Clinical Nutrition, 36(2), 359–365. Treacy, E., Clow, C. L., Reade, T. R., Chitayat, D., Mamer, O. A., & Scriver, C. R. (1992). Maple syrup urine disease: Interrelationship between branched chain amino-, oxo-, and hydroxyacids implications for treatment association with CNS dysmelination. Journal of Inherited Metabolic Disease, 15, 121–135. Wendel, U., Langenbeck, U., Lombeck, I., & Bremer, H. J. (1982). Maple syrup urine disease — therapeutic use of insulin in catabolic states. European Journal of Pediatrics, 139(3), 172–175. Yeman, S. J. (1986). The mammalian 2-oxoacid dehydrogenase: A complex family. Trends in Biochemical Science, 11, 293–296.

MATHEMATICS DISORDERS DESCRIPTION

To meet criteria for mathematics disorder, an individual’s mathematics ability must be substantially below that expected given the person’s measured intelligence, age, and age-appropriate education (American Psychiatric Association [APA], 2000). Mathematics ability must be assessed via individually administered standardized tests, and the impairment must show significant interference with academic achievement or daily activities that require math skills. It is estimated that one in every five learning disorder cases is mathematics disorder, and approximately 1% of school-age children have mathematics disorder (APA, 2000). Some studies estimate that the prevalence rate of mathematics disorder is as much as 4.6% (Lewis, Hitch, & Walker, 1994) or 5% to 6% (Shalev, Auerback, Manor, & Gross-Tsur, 2000). Mathematics deficits are often associated with other learning disabilities (Fleishner, 1994; L. S. Fuchs, D. Fuchs, & Prentice, 2004). Shalev, Manor, and GrossTsur (1997) found that nearly 17% of children with mathematics disorder also have dyslexia, and an additional 26% have attention deficit hyperactivity disorder. Dyscalculia is a term often used in mathematics disorder research and is defined by both the inability to demonstrate appropriate mathematics competence (Butterworth, 2003) and the inability

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to successfully create mathematical relationships (Beachman & Trott, 2005). The APA (2000) notes that in mathematics disorder, impairment may present amidst a number of skills including perceptual skills (e.g., reading or recognizing arithmetic signs or numerical symbols, and grouping objects), linguistic skills (e.g., naming or understanding mathematical operations or terms, and decoding problems into mathematical symbols), attention skills (e.g., remembering to add carried numbers, observing operational signs, and copying figures or numbers correctly), and mathematical skills (e.g., counting objects, learning multiplication tables, and following mathematical sequences). Mathematics disorder typically becomes apparent in the second or third grade, as formal mathematics instruction is typically not administered until this point. Among children with high IQ, mathematics disorder may not appear until fifth grade or later, as the child may be able to function near grade level in earlier grades (APA, 2000). Lyon, Fletcher, and Barnes (2003) note several recent studies that point to heritable factors in math disabilities. Gross-Tsur, Manor, and Shalev (1996) examined children with a specific math disability and 10% reported having at least one family member who also had difficulties with math. Shalev et al. (2001) report that the prevalence of math disabilities is about 10 times greater among individuals with family members who also have math disorders when compared with the general population. Finally, Alarcon, DeFries, Light, and Pennington (1997) found that 58% of monozygotic twins shared a math disability, versus only 39% among dizygotic twins. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Lyon et al. (2003) note that neither studies of brain structure nor brain function have been conducted in children with mathematics disorder, though studies of brain lesions in adults have shown that fairly specific math skills can be preserved or lost, depending upon brain injury patterns. Dehaene and Cohen (1997) found that dissociable neural networks comprise mathematical knowledge. One network in the left hemisphere is involved in storage and retrieval of arithmetic fact. Another parietal network is involved in manipulation of numerical quantities. Lyon et al. note that similar findings have been demonstrated in other studies (Chochon, Cohen, van de Moortele, & Dehaene, 1999). PET and fMRI studies have examined math processes in normal adults (Lyon et al., 2003). Precise calculation and estimation have demonstrated different

neural correlates (Dehaene, Spelke, Pinel, Stanescu, & Tsivkin, 1999). The left hemisphere’s inferior prefrontal cortex and the left angular gyrus are involved in precise calculation. Bilateral activation among the inferior parietal lobes is involved in estimation. Regarding nonphysiological causes of mathematics disorder, Michaelson (2007) notes several potential culprits in the literature. Miller and Mercer (1997) believed that low intelligence is a contributor to the development of dyscalculia. Ashcraft (1995) believed that mathematical anxiety plays a part in the development of symptoms even after some remediation following the implementation of psychological intervention. Two other studies cite ineffective teaching strategies as a culprit, emphasizing the early childhood years as a particularly sensitive time frame that may impact vulnerable students (Butterworth, 2003; Shalev et al., 2001). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Young children experiencing mathematical impairments often have problems with both procedural knowledge and math facts (Geary, Hamson, & Hoard, 1999). Although these difficulties persist in some children, other children develop an ability to retrieve math facts, though subsequent procedural knowledge difficulties persist (Lyon et al., 2003). Lyon et al. (2003) note differences between individuals with both reading and mathematics deficits and individuals with mathematics deficits alone. Children demonstrating mathematical impairments without reading deficits show difficulties with several aspects of nonverbal processing, such as somatosensory and motor skills, visuospatial skills, and problem-solving abilities (Rourke, 1993). Further, they are more likely to show procedural problems related to math. Alternatively, children with both reading and math impairments demonstrate pervasive problems with concept formation and language formation skills (Rourk, 1993). These dually diagnosed comorbid children are more likely to show difficulties with fact representation and retrieval. Lyon et al. (2003) reviewed a study by Geary, Hamson, and Hoard (2000) that is in line with the above findings. It was found that children with comorbid reading and math disabilities struggled with number comprehension tasks and counting. Children with math disability alone did not struggle with number comprehension tasks, although they did struggle with counting in both the first and second grades. In the first grade, both groups struggled with fact retrieval. Retrieval errors decreased among

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children with math disability alone, though continued among children with comorbid math and reading disabilities. Indeed, math difficulties among children with comorbid mathematics and reading disabilities are typically different from math difficulties among children with mathematics disabilities in isolation. Research with brain-injured children provides some evidence for the hypothesis that children with poor math skills but adequate reading skills have procedural deficits that involve trying to solve written computations with inadequate, developmentally immature algorithms (Lyon et al., 2003). Children with brain injury as well as developmental disability often experience math difficulties (Shalev et al., 2000). Children with hydrocephalus or spina bifida who demonstrate good word recognition and poor math skills have shown more frequent procedural errors when compared with age-matched controls (Barnes et al., 2002). In this study, both groups made similar errors in visuospatial processing and math fact retrieval. Notably, the procedural errors made by the brain-injured children were similar to those made by younger, math ability-matched controls. Therefore, the children with brain injury made written computation errors that were developmentally immature, as they were similar to younger children with their same level of ability (Lyon et al., 2003). Regarding social and occupational functioning deficits, Bynner and Parsons (1997) found that inadequate numeracy skills are more harmful to an individual’s employability versus inadequate literacy skills. Beachman and Trott (2005) note that general life skills involve a certain level of numerical aptitude, and children with dyscalculia develop into adults who are impaired by their inadequate quantitative reasoning skills, which in turn affects their understanding of money, time, space, and direction. Indeed, mathematics disorder is significant as it can impair functioning not only in the child as a student, but in the adult as a functioning member of society. DIAGNOSIS

Michaelson (2007) notes three well-documented methods of diagnosing dyscalculia. The first is measurement of the child’s attainment of age-appropriate mathematical skills. This can be achieved through administration of standardized assessments that measure such skills (Shalev et al., 2001). Diagnosis can be reached if there is an inconsistency between intellectual capability and assessment results (Geary, 2004) or if there is a disparity, typically of about 2 year levels, between the child’s performance and ageexpected performance (Semrud-Clikeman et al.,

1992). The second method is a direct observation of several mathematical behaviors such as underdeveloped problem-solving strategies (Geary, 1990), errors due to poor working memory span (Siegel & Ryan, 1989), deficient long-term recall of arithmetic facts (Geary et al., 2000), or overall high error rates (Geary, 1993). Finally, the third method is a software program developed by Butterworth (2003) called the dyscalculia screener. This program assesses numerical proficiency in children between ages 6 and 14. This program calculates a standardized score based on median reaction time and accuracy in three categories: number comparison, dot enumeration, and arithmetic achievement (based on addition and multiplication). Traditional assessment of learning disabilities involves a model focused on problems within the individual. Diagnostic assessment is determined through an ability-achievement discrepancy in which achievement test(s) and ability test(s) are given, and discrepancies between one and two standard deviation warrant diagnosis. Further, ‘‘severe’’ discrepancies allow access to special education services (Shinn, 2005). Shinn (2005) criticizes this method as 19 states require a severe ability-achievement discrepancy; however, they do not define ‘‘severe’’ and therefore schools and local education agencies create their own criteria. Further, students often must fail for a considerable period of time before becoming eligible for formal assessment and services. Shinn notes that if all students in a school or school district demonstrate severe academic deficits, the problem is not within the student but within the system; therefore, it is also important to assess the system. In line with the criticisms above, Peterson and Shinn (2002) recommend that students be identified based on their achievement discrepancies within a particular context such as school or school district. In this problem-solving model, it is important to assess the level of performance of typical students, and a local achievement norm must be created. Curriculum-based measurement (CBM) involves the use of validated and standardized short-duration tests (Fuchs & Deno, 1991) that assess basic skills in mathematics computation as well as reading, spelling, and written expression (Deno, 1985, 1986, 1989, 2003; Shinn, 1989, 1998). Mathematics computation CBMs involve 2–5 mintue probes in which students write answers to computational problems. CBMs are time-efficient, reasonably inexpensive, and easy to learn (Shinn, 2005). They may be used to identify atrisk students (Shinn & Marston, 1985), aid in progress monitoring (Marston & Magnusson, 1985), and develop local norms (Shinn, 1988).

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In 2004, the Individuals with Disabilities Education Act enabled schools to use response to intervention (RTI) to determine learning disability status (Daly, Martens, Barnett, Witt, & Olson, 2007). RTI models involve continuous assessment of student response to evidence-based interventions and consist of a three-tier, fixed sequence delivery of strength and type of intervention (Daly et al., 2007). Tier 1 involves universal screening and intervention, delivered on both the class and school-wide levels, ruling out inadequate instruction as a source of low performance (Gresham, 2004). Tier 2 involves administering select interventions to children that do not adequately respond to Tier 1. Tier 3 provides more intensive intervention to children that do not respond to the first two tiers. Notably, teacher estimates of student academic skill can be utilized to identify target skills for academic intervention and assess whether intervention is effective (Eckert & Arbolino, 2005). Several standardized measures are available for this purpose. Eckert and Arbolino (2005) note that only three standardized measures currently exist that assess teacher perception of student academic skill in the classroom. These include the Academic Competence Evaluation Scales (ACES; DiPerna & Elliott, 2000), the Academic Performance Rating Scale (APRS; DuPaul, Rapport, & Perriello, 1991), and the Teacher Rating of Academic Performance (TRAP; Gresham, Reschly, & Carey, 1987). The ACES assesses children in kindergarten through grade 12. This measure contains two scales that assess academic skill in areas such as reading and mathematics, and academic enablers, such as study skills, engagement, and motivation. Item number ranges from 66 to 73, depending upon student grade level. The APRS assesses academic skills and work performance in the areas of reading, mathematics, spelling, and written language based on 19 questions on a 5-point Likert-type scale. The TRAP consists of 5 items that measure overall academic achievement, as well as items that assess reading and mathematics. This TRAP has shown a 91% accuracy rate when differentiating students with specific learning disabilities from students without academic difficulties. TREATMENT

Lyon, Fletcher, Fuchs, and Chhabra (2006) summarized three studies that examined instructional components that enhance student math competence in grades 2–6 (L. S. Fuchs, D. Fuchs, Hamlett, Phillips, & Bentz, 1994; Fuchs et al., 1997; L. S. Fuchs, D. Fuchs, Phillips, Hamlett, & Karns, 1995) — one that did so in

kindergarten (L. S. Fuchs, D. Fuchs, & Karns, 2001), and one in first grade (L. S. Fuchs, D. Fuchs, Yazdian, & Powell, 2002). A combination of five components were found to yield significant improvement in children with mathematics disorder as well as those with low-, average-, and high-achievement: (1) clear, procedurally explicit, concept-based explanations, (2) pictorial representations, (3) gradually faded verbal rehearsal, (4) timed practice with mixed problem sets, and (5) cumulative review with previously mastered problem types. Regarding mathematics problem solving, it has been demonstrated that a framework of teaching methods (which specifically helps students find connections between familiar and novel tasks and broadens student schemas) is more effective than teacher instruction in word problem solution rules alone (Fuchs et al., 2003a, 2003b). This framework includes (1) teaching students to explore novel-looking problems by recognizing irrelevant problem components and thus indentifying familiar problem components for which solutions are known, (2) teaching students to create schemas by demonstrating how irrelevant problem components can change without altering problem-solving rules, and (3) familiarizing students with the idea of transfer in the context of learning to solve problems never before seen. Trott (2003) noted several strategies that have brought improvements in students with dyscalculia. Among them he reports the importance of breaking multistep problems into small, manageable parts. Further, colored pens and markers can be used to highlight question parts. Regarding teacher instruction, Trott recommends using large posters to serve as a memory trigger of basic concepts, which are not easily retained in short-term memory. He also recommends the use of flow diagrams to clarify procedures, flash cards for memorization, and giving guidance to students regarding the basic study skills of time management, organization, and studying. Michaelson (2007) notes that these tips would facilitate learning in all students, not only those with a learning disorder. Cognitive-behavioral intervention models have resulted in self-instruction strategy techniques (Hallahan, Kauffman, & Lloyd, 1996) that have proven effective (Seabaugh & Schumaker, 1993). A main component of this approach involves teaching students to verbalize the steps that must be used to solve a particular problem. After the student has mastered application of the problem-solving method, he or she is taught to utilize subvocal self-instruction. Provision of feedback to the student has proven a useful tool in improving mathematics skills in individuals afflicted with mathematics disorder. For 20

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weeks, L. S. Fuchs, D. Fuchs, Hamlett, and Whinnery (1991) administered math tests twice per week to students via computers that provided immediate feedback. Forty students with mathematics disorder were identified prior to the study. Half of these students were given a performance feedback graph with a goal line superimposed over the graph throughout the study. The other half of the students were shown the graph without the goal line. Greater performance stability was found among students who were provided a goal line on their feedback graph. Lyon et al. (2006) highlight the benefits that can be found through engaging students in performance monitoring when learning both math fact retrieval skills and procedural math skills. Lyon et al. (2006) described several specific programs that have been effectively used with students with mathematics disorder. Connecting math concepts (S. Engelmann, Carnine, O. Engelmann, & Kelly, 1991) utilizes highly structured lessons that involve frequent teacher questions and student answers. This program was developed out of the DISTAR arithmetic program (Engelman & Carnine, 1975) and several studies have documented the efficacy of both programs among children with mathematics disorder (Carnine, 1991). Lyon et al. further note that research regarding math peer-assisted learning strategies (PALS) has documented the importance of instruction that targets both procedural skill and conceptual knowledge along with the use of guided peermediated practice. Such approaches have been found to improve performance in kindergarten through 6th grade, not only for students with mathematics disorder, but also low-, average-, and high-achieving peers (Fuchs et al., 2001; Fuchs et al., 2002). Audrey L. Baumeister William Drew Gouvier

Alarcon, M., DeFries, J. C., Light, J. C., & Pennington, B. F. (1997). A twin study of mathematics disability. Journal of Learning Disabilities, 30, 617–623. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (DSM-IV-TR). Washington, DC: Author Ashcraft, M. H. (1995). Cognitive psychology and simple arithmetic: A review and summary of new directions. Mathematical Cognition, 1, 3–34. Barnes, M. A., Pengelly, S., Dennis, M., Wilkinson, M., Rogers, T., & Faulkner, H. (2002). Mathematics skills in good readers with hydrocephalus. Journal of the International Neuropsychological Society, 8, 72–82. Beachman, N., & Trott, C. (2005). Screening for dyscalculia within HE (Higher Education). MSOR Connections, 5(1), 1–4.

Butterworth, B. (2003). Dyscalculia screener: Highlighting pupils with specific learning difficulties in math. London: Nelson Publishing Company. Bynner, J., & Parsons, S. (1997). Does numeracy matter? London: The Basic Skills Agency. Carnine, D. W. (1991). Increasing the amount and quality of learning through direct instruction: Implications for mathematics. In J. W. Lloyd, N. N. Singh, & A. C. Repp (Eds.), The regular education initiative: Alternative perspectives on concepts, issues, and models (pp. 163–175). Sycamore, IL: Sycamore. Chochon, F., Cohen, L., van de Moortele, P. F., & Dehaene, S. (1999). Differential contributions of the left and right inferior parietal lobules to number processing. Journal of Cognitive Neuroscience, 11, 617–630. Daly, E. J., Martens, B. K., Barnett, D., Witt, J. C., & Olson, S. C. (2007). Varying intervention delivery in response to intervention: Confronting and resolving challenges with measurement, instruction, and intensity. School Psychology Review, 36(4), 562–581. Dehaene, S., & Cohen, L. (1997). Cerebral pathways for calculation: Double dissociation between rote verbal and quantitative knowledge of arithmetic. Cortex, 33, 219–250. Dehaene, S., Spelke, E., Pinel, P., Stanescu, R., & Tsivkin, S. (1999). Sources of mathematical thinking: Behavioral and brain-injury evidence. Science, 284, 970–974. Deno, S. L. (1985). Curriculum-based measurement: The emerging alternative. Exceptional Children, 52, 219–232. Deno, S. L. (1986). Formative evaluation of individual student programs: A new rule for school psychologists. School Psychology Review, 15, 358–374. Deno, S. L. (1989). Curriculum-based measurement and alternative special education services: A fundamental and direct relationship. In M. R. Shinn (Ed.), Curriculum-based measurement: Assessing special children (pp. 1–17). New York: Guilford Press. Deno, S. L. (2003). Developments in curriculumbased measurement. Journal of Special Education, 37, 184–192. DiPerna, J. C., & Elliott, S. N. (2000). Academic competence evaluation scales. San Antonio, TX: Psychological Corporation. DuPaul, G. J., Rapport, M. D., & Perriello, L. M. (1991). Teacher ratings of academic skills: The development of the Academic Performance Rating Scale. School Psychology Review, 20, 284–300. Eckert, T. L., & Arbolino, L. A. (2005). The role of teacher perspectives in diagnostic and program evaluation decision making. In R. Brown-Chidsey (Ed.), Assessment for intervention: A problem-solving approach (pp. 65–81). New York: Guilford. Engelman, S., & Carnine, D. W. (1975). DISTAR arithmetic I (2nd ed.). Chicago: Science Research Associates.

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Engelmann, S., Carnine, D. W., Engelmann, O., & Kelly, B. (1991). Connecting math concepts. Chicago: Science Research Associates. Fleishner, J. E. (1994). Diagnosis and assessment of mathematics learning disabilities. In G. R. Lyon (Ed.), Frames of reference for the assessment of learning disabilities: New views on measurement issues (pp. 441–458). Baltimore: Brookes. Fuchs, L. S., & Deno, S. L. (1991). Paradigmatic distinctions between instructionally relevant measurement models. Exceptional Children, 57(6), 488–500. Fuchs, L. S., Fuchs, D., Hamlett, C. L., Phillips, N. B., & Bentz, J. (1994). Class wide curriculum-based measurement: Helping general educators meet the challenge of student diversity. Exceptional Children, 60, 518–537. Fuchs, L. S., Fuchs, D., Hamlett, C. L., Phillips, N. B., Karns, K., & Dutka, S. (1997). Enhancing students’ helping behavior during peer-mediated instruction with conceptual mathematical explanations. Elementary School Journal, 97, 223–250. Fuchs, L. S., Fuchs, D., Hamlett, C. L., & Whinnery, K. (1991). Effects of goal line feedback on level, slope, and stability of performance within curriculum based measurement. Learning Disabilities Research and Practice, 6, 65–73. Fuchs, L. S., Fuchs, D., & Karns, K. (2001). Enhancing kindergartners’ mathematical development: Effects of peer-assisted learning strategies. Elementary School Journal, 101, 495–510. Fuchs, L. S., Fuchs, D., Phillips, N. B., Hamlett, C. L., & Karns, K. (1995). Acquisition and transfer effects of class wide peer-assisted learning strategies in mathematics for students with varying learning histories. School Psychology Review, 24, 604–620. Fuchs, L. S., Fuchs, D., & Prentice, K. (2004). Responsiveness to mathematical problem-solving instruction: Comparing students at risk of mathematics disability with and without risk of reading disability. Journal of Learning Disabilities, 37(4), 293–306. Fuchs, L. S., Fuchs, D., Prentice, K., Burch, M., Hamlett, C. L., Owen, R., et al. (2003a). Explicitly teaching for transfer: Effects on third-grade students’ mathematical problem solving. Journal of Educational Psychology, 95(2), 293–305. Fuchs, L. S., Fuchs, D., Prentice, K., Burch, M., Hamlett, C. L., Owen, R., et al. (2003b). Enhancing third-grade students’ mathematical problem solving with selfregulated learning strategies. Journal of Educational Psychology, 95(2), 306–315. Fuchs, L. S., Fuchs, D., Yazdian, L., & Powell, S. R. (2002). Enhancing first-grade children’s mathematical development with peer-assisted learning strategies. School Psychology Review, 31, 569–584. Geary, D. C. (1990). A componential analysis of an early learning deficits in mathematics. Journal of Experimental Child Psychology, 498, 363–383.

Geary, D. C. (1993). Mathematical disabilities: Cognitive, neuropsychological and genetic components. Psychological Bulletin, 114, 345–362. Geary, D. C. (2004). Mathematics and learning disabilities. Journal of Learning Disabilities, 37(1), 4–15. Geary, D. C., Hamson, C. O., & Hoard, M. K. (2000). Numerical and arithmetical cognition: A longitudinal study of process and concept deficits in children with learning disability. Journal of Experimental Child Psychology, 77, 236–263. Geary, D. C., Hoard, M. K., & Hamson, C. O. (1999). Numerical and arithmetical cognition: Patterns of functions and deficits in children at risk for a mathematical disability. Journal of Experimental Child Psychology, 74, 213–239. Gresham, F. M. (2004). Current status and future directions of school-based behavioral interventions. School Psychology Review, 33, 326–343. Gresham, F. M., Reschly, D., & Carey, M. P. (1987). Teachers as ‘‘tests’’: Classification accuracy and concurrent validation in the identification of learning disabled children. School Psychology Review, 26, 543–553. Gross-Tsur, V., Manor, O., & Shalev, R. S. (1996). Developmental dyscalculia: Prevalence and demographic features. Developmental Medicine and Child Neurology, 38, 25–33. Hallahan, D. P., Kauffman, J. M., & Lloyd, J. (1996). Introduction to learning disabilities. Needham Heights, MA: Allyn & Bacon. Lewis, C., Hitch, G. J., & Walker, P. (1994). The prevalence of specific arithmetic difficulties and specific reading difficulties in 9- to 10-year-old boys and girls. Journal of Child Psychology and Psychiatry, 35, 283–292. Lyon, G. R., Fletcher, J. M., & Barnes, M. C. (2003). Learning disabilities. In E. J. Mash & R. A. Barkley (Eds.), Child psychopathology (pp. 520–586). New York: Guilford. Lyon, G. R., Fletcher, J. M., Fuchs, L. S., & Chhabra, V. (2006). Learning disabilities. In E. J. Mash & R. A. Barkley (Eds.), Treatment of childhood disorders (3rd ed., pp. 512–591). New York: Guilford. Marston, D., & Magnusson, D. (1985). Implementing curriculum-based measurement in special and regular education settings. Exceptional Children, 52, 266–276. Michaelson, M. T. (2007). An overview of dyscalculia: Methods for ascertaining and accommodating dyscalculic children in the classroom. The Australian Mathematics Teacher, 63(3), 17–22. Miller, S. P., & Mercer, C. D. (1997). Educational aspects of mathematics disabilities. Journal of Learning Disabilities, 30, 47–56. Peterson, K. M., & Shinn, M. R. (2002). Severe discrepancy models: Which best explains school identification practices for learning disabilities? School Psychology Review, 31, 459–476.

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Rourke, B. P. (1993). Arithmetic disabilities specific and otherwise: A neuropsychological perspective. Journal of Learning Disabilities, 26, 214–226. Seabaugh, G. O., & Schumaker, J. B. (1993). The effects of self-regulation training on the academic productivity of secondary students with learning problems. Journal of Behavioral Education, 4, 109–133. Semrud-Clikeman, M., Biederman, J., Sprich-Buckminster, S., Krifcher-Lehman, B., Faraone, S. V., & Norman, D. (1992). Comorbidity between ADHD and learning disability: A review and report in a clinically referred sample. Journal of the American Academy of Child and Adolescent Psychiatry, 31, 439–448. Shalev, R. S., Auerbach, J., Manor, O., & Gross-Tsur, V. (2000). Developmental dyscalculia: Prevalence and prognosis. European Child and Adolescent Psychiatry, 9, 58–64. Shalev, R. S., Manor, O., & Gross-Tsur, V. (1997). Neuropsychological aspects of developmental dyscalculia. Mathematical Cognition, 33, 105–120. Shalev, R. S., Manor, O., Kerem, B., Ayali, M., Badichi, N., Friedlander, Y., et al. (2001). Developmental dyscalculia is a familial learning disability. Journal of Learning Disabilities, 34, 59–65. Shinn, M. R. (1988). Development of curriculum-based local norms for use in special education decision making. School Psychology Review, 17, 61–80. Shinn, M. R. (Ed.). (1989). Curriculum-based measurement: Assessing special children. New York: Guilford Press. Shinn, M. R. (Ed.). (1998). Advanced applications of curriculumbased measurement. New York: Guilford Press. Shinn, M. R. (2005). Identifying and validating academic problems in a problem-solving model. In R. Brown-Chidsey (Ed.), Assessment for intervention: A problem-solving approach (pp. 219–246). New York: Guilford. Shinn, M. R., & Marston, D. (1985). Differentiating mildly handicapped, low-achieving and regular education students: A curriculum-based approach. Remedial and Special Education, 6, 31–45. Siegel, L. S., & Ryan, E. B. (1989). The development of working memory in normally achieving and subtypes of learning disabled children. Child Development, 60, 973–980. Trott, C. (2003). Mathematics support for dyslexic students. MSOR Connections, 3(4), 17–20.

MELKERSSON–ROSENTHAL’S SYNDROME DESCRIPTION

Melkersson–Rosenthal’s syndrome (MRS) is a systemic neurological disorder characterized by

recurring facial paralysis, swelling of the face and lips (usually the upper lip), and the development of folds and grooves on the tongue. After recurrent attacks (ranging from days to years in between), swelling may persist and increase, eventually becoming permanent. The lip may become hard, cracked, and fissured with a reddish-brown discoloration. Swellings may occur on extra-facial regions, such as the lumbar region and the dorsal aspect of the hands and feet (Odom, James, & Berger, 2000). Although early manifestations of the syndrome can start at any age, onset usually is in young adulthood, and it affects females two to three times as often as males (Greene & Rogers, 1989; Hornstein, Stosiek, Scho¨nberger, & Meisel-Stosiek, 1987). The disorder is named after Ernst Melkersson and Curt Rosenthal. Prevalence of this syndrome is about 0.08%. The typical course is chronic recurrent or progressive involvement over decades (Aliag˘og˘lu et al., 2008; Minor, Fox, Bukantz, & Lockey, 1987; Stein & Mancini, 1999). NEUROPATHOLOGY/PATHOPHYSIOLOGY

MRS is characterized by oral noncaseating granulomatous lesions, similar to those associated with Crohn’s disease, sarcoidosis, food allergies, contact allergies, and focal dental sepsis. MRS is also reported to occur in childhood. The etiology and the mechanism of the disease are still not known, although genetic factors, infectious agents, allergic reactions to various foods and food additives, and autoimmune diseases have all been considered in the etiology of MRS (Ozgursoy et al., 2009; Pisanty & Sharav, 1969). It can be symptomatic of Crohn’s disease or sarcoidosis; temporal MRI revealed no pathological finding in patients with recurrent PFP, and chest X-ray was normal in all patients. Although there is no specific radiological finding for MRS, chest X-ray and temporal and cranial CT or MRI can be used to exclude other diseases (Ozgursoy et al., 2009). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The disorder is characterized by recurring facial paralysis, swelling of the face and lips (usually the upper lip), and the development of folds and grooves on the tongue. After recurrent attacks (ranging from days to years in between), swelling may persist and increase, eventually becoming permanent. The lip may become hard, cracked, and fissured with a reddish-brown discoloration. Swellings may occur on extrafacial regions,

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such as the lumbar region and the dorsal aspect of the hands and feet (Odom et al., 2000). Facial palsy occurs in 30–50% of cases. The paralyzed side is generally the side with swelling (Stein & Mancini, 1999). There has been no report of any cognitive or psychological impairment directly associated with MRS in the literature. DIAGNOSIS

MRS is a rare disorder characterized by a triad of recurrent orofacial swelling and recurrent paralysis of the facial nerve and lingua plicata. The complete triad only occurs in 25% of MRS cases. Other symptoms may include granulomas in other facial sites, regional lymphadenopathy, fever, psychotic disorders, and hyperplastic gingivitis are associated with MRS (Nagel & Foelster-Holst, 2006). The most dominant manifestation of the syndrome is facial edema, which is acute, diffuse, painless, nonpitting, and mostly confined to the lips (Zimmer, Rogers, Reeve, & Sheridan, 1992). Ozgursoy et al. (2009) reported that the clinical picture of MRS can vary according to the department specialty where the patient was treated. TREATMENT

Corticosteroids or clofazimine appear to be the best therapeutic options (Nagel & Foelster-Holst, 2006). Decompression of facial nerve throughout its bony canal may be indicated for patients with recurrent or persistent attacks of facial paralysis despite medical treatment (Dutt, Mirza, Irving, & Donaldson, 2000). Surgical procedures such as mucosa, submucosa and tangential muscle resection, crescent-shaped commissuroplasty, and facial liposuction have been deemed effective when orofacial swelling becomes unrelenting (Tan, Atik, & Calka, 2006). Reported successfully treating two patients with infliximab, which has strong anti-inflammatory properties and has been used successfully in Crohn’s disease, rheumatoid arthritis, or psoriasis. MRS may recur intermittently after its first appearance. It can become a chronic disorder. Intravenous high dosage of methylprednisolone has also shown some relief of symptoms (Kesler, Vainstein, & Gadoth, 1998). Spontaneous recovery of the majority of symptoms occurs in some cases, although reoccurrence is common with repeated episodes resulting in progressively worse recovery (Samuels & Feske, 2003). Issac Tourgeman Charles Golden

Aliag˘og˘lu, C., Yildirim, U., Albayrak, H., Gosugur, N., Memi¸s og˘ullari, R., & Kavak, A. (2008). MelkerssonRosenthal syndrome associated with ipsilateral facial, hand, and foot swelling. Dermatology Online Journal, 14(1), 7. Dutt, S. N., Mirza, S., Irving, R. M., & Donaldson, I. (2000). Total decompression of facial nerve for MelkerssonRosenthal syndrome. The Journal of Laryngology and Otology, 114, 870–873. Greene, R. M., & Rogers, R. S. (1989). Melkersson-Rosenthal syndrome: A review of 36 patients. Journal of American Academy of Dermatology, 2, 1263–1270. Hornstein, O. P., Stosiek, N., Scho¨nberger, A., & MeiselStosiek, M. (1987). Classification and scope of clinical variations of Melkersson-Rosenthal syndrome. Zeitschrift Fu¨r Hautkrankheiten, 62, 1453–1466. Kesler, A., Vainstein, G., & Gadoth, N. (1998). MelkerssonRosenthal syndrome treated by methylprednisolone. Neurology, 51(5), 1440–1441. Minor, M. W., Fox, R. W., Bukantz, S. C., & Lockey, R. F. (1987). Melkersson-Rosenthal syndrome. Journal of Allergy and Clinical Immunology, 80, 64–67. Nagel, F., & Foelster-Holst, R. (2006). Cheilitis granulomatosa Melkersson-Rosenthal syndrome. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete, 57(2), 121–126. Odom, R. B., James, W. D., & Berger, T. G. (2000). Diseases of the skin: Clinical dermatology (9th ed.). Philadelphia: W. B. Saunders Company. Ozgursoy, O. B., Karatayli Ozgursoy, S., Tulunay, O., Kemal, O., Akyol, A., & Dursun, G. (2009). The etiology of MRS is still unknown Melkersson-Rosenthal syndrome revisited as a misdiagnosed disease. American Journal of Otolaryngology, 30(1), 33–37. Pisanty, S., & Sharav, Y. (1969). The Melkersson-Rosenthal syndrome. Oral Surgery, Oral Medicine, and Oral Pathology, 27, 729–733. Samuels, M., & Feske, S. K. (2003). Office practice of neurology (2nd ed.). New York: Churchill Livingstone. Stein, S. L., & Mancini, A. J.,(1999). Melkersson-Rosenthal syndrome in childhood: Successful management with combination steroid and minocycline therapy. Journal of American Academy of Dermatology, 41, 746–748. Tan, O., Atik, B., & Calka, O. (2006). Plastic surgical solutions for Melkersson-Rosenthal syndrome: Facial liposuction and cheiloplasty procedures. Annals of Plastic Surgery, 56(3), 268–273. Zimmer, W. M., Rogers, R. S., Reeve, C. M., & Sheridan, P. J. (1992). Orofacial manifestations of MelkerssonRosenthal syndrome: A study of 42 patients and review of 220 cases from the literature. Oral Surgery, Oral Medicine, and Oral Pathology, 76, 610–619.

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MENINGITIS M DESCRIPTION

Meningitis refers to a potentially lethal medical condition characterized by inflammation of the meninges. Common symptoms of meningitis include headache, fever, nuchal rigidity, photophobia, and altered level of consciousness. A variety of pathogens can cause meningitis, including viruses, bacteria, and fungi, as well as ingested agents such as drugs or chemicals. The condition is often categorized by its etiology. Viral meningitis is the most common type of meningitis and is typically not life-threatening. A wide variety of viral agents, including enteroviruses, herpes simplex virus, West Nile virus, varicella zoster virus (VSV), mumps, polio, and HIV, can cause viral meningitis. Bacterial meningitis is less common than viral meningitis, but more often results in residual neurological impairments or death. Pathogens responsible for the most common types of bacterial meningitis include Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, Listeria, monocytogenes, Haemophilus influenzae, and group B streptococcus. Fungal meningitis can be caused by a wide variety of pathogens, including Cryptococcus, Blastomyces, Histoplasma, Coccidioides, Aspergillus, Candida, and other molds (Gottfredsson & Perfect, 2000). An assortment of drugs and chemicals has also been implicated as causal agents of meningitis. These include nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, sulindac, tolmetin, naproxen), antimicrobial drugs (e.g., sulfonamindes, trimethoprim), radiographic agents, chemotherapeutic drugs, and corticosteroids (Marinac, 1992). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Viruses can enter the central nervous system (CNS) and cause inflammation of the meninges through many different mechanisms. Some viral agents that cause meningitis infect leukocytes, multiply in the bloodstream, and enter the brain via the vascular system. Viral pathogens can also bypass the blood–brain barrier via transport through neural tissue. After infiltrating the CNS, the viral agents may travel through the cerebrospinal fluid (CSF). When CSF containing viral pathogens enters the subarachnoid space, inflammation of the meninges can result (Chadwick, 2005). Bacterial meningitis typically initiates from colonization of a pathogen on the nasopharynx of the host

organism. The bacteria may enter the bloodstream and then the CSF through the choroid plexus. After bacterial pathogens infiltrate the blood–brain barrier, the host’s defense system is activated, and cytokines, chemokines, and proteolytic enzymes are released. These defenses are usually insufficient in managing the resultant inflammation. Increased permeability of the blood–brain barrier, increased intracranial pressure, and cerebral edema often result. Cell wall slough and excretia byproducts of the pathogen may increase the host’s immune response to such a degree that neuronal injury results from the host’s own immune response (Tunkel & Scheld, 1993). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Fever, neck stiffness, and altered mental status are the classic triad of meningitis symptoms. However, research has shown that many individuals do not display all of these symptoms (van de Beek et al., 2004). Along with the classic triad, headache is another common symptom of meningitis. Individuals with meningitis may also experience photophobia, vomiting, chills, seizures, and/or papilledema. Depending upon the type of meningitis, a petechial or purpuric rash may also be present. The Kernig and Brudzinski signs have also been used as clinical indicators of meningeal inflammation. The clinical presentation of meningitis varies depending upon the etiology and age of the individual. Viral meningitis usually runs a benign course. Children with viral meningitis may present with meningism (neck stiffness, photophobia, and headache), fever, vomiting, respiratory problems, lethargy, irritability, poor appetite, and/or a rash (Chadwick, 1995; Dagan, Jenista, & Menegus, 1988). Infants with viral meningitis are more likely to suffer from seizures and present with focal neurological signs than older patients. Headache, fever, photophobia, and neck stiffness are common symptoms seen in adults with viral meningitis as well. The presentation of bacterial meningitis is very similar to that of viral meningitis; however, bacterial meningitis typically runs a longer and more complicated course. Research has shown that most adults with acute community-acquired bacterial meningitis present with two or more of the following symptoms: headache, fever, neck stiffness, or a compromised mental state (van de Beek et al., 2004). Young children with bacterial meningitis are more likely than older children and adults to present with nonspecific symptoms, including fever, lethargy, anorexia, vomiting, and irritability (Stechenberg, 2008).

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The prevalence of residual neurological deficits resulting from meningitis varies depending upon the age of the individual and etiology of the inflammation. Young children, immunocompromised adults, the elderly, and bacterial meningitis survivors are more likely to suffer from neurological sequelae. Grimwood et al. (1995) found that 26.9% of individuals who survive school-age bacterial meningitis suffer from functional impairments. Hearing disabilities are a common residual of bacterial meningitis. Other less common sequelae include mental retardation, spasticity, paresis, and seizure disorders (Baraff, Lee, & Schriger, 1993). A childhood history of bacterial meningitis is associated with a variety of cognitive, educational, and behavioral deficits. Bacterial meningitis survivors often exhibit IQ deficits as well as memory and learning deficits (Anderson, Anderson, Grimwood, & Nolan, 2004; Grimwood et al., 1995). Bacterial meningitis survivors also display executive control deficits and are poorer readers than controls (Anderson et al., 2004; Grimwood et al., 1995). Parent and teacher ratings indicate bacterial meningitis survivors have more behavioral problems than controls and show poorer psychological adjustment (Grimwood et al., 1995). Schmidt et al. (2006) found that survivors of bacterial meningitis reported significantly more difficulties performing daily activities than survivors of viral meningitis and controls. In the same study, both survivors of bacterial meningitis and viral meningitis showed deficits in executive functions and visuoconstructive functions when compared with healthy controls. Survivors of bacterial meningitis also performed significantly poorer on measures of working memory than survivors of viral meningitis and healthy controls. Occupational impairment led to retirement in a small minority (0.07%) of bacterial meningitis survivors and none of the viral meningitis survivors. MRI findings revealed lower brain volume and higher ventricular volume in survivors of bacterial meningitis compared with survivors of viral meningitis (Schmidt et al., 2006). DIAGNOSIS

An analysis of CSF extracted through a lumbar puncture is important in diagnosing meningitis. Biochemical markers of meningitis include reduced glucose concentration in CSF, increased CSF white blood cell counts, and elevated protein levels. In the case of bacterial meningitis, the results of CSF Gram stains can be helpful in identifying the causal agent and appropriate antibiotic treatments. If a Gram stain is negative, CSF biochemical markers are sometimes helpful in differentiating viral

meningitis from bacterial meningitis. Normal CSF glucose concentration is common in viral meningitis. Also, very seldom are leukocyte counts greater than 1,000 leukocytes/mm3 in individuals with viral meningitis (Marinac, 1992). Extraction of CSF through a lumbar puncture is contraindicated when brain abnormalities that could lead to herniation are suspected. Clinicians may order a computed tomography (CT) scan before a lumbar puncture is performed in order to assess for brain abnormalities predisposing the individual to brain herniation. Because ordering a CT scan often delays treatment, the scan may not be ordered unless the patient presents with neurological deficits, a compromised state of consciousness, papilledema, previous brain pathology, or a suppressed immune system. Even if a lumbar puncture cannot be performed, it is recommended that antibiotic therapy be given promptly if bacterial meningitis is suspected. For individuals with bacterial meningitis, early diagnosis and antibiotic treatment greatly improve prognosis. TREATMENT

Treatment of meningitis depends upon the causal agent. Bacterial meningitis warrants antibiotic treatment. A positive Gram stain can be used to identify the pathogen that should be targeted and guide antibiotic treatment. Drugs used to treat bacterial meningitis include ampicillin, chloramphenicol, ceftriaxone, cefotaxime, and vancomycin (Quagliarello & Scheld, 1997). Corticosteroids, such as dexamethasone, may also be used to reduce the often injurious immune response of the host organism (de Gans & van de Beek, 2002). Viral meningitis typically improves on its own without specific treatment. Aciclovir, an antiviral drug, may be given if meningitis is caused by the herpes simplex virus or VSV (Chadwick, 2005). However, in general, viral meningitis only warrants palliative care. With regard to prophylactic treatment of meningitis, vaccines are now available for meningitis caused by meningococci, H. influenzae type B, pneumococci, and the mumps virus. Antifungal drugs, including amphotericin B, flucytosine, and fluconazole, have been used to treat fungal meningitis (Bicanic & Harrison, 2004). Individuals with drugor chemical-induced aseptic meningitis should receive symptomatic treatment, and, if possible, administration of the drug or chemical exposure believed to be causing the inflammation should be discontinued. Alyse Barker Mandi Musso William Drew Gouvier

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Anderson, V., Anderson, P., Grimwood, K., & Nolan, T. (2004). Cognitive and executive function 12 years after childhood bacterial meningitis: Effect of acute neurologic complications and age of onset. Journal of Pediatric Psychology, 29(2), 67–81. Baraff, L. J., Lee, S. I., & Schriger, D. L. (1993). Outcomes of bacterial meningitis in children — A meta-analysis. Pediatric Infectious Disease Journal, 12(5), 389–394. Bicanic, T., & Harrison, T. S. (2004). Cryptococcal meningitis. British Medical Bulletin, 72, 99–118. Chadwick, D. R. (2005). Viral Meningitis. British Medical Bulletin, 75, 1–14. Dagan, R., Jenista, J. A., & Menegus, M. A. (1988). Association of clinical presentation, laboratory findings, and virus serotypes with the presence of meningitis in hospitalized infants with enterovirus infection. The Journal of Pediatrics, 113, 975–978. de Gans, J., & van de Beek, D. (2002). Dexamethasone in adults with bacterial meningitis. The New England Journal of Medicine. 347(20), 1549–1556. Gottfredsson, M., & Perfect, J. R. (2000). Fungal meningitis. Seminars in Neurology, 20(3), 307–322. Grimwood, K., Anderson, V. A., Bond, L., Catroppa, C., Hore, R. L., Keir, E. H., et al. (1995). Adverse outcomes of bacterial meningitis in school-age survivors. Pediatrics, 95(5), 646–656. Marinac, J. S. (1992). Drug- and chemical-induced aseptic meninigitis: A review of the literature. The Annals of Pharmacotherapy, 26, 813–822. Quagliarello, V. J., & Scheld, W. M. (1997). Treatment of bacterial meningitis. The New England Journal of Medicine, 336(10), 708–717. Schmidt, H., Heimann, B., Djukic, M., Mazurek, C., Fels, C., Wallesch, C. W., et al. (2006). Neuropsychological sequelae of bacterial and viral meningitis. Brain, 129, 333–345. Stechenberg, B. (2008). Bacterial meningitis. In L. L. Barton & N. R. Friedman (Eds.), The neurological manifestations of pediatric infectious diseases and immunodeficiency syndromes (pp. 193–198). Totowa, NJ: Humana Press. Tunkel, A. R., & Scheld, W. M. (1993). Pathogenesis and pathophysiology of bacterial meningitis. Annual Review of Medicine, 44, 103–120. van de Beek, D., de Gans, J., Spanjaard, L., Weisfelt, M., Reitsma, J. B., & Vermeulen, M. (2004). The New England Journal of Medicine, 351(18), 1849–1859.

MENKES’S DISEASE

caused by a defect in copper transport (Barnerias et al., 2008; Buisson et al., 2006; Danks et al, 1973; Menkes et al., 1962; Robertson, 2004). It is characterized by progressive cerebral degeneration with psychomotor deterioration and seizures, connective tissue alteration with hypopigmentation of skin and hair, and recurrent episodes of hypothermia with failure to thrive. MD has an incidence ranging from 1 of 100,000 to 1 to 250,000 live births (Kaler, 1994). An estimated 15–30 affected babies are expected to be born in the United States each year (Robertson, 2004). One-third of these cases are predicted to be nonfamilial cases, representing new mutations. About one-third of cases result from new mutations in the gene and occur in people with no history of the disorder in their family. Affected infants may be born prematurely. Symptoms appear during infancy and are largely a result of abnormal intestinal copper absorption with secondary deficiency in copperdependent mitochondrial enzymes. Normal or slightly slowed development may proceed for 2–3 months, and then there will be severe developmental delay and a loss of early developmental skills. Death usually occurs by 3 years of age. MD is related to the loss of a copper transporting adenosine triphosphatase (ATPase; ATP7A) involved in the export of dietary copper from the gastrointestinal tract and its transport into organelles (Buisson et al, 2006; Chelly et al., 1993; Tumer, Moller, & Horn, 1999). As a result of a mutation in the ATP7A gene, copper is poorly distributed to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels. The decreased supply of copper can reduce the activity of numerous coppercontaining enzymes that are necessary for the structure and function of bone, skin, hair, blood vessels, and the nervous system. It is caused by defects in an X-chromosome gene that encodes an intracellular copper transporting adenosine phosphatase. This gene product is localized to the trans-Golgi network and normally governs incorporation of copper into secreted copper enzymes (Robertson, 2004). MD affects all tissues and organs in the body, except for the liver where ATP7A is not expressed. The copper transport across the blood–brain barrier is also defective resulting in severe brain copper deficiency, which leads to mental retardation (de Bie, Wijmenga & Klomp, 2007).

DESCRIPTION

NEUROPATHOLOGY/PATHOPHYSIOLOGY

Menkes’s disease (MD) or kinky hair syndrome is a rare X-linked neurodegenerative disorder of infancy

MD presents with low levels of copper in plasma, liver, and brain because of impaired intestinal

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absorption. There is reduced activity of numerous copper-dependent enzymes and paradoxic accumulation of copper in certain tissues, kidney, spleen, skeletal muscle, and pancreas. Cultured fibroblasts in which reduced egress of radiolabeled copper is demonstrated in pulse chase experiments. Levels of plasma and cerebrospinal fluid catechols influenced by dopamine beta hydroxylase (DBH) activity are distinctly abnormal and provide a highly sensitive and specific diagnostic marker for this disorder. Plasma catechol analysis is arguably the best diagnostic test for at-risk newborns during the first month of life because other biochemical parameters are unreliable in this period and molecular analysis is less rapid. Early identification of affected infants is a fundamental requirement for successful intervention, underscoring the assay’s importance (Kaler et al., 2008; Robertson, 2004). There can be extensive neurodegeneration in the gray matter of the brain. Arteries in the brain can also be twisted with frayed and split inner walls. This can lead to rupture or blockage of the arteries and weakened bones (i.e., osteoporosis) may result in fractures. Barnerias et al. (2008) demonstrated the possible coexistence of cytotoxic oedema of the putamen and head of caudate nuclei with white matter vasogenic oedema of the temporal lobes in MD. Acute cerebral damage observed on MRI might result from the combined effects of acute metabolic stress due to infectious disease and prolonged status epilepticus, acting on a highly susceptible developing brain. Moreover, vascular dysfunction and defect of energy production, due to superoxide dismutase and COX deficiencies, strongly increase the damage observed. In MD, this vasogenic oedema observed during status epilepticus, not only results from thrombotic occlusion but also from deficiency of blood supply to the developing brain, induced by progressive vasculopathy secondary to impairment of lysyl oxidase (Danks, Cartwright, Stevens, & Townley, 1973). In MD, secondary mitochondrial energy failure is also observed and results from dysfunction of cytochrome oxidase and superoxide dismutase. Neuronal damage is caused by the dysfunction of oxidative phosphorylation and the increased mitochondrial production of free radicals (Barkovich et al., 1993). CT and MRI reveal progressive cerebral atrophy with a subdural hematoma or effusion in the neocortex, cerebellum, basal ganglia, and thalami (Robain, Aubourg, Routon, Dulac, & Ponsot, 1988; Takahashi et al., 1993). Neuronal degeneration predominates in cerebral and cerebellar cortices and in the basal ganglia (Buisson, 2008; Robain et al., 1988; Uno & Arya, 1987). Hsich, Robertson, Irons, Soul, and du Plessis (2000) reported bilateral infarctions of deep gray matter nuclei,

a finding not previously described in MD. Potential mechanisms for these cerebrovascular lesions in MD include the susceptibility to free radical attack and inadequate energy supply from oxidative phosphorylation. Hypopigmentation results from deficiency of tyrosinase, low lysyl oxidase activity causes numerous connective tissue disturbances, deficient DBH results in faulty catecholamine production, and poor cross linking of keratin with resulting steely hair is secondary to inadequate sulfhydryl oxidase activity. In the brain, lack of cytochrome c-oxidase, superoxide dismutase, and peptidyl alpha amidating activity in combination with aneurysm due to deficient lysyl oxidase will lead to severe dysfunction with progressive mental retardation (Barnerias et al., 2008; de Bie et al., 2007). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The disease is characterized by severe mental retardation and progressive deterioration that develops at an early stage. Patients also fail to achieve developmental milestones. Spontaneous movement is limited. Drowsiness and lethargy are also present (Danks, 1972; Menkes, 1962; Robertson, 2004). It is characterized by progressive cerebral degeneration with psychomotor deterioration and seizures, connective tissue alteration with hypopigmentation of skin and hair, and recurrent episodes of hypothermia with failure to thrive; so symptoms exist across all neurological and cognitive functions. DIAGNOSIS

The hallmark feature of MD is kinky hair, eyebrows, and eyelashes that are colorless or steel-colored and easily broken. In ethnic groups with black hair, the hair can also be blonde or brown. Onset of MD typically begins during infancy. Signs and symptoms of this disorder include depressed nasal bridge, sagging facial features, mental retardation, and developmental delay. At 2–3 months, there is a loss of previously obtained developmental milestones and the onset of hypotonia, failure to thrive, and seizures. In rare cases, symptoms begin later in childhood and are less severe. Patients may also present with temperature instability, hypoglycemia, and eyelid ptosis. Autonomic abnormalities may also result from selective loss of sympathetic adrenergic function (Barnerias et al., 2008; Buisson et al., 2006; Danks, 1972; Kaler, 1994; Menkes, 1962; Robertson, 2004). MD should be differentiated from other diagnoses that have an onset in infancy and present with similar symptoms. Leigh’s disease is a neurometabolic

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disorder characterized by loss of motor ability, hypotonia, and seizures with a rapidly progressing onset between the ages of 3 months and 2 years. Phenylketonuria, an autosomal recessive genetic disorder, also presents with seizures and mental retardation. Laboratory screening can be used to differentiate these diseases from MD. Also, both of the diseases do not present with the short and brittle hair as seen in MD. Pollitt’s syndrome, biotin deficiency, and argininosuccinic aciduria also present with similar symptoms and should be ruled out in diagnosis (Beers & Berkow, 1999). Occipital horn syndrome is a milder form of MD in which the overall neurologic function is great with complaints of orthostatic hypotension and chronic diarrhea (Robertson, 2004). TREATMENT

Early diagnosis and institution of subcutaneous copper injections have been successful in about 20% of infants treated within 2 weeks of life (n ¼ 18). The type and severity of the underlying mutation appear to be an important factor in response to early treatment (Robertson, 2004). Early treatment with subcutaneous (under the skin) or intravenous (in a vein) injections of copper supplements (in the form of acetate salts) may be of some benefit. Neonatal diagnosis of MD by plasma neurochemical measurements and early treatment with copper may improve clinical outcomes. Affected newborns who have mutations that do not completely abrogate ATP7A function may be especially responsive to early copper treatment (Kaler et al., 2008). Isaac Tourgeman Charles Golden Barkovich, A. J., Good, W. V., Koch, T. K., & Berg, B. O. (1993). Mitochondrial disorders: Analysis of their clinical and imaging characteristics. AJNR American Journal of Neuroradiology, 14, 1119–1137. Barnerias, C., Boddart, N., Pascale, G., Isabelle, D., Pannier, L. H., Dulac, O., et al. (2008). Unusual magnetic resonance imaging features in Menkes disease. Brain & Development, 30, 489–492. Beers, M. H., & Berkow, R. (1999). The Merck manual of diagnosis and therapy (17th ed.). Rathway, NJ: Merck Research Laboratories. Buisson, N. B., Kaminska, A., Nabbout, R., Barnerias, C., Isabelle, D., de Lonlay, P., et al. (2006). Epilepsy in Menkes disease: Analysis of clinical stages. Epilepsia, 47, 380–386. Chelly, J., Tumer, Z., Tonnesen, T., Petterson, A., IshikawaBrush, Y., Tommerup, N., et al. (1993). Isolation of

a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nature Genetics, 3, 14–19. Danks, D. M., Campbell, P. E., Stevens, B. J., Mayne, V., & Cartwright, E. (1973). Menkes’s kinky hair syndrome: An inherited defect in copper absorption with widespread effects. Pediatrics, 50, 188–201. Danks, D. M., Cartwright, E., Stevens, B. J., & Townley, R. R. (1973). Menkes’ kinky hair disease: Further definition of the defect in copper transport, Science, 179, 1140–1142. Hsich, G. E., Robertson, R. L., Irons, M., Soul, J. S., & du Plessis, A. J. (2000) Cerebral infarction in Menkes’ disease. Pediatric Neurology, 23, 425–428. Kaler, S. G. (1994). Menkes disease. Advances in Pediatrics, 41, 263–304. Kaler, S. G., Holmes, C. S., Goldstein, D. S., Tang, J., Godwin, S. C., Donsante, A., et al. (2008). Neonatal diagnosis and treatment of Menkes disease. The New England Journal of Medicine. 358(6), 605. Menkes, J. H., Alter, M., Steigleder, G. K., Weakley, D. R., & Sung, J. H. (1962). A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics, 29, 764–779. Robain, O., Aubourg, P., Routon, M. C., Dulac, O., & Ponsot, G. (1988). Menkes disease: A golgi and electron microscopic study of the cerebellar cortex. Clinical Neuropathology, 7, 47–52. Robertson, D. (2004). Primer on the autonomic nervous system. American Press. Takahashi, S. Ishii, K., Matsumoto, K., Higano, S., Ishibashi, T., Zuguchi, M., et al. (1993). Cranial MRI and MR angiography in Menkes’ syndrome. Neuroradiology, 35, 556–558. Tumer, Z., Moller, L. B., & Horn, N. (1999). Mutation spectrum of ATP7A, the gene defective in Menkes disease. Advances in Experimental Medicine and Biology, 448, 83–95. Uno, H., & Arya, S. (1987). Neuronal and vascular disorders of the brain and spinal cord in Menkes kinky hair disease. American Journal of Medical Genetics, (Suppl. 3), 367–377.

MENTAL RETARDATION DESCRIPTION

Mental retardation has been recognized through history as an abnormality. In 1799, French physician Marc Itard worked with a child, known as the ‘‘wild boy of Aveyron,’’ with the goal of adapting him to society. Although Dr. Itard failed to cure the boy,

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who he named ‘‘Victor,’’ it was one of the first attempts to treat an individual with mental retardation (Lane, 1976). During the summer of 1846, Dr. Buckminster Brown visited the Hospital for the Cure and Education of Cretins on the Abendberg, canton of Berne, Switzerland. According to Dr. Brown, cretins and idiots were isolated from the population of the institution, which was located on the Swiss Alps, with the hope that they could be treated using treatments such as gymnastic exercise. At that time, individuals with mental retardation were known as innocents, simpletons, cretins, or idiots (Brown, 1847). In fact, derogatory terms such as idiot, fool, moron, and imbecile were applied in diagnostic and legal terminology to refer to individuals with mental retardation (Volkmar & Dykens, 2002). Today, individuals with mental retardation are still associated with their deficits such as lack of intelligence (IQ test scores of 70 or less) or lack of adaptive social skills. However, there has been a change in the focus on mental retardation from what a person cannot do to what a person can do. In addition, there is greater emphasis on inclusion rather than exclusion. With treatment and assistance, some individuals with mental retardation have overcome their condition in order to function in society with relative normality. For instance, consider the case of Christopher Burke (1995) who suffers from Down’s syndrome (a form of mental retardation), yet he became an actor who starred in the TV show Life Goes On, despite his condition. The purpose of this chapter is to present a detailed coverage of the essential neurological, neuropsychological, and other aspects of mental retardation. NEUROPATHOLOGY/PATHOPHYSIOLOGY

In many ways, it is futile to attempt to discuss the neuropathological underpinnings of mental retardation. In essence, it is best conceptualized as a symptom as opposed to a disorder in and of itself. Mental retardation has been seen as a consequence of genetic/ chromosomal abnormalities, disrupted neurological development, and perinatal factors. Genetic/chromosomal abnormalities constitute the most common basis for mental retardation. Trisomy 21 (i.e., Down’s syndrome), Trisomy 18 (Edward’s syndrome), Trisomy 13 (Pautau’s syndrome), Trisomy 8, Trisomy 5 (Cri-du-chat syndrome), Fragile X syndrome, Klinefelter’s syndrome, Turner’s syndrome, and phenylketonuria are just a few of the genetic chromosomal disorders in which mental retardation commonly presents as a symptom. All cephalic disorders, when children survive, have shown a substantial risk of mental retardation in

addition to an array of other neurological symptoms. These include colpocephaly, holoprosencephaly, hydranencephaly, lissencephaly, porencephaly, and schizencephaly. This list obviously does not include cephalic presentations such as anencephaly as death often occurs prior to or immediately following birth. For some of these more severe forms, infants may live for up to a year or slightly more, but this is quite rare. Perinatal factors linked with increased risk of mental retardation, among other neurological defects, include infectious processes, drug or toxic substance exposure, and trauma. Infectious processes include cytomegalovirus, herpes simplex, and rubella. Drug and toxic substance exposure include alcohol, cocaine, and the array of other illicit substances. Finally, maternal trauma can include irradiation, maternal suffocation, or physical injury among other things. By all means, the presentations reported are not all inclusive. Rather, the emphasis is on the broad correlates of genetic/chromosomal abnormalities, infectious processes, and prenatal trauma. The interested reader is encouraged to read the literature on these individual presentations in regard to their pathological link to mental retardation. Many of which are included in this text. Beyond these, there is literature demonstrating links between gestational time, birth weight, and neonatal and early childhood environment and intellectual capacities. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The clinical presentation of mental retardation remains consistent with its diagnostic criteria. Mental retardation is marked by significant limitations in both intellectual functioning and adaptive functioning, occurring prior to age 18. In regard to intellectual functioning, this corresponds with abilities two standard deviations or more below the population mean. Given mental retardation itself is best conceptualized as a symptom, it commonly coincides with other neuropsychological, academic, behavioral, emotional, and/or social deficits that may be specific to an underlying disease or disorder but not specific to mental retardation. DIAGNOSIS

There are multiple definitions of mental retardation, which share common points. The American Association on Mental Retardation (Luckasson et al., 2002) provides the following definition: Mental retardation is a disability characterized by significant limitations both in intellectual functioning and in adaptive behavior as expressed in

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conceptual, social, practical adaptive skills. This disability originates before age 18. (p. 8)

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The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) (American Psychiatric Association [APA], 2000) defines mental retardation similarly. It states that the disorder is characterized by intellectual functioning that is significantly subaverage (that is, an IQ of approximately 70 or below) with onset before 18 years of age and concurrent deficits or impairments in adaptive functioning. The DSM-IV-TR provides separate codes for Mild, Moderate, Severe, and Profound Mental Retardation and for Mental Retardation, Severity Unspecified (APA, 2000). Both definitions focus on deficits on intellectual and adaptive functioning and they agree that the mental retardation symptoms must appear before the age of 18. Through time, the primary tool to assess mental retardation, intellectual deficits, has been the use of IQ (intelligence quotient) tests such as the Wechsler Intelligence Scales for Children, 3rd Edition (WISC-III; Wechsler, 1991) Stanford-Binet Intelligence Scales, 4th Edition (Thorndike, Hagen, & Sattler, 1986a, 1986b), and Kaufman Assessment Battery for Children (K-ABC; Kaufman & Kaufman, 1983). Recently, adaptive skills have been incorporated in the definition of mental retardation; thus, adaptive tests are used in the assessment of mental retardation including the Vineland Adaptive Behavior Scales (Sparrow, Balla, & Cicchetti, 1984) and the Adaptive Behavior Assessment System (Harrison & Oakland, 2000). Today, the combination of intelligence and social adaptive measures of functioning are applied in the diagnosis of mental retardation. Neuropsychological testing has been used to distinguish among individuals with mental retardation that might have another disorder. For instance, Palmer (2006) compared performances in neuropsychological testing among 10 individuals with comorbid mental retardation and dementia with 12 individuals with only mental retardation. The comparison was based on measures of attention, executive functions, language, dementia screening, as well as memory and learning. Palmer’s results indicated that there are significant differences in neurocognitive measures between the two groups. Although participants from the dementia group showed more severe defects in memory and learning, agnosia, semantic verbal fluency as well as attention and executive functions, both groups did show significant neuropsychological deficits. In another study, Shultz et al. (2004) evaluated screening tools for dementia in 38 older adults with mental retardation. The instruments used included

the dementia scale for Down’s syndrome (Gedye, 1995), the Dementia Questionnaire for Mentally Retarded Persons, and the Reiss Screen for Maladaptive Behavior. It was found that the dementia scale for Down’s syndrome and the Dementia Questionnaire were accurate in assessing dementia. However, a slight difference in effectiveness from the Dementia Questionnaire might be because mentally retarded individuals show less cognitive symptoms of dementia, which puts the dementia scale for Down’s syndrome at a disadvantage against the Dementia Questionnaire. Neuropsychological tests have also been used in the assessment of cognitive deficits in individuals with mental retardation. Vicari, Albertini, and Caltagirone (1992) identified cognitive profiles of 32 adolescents with mental retardation using neuropsychological assessment, which included measures of verbal functions, memory, visuoconstructive and visuospatial skills. Results from Vicari et al. indicated that the neuropsychological test battery distinguished cognitive profiles of participants with mental retardation. Furthermore, findings suggest that (a) since cognitive deficits of mental retardation vary depending on the skills impaired and the severity of the deficits, then mental retardation impairment is heterogeneous across all skills; and (b) a set of neuropsychological assessments exploring single cognitive functions is necessary to accurately identify and understand cognitive profiles from individuals with mental retardation. Assessment of mental retardation has been a complicated issue for educators, psychologists, and mental health professionals particularly because the cognitive and language skills of individuals with mental retardation make the assessment difficult (Smith, 2005). For instance, Flynn (2000) suggested a change to adaptive behavior tests instead of intelligence tests because of the lack of justification of an IQ criterion as related with impaired adaptive behavior. Similarly, Graue et al. (2007) compared Wechsler Adult Intelligence Scale, 3rd Edition (WAIS III) scores among 26 participants with mild mental retardation and 25 community volunteers who feigned mental retardation. Consistent with criticisms toward intelligence measures, Graue et al. found no significant difference between IQ scores, thus the scores from WAIS III did not distinguish individuals who feigned from individuals with genuine mental retardation. Despite the social and professional criticisms, intelligence measures are supported as the primary tool in the diagnosis of mental retardation. Umphress (2008) compared IQ test scores from the Reynolds Intellectual Assessment Scales (RIAS; Reynolds &

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Kamphaus, 1998) and the WAIS III to investigate whether results are comparable when measures are given by a same tester on the same day. Umphress found similar IQ scores in general, but significant difference between RIAS and WAIS III scores less than 80 was present. Similarly, Watkins and Campbell (1992) found the WAIS-R to be stable and reliable in a sample of 50 adults with mental retardation during 2–5 years, which was consistent with results from Rosen, Stallings, Floor, and Nowakiwska (1968). Neuropsychological testing has also been applied to identify individuals who might be feigning mental retardation. For example, Marshall and Happe (2007) studied which neuropsychological tests of effort and motivation would be appropriate if feigning of cognitive deficits might be present. They administered a comprehensive neuropsychological battery to 100 mentally retarded participants including the WAIS III (Wechsler, 1997), the Wechsler Memory Scale (WMS) III (Wechsler, 1997), the forced choice recognition portion of the California Verbal Learning Test II (CVLT-II; Delis, Kramer, Kaplan, & Ober, 2000), and Vocabulary Digit Span Test from the WAIS III Digit Span Test (Mittenberg, Theroux-Fichera, Zilinski, & Heibronner, 1995). It was found by Marshall and Happe that the scores from the forced portion of the CVLT-II, WMS III, and V-DS difference score are appropriate to distinguish individuals who might be feigning mental retardation. TREATMENT

John F. Kennedy’s administration proposed a new approach toward mental retardation in the 1960s with a focus on prevention, treatment, and rehabilitation (Kennedy, 1963). Such a policy marked a shift in terms of the importance of mental retardation as a relevant issue in society. Thus, an emphasis has been placed not only on the treatment of mental retardation as a disorder but also efforts have been directed toward finding ways to promote increased social engagement of individuals with mental retardation. Dykens (2006) supported the application of positive psychology on mental retardation with a focus on positive mental states such as happiness, contentment, hope, engagement, and strengths. Similarly, Favell, Realon, and Sutton (1996) examined individuals with severe and profound mental retardation from two intermediate care facilities. According to Favell et al. facial expressions could be applied as a practical method of measuring happiness in individuals with mental retardation. Other treatments of mental retardation have the objective of integrating individuals with mental

retardation to relatively normal life. For instance, LeBlanc, Hagopian, and Maglieri (2000) found that token economy with response cost procedure is effective in eliminating inappropriate social interaction, verbal aggression, and inappropriate sexual behavior in 26-year-old mentally retarded males. In another study, it was found that interactions between peer buddies improved communication behaviors, reciprocity of interactions, and enhanced range of communication behaviors in five high school students with mental retardation (Hughes et al., 2002). Carlos Ojeda Antonio E. Puente American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text revision). Washington, DC: Author. Brown, B. (1847). The treatment and cure of cretins and idiots: With an account of a visit to the institution on the Abendberg, canton of Berne, Switzerland, during the summer of 1846. Boston: William D. Ticknor & Co. Burke, C. (1995). Foreword. In L. Nadel & D. Rosenthal (Eds.), Down syndrome: Living and learning in the community (p. ix). New York: Willey. Delis, D. C., Kramer, J. H., Kaplan, E., & Ober, B. A. (2000). California Verbal Learning Test (2nd ed.). San Antonio, TX: The Psychological Corporation, Harcourt Assessment Company. Dykens, E. M. (2006). Toward a positive psychology of mental retardation. American Journal of Orthopsychiatry, 76, 185–193. Favell, J., Realon, R., & Sutton, K. (1996). Measuring and increasing the happiness of people with profound mental retardation and physical handicaps. Behavioral Interventions, 11, 47–58. Flynn, J. (2000). The hidden history of IQ and special education: Can the problems be solved? Psychology, Public Policy, and Law, 6, 191–198. Gedye, A. (1995). Dementia Scale for Down Syndrome. Manual. Vancouver, BC: Gedye Research and Consulting. Graue, L. O., Berry, D. T., Clark, J. A., Sollman, M. J., Cardi, M., Hopkins, J., et al. (2007). Identification of feigned mental retardation using the new generation of malingering detection instruments: Preliminary findings. Clinical Neuropsychologist, 21, 929–942. Harrison, P. L., & Oakland, T. (2000). Adaptive behavior assessment system. San Antonio, TX: The Psychological Corporation. Hughes, C., Copeland, S. R., Wehmeyer, M. L., Agran, M., Cai, X., & Hwang, B. (2002). Increasing social interaction between general education high school students and their peers with mental retardation. Journal of Developmental and Physical Disabilities, 14, 387–402.

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Kaufman, A. S., & Kaufman, N. L. (1983). K-ABC; Kaufman Assessment Battery for Children. Circles Pines, MN: American Guidance Service. Kennedy, J. (1963). Mental illness and mental retardation. Message from the president of the United States relative to mental illness and mental retardation. American Psychologist, 18, 280–289. Lane, H. L. (1976). The wild boy of Aveyron. Cambridge: Harvard University Press. LeBlanc, L., Hagopian, L., & Maglieri, K. (2000). Use of a token economy to eliminate excessive inappropriate social behavior in an adult with developmental disabilities. Behavioral Interventions, 15, 135–143. Luckasson, R., Borthwick-Duffy, S., Buntinx, W., Coulter, D., Craig, E., Reeve, A., et al. (2002). Mental retardation: Definition, classification, and systems of supports (10th ed.). Washington, DC: American Association on Mental Retardation. Marshall, P., & Happe, M. (2007). The performance of individuals with mental retardation on cognitive tests assessing effort and motivation. The Clinical Neuropsychologist, 21, 826–840. Mittenberg, W., Theroux-Fichera, S., Zilinski, R., & Heibronner, R. (1995). Identification of malingered head injury on the Wechsler Adult Intelligence Scale-Revised. Professional Psychology: Research and Practice, 26, 491–498. Palmer, G. A. (2006). Neuropsychological profiles of persons with mental retardation and dementia. Research in Developmental Disabilities, 27, 299–308. Reynolds, C. R., & Kamphaus, R. W. (2003). Manual for the Reynolds Intellectual Assessment Scales and the Reynolds Intellectual Screening Test. Lutz, FL: Psychological Assessment Resources. Rosen, M., Stallings, L., Floor, L., & Nowakiwska, M. (1968). Reliability and stability of Wechsler IQ scores for institutionalized mental subnormals. American Journal of Mental Deficiency, 73, 218–225. Shultz, J., Aman, M., Kelbey, T., Wallace, C. L., Burt, D. B., Primeaux-Hart, S., et al. (2004). Evaluation of screening tools for dementia in older adults with mental retardation. American Journal of Mental Retardation, 109(2), 98–110. Smith, T. C. (2005). Assessment of individuals with mental retardation: Introduction to special issue. Assessment for Effective Intervention, 30(4), 1–4. Sparrow, S., Balla, D. A., & Cicchetti, D. V. (1984). Vineland Adaptive Behavior Scales. Circle Pines, MN: American Guidance Service. Thorndike, R. L., Hagen, E. P., & Sattler, J. M. (1986a) Stanford-Binet Intelligence Scale (4th ed.). Chicago: Riverside. Thorndike, R. L., Hagen, E. P., & Sattler, J. M. (1986b). Technical manual for the Stanford-Binet Intelligence Scale (4th ed.). Chicago: Riverside. Umphress, T. B. (2008). A comparison of low IQ scores from the Reynolds Intellectual Assessment Scales and the

Wechsler Adult Intelligence Scale — Third Edition. Intellectual and Developmental Disabilities, 46, 229–233. Vicari, S., Albertini, G., & Caltagirone, C. (1992). Cognitive profiles in adolescents with mental retardation. Journal of Intellectual Disability Research, 36, 415–423. Volkmar, F., & Dykens, E. (2002). Mental retardation. In M. Rutter & E. Taylor (Eds.). Child and adolescent psychiatry (4th ed., pp. 697–710). Oxford: Blackwell. Watkins, C. Jr., & Campbell, V. (1992). The test-retest reliability and stability of the WAIS-R in a sample of mentally retarded adults. Journal of Intellectual Disability Research, 36, 265–268. Wechsler, D. (1991). Wechsler Intelligence Scale for Children (3rd ed.). New York: Psychological Corporation. Wechsler, D. (1997). Manual for Wechsler Adult Intelligence Scale (3rd ed.). San Antonio, TX: The Psychological Corporation.

METACHROMATIC LEUKODYSTROPHY DESCRIPTION

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder marked by the accumulation of cerebroside sulfate (sulfatide) within the nervous system and other tissue (Austin, 1959, 1973). Although first described in 1910 by Alzheimer (Austin, 1959), the condition was not fully delineated until 1933 when Greenfield (1933) noted it to be a form of diffuse sclerosis in which oligodendroglial degeneration (Kolodny, 1997) was characteristic. So far, three different clinical subtypes have been described for this disorder — a late infantile form (the most common), a juvenile form (may be subdivided into early and late juvenile forms), and an adult form (Polten et al., 1991). All forms of the disease involve a progressive deterioration of motor and neurocognitive function. The typing is somewhat arbitrary because the types overlap and some cases do not fall neatly within a single type. MLD actually describes a continuum of clinical severity. However, mortality and morbidity rates do vary with earlier onset being associated with a more rapid progression. Collectively, an approximate incidence of 1 out 40,000 births has been suggested with no discrepancies among racial/ethnic groups or sexes. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Mitochondrial leukodystrophy represents an autosomal-recessive disorder localized to chromosome 22

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q13.31 (Moraes et al., 1989). To date more than 60 mutations have been identified (Polten et al., 1991). It results from a deficiency of the lysosomal enzyme arylsulfatase A (ARSA). This deficiency leads to an accumulation of the sulfatides within the central nervous system (CNS) and peripheral nervous system (PNS), especially cerebroside sulfate. This is due to the fact that the sulfatides are stored in the lysosomes of miroglia and neuronal cells within the CNS and Schwann cells of the PNS. The overabundance of the sulfatides (as much as 4–8 times normal amounts) leads to a breakdown of the myelin within these systems. Less commonly, MLD may stem from a deficient cerebroside sulfatase activator protein, saposin B (Kolodny, 1997; Polten et al., 1991). This results in near normal ARSA activity, yet individuals excrete globotriaosylceramide and digalactosylceramide in addition to sulfatides (Wallace et al., 1988) owing to the clinical and pathological overlap. Variations in the allele mutation have been linked with subtype expression. One variation is pathologically characterized by a G to A transition that eliminates the splice donor site at the start of intron 2, with the resultant total loss of enzyme activity. Homozygosity for this allele and compound heterozygotes (with other unknown allele) are usually associated with late infantile onset. The second pathological variation is characterized by a C to T transition that results in the substitution of leucine for proline at amino acid 426 producing an enzyme with 3% residual activity. It is most commonly associated with the adult onset forms for both homozygous and compound heterozygotes forms. The presence of both alleles is associated with juvenile onset. A reduction in ARSA activity from 5% to 10% of control values is seen in up to 20% of the healthy population. This nonpathogenic reduction in enzyme activity is caused by homozygosity for a pseudodeficiency allele (Harvey, Carey, & Morris, 1998; Penzien et al., 1993). Individuals who are homozygous for this allele are asymptomatic, although in some, MRI shows lesions of white matter (McFaul, 1982; Zhang et al., 1991). Histopathological evaluation commonly demonstrates demyelination, gliosis, and macrophages with vacuolated cytoplasm throughout the white matter (Harvey et al., 1998; Kolodny, 1997; Polten et al., 1991, pp. 4–6). The membrane-bound sulfatide containing vacuoles exhibit ‘‘metachromasia’’ when toluidine blue staining is employed presenting as brown or with a golden hue as opposed to the usual blue of myelin. All the involved areas have loss of oligodendroglia. Metachromatic bodies stain strongly positive

with periodic acid–Schiff (PAS) and alcian blue in white matter of the brain. Metachromatic granules also are found in the renal tubules, bile duct epithelium, gallbladder, islet cell and ductal epithelium of the pancreas, reticular zone of the adrenal cortex, and liver (Iizuka et al., 2003). Similar changes in peripheral nerves are observed and can be detected in urine also. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The clinical presentations are discussed separately in relation to the three disease subtype forms. Late Infantile Subtype

In the late infantile variant, the typical age of onset is between 12 and 18 months. It is characterized by a gait disorder, strabismus, impairment of speech, spasticity, intellectual deterioration that appears gradually, and coarse tremors or athetoid movements of the extremities develop later. Reduced or even absent deep tendon reflexes are also seen. Unexplained bouts of fever, severe abdominal pain, optic atrophy, and seizures are seen as the disease progresses. Death occurs within 6 months to 4 years after the onset of symptoms (Brown et al., 1981). Elevated cerebrospinal fluid (CSF) protein, decreased conduction velocity in the peripheral nerves, and normal electroretinograms are seen (Kim et al., 1997). On MRI, the areas of demyelination are marked by high signal intensity on T2-weighted images seen in the periventricular regions, the centrum semiovale, the splenium, the genu of the corpus callosum, the internal capsule, and the pyramidal tracts. Characteristically, the subcortical white matter, including the arcuate fibers, is spared until late in the disease. Juvenile Subtype

The juvenile subtype MLD is the most rare in comparison with the infantile (most common) and adult variants (Austin et al., 1968) with neurologic symptoms becoming evident at around 5 years of age, characterized by loss of motor developmental milestones, decreased attention span, speech disturbances, decline in school performance, gait disturbances, tremors, clumsiness, loss of previously achieved skills, intellectual decline, behavioral changes (Alves, Pires, Guimara˜es, & Miranda, 1986). Older patients develop an organic mental syndrome and progressive corticospinal, corticobulbar, cerebellar, or, rarely, extrapyramidal signs.

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Adult Subtype

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The adult subtype has been observed as early as 15 years of age (Black, Taber, & Hurley, 2003). Clinically, it often first presents with dementia or psychiatric manifestations (Bagary et al., 2003; Denier et al., 2007; Hagberg, Sourander, & Thoren, 1962) — features similar to schizophrenia, post partum psychosis or any nonspecific psychoses. Rarely, the disease begins as a peripheral neuropathy. The variant forms with arylsulfatase-activator deficiency present a clinical picture of late infantile or juvenile MLD. DIAGNOSIS

The time of onset of neurological symptoms, the presence of ataxia, spasticity, and depressed deep tendon reflexes with elevated CSF protein content and reduced nerve conduction velocity suggest the diagnosis (Maertens & Dyken, 2007). Marked reduction in or absent urinary or leukocyte ARSA activity is seen. Brain MRI shows white matter lesions and atrophy characteristic of MLD but nonspecific. Other nonspecific abnormal laboratory test results include slowed motor nerve conduction velocities, a reduced auditory-evoked brainstem response, and a nonfunctioning gallbladder. Brown metachromatic bodies can be found on biopsy of various peripheral nerves as early as 15 months after the onset of symptoms. Segmental demyelination of peripheral nerves is also seen (Barth, Ward, Harris, Saad, & Fensom, 1994). The confirmation of diagnosis is based on the demonstration of reduced action of ARSA activity in the leucocytes or cultured skin fibroblast (Eto, Tahara, Tokoro, & Maekawa, 1983). From a differential diagnosis standpoint, in general, ARSA pseudodeficiency, attention deficit hyper-kinetic disorder, Kabre’s disease, schizophrenia and other psychoses, antisocial personality disorder, X-linked adrenoleukodystrophy and multiple sulfatase deficiency must all be considered. TREATMENT

The treatment for this disease requires a multidisciplinary approach. No effective treatment is present to reverse the disease so far. Pharmacological intervention varies and is employed as a means of controlling symptoms. This includes treatment of behavioral problems, feeding difficulties, and for controlling seizures. Bone marrow transplantation (Kapaun et al., 1999; Kidd et al., 1998) may slow the progression of the disease. Recombinant human arylsulfatase A (rhARSA) enzyme (Sevin, Aubourg, & Cartier, 2007)

and gene therapy (Biffi et al., 2006) have shown some efficacy in treatment although these remain experimental. Rehabilitative efforts also play a role in ongoing care. This is often multidisciplinary in approach and involves or may involve occupational therapists, physical therapists, neurologists, ophthalmologists, pediatricians, orthopedists, genetic counselors, psychologists, bone marrow transplant physicians, and metabolic disease specialists. Patient and family education is available from numerous sources and is strongly recommended. In general, prognosis is very poor. In infants, as suggested, progression is relatively rapid. In adults, progression is slower yet insidious. Gaurav Jain Sarita Singhal Chad A. Noggle Alves, D., Pires, M. M., Guimara˜es, A., & Miranda, M. C. (1986). Four cases of late onset metachromatic leucodystrophy in a family: Clinical, biochemical and neuropathological studies. Journal of Neurology, Neurosurgery, & Psychiatry, 49, 1417–1422. Austin, J. (1959). Metachromatic sulfatides in cerebral white matter and kidney. Proceedings of the Society for Experimental Biology and Medicine, 100, 361–364. Austin, J. H. (1973). Studies in metachromatic leukodystrophy. Archives of Neurology, 28, 258–264. Austin, J., Armstrong, D., Fouch, S., Mitchell, C., Stumpf, D., Shearer, L., et al. (1968). Metachromatic leukodystrophy (MLD): VIII. MLD in adults: Diagnosis and pathogenesis. Archives of Neurology, 18, 225–240. Bagary, M. S., Symms, M. R., Barker, G. J., Mutsatsa, S. H., Joyce, E. M., & Ron, M. A. (2003). Gray and white matter brain abnormalities in first-episode schizophrenia inferred from magnetization transfer imaging. Archives of General Psychiatry, 60, 779–788. Barth, M. L., Ward, C., Harris, A., Saad, A., & Fensom, A. (1994). Frequency of arylsulphatase A pseudodeficiency associated mutations in a healthy population. Journal of Medical Genetics, 31, 667–671. Biffi, A., Capotondo, A., Fasano, S., del Carro, U., Marchesini, S., Azuma, H., et al. (2006). Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. The Journal of Clinical Investigation, 116(11), 3070–3082. Black, D. N., Taber, K. H., & Hurley, R. A. (2003). Metachromatic leukodystrophy: A model for the study of psychosis. The Journal of Neuropsychiatry and Clinical Neurosciences, 15, 289–293. Brown, F. R., III., Shimizu, H., McDonald, J. M., Moser, A. B., Marquis, P., Chen, W. W., et al. (1981). Auditory evoked brainstem response and high-performance liquid chromatography sulfatide assay as early indices

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of metachromatic leukodystrophy. Neurology, 31, 980–985. Denier, C., Orgibet, A., Roffi, F., Jouvent, E., Buhl, C., Niel, F., et al. (2007). Adult-onset vanishing white matter leukoencephalopathy presenting as psychosis. Neurology, 68, 1538–1539. Eto, Y., Tahara, T., Tokoro, T., & Maekawa, K. (1983). Various sulfatase activities in leukocytes and cultured skin fibroblasts from heterozygotes for the multiple sulfatase deficiency (Mukosulfatidosis). Pediatric Research, 17, 97–100. Greenfield, J. G. (1933). A form of progressive cerebral sclerosis in infants associated with primary degeneration of the interfascicular glia. The Journal of Neurology and Psychopathology, 13, 289–302. Hagberg, B., Sourander, P., & Thoren, L. (1962). Peripheral nerve changes in the diagnosis of metachromatic leucodystrophy. Acta Paediatrica Scandinavica, 51(Suppl. 13S), 63–71. Harvey, J. S., Carey, W. F., & Morris, C. P. (1998). Importance of the glycosylation and polyadenylation variants in metachromatic leukodystrophy pseudodeficiency phenotype. Human Molecular Genetics, 7, 1215–1219. Kapaun, P., Dittmann, R. W., Granitzny, B., Eickhoff, W., Wulbrand, H., & Neumaier-Probst, E. (1999). Slow progression of juvenile metachromatic leukodystrophy 6 years after bone marrow transplantation. Journal of Child Neurology, 14, 222–228. Kidd, D., Nelson, J., Jones, F., Dusoir, H., Wallace, I., McKinstry, S., et al. (1998). Long-term stabilization after bone marrow transplantation in juvenile metachromatic leukodystrophy. Archives of Neurology, 55, 98–99. Kim, T. S., Kim, I. O., Kim, W. S., Choi, Y. S., Lee, J. Y., Kim, O. W., et al. (1997). MR of childhood metachromatic leukodystrophy. AJNR. American Journal of Neuroradiology, 18, 733–738. Kolodny, E. H. (1997). Metachromatic leukodystrophy and multiple sulfatase deficiency: Sulfatide lipidosis. In R. N. Rosenberg, et al. (Ed.), The molecular and genetic basis of neurological disease (2nd ed., pp. 433–442). Boston: Butterworth–Heinemann. Martens, P., & Dyken, R. (2007). Storage diseases: Neuronal ceroid-lipofuscinoses, lipidoses, glycogenoses, and leukodystrophies. In C. Goetz (Ed.), Textbook of clinical neurology (pp. 612–639). Philadelphia, PA: Saunders Elsevier. McFaul, R. (1982). Metachromatic leucodystrophy: Review of 38 cases. Archives of Disease in Childhood, 57, 168–175. Menkes, J. H. (1966). Chemical studies of two cerebral biopsies in juvenile metachromatic leukodystrophy: The molecular composition of cerebroside and sulfatides. Journal of Pediatrics, 69, 422–431.

Penzien, J. M., Kappler, J., Herschkowitz, N., Schuknecht, B., Leinekugel, P., Propping, P., et al. (1993). Compound heterozygosity for metachromatic leukodystrophy and arylsulfatase: A pseudodeficiency allele is not associated with progressive neurological disease. American Journal of Human Genetics, 52, 557–564. Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., & Gieselmann, V. (1991). Molecular basis of different forms of metachromatic leukodystrophy. The New England Journal of Medicine, 324, 18–22. Sevin, C., Aubourg, P., & Cartier, N. (2007). Enzyme, cell and gene-based therapies for metachromatic leukodystrophy. Journal of Inherited Metabolic Disease, 30(2), 175–183. Zhang, X. L., Rafi, M. A., DeGala, G., & Wenger, D. A. (1991). The mechanism for a 33 nucleotide insertion in mRNA causing sphingolipid activator protein (SAP1) deficient metachromatic leukodystrophy. Human Genetics, 87, 211–215.

MICROCEPHALY DESCRIPTION

Microcephaly is a neurodevelopment disorder describing a patient with an abnormally smaller head circumference than others. Head measurements tend to be smaller by more than two standard deviations compared with average size for the age, sex, race, and period of gestation of the individual. Development of the disorder may occur congenitally, being present at birth, or over the first few years of life. The comparison is normally obvious when comparing the head size to the rest of the body. The smaller head is normally a result of an underdeveloped brain (Dekaban & Sadowsky, 1978), which indicates high propensities toward mental retardation. The presentation is largely descriptive in nature representing a feature/symptom of a primary presentation. Specifically, microcephaly is associated with a number of presentations including but not limited to certain cephalic, genetic/chromosomal disorders, neurometabolic syndromes, and prenatal teratogenic processes. In many respects, the degree of growth impairment (i.e., how small the head is) demonstrates a negative linear relationship with the severity of functional impairments such that the smaller the head is the greater the deficits. These deficits may present as general mental retardation or as domain-specific abnormalities such as speech and language delays or sensorimotor deficits. There is also increased

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prevalence of other neurological issues such as seizures as well as additional morphological anomalies such as facial-structural anomalies and widespread musculoskeletal dwarfism. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Microcephaly presents secondary to either halted growth of the cortex or premature closure and fusion of cranial plates. In both instances, microcephaly is best categorized as a symptom of a large-scale presentation that constitutes the underlying pathology. Ross and colleagues (1977) classified microcephaly dichotomously based on whether there is or is no associated malformations. Microcephaly vera represents a primary hereditary form of microcephaly in which by adulthood the skull is as much as 3–5 standard deviations below the mean for circumference (Golden & Bonnemann, 2007). The presentation is associated with other morphological traits including normal facial size but with a narrow and sharply receding forehead, and globally reduced stature. At birth infants present with an anthropoid appearance (Ropper & Brown, 2005). As would be expected, the staunch reduction in head circumference corresponds with prominent functional impairments including moderate to severe mental retardation and motor limitations. Two genes have been identified thus far in relation to this presentation including microcephalin (MCPH1) and ASPM (Bond et al., 2002) In regard to microcephaly occurring secondary to disrupted brain growth, this has been noted in association with genetic/chromosomal disorders, neurometabolic disorders, and neurodevelopmental/ neuromigrational disorders that have their own pathological bases. Some examples include lissencephaly, Down’s syndrome, and phenylketonuria (PKU) (untreated). To date, microcephaly has been associated with 176 different syndromes in which at least one case of microcephaly has been reported (Van Allen et al., 1993). A more refined synthesis of the literature by Jones and colleagues (MRC, 1991) demonstrated that 39 syndromes have been identified in which microcephaly is seen as a primary characteristic whereas 21 others are occasionally associated with resulting microcephaly. Sporadic microcephaly that seems unassociated with other structural anomalies often suggests a teratogenic (e.g., infectious or toxic) basis (Hanshaw et al., 1985). These include maternal substance use/abuse such as alcohol or cocaine and diseases such as cytomegalovirus, measles, and/or chickenpox. Other developments of microcephaly may be due to instances of trauma particularly in the third trimester of pregnancy.

The brain is characterized by a general reduction in the number of primary and secondary sulci. The cortex oftentimes is thicker than usual with diminished numbers of neurons, and there are higher rates of associated cerebellar hypoplasia and degeneration of the substantia nigra (Golden & Bonnemann, 2007; Ropper & Brown, 2005). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

As noted, microcephaly commonly manifests secondary to other primary presentations (e.g., Down’s syndrome). Consequently, these presentations correspond with their own clinical picture that goes beyond the functional afflictions purely associated with microcephaly itself. Still, particular features have been correlated with microcephaly. Morphologically, patients with microcephaly are often easy to notice because of their narrow, receded forehead, pointed vortex, and flattened occiput. However, they generally have normal facial features. This is a result of the face growing at normal rates despite the lack of head growth. Depending on brain development, patients may present with hyperactivity and mental retardation, varying in degree based on severity of cognitive deficit. Increased prevalence of seizures and convulsions has been associated with the presentation, and varying degrees of motor impairments are observed. DIAGNOSIS

Diagnosis of microcephaly is purely morphologically based. Current guidelines stipulate a threshold of head circumference of approximately two standard deviations below the mean in comparison with normative data based on sex, body size, and developmental stage (Droghari et al., 1987). X-ray may be utilized to evaluate cranial sutures and plates whereas MRI and CT may be employed to evaluate brain integrity. Genetic testing and metabolic evaluations may be utilized to evaluate for potential underlying causes. Neuropsychological evaluation, physical and occupational therapy evaluations, and speech evaluations are useful in identifying potential underlying impairments. TREATMENT

There is no standard treatment for microcephaly. Treatment is symptom based, corresponding with the functional deficits associated with the microcephaly itself or in relation to the underlying pathology.

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Consequently, treatment may include speech, occupational, or physical therapy. Special education services may be required to address academic deficits if they exist. If neurological symptoms such as seizures or convulsions present, medicinal intervention may be used. In instances where the presentation occurs secondary to premature fusion of cranial plates, surgical intervention may be used. Although such interventions can be employed to promote a normal lifestyle as much as possible, microcephaly is still associated with a reduced life expectancy compared with normal healthy persons. J. Aaron Albritton Chad A. Noggle Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., et al. (2002). ASPM is a major determinant of cerebral cortical size. Nature Genetics, 32, 316–320. Dekaban, A. S., & Sadowsky, D. (1978). Changes in brain weights during the span of human life: Relation of brain weights to body heights and body weights. Annals of Neurology, 4, 345–356. Droghari, E., Smith, I., Beasley, M., & Lloyd, J. K. (1987). Timing of strict diet in relation to fetal damage in maternal phenylketonuria. Lancet, ii, 927–930. Eichorn, D. H., & Bayley, N. (1962). Growth in head circumference from birth through adulthood. Child Development, 33, 257–271. Golden, J., & Bonnemann, C. (2007). Developmental structural disorders. In C. Goetz (Ed), Textbook of clinical neurology (pp. 562–591). Philadelphia, PA: Saunders Elsevier. Gruenwald, P., & Minh, H. (1960). Evaluation of body and organ weights in perinatal pathology. I. Normal standard derived from autopsies. American Journal of Clinical Pathology, 39, 247–253. Hanshaw, J. B., Dudgeon, J. A., & Marshall, W. C. (1985). Viral diseases of the fetus and newborn (2nd ed.). Philadelphia, PA: W. B. Saunders. Larroche, J. C., & Maunoury, T. (1973). Analyse statistique de la croissance ponderale des foetus et des visceres pendant la vie intrauterine. Archives Francaises de Pediatrie, 30, 927–949. MRC Vitamin Study Research Group. (1991). Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet, 338, 131–137. Nellhaus, G. (1968). Head circumference from birth to eighteen years. Practical composite international and interracial graphs. Pediatrics, 41, 106–119. Potter, E. L., & Craig, J. M. (Eds.) (1976). Pathology of the fetus and infant (3rd ed.). Chicago, IL: Year Book Publishers.

Remington, J. S., & Klein, J. O. (1976). Infectious disease of the fetus and newborn infant. Philadelphia, PA: W. B. Saunders. Ropper, A. H., & Brown, R. H. (2005). Adams and Victor’s principles of neurology (8th ed.). New York, NY: McGrawHill. Ross, J. J., Frias, J. L., Vinken, P. J., & Bruyn, G. W. (Eds.) (1977). Microcephaly. In Handbook of clinical neurology (pp. 507–524). Amsterdam, The Netherlands: NorthHolland Publishing Co. Van Allen, M. I., Kalousek, D. K., Chernoff, G. F., Jurilloff, D., Harris, M., McGillivray, B. C., et al. (1993). Evidence for multisite closure of the neural tube in humans. American Journal of Medical Genetics, 47, 723–743.

MIGRAINES DESCRIPTION

A survey of neurologists found that patients seek consultation for headaches more than any other complaint and represent up to one-third of total patients in their care (World Health Organization [WHO], 2004). Migraines constitute a common primary headache disorder that are marked by severe pain on one or both sides of the head, nausea or upset stomach, and hypersensitivity to sound or light (International Headache Society, 2004). The pain is often described as pulsating and of moderate to severe intensity. A majority of patients experience pain localized to one side of the head, though this pain may eventually spread to the other side. A subset of migraine sufferers experience neurological symptoms that may include sensory, perceptual, motor, and/or cognitive disturbances; these symptoms are known as the migraine aura (Hooker & Raskin, 1986). These symptoms tend to resolve within 1 hour but lead to the onset of a migraine. Migraine attacks can last from 4 to 72 hours and most commonly affect adults between the ages of 35 and 45 years. It is estimated that approximately 6–8% of men and 15–18% of women experience some form of migraine each year. Further, migraines have been identified as one of the top 20 causes of disability among adults of all ages; as a result, estimates of their financial cost to society are high (WHO, 2004). NEUROPATHOLOGY/PATHOPHYSIOLOGY

As a primary headache disorder, migraines are believed to have a genetic basis, though exact etiology remains largely unknown (Gardner, 2006). A vascular

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theory of migraine was widely accepted for many years, wherein it was thought that the pain associated with migraine headaches was the result of dilated cranial vessels (Wolff, 1948). This model has been criticized due to recent research suggesting that cranial vessel dilation is not necessary for migraine pain to occur (e.g., Schoonman et al., 2008). A more recent theory of migraine pathophysiology points to a neurogenic origin and classifies migraine as a CNS disorder (Agnoli & De Marinis, 1985; Cutrer & Charles, 2008). Headache pain is believed to be generated centrally and to involve the serotonergic system (Goadsby, 2000; Hamel, 2007; Hargreaves & Shepheard, 1999; Silberstein, 2004). A range of evidence implicating serotonin in the experience and prevention of acute attacks supports this theory (e.g., Ferrari, Roon, Lipton, & Goadsby, 2001; Silberstein, 2005). Today clinicians widely agree that migraine is a neurovascular disorder, though recent evidence from human imaging studies suggests that vasodilation may not play an important role in headache pathophysiology (Schoonman et al., 2008). Future research utilizing technological advancements will likely elucidate the neuropathological mechanisms of migraine. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Neuropsychological testing may play a role in determining the impact of migraines on an individual’s cognitive functioning, but evidence of cognitive declines in migraine sufferers is presently inconclusive (O’Bryant, Marcus, Rains, & Penzien, 2006). In reality, research on neuropsychological profiles associated with migraine is limited despite the prevalence and severity of migraine headaches. Even those studies examining relationships between cognitive performance and migraines have led to conflicting findings. Although some studies suggest that there are no significant differences in cognitive functioning between migraine sufferers and healthy controls (e.g., Bell, Primeau, Sweet, & Lofland, 1999), other studies indicate that migraine patients show deficits across a number of neuropsychological domains (e.g., Hooker & Raskin, 1986). In a study by Bell et al. (1999), cognitive performance of patients with chronic migraines, patients with nonheadache chronic pain, and patients with mild traumatic brain injury (TBI) were compared. Across domains of cognitive efficiency, memory, and visuoperceptual ability, no differences between chronic pain and migraine patients were found,

though the mild TBI patients performed significantly worse. Notably, this study did not include a control group of healthy subjects. However, a large community study suggests that these findings hold across the life span among people with and without migraine; though age is predictive of cognitive functioning, migraine diagnosis is not (Jelicic, van Boxtel, Houx, & Jolles, 2000). That being said, a body of literature suggests that the cognitive abilities of migraine sufferers versus healthy controls do indeed differ, especially across memory and attention domains. There is some evidence suggesting that cognitive functioning is impaired among migraine sufferers only when they are experiencing an acute attack (Meyer, Thornby, Crawford, & Rauch, 2000). Other investigations suggest more lasting impairment in cognitive functioning. For example, Hooker and Raskin (1986) compared migraine patients with and without aura to healthy controls, finding that both migraine groups obtained significantly lower scores than the control group on a tactual learning task and delayed story recall. Furthermore, migraine without aura patients significantly outperformed migraine with aura patients on the grooved pegboard and aphasia screening tasks. These results led Hooker and Raskin to conclude that migraine sufferers experience greater impairment on a neuropsychological battery than those without migraines. In addition, they argue that migraine with aura may lead to greater functional impairment than migraine without aura, though other evidence suggests that impairments are greater for those with migraine without aura across verbal memory domains (Le Pira et al., 2000). Another line of research suggests that the length of headache history and frequency of attacks may predict level of impairment (Calandre, Bembibre, Arnedo, & Becerra, 2002). Clearly, additional research is necessary to elucidate the relationships between migraine and neuropsychological functioning. Associations between migraine and psychological functioning are more straightforward. For example, the experience of migraines increases a person’s likelihood of experiencing depression (and vice versa; see Breslau, Lipton, Stewart, Schultz, & Welch, 2003). Relationships between migraine and anxiety have also been uncovered; migraine sufferers are more likely to develop panic disorder than individuals without migraine, and associations between migraine and other anxiety disorders are currently being researched (Silberstein, 2001; Smitherman, Penzien, & Maizels, 2008). Due to the well-established effects of anxiety and depression on cognitive functioning, it is important to consider possible psychiatric

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comorbidities when evaluating the emotional and cognitive functioning of migraine patients. DIAGNOSIS

Diagnosis of migraines is largely based on clinical presentation and symptom report. As suggested earlier, migraines are divided into two major subtypes: migraine with aura and migraine without aura (International Headache Society, 2004). To meet criteria for migraine without aura, a patient must have experienced five or more headache attacks lasting anywhere from 4 to 72 hours. The headaches must be characterized by two or more of the following symptoms: moderate to severe pain, pulsating quality, unilateralization, and exacerbation by routine physical activity. Furthermore, at least one of the following symptoms should accompany the attack: nausea or vomiting, sensitivity to light, and/or sensitivity to sound. Migraine with aura was previously identified as ‘‘classic’’ migraine. To meet criteria for migraine with aura, the patient must have experienced neurological symptoms that last for less than 60 minutes; these neurological symptoms must occur either before, during, or after a headache with symptoms similar to those of migraine without aura. Although this offers some distinction between migraine types from a descriptor standpoint, diagnosis must more specifically attempt to determine the underlying etiology as they may result from a variety of structural anomalies including tumors, infections, and vascular malformations. Cerebrovascular presentation must also be considered as should metabolic issues, hypoxia, hypoglycemia, as well as various other presentations. Differential diagnosis must consider other primary headache disorders such as cluster headaches, hypnic headaches, short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing headaches, and tension-type headaches (Siloberstein & Young, 1995). TREATMENT

Treatment for migraines typically involves some form of pharmacological intervention. Serotonin agonists have been shown to be successful in the treatment of acute headache attacks and several preventive forms of pharmacotherapy are effective, including GABA inhibitors, beta-adrenergic blocking agents, and tricyclic antidepressants (Goadsby, 2000). Analgesics and antiinflammatory medications have also been shown to successfully treat acute attacks (Lipton et al., 1998). Biofeedback and relaxation training are also sometimes used to provide relief from migraine

pain. Research suggests that such techniques are effective, with comparable effectiveness to prophylactic medication (Andrasik, 2004). Amy R. Steiner Chad A. Noggle Amanda R. W. Steiner Agnoli, A., & De Marinis, M. (1985). Vascular headaches and cerebral circulation: An overview. Cephalagia, 5, 9–15. Andrasik, F. (2004). Behavioral treatment of migraine: Current status and future directions. Expert Review of Neurotherapeutics, 4, 403–413. Bell, B. D., Primeau, M., Sweet, J. J., & Lofland, K. R. (1999). Neuropsychological functioning in migraine headache, nonheadache chronic pain, and mild traumatic brain injury patients. Archives of Clinical Neuropsychology, 14, 389–399. Breslau, N., Lipton, R. B., Stewart, W. F., Schultz, L. R., & Welch, K. M. (2003). Comorbidity of migraine and depression: Investigating potential etiology and prognosis. Neurology, 60, 1308–1312. Calandre, E. P., Bembibre, J., Arnedo, M. L., & Becerra, D. (2002). Cognitive disturbances and regional cerebral blood flow abnormalities in migraine patients: Their relationship with the clinical manifestations of the illness. Cephalalgia, 22, 291–302. Cutrer, F. M., & Charles, A. (2008). The neurogenic basis of migraine. Headache, 48, 1411–1414. Ferrari, M. D., Roon, K. I., Lipton, R. B., & Goadsby, P. J. (2001). Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: A meta-analysis of 53 trials. Lancet, 42, 1668–1675. Gardner, K. L. (2006). Genetics of migraine: An update. Headache, 46, S19–S24. Goadsby, P. J. (2000). The pharmacology of headache. Progress in Neurobiology, 62, 509–525. Hamel, E. (2007). Serotonin and migraine: Biology and clinical implications. Cephalalgia, 27, 1293–1300. Hargreaves, R. J., & Shepheard, S. L. (1999). Pathophysiology of migraine: New insights. Canadian Journal of Neurological Sciences, 26, 12–19. Hooker, W. D., & Raskin, N. H. (1986). Neuropsychologic alterations in classic and common migraine. Archives of Neurology, 43, 709–712. International Headache Society (2004). Migraine. Cephalalgia: An International Journal of Headache, 24, 24–36. Jelicic, M., van Boxtel, M. P., Houx, P. J., & Jolles, J. (2000). Does migraine headache affect cognitive function in the elderly? Report from the Maastricht Aging Study (MAAS). Headache, 40, 715–719. Le Pira, F., Zappala, G., Guiffrida, S., Lo Batolo, M. L., Reggio, E., Morana, R., et al. (2000). Memory disturbances

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in migraine with and without aura: A strategy problem? Cephalalgia, 20, 475–478. Lipton, R. B., Stewart, W. F., Ryan, R. E., Saper, J., Silberstein, S., & Sheftell, F. (1998). Efficacy and safety of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain. Archives of Neurology, 55, 210–217. Meyer, J. S., Thornby, J., Crawford, K., & Rauch, G. M. (2000). Reversible cognitive decline accompanies migraine and cluster headaches. Headache, 40, 638–646. O’Bryant, S. E., Marcus, D. A., Rains, J. C., & Penzien, D. B. (2006). The neuropsychology of recurrent headache. Headache, 46, 1364–1376. Schoonman, G. G., van der Ground, J., Kortmann, C., van der Geest, R. J., Terwindt, G. M., & Ferrari, M. D. (2008). Migraine headache is not associated with cerebral or meningeal vasodilation: A 3T magnetic resonance angiography study. Brain, 131, 2192–2200. Silberstein, S. D. (2001). Shared mechanisms and comorbidities in neurologic and psychiatric disorders. Headache, 41, 11–17. Silberstein, S. D. (2004). Migraine pathophysiology and its clinical implications. Cephalalgia, 24, 2–7. Silberstein, S. D. (2005). Preventive treatment of migraine. Review of Neurological Diseases, 2, 167–175. Silberstein, S. D., & Young, W. B. (1995). Migraine aura and prodrome. Seminal Neurology, 45, 175–182. Smitherman, T. A., Penzien, D. B., & Maizels, M. (2008). Anxiety disorders and migraine intractability and progression. Current Pain and Headache Reports, 12, 224–229. Wolff, H. G. (1948). Headache and other head pain. New York: Oxford University Press. World Health Organization. (2004, March). Headache disorders. Fact Sheet, 277.

MILLER FISHER SYNDROME DESCRIPTION

Miller Fisher syndrome (MFS) is a rare variant of Guillain–Barre´ syndrome (GBS) (also known as acute inflammatory demyelinating polyneuropathy, acute idiopathic polyradiculoneuritis, acute idiopathic polyneuritis, French polio, Landry’s ascending paralysis, and Landry–Guillain–Barre´ syndrome), which is an acquired nerve disease that is characterized by abnormal muscle coordination, paralysis of the eye muscles, and absence of the tendon reflexes. Several variants of GBS exist, but MFS is relatively common, representing approximately 5% of GBS cases. The key symptoms of the disorder involve a triad of ataxia (gross lack of coordination of muscle

movements), areflexia (complete loss of deep tendon reflexes), and ophthalmoplegia (paralysis of the extraocular muscles). The major difference in the presentation of MFS is that the disease causes a descending paralysis that begins in the upper body and gradually spreads downward, whereas GBS cases tend to cause an ascending paralysis, starting in the legs and moving upward. MFS symptoms typically start in the eye muscles, then slowly descend to the neck and arms. (Mori, Kuwabara, Fukutake, Yuki, & Hattori, 2001). The disease is considered an acute inflammatory demyelinating polyneuropathy (Scelsa & Herskovitz, 2000). MFS is not typically life-threatening like GBS, but its symptoms can include respiratory failure and are very debilitating. Similar to GBS, MFS may be preceded by a viral illness (Guarino, Stracciari, Cirignotta, D’Alessandro, & Pazzaglia, 1995; Roos, 2007). The majority of individuals with MFS have a unique antibody that characterizes the disorder (Plomp, Molenaar, O’Hanlon, Jacobs, Veitch, Daha, et al., 1999). The disease is considered an acute inflammatory demyelinating polyneuropathy. GBS was first described by the French physician Jean Landry in 1859. Then, in 1916, Georges Guillain, Jean Alexandre Barre´, and Andre Strohl diagnosed two soldiers with the syndrome, but also discovered the key diagnostic abnormalities of the disorder. In 1956, C. Miller Fisher was the first to describe the classic triad of ophthalmoplegia, ataxia, and areflexia as being the hallmark pathology of the disorder (Fisher, 1956). NEUROPATHOLOGY/PATHOPHYSIOLOGY

All forms of GBS constitute acute inflammatory demyelinating polyneuropathies that are caused by an immune response to a foreign antigen that is mistargeted to nerve tissues. Gangliosides are the faulty targets of the immune system, which are composed of glycosphingolipids and are components of the cell plasma membrane that modulates cell signal transduction events. Gangliosides are present especially in the nodes of Ranvier of nerve tissue (Mori, et al., 2001). Specifically, the GQ1b ganglioside is the target in the MFS. Elevated antibodies to GQ1b are found in MFS and suggest an immune attack against GQ1b gangliosides that are concentrated in the paranodal regions of extraocular nerves (Willison, Veitch, Paterson, & Kennedy, 1993). GBS patients who present with ophthalmoplegia as a symptom also display elevated antibodies to GQ1b (Plomp, et al., 1999). The symptoms of generalized weakness in MFS may be due to motor nerve terminal blockade (Halstead, Humphreys, Goodfellow, Wagner, Smith, & Willison,

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2005). The autoimmune attack on the peripheral nerves causes inflammation of the myelin and nerve conduction block, which leads to the symptoms of muscle paralysis, sensory, and/or autonomic disturbances (Mori, et al., 2001). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

MFS typically presents with the classic triad of ataxia (gross lack of coordination of muscle movements), areflexia (complete loss of deep tendon reflexes), and ophthalmoplegia (paralysis of the extraocular muscles). The differentiation from GBS is that MFS symptoms present as a descending paralysis, proceeding in the reverse order of GBS. The acute onset of paralysis of the extraocular muscles is a cardinal feature of MFS. The degree of ataxia in patients tends to be more debilitating than the accompanying sensory loss and is primarily noted during gait and in the trunk, with lesser involvement of the limbs. MFS patient’s symptoms may also include ptosis, facial palsy, or bulbar palsy. Symptoms may include mild limb weakness, but motor strength is typically spared (Mori, et al., 2001). Anti-GQ1b antibodies are prominent in MFS, and dense concentrations of GQ1b ganglioside are found in the oculomotor, trochlear, and abducens nerves, which may explain the relationship between anti-GQ1b antibodies and ophthalmoplegia found in the disorder (Plomp, et al., 1999; Willison, et al., 1993). Patients may have reduced or absent sensory nerve action potentials and an absent tibial H reflex. Neuropsychological findings are dependent upon the severity and nature of the deficits found, but may include visual and motor disturbances. Recovery from MFS typically occurs within 1–3 months of the onset of the disorder, so clinical symptoms of the disorder are time limited (Mori, et al., 2001). DIAGNOSIS

The evaluation and diagnosis of MFS will typically include a thorough physical examination and medical history. The acute onset of the classic triad of ataxia (gross lack of coordination of muscle movements), areflexia (complete loss of deep tendon reflexes), and ophthalmoplegia (paralysis of the extraocular muscles) are typically the presenting symptoms of the disorder. The diagnosis typically also includes the development of descending muscle paralysis, absence of fever, and a likely inciting event. Patients may report problems with coordination, walking, standing, vision problems, tingling, numbness, dizziness, and/or nausea. A spinal tap is typically

performed in order to assess the cerebral spinal fluid for elevations in protein levels without an accompanying increase in cell count. Electromyography (EMG) and/or nerve conduction velocity (NCV) tests can also measure nerve conductivity to the muscles by inserting an electrode into the muscle that appears to be affected by the nerve damage. Electrodiagnostic testing is almost always used to diagnose conduction abnormalities and verify the symptoms of the disorder. Neuropsychological findings may include visual and motor disturbances. Unfortunately, due to the acute nature of the disorder, clinical findings may not become abnormal until after the onset symptoms or may be limited to 1–3 months due to recovery from the disorder (Mori, et al., 2001). TREATMENT

The treatment for MFS is intravenous immunoglobulin (IVIg) or plasmapheresis and supportive care, which is identical to the treatment for GBS (Hughes, Raphael, Swan, & van Doorn, 2006). The immediate concern in treatment is the potential for respiratory failure. Once the patient’s vital signs are stabilized and the diagnosis is confirmed, treatment should be initiated immediately because treatment is no longer effective after 2 weeks of the onset of symptoms. Both plasmapheresis and immunoglobulin have been shown to be equally effective and a combination of the two is not significantly better than either alone in treatment. Plasmapheresis, where blood plasma is removed and replaced with fluid, is a procedure in which antibodies are removed from the blood. IVIg is considered an immunomodulator and is beneficial in treating autoimmune disorders (Hughes, et al., 2006). Physical therapy and occupational therapy may be utilized depending on the nature of the patient’s deficits. Psychosocial interventions may also be utilized to help the patient overcome any psychological or social ramifications of the disorder. Eric Silk Charles Golden Fisher, M. (1956). An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). New England Journal of Medicine, 1956(255), 57-65. Guarino, M., Stracciari, A., Cirignotta, F., D’Alessandro, R., & Pazzaglia, P. (1995). Neoplastic meningitis presenting with ophthalmoplegia, ataxia, and areflexia (Miller Fisher syndrome). Archieves of Neurology, 52, 443-444. Halstead, S., Humphreys, P. D., Goodfellow, J. A., Wagner, E. R., Smith, R. A. G., & Willison, H. J. (2005).

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Complement inhibition abrogates nerve terminal injury in Miller Fisher syndrome. Annals of Neurology, 58, 203-210. Hughes, R. A., Raphael, J. C., Swan, A. V., & van Doorn, P. A. (2006). Intravenous immunoglobulin of Guillian-Barre syndrome. Cochrane Database of Systematic Reviews, 25(1). Mori, M., Kuwabara, S., Fukutake, T., Yuki, N., & Hattori, T. (2001). Clinical features and prognosis of Miller Fisher syndrome. Neurology, 56, 1104-1106. Plomp, J. J., Molenaar, P. C., O’Hanlon, G. M., Jacobs, B. C., Veitch, J., Daha, et al. (1999). Miller Fisher anti-GQ1b antibodies: Alpha-latrotoxin-like effects on motor end plates. Annals of Neurology, 45(6), 189-199. Roos, K. L. (2007). Viral infections. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., chap. 41). Philadelphia: Saunders Elsevier. Scelsa, S. N., & Herskovitz, S. (2000). Miller Fisher syndrome: Axonal, demyelinating or both? Electromyography and Clinical Neurophysiology, 40, 497-502. Sharar, E. (2006). Current therapeutic techniques in severe Guillain-Barre syndrome. Clinical Neuropharmacology, 29(1), 45–51. Willison, H. J., Veitch, J., Paterson, G., & Kennedy, P. G. E. (1993). Miller Fisher syndrome is associated with serum antibodies to GQlb ganglioside. Journal of Neurology, Neurosurgery, and Psychiatry, 56, 204-206.

MITOCHONDRIAL CARDIOMYOPATHY DESCRIPTION

Since discovery of the first pathogenic mutation of mitochondrial DNA (mtDNA) in 1988, more than 150 distinct mutations of mtDNA have been identified (Ruiz-Pesini et al., 2007). These mutations are associated with a number of different disorders, as nearly all tissues of the body rely upon mitochondrial oxidative phosphorylation for production of adenosine triphosphate. Many of these disorders affect the myocardium because this tissue relies heavily upon oxidative metabolism. mtDNA is a 16.5-kb circular molecule of doublestranded DNA. Cardiomyopathy is one such manifestation of mitochondrial cytopathies. It rarely constitutes the dominant feature, especially in adults, but case reports have demonstrated that this can be seen (Azevedo et al., 2010). However, epidemiological evidence suggests a relative occurrence in approximately 20% of cases of mitochondrial diseases (Darin et al., 2001). Cardiomyopathy, along with myopathy with encephalopathy, lactic acidosis and stroke-like episodes, chronic progressive external ophthalmoplegia

(PEO), deafness, pure myopathy, maternal inherited diabetes, and kidney disease, may all present as phenotypical by-products of these mitochondrial cytopathies inherited from the mother (Chinnery, Howell, Andrews, & Turnbunll, 1999; Donovan & Severin, 2006; Guillausseau et al., 2001; Vilarinho et al., 1999). The presentations manifest as weakness due to defects in energy metabolism and thus muscular weakness. With cardiomyopathy (i.e., weakness of the heart muscles), this can contribute to depleted oxidation and blood flow, most commonly diagnosed with echo Doppler and echocardiogram. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Mitochondrial cardiomyopathy may result from mutations in nuclear- or mitochondrial-encoded genes and this conveys the complexity of the potential inheritance patterns (e.g., maternal, autosomal recessive). mtDNA is transmitted vertically in a nonmendelian manner from the mother to both male and female progeny due to the fact that during formation of the zygote, the mtDNA is derived exclusively from the oocyte (Hirano, Davidson, & DiMauro, 2001). Thus, it is important to recognize this pattern of inheritance when determining whether a particular family may possess an mtDNA mutation. A problem arises, however, in that maternal relatives with a lower percentage of an mtDNA mutation may possess fewer symptoms (oligosymptomatic) or even be asymptomatic as compared with the proband. Thus, it is important for clinicians to inquire as to the presence of the more subtle symptoms or signs in maternally related members of the family when noting the history of the patient (Hirano et al., 2001). Polyplasmy is an important principle to consider with regard to mtDNA genetics (Fadic & Johns, 2000). Essentially, each mitochondrian contains several copies of mtDNA and each cell contains multiple mitochondria. As a result, there are potentially many thousands of copies of mtDNA in each cell and alteration of mtDNA may be present in some of the mtDNA molecules (heteroplasmy) or in all of them (homoplasmy). Clinical severity is dependent upon the proportion of mutant mtDNA (Hirano et al., 2001). Mitotic segregation may also influence the expression of mtDNA. As heteroplasmic cells divide, the proportion of mutant mtDNA allocated to daughter cells may shift and vary, altering the degree of heteroplasmy in subsequent generations of cells. This mitotic segregation may partially explain the different phenotypic expressions in patients with mtDNA mutations (Fadic & Johns, 2000; Hirano et al., 2001). Another factor that can influence clinical manifestations of mtDNA mutation

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is related to the tissue threshold effect, which refers to the balance between energy supply and the oxidative demands of various organs (Fadic & Johns, 2000). Organs and tissues that are metabolically active and more dependent on oxidative metabolism, such as the heart, will be more vulnerable and more frequently affected by mtDNA mutations (Fadic & Johns, 2000; Hirano et al., 2001). Thus, the critical threshold will vary in different tissues and organs (Hirano et al., 2001). A number of investigations have also examined structural brain changes associated with mitochondrial cardiomyopathy. Mitochondrial diseases may result in structural changes in deep gray matter structures and stroke-like lesions that do not necessarily conform to vascular territories (Saneto, Friedman, & Shaw, 2008). Several case reports have been published detailing MRI findings in patients with Kearns–Sayres syndrome (KSS). These studies have reported that KSS is associated with high-intensity foci (Kamata et al., 1998) and changes in deep gray matter nuclei, (Sacher, Fatterpekar, Edelstein, Sansaricq, & Naidich, 2005) as well as white matter hyperintensities (Hourani, Barada, Al-Kutoubi, & Hourani, 2006; Sacher et al., 2005). Wray, Provenzale, Johns, and Thulborn (1995) examined structural changes based on MRI in a group of patients with mitochondrial myopathy (three with KSS and five with chronic PEO). A variety of abnormal MRI findings were reported, including cerebral cortical and cerebellar atrophy, as well as hyperintensities in the cerebral and cerebellar white matter, basal ganglia, brainstem, and thalamus. It was also noted that the MRI findings did not always conform to specific neurological signs and symptoms.

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Three major clinical entities are associated with sporadic mtDNA deletions and duplications, including KSS, Pearson bone marrow/pancreas syndrome, and sporadic PEO with ragged red fibers (DiMauro et al., 2003). Of these three clinical disorders, cardiac involvement is most prominent in KSS, a multisystem disease defined by an onset before age 20, PEO, and pigmentary retinopathy, in addition to at least one of the following: cardiac conduction block, cerebellar syndrome, and CSF protein greater than 100 mg/dl (Gallastegui, Hariman, Handler, Lev, & Bharati, 1987; Rowland, Hays, DiMauro, DeVivo, & Behrens, 1983). Cardiac conduction abnormalities often appear years after the development of ptosis and ophthalmoplegia (Channer, Channer, Campbell, & Rees, 1988;

Charles, Holt, Kay, Epstein, & Rees, 1981; MarinGarcia, Goldenthal, Flores-Sarnat, & Sarnat, 2002; Roberts, Perloff, & Kark, 1979) and may include prolonged intraventricular conduction time, bundlebranch block, and atrioventricular block (Hirano et al., 2001). Many patients experience a third-degree atrioventricular block, which is a complete blockage of the electrical conduction from the atrium to the ventricle (Lee et al., 2001; Welzing et al., 2009) and placement of a pacemaker may be a lifesaver for these patients and patients with bifascicular block (Anan et al., 1995; Rheuban, Ayres, Sellers, & DiMarco, 1983). Cardiomyopathy seems to be a less frequent condition and appears much later in the course of illness (Hirano & DiMauro, 1996). Because cardiomyopathy can be fatal (Hubner, Gokel, Pongratz, Johannes, & Park, 1986) and cardioembolic strokes have been reported (Kosinski, Mull, Lethen, & Topper, 1995; Provenzale & VanLandingham, 1996), cardiac transplant may be warranted for some KSS patients (Hirano et al., 2001). Although primarily considered a disorder of cardiac functioning, recent research has demonstrated that mitochondrial cardiomyopathy can affect cerebral functioning. The cardiogenic embolisms that may arise from mitochondrial cardiomyopathy are thought to be a source of ischemic strokes in this patient population. Provenzale and VanLangingham (1996) reported the case of an individual with KSS who experienced a stroke in the territory of the left middle cerebral artery that was thought to arise from a cardiogenic embolism. Kosinski, Mull, Lethen, and Topper (1995) also reported the case of a patient with KSS who experienced sudden onset of left-sided hemiparesis and was found to have experienced a stroke in the right striatocapsular region. A recent review of the literature suggests that episodes of stroke are a dominant feature of some mitochondrial disorders, including KSS (Finsterer, 2009). Given the effect of mitochondrial cardiomyopathy on the brain, it is reasonable to conclude that this condition may affect memory and cognitive functioning. However, to date there have been very few studies reported that sought to examine the relationship between mitochondrial cardiomyopathy and neuropsychological functioning. Indeed, a review of the literature found only one such investigation. Bosbach, Kornblum, Schroder, and Wagner (2003) examined neuropsychological functioning in a group of patients with chronic PEO and KSS. They reported a range of neuropsychological deficits within the sample, including visuoconstructional abilities, attention, and cognitive flexibility. Certainly, more research needs to be

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conducted to further explore the types of neuropsychological deficits seen in patients with mitochondrial cardiomyopathy, including cognitive and memory functioning. Given that stroke is common in these patients and that this disease is associated with diabetes, the possibility also seems to exist that they are at increased risk for vascular dementia as these symptoms are risk factors. Future research will need to explore the validity of this proposition. DIAGNOSIS

Diagnosis is multifaceted. Given that cardiomyopathy often presents as a secondary manifestation, diagnosis of the broader presentation is also a common part of diagnostic workup. Diagnosis of cardiomyopathy commonly entails a combination of echo Doppler and echocardiogram investigations. The prior allows for evaluation of possible hypertrophic and obstructive properties. Maximal flow velocities permit determination of hypertensive properties and locality. Echocardiogram should be performed to evaluate for features of pericardial effusion, while also giving readings on heart rate as well as QTc and PR intervals (Davignon et al., 1979). Chest X-ray may also be employed. For consideration of underlying mitochondrial pathology, oximetric measurements and spectrophotometric enzyme analyses on mitochondria, and ultrastructural and enzyme histochemical analyses on muscle biopsies are commonly employed (Tiranti et al., 1999; Tulinius, Holme, Kristiansson, Larsson, & Oldfors, 1991). mtDNA investigation may be undertaken by way of Southern blotting with point mutation investigations (Manouvrier et al., 1995). TREATMENT

Treatment is symptom based. Some patients require oxygen to counteract deoxygenation. With hypertensive effects, medicinal intervention may be employed; however, this is only used on a case-by-case basis given the risk of cerebrovascular events. Heart transplantation has been employed in instances where patients are deemed viable candidates. Given cardiomyopathy may be seen in conjunction with other phenotypical manifestation such as diabetes and kidney failure, these entities often require medical intervention ranging from medicinal treatment to dialysis. Prognosis can be poor depending on the severity of the constellation of symptoms; interventions can take on a supportive mind-set. Genetic counseling may also be recommended for mothers. Paul S. Foster Valeria Drago

Anan, R., Nakagawa, M., Miyata, M., Higuchi, I., Nakao, S., Suehara, M., et al. (1995). Cardiac involvement in mitochondrial diseases: A study on 17 patients with documented mitochondrial DNA defects. Circulation, 91, 955–961. Azevedo, O., Vilarinho, L., Almeida, F., Ferreira, F., Guardado, J., Ferreira, M., et al. (2010). Cardiomyopathy and kidney disease in a patient with maternally inherited diabetes and deafness caused by the 3243A 1 G mutation of mitochondrial DNA. Cardiology, 115, 71–74. Bosbach, S., Kornblum, C., Schroder, R., & Wagner, M. (2003). Executive and visuospatial deficits in patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. Brain, 126, 1231–1240. Channer, K. S., Channer, J. L., Campbell, M. J., & Rees, J. R. (1988). Cardiomyopathy in the Kearns-Sayre syndrome. British Heart Journal, 59, 486–490. Charles, R., Holt, S., Kay, J. M., Epstein, E. J., & Rees, J. R. (1981). Myocardial ultrastructure and the development of atrioventricular block in Kearns-Sayre syndrome. Circulation, 63, 214–219. Chinnery, P. F., Howell, N., Andrews, R. M., & Turnbull, D. M. (1999). Clinical mitochondrial genetics. Journal of Medical Genetics, 36, 425–436. Darin, N., Oldfors, A., Moslemi, A. R., Holme, E., & Tulinius, M. (2001). The incidence of mitochondrial encephalomyopathies in childhood: Clinical features, morphological, biochemical, and DNA abnormalities. Annals of Neurology, 49, 377–383. Davignon, A., Rautaharju, P., Boisselle, E., Soumis, F., Megelas, M., & Choquette, A. (1979). Percentile charts: ECG standards for children. Pediatric Cardiology, 1, 133–152. DiMauro, S., Bonilla, E., Mancuso, M., Filosto, M., Sacconi, S., Salviati, L., et al. (2003). Mitochondrial myopathies. Basic and Applied Myology, 13, 145–155. DiMauro, S., & Hirano, M. (1998). Mitochondria and heart disease. Current Opinion in Cardiology, 13, 190– 197. Donovan, L. E., & Severin, N. E. (2006). Maternally inherited diabetes and deafness in a North American kindred: Tips for making the diagnosis and review of unique management issues. Journal of Clinical Endocrinology & Metabolism, 91, 4737–4742. Fadic, R., & Johns, D. R. (2000). Mitochondrial DNA and the genetics of mitochondrial disease. In S. M. Pulst (Ed.), Neurogenetics (pp. 293–315). New York: Oxford University Press. Finsterer, J. (2009). Management of mitochondrial strokelike-episodes. European Journal of Neurology, 16, 1178– 1184.

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Gallastegui, J., Hariman, R. J., Handler, B., Lev, M., & Bharati, S. (1987). Cardiac involvement in the Kearns-Sayre syndrome. American Journal of Cardiology, 60, 385–388. Guillausseau, P. J., Massin, P., Dubois-La-Forgue, D., Timsit, J., Virally, M., Gin, H., et al. (2001). Maternally inherited diabetes and deafness: A multicenter study. Annals of Internal Medicine, 134, 721–728. Hirano, M., Davidson, M., & DiMauro, S. (2001). Mitochondria and the heart. Current Opinion in Cardiology, 16, 201–210. Hirano, M., & DiMauro, S. (1996). Clinical features of mitochondrial myopathies and encephalomyopathies. In R. J. M. Lane (Ed.), Handbook of muscle disease (pp. 479–504). New York: Marcel Dekker. Hourani, R. G., Barada, W. M., Al-Kutoubi, A. M., & Hourani, M. H. (2006). Atypical MRI findings in KearnsSayre syndrome: T2 radial stripes. Neuropediatrics, 37, 110–113. Hubner, G., Gokel, J. M., Pongratz, D., Johannes, A., & Park, J. W. (1986). Fatal mitochondrial cardiomyopathy in Kearns-Sayre syndrome. Virchows Archiv: A, Pathological Anatomy and Histopathology, 408, 611–621. Kamata, Y., Mashima, Y., Yokoyama, M., Tanaka, K., Goto, Y., & Oguchi, Y. (1998). Patient with Kearns-Sayre syndrome exhibiting abnormal magnetic resonance image of the brain. Journal of Neuro-ophthalmology, 18, 284–288. Kosinski, C., Mull, M., Lethen, H., & Topper, R. (1995). Evidence for cardioembolic stroke in a case of KearnsSayre syndrome. Stroke, 26, 1950–1952. Lee, K. T., Lai, W. T., Lu, Y. H., Hwang, C. H., Yen, H. W., Voon, W. C., & Sheu, S. H. (2001). Atrioventricular block in Kearns-Sayre syndrome: A case report. Kaohsiung Journal of Medical Sciences, 17, 336–229. Manouvrier, S., Ro¨tig, A., Hannebique, G., Gheerbrandt, J. D., Royer-Legrain, G., Munnich, A., (1995). Point mutation of the mitochondrial tRNA (Leu) gene (A 3243 G) in maternally inherited hypertrophic cardiomyopathy, diabetes mellitus, renal failure, and sensorineural deafness. Journal of Medical Genetics, 32, 654–656. Marin-Garcia, J., Goldenthal, M. J., Flores-Sarnat, L., & Sarnat, H. B. (2002). Severe mitochondrial cytopathy with complete A-V block, PEO, and mtDNA deletions. Pediatric Neurology, 27, 213–216. Provenzale, J. M., & VanLandingham, K. (1996). Cerebral infarction associated with Kearns-Sayre syndromerelated cardiomyopathy. Neurology, 46, 826–828. Rheuban, K. S., Ayres, N. A., Sellers, T. D., & DiMarco, J. P. (1983). Near-fatal Kearns-Sayre syndrome: A case report and review of clinical manifestations. Clinical Pediatrics, 22, 822–825. Roberts, N. K., Perloff, J. K., & Kark, R. A. P. (1979). Cardiac conduction in the Kearns-Sayre syndrome (A neuromuscular disorder associated with progressive external

ophthalmoplegia and pigmentary retinopathy): Report of 2 cases and review of 17 published cases. American Journal of Cardiology, 44, 1396–1400. Rowland, L. P., Hays, A. P., DiMauro, S., DeVivo, D. C., & Behrens, M. (1983). Diverse clinical disorders associated with morphological abnormalities of mitochondria. In C. Cerri & G. Scarlato (Eds.), Mitochondrial pathology in muscle diseases (pp. 141–158). Padua: Piccin Medical Publishers. Ruiz-Pesini, E., Lott, M. T., Procaccio, V., Poole, J. C., Brandon, M. C., Mishmar, D., et al. (2007). An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Research, 235(database issue), D823–D828. Sacher, M., Fatterpekar, G. M., Edelstein, S., Sansaricq, C., & Naidich, T. P. (2005). MRI findings in an atypical case of Kearns-Sayre syndrome: A case report. Neuroradiology, 47, 241–244. Saneto, R. P., Friedman, S. D., & Shaw, D. W. (2008). Neuroimaging of mitochondrial disease. Mitochondrion, 8, 396–413. Tiranti, V., Jaksch, M., Hofmann, S., Galimberti, C., Hoertnagel, K., Lulli, L., et al. (1999). Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome C oxidase deficiency. Annals of Neurology, 46, 161–166. Tulinius, M. H., Holme, E., Kristiansson, B., Larsson, N. G., & Oldfors, A. (1991). Mitochondrial encephalomyopathies in childhood: I. Biochemical and morphological investigations. The Journal of Pediatrics, 119, 242–250. Vilarinho, L., Santorelli, F. M., Coelho, I., Rodrigues, L., Maia, M., Barata, I., et al. (1999). The mitochondrial DNA A3243G mutation in Portugal: Clinical and molecular studies in 5 families. Journal of the Neurological Sciences, 163, 168–174. Welzing, L., von Kleist-Retzow, J. C., Kribs, A., Eifinger, F., Huenseler, C., & Sreeram, N. (2009). Rapid development of life-threatening complete atrioventricular block in Kearns-Sayre syndrome. European Journal of Pediatrics, 168, 757–759. Wray, S. H., Provenzale, J. M., Johns, D. R., & Thulborn, K. R. (1995). MR of the brain in mitochondrial myopathy. American Journal of Neuroradiology, 16, 1167–1173.

MITOCHONDRIAL MYOPATHIES DESCRIPTION

Mitochondrial myopathies and mitochondrial encephalomyopathies (collectively, MMPs) are a heterogenous group of disorders characterized by muscle weakness,

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often presenting as progressive external ophthalmoplegia (PEO) (Fitzsimons, 1981), and neurological symptoms due to inefficient mitochondria. Mitochondria are responsible for metabolizing nutrients, such as fat, protein, and sugar, into energy for use by the cell. Inefficient mitochondria cannot convert these nutrients, which may result in a lack of energy for cellular processes and an accumulation of nutrient molecules that are toxic to the cell and its organelles. Cells with high energy demands, such as neurons and muscle cells, are most strongly affected by MMP. Over 40 types of mitochondrial diseases have been identified (Neargarder, Murtagh, Wong, & Hill, 2007), each with its own unique cluster of symptoms, ranging in severity from mild to life threatening. Neurological symptoms may include seizures, strokelike episodes, migraines, ataxia, and deafness (Finsterer, 2006; Kelly, 2008). NEUROPATHOLOGY/PATHOPHYSIOLOGY

MMP is typically a matrilineal hereditary disease; however, some adult-onset cases may be the result of a point mutation or deletion within the mitochondrial DNA (Taivassalo, Fu, et al., 1999; Wallace, Lott, Shoffner, & Ballinger, 1994). The severity of the symptoms’ expression depends largely upon the percentage of mutant mitochondria inherited from the mother (Kelly, 2008; Wallace et al., 1994). In general, mitochondrial abnormalities occur in skeletal muscle fibers in aged humans. These deficits occur secondary to defects in the respiratory chain enzymes and abnormalities of preoxidation associated with mitochondrial DNA deletions (Hruszkewcyz, 1992; Weller, Cumming, & Mahon, 1997). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Ataxia and muscle weakness, two of the most common symptoms in MMPs (Kelly, 2008), may present in any muscle tissue — skeletal, cardiac, or smooth — depending upon the specific syndrome. PEO (progressive paralysis of the external ocular muscles) and ptosis (drooping of the eyelid) may cause vision problems that are especially serious in children, due to children’s sensitivity to sensory input during certain critical periods. Weakness of the head, neck, mouth, or throat may cause postural difficulties, articulation problems, or difficulty in eating and swallowing. Focal limb paralysis and flaccid paralysis may inhibit an individual’s ability to perform daily living tasks and may impair or slow the fine motor control required for many academic tasks, such as writing and

typing. Young children with MMP may have delays in achieving developmental motor milestones such as sitting up, crawling, standing, and walking without support (Kelly, 2008). Conduction block, an abnormality in the heart’s ability to maintain a steady pulse, is the result of mitochondrial dysfunction and muscle weakness at the heart’s nodes (Kelly, 2008). This may present as either tachycardia (Kitagawa, Odachi, Taniguchi, & Kuzuhara, 2000) or bradycardia (Finsterer, Sto¨llberger, Steger, & Cozzarini, 2007) and can result in sudden death. Gastrointestinal problems are also common, resulting from dysfunction of the smooth muscle tissue in the digestive tract. Painful gastrointestinal cramping, feelings of fullness, diarrhea, and vomiting are common symptoms (Kelly, 2008) that may affect a patient’s vigor and involvement in daily living, social, or academic activities. Seizures, stroke-like symptoms, and cognitive delays may result from insufficient ATP to fuel neuronal processes. Impairment of executive function, attention, language, memory, and visuospatial functioning has been demonstrated (Neargarder et al., 2007). The stroke-like events commonly seen in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) increase neuronal excitability, creating greater energy demands, and initiate cascades of seizures. If left unchecked, these seizures can create additional stroke-like lesions, beginning the cycle again (Iizuka, 2008). This cycle may lead to permanent, global neural deterioration and dementia. Diabetes is another common symptom of MMPs that impairs blood flow and significantly increases the patient’s risk of developing peripheral neuropathy (Fitzsimons, 1981; Kelly, 2008). Peripheral neuropathy impairs the individual’s sensorimotor ability, creating difficulties with coordination and pain perception in distal limb areas. Thus, mild injuries may be common and may become severe infections due to poor circulation and lack of awareness of the presence of the injuries. DIAGNOSIS

Patients who present with PEO, ptosis (drooping eyelid), progressive muscle weakness, exercise intolerance (unusually intense feelings of exhaustion following physical exertion), stroke-like episodes, epilepsy, diabetes mellitus, ataxia, wasting of the neck and shoulder muscles, difficulty swallowing, or a combination of these symptoms affecting multiple organ systems should be screened for the presence of MMP (Kelly, 2008). A thorough family history that reveals matrilineal soft signs, such as deafness, short stature, migraine headaches, and PEO, may indicate the presence of MMP. If MMP is present, lactate

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acid stress test (LST) and muscle biopsy should reveal the presence of ragged red fibers, abnormal proliferation of mitochondria, and cytochrome c oxidase (COX) deficiencies (Finsterer & Milvay, 2004; Matsuoka, Goto, Yoneda, & Nonaka, 1991; Melone et al., 2004), while blood enzyme tests should show elevated lactate and pyruvate levels. Elevated levels of serum creatine kinase may indicate mitochondrial DNA depletion syndrome, a specific MMP (Kelly, 2008). Genetic tests of mitochondria from blood or muscle samples will indicate the particular nature of the mitochondrial mutation, and pinpoint the specific syndrome. A simple yet effective screening method for MMP is the lactate stress test (LST). In this test, patients perform an aerobic exercise under a continuous, unadjusted, low workload. Serum levels of lactic acid, a by-product of anaerobic metabolism, are measured before, during, and after exercise. Patients with MMP show abnormally high levels of lactic acid following exercise compared with their resting state or non-MMP controls. Thus, LST is an effective, inexpensive diagnostic method for identifying the impaired oxidative process in patients with MMP (Finsterer & Milvay, 2004). Furthermore, comparing the ratio of lactate versus pyruvate may help indicate which part of the electron transport chain is blocked (Kelly, 2008). Patients with stroke-like symptoms should be examined using both conventional MRI and diffusionweighted MRI (dwMRI) to determine whether the lesion is related to an ischemic event or MMP. Patients with MELAS, a specific MMP syndrome, often present with stroke-like symptoms. Conventional MRI may reveal infarct-like lesions, which should be further examined with dwMRI. Normal or increased apparent diffusion coefficient values indicate the probable presence of MELAS (Kolb et al., 2003; Oppenheim et al., 2000). In addition, dynamic computerized tomography, serial cerebral angiography, and xenon-enhanced computed tomography for some patients has revealed vasodilation and normal blood flow within the affected regions, precluding the probability of ischemic stroke (Ooiwa et al., 1993). Modified Gomori trichrome staining sometimes reveals clusters of diseased mitochondria accumulated in the subsarcolemmal region of the muscle fiber, making the fiber appear ragged red. Ragged red fibers are a hallmark of myoclonic epilepsy and ragged red fiber disease (MERRF, myoclonic epilepsy with ragged red fibers). In addition, histocytological studies have revealed that the mitochondria in ragged red fibers is frequently COX deficient, often lacking the COX-I, COX-II, or COX-IV complexes (Matsuoka et al., 1991; Melone et al., 2004; Rifai, Welle, Kamp, & Thornton, 2005; Shoffner et al., 1990).

Differential diagnosis of patients presenting with PEO or ptosis should rule out myasthenia gravis, ocular myositis, oculopharyngeal muscular dystrophy, thyroid associated orbitopathy, and congenital fibrosis of the extraocular muscles. Serum creatine kinase and lactate levels should be investigated, while electromyography, nerve conduction studies, and MRI of the orbits should be performed. The presence of multiple-organ symptoms in conjunction with the imaging and conduction studies supports the diagnosis of MMP (Schoser & Pongratz, 2006). When patients’ muscle weakness presents in the neck and shoulder region, polymyositis and amyotrophic lateral sclerosis (ALS) should be considered the differential diagnoses (Rahim, Gupta, Bertorini, & Ledoux, 2003). The early stages of MMP closely mimic the clinical and electrophysiological symptoms of ALS. LST and muscle biopsy should indicate the presence of mitochondrial proliferation, if MMP is present (Finsterer, 2002).

TREATMENT

Treatment of MMP is symptom oriented. Patients with motor deficits or dystonia may require the support of a wheelchair or a walker for locomotion. If the diaphragm is affected by muscle weakness, a respirator will facilitate breathing. If neck or throat weakness creates significant impairment in swallowing, a feeding tube may be necessary, and individuals with heart block may benefit from the use of a pacemaker (Finsterer, 2006; Finsterer et al., 2007; Kelly, 2008). Diabetic symptoms can be managed with insulin and diet monitoring, and seizures can be controlled with medication (Kelly, 2008). Hearing and vision impairments can be corrected or partially corrected with hearing aids and glasses (Kelly, 2008; Zwirner & Wilichowski, 2001). For patients with ptosis there are specially modified glasses with ‘‘ptosis props,’’ small bars that help support the upper eyelids. Physical therapy may improve the overall strength, motility, and endurance of individuals with MMP (Kelly, 2008). Research indicates improvements in both human (Taivassalo, DeStefano et al., 1999; Taivassalo, Fu et al. 1999) and animal (Wenz, Diaz, Hernandez, & Moraes, 2009) models. It appears that resistance exercise and short-term endurance exercise at low intensities can delay MMP onset, induce antioxidant enzymes, increase the ratio of wild-type to mutant mitochondria, and prolong the life span of affected individuals. Amanda Ballenger Raymond S. Dean

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Finsterer, J. (2002). Mitochondriopathy as a differential diagnosis of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders, 3, 4, 219–224. Finsterer, J. (2006). Central nervous system manifestations of mitochondrial disorders. Acta Neurologica Scandinavica, 114, 4, 217–238. Finsterer, J., & Milvay, E. (2004). Stress lactate in mitochondrial myopathy under constant, unadjusted workload. European Journal of Neurology, 11, 12, 811–816. Finsterer, J., Sto¨llberger, C., Steger, C., & Cozzarini, W. (2007). Complete heart block associated with noncompaction, nail-patella syndrome, and mitochondrial myopathy. Journal of Electrocardiology, 40, 4, 352–354. Fitzsimons, R. B. (1981). The mitochondrial myopathies: 9 case reports and a literature review. Clinical and Experimental Neurology, 17, 185–210. Hruszkewcyz, A. M. (1992). Lipid preoxidation and mtDNA degeneration. A hypothesis. Mutational Research, 275, 243–248. Iizuka, T. (2008). Pathogenesis and treatment of stroke-like episodes in MELAS. Rinsho Shinkeigaku, 48, 11, 1006– 1009. Kelly, R. (2008). Facts about mitochondrial myopathies. MDA Publications. Retrieved April 29, 2009, from http:// mda.org/Publications/mitochondrial_myopathies.html Kitagawa, T., Odachi, K., Taniguchi, A., & Kuzuhara, S. (2000). Sudden death due to ventricular tachycardia in a case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Neurological Medicine, 53, 1, 45–50. Kolb, S. J., Costello, F., Lee, A. G., White, M., Wong, S., Schwartz, E. D., et al. (2003). Distinguishing ischemic stroke from the stroke-like lesions of MELAS using apparent diffusion coefficient mapping. Journal of Neurological Science, 216, 1, 11–15. Matsuoka, T., Goto, Y., Yoneda, M., & Nonaka, I. (1991). Muscle histopathology in myoclonus epilepsy with ragged-red fibers (MERRF). Journal of Neurological Science, 106, 2, 193–198. Melone, M. A., Tessa, A., Petrini, S., Lus, G., Sampaolo, S., di Fede, G., et al. (2004). Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERRF phenotype. Archives of Neurology, 61, 2, 269–272. Neargarder, S. A, Murtagh, M. P., Wong, B., & Hill, E. K. (2007). The neuropsychologic deficits of MELAS: Evidence of global impairment. Cognitive and Behavioral Neurology, 20, 2, 83–92. Ooiwa, Y., Uematsu, Y., Terada, T., Nakai, K., Itakura, T., Komai, N., et al. (1993). Cerebral blood flow in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Stroke, 24, 2, 304–309. Oppenheim, C., Galanaud, D., Samson, Y., Sahel, M., Dormont, D., Wechsler, B., et al. (2000). Can diffusion-

weighted magnetic resonance imaging help differentiate stroke from stroke-like events in MELAS? Journal of Neurology, Neurosurgery, and Psychiatry, 69, 2, 248–250. Rahim, F., Gupta, D., Bertorini, T. E., & Ledoux, M. S. (2003). Dropped head presentation of mitochondrial myopathy. Journal of Clinical Neuromuscular Disorders, 5, 2, 108–114. Rifai, Z., Welle, S., Kamp, C., & Thornton, C. A. (2005). Ragged red fibers in normal aging and inflammatory myopathy. Annals of Neurology, 37, 1, 24–29. Schoser, B. G., & Pongratz, D. (2006). Extraocular mitochondrial myopathies and their differential diagnoses. Strabismus, 14, 2, 107–113. Shoffner, J. M., Lott, M. T., Lezza, A. M., Seibel, P., Ballinger, S. W., & Wallace, D. C. (1990). Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell, 61, 6, 931–937. Taivassalo, T., DeStefano, N., Chen, J., Karpati, G., Arnold, D. L., & Argov, Z. (1999). Short-term aerobic training response in chronic myopathies. Muscle and Nerves, 22, 9, 1239–1243. Taivassalo, T., Fu, K., Johns, T., Arnold, D., Karpati, G., & Shoubridge, E. A. (1999). Gene shifting: A novel therapy for mitochondrial myopathy. Human Molecular Genetics, 8, 6, 1047–1052. Wallace, D. C., Lott, M. T., Shoffner, J. M., & Ballinger, S. (1994). Mitochondrial DNA mutations in epilepsy and neurological disease. Epilepsia, 35, Suppl. 1, 43–50. Weller, R. O., Cumming, W. J. K., & Mahon, M. (1997). Diseases of muscle. In D. I. Graham & P. L. Lantos (Eds.), Greenfield’s neuropathology (6th ed.). New York: Oxford University Press. Wenz, T., Diaz, F., Hernandez, D., & Moraes, C. T. (2009). Endurance exercise is protective for mice with mitochondrial myopathy. Journal of Applied Physiology, 106, 5, 1712–1719. Zwirner, P., & Wilichowski, E. (2001). Progressive sensorineural hearing loss in children with mitochondrial encephalomyopathies. Laryngoscope, 111, 3, 515–521.

MOEBIUS SYNDROME DESCRIPTION

Moebius syndrome is a rare congenital disorder characterized by congenital facial diplegia with convergent strabismus due to absence or underdevelopment of the 6th and 7th cranial nerves. In some instances, the facial paralysis is complete with individuals not being able to even close their eyes.

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Furthermore, though structural degradation of the 6th and 7th cranial nerves define Moebius syndrome, the 3rd, 5th, 8th, 9th, 11th, and/or 12th cranial nerves may also be affected. Facial weakness is often noted soon after birth due to infants exhibiting an inability to suck in combination with an inability to move their eyes back and forth. Additional symptoms may also be seen and are discussed below. To date the pathophysiological basis of Moebius syndrome remains unclear. Both ischemic and hypoxic theories remain the most prevalent. Furthermore, though there is no cure for Moebius syndrome, symptom-based treatment and support can promote a normal life. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Absence or underdevelopment of the 6th and 7th cranial nerves produces a mask-like expressionless face in neonates characterized by internal strabismus, facial diplegia, and bilateral abducens palsies (Mobius, 1888). The cause of these cranial nerve anomalies is unknown. Some have suggested a vascular etiology for the structural decay, either by way of intrauterine hypoxic or ischemic trauma (Briegel, 2006). However, teratogenic exposure has also been suggested. For example, cocaine usage by the mother has been associated with increased risks of Moebius syndrome (Puvabanditsin, Garrow, Augustin, Titapiwatanakul, & Kuniyoshi, 2005). The morphological anomalies noted on the 6th and 7th cranial nerves in combination with other pathological features have been utilized to suggest multiple classifications, some supporting a vascularor trauma-based etiology and others not (Towfight, Marks, Palmer, & Vannucci, 1979). In some instances, there is a relative lack of necrosis or degenerative change. In combination with brainstem anomalies such as olivary dysplasia, this would suggest against an acquired defect pointing more toward a primary malformation (Richter, 1960). Still, focal necrosis and calcification in brainstem nuclei supporting an infectious or hypoxic basis has also been noted as has aplasia and/or hypoplasia of cranial nerve nuclei (Sudarshan & Goldie, 1985). Beyond the 6th and 7th cranial nerves, other oculomotor and lower cranial nerves including the 3rd, 5th, 8th, 9th, 11th, and 12th cranial nerves may also be involved. Cerebellar hypoplasia has also been noted in isolated incidence presumed to be also explained by ischemia occurring between 5th and 6th weeks of gestation (Harbord, Finn, Hall-Craggs, Brett, & Baraitser, 1989). Children with Moebius syndrome are at higher risk for mental retardation and autism

suggesting the potential for involvement of the cerebral cortex in addition to brainstem regions. Peripherally, musculoskeletal abnormalities may present.

M NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The hallmark feature of Moebius syndrome is congenital facial diplegia with convergent strabismus. At birth, infants are often unable to suck and may also have difficulties swallowing, which together or even singularly impede their ability to feed. Simultaneously, infants are often unable to close their eyes completely. Facial diplegia may present as mask-like expressions. Difficulties in smiling are common. In addition, speech may be disturbed secondary to motoric limitations. Furthermore, it can be complicated by congenital deafness of a neurosensory origin (Golden & Bonnemann, 2007). Abducens palsy, complete external ophthalmoplegia, lingual palsy, clubfeet, brachial disorder, and/or an absent pectoral muscle may all be seen as they have been noted in higher rates in children with Moebius syndrome (Henderson, 1939). Neurocognitive deficits are varied with no unitary profile emerging. Mild mental retardation is seen in approximately 10% to 15% of cases (Golden & Bonnemann, 2007). DIAGNOSIS

Diagnosis is commonly symptom based. Given it is observed soon after birth, the most common differential is from the facial palsy associated with forceps or other birth injury. Oftentimes this differential is easy as Moebius syndrome presents bilaterally and often has other associated weaknesses. Centronuclear myopathy, mitochondrial myopathies, myasthenic syndromes, myotonic dystrophy, facioscapulohumeral dystrophy, structural congenital myopathies, inflammation, infection, and neoplasms must all be considered as well. Aside from clinical evaluation of the functional impairments, diagnostic workup includes MRI and skeletal X-ray to evaluate for the various aforementioned presentations that must be ruled out. TREATMENT

There is no cure for Moebius syndrome; rather, treatment is symptom based. Because affected infants commonly have difficulties sucking and swallowing, feeding tubes may be required. Speech therapy is commonly required to improve oral-motor functioning to improve pronunciation capabilities while also seeking

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to improve potential eating and/or swallowing difficulties. Surgical intervention may be attempted in some instances to offer some increased movement of facial muscles. Chad A. Noggle Amy R. Steiner Briegel, W. (2006). Neuropsychiatric findings of Mo¨bius sequence: a review. Clinical Genetics, 70, 91–97. Golden, J., & Bonnemann, C. (2007). Developmental structures disorders. In C. Goetz (Ed.), Textbook of clinical neurology (pp. 561–591). Philadelphia, PA: Saunders Elsevier. Harbord, M. G., Finn, J. P., Hall-Craggs, M. A., Brett, E. M., & Baraitser, M. (1989). Moebius’ syndrome with unilateral cerebellar hypoplasia. Journal of Medical Genetics, 26, 579–582. Henderson, J. L. (1939). The congenital facial diplegia syndrome: Clinical features, pathology and etiology. Brain, 62, 381. Heubner, O. (1900). Ueber angeborene Kernmangel (infantiler Kernschwund, Moebius). Charite-annalen, 25, 211–243. Mobius, P. J. (1888). Ueber angeborene doppelseitige Abducens-Facialis-Lahmung. Munchner Med Wochenschr, 35, 108–111. Puvabanditsin, S., Garrow, E., Augustin, G., Titapiwatanakul, R., & Kuniyoshi, K. M. (2005). Poland-Mobius syndrome and cocaine abuse: A relook at vascular etiology. Pediatric Neurology, 32(4), 285–287. Richter, R. B. (1960). Unilateral congenital hypoplasia of the facial nucleus. Journal of Neuropathology & Experimental Neurology, 19, 33–41. Ropper, A. H., & Brown, R. H. (2005). Adams and Victor’s principles of neurology (8th ed.). New York: McGrawHill. Sudarshan, A., & Goldie, W. D. (1985). The spectrum of congenital facial diplegia (Moebius syndrome). Pediatric Neurology, 1, 180–184. Towfight, J., Marks, K., Palmer, E., & Vannucci, R. (1979). Moebius syndrome. Neuropathological observations. Acta Neuropathologica (Berlin), 48, 11–17.

MONOMELIC AMYOTROPHY DESCRIPTION

Monomelic amyotrophy (MMA), also known as Hirayama’s disease, is a disease characterized by progressive loss of lower motor neurons, leading to

muscular atrophy in a single limb (usually an arm). It was first described by Hirayama in 1959. Regionally based, MMA has primarily been reported in Asian countries, including Japan, India, and Korea among others. It is extremely rare in the Western hemisphere (de Visser, de Visser, & Verbeeten, 1988; Serratrice, Pellissier, & Pouget, 1987). The presentation often first arises in the late teens and early 20s in males. As lower motor neurons deteriorate, muscular wasting takes place in the affected limb. The progression is insidious, spanning 2–5 years after which time the degeneration ceases. To date, the underlying cause remains unknown and no cure or treatment has proven very effective. Although muscular wasting, and consequently strength and coordination of voluntary movement, in the affected limb is a hallmark of the presentation, pain or sensory loss often do not occur. Although the upper extremities are most commonly affected, it can present in the lower extremities. When an upper limb is involved, it is referred to as brachial MMA (BMMA) or classic Hirayama’s disease (Hirayama, Toyukura, & Tsubaki, 1959), whereas, in the rare instance where a lower limb is affected, it is termed crural MMA (Gourie-Devi & Nalini, 2003). O’Sullivan–McLeod syndrome is a variant of MMA. In this presentation, progression is particularly slow and results in wasting of only the hand and forearm as opposed to the whole arm. NEUROPATHOLOGY/PATHOPHYSIOLOGY

The pathological basis of MMA remains unknown. Viral infections (Kao, Liu, Wang, & Chern, 1993; Kao, Wu, & Chern, 1993), vascular insufficiency of the spinal cord (Hirayama et al., 1987), heavy physical activity (Gourie-Devi, Gururaj, Vasisth, & Subbakrishna, 1993) and focal cord atrophy as a result of stretching of the cord during flexion of the neck (Gourie-Devi, Rao, & Suresh, 1992; Metcalf, Wood, & Bertorini, 1987; Mukai, Matsuo, Muto, Takahashi, & Sobue, 1987), and microcirculatory disturbances in the territory of the anterior spinal artery territory (Hirayama, 1991; Sethi et al., 2006) have all been suggested as potential bases, though none can explain the geographical predominance in Asia (Gourie-Devi, 2007). From a neuropathological standpoint, the presentation is characterized by segmental anterior horn cell involvement causing wasting and weakness of predominantly one upper or lower limb, without evidence of sensory dysfunction (Hirayama et al., 1959). Forward displacement of the lower dural sac and flattening of the lower cervical spinal cord during flexion movements are common and related to

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transient cord compression (Fu et al., 2007; Hirayama & Tokumaru, 2000). This flattening presents more prominently on the side of the affected limb. Over time, the cervical spin may demonstrate relative atrophy and increased signal intensity (Pradhan & Gupta, 1997). MRI showing signal void in posterior epidural space pulsating synchronously with cardiac beat suggesting passive dilatation of the epidural venous plexus has been reported (Pal et al., 2008).

neuron disease. Measurement of central motor conduction time may also be a useful tool to determine the prevalence of subclinical involvement of motor pathways (Pal et al., 2008). MRI and CT of the entire CNS should be employed to rule out more expansive presentations. Neuropsychological testing often does not aid in diagnosis as MMA does not involve the cortex. TREATMENT

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The prototypical feature of MMA is an atrophied limb, usually an upper extremity, although involvement of lower extremities has been noted. Reduced strength, coordination, and absence of stretch reflexes are noted in the affected limb. However, hyporeflexia may also be present in other limbs, suggesting a more diffuse pathology (Pal et al., 2008). Coldness of hands, hyperhidrosis, and aggravation of motor symptoms on exposure to cold and abnormalities of sympathetic skin response are also sometimes noted (GourieDevi & Nalini, 2001). The presentation is marked purely by lower motor neuron features, whereas upper motor neuron signs are not seen in conjunction with the presentation (Gourie-Devi & Nalini, 2003). Furthermore, MMA presents without involvement of cranial nerves, pyramidal tracts, sensory, cerebellar, or extrapyramidal systems and cortical functions (Gourie-Devi & Nalini, 2003). Neurocognitive deficits are not associated with the presentation as the cortex is spared. DIAGNOSIS

Diagnosis is based on clinical presentation and taking of a thorough history. Particularly, the focal wasting of a limb in conjunction with those features previously described, as well as the absence of those features not associated with the presentation (e.g., upper motor neuron signs). Beyond description and assessment of the clinical features, diagnosis is often aided by MRI and EMG. Hirayama and colleagues (Hirayama & Tokumaru, 2000) demonstrated cinematographic MRI patterns involving signal void in the posterior epidural space with synchrony with cardiac pulse. This was related to passive dilatation of the epidural venous plexus. EMG can be used to demonstrate denervation in the affected limb. MRI as well as CT can also be useful in demonstrating muscular atrophy. Sequential clinical assessment is essential to ensure that more expansive clinical features do not emerge suggesting another motor

There is no cure or standard treatment for MMA. As previously noted, an insidious progression of muscular wasting takes place over the course of 2–5 years, reaching a plateau where further deterioration is not seen. Although interventions may be offered during this progression, particularly after the wasting stabilizes, muscle strengthening exercises and training in hand coordination through physical therapy/occupational therapy is most useful. Michelle R. Pagoria Chad A. Noggle de Visser, M., de Visser, B. W. O., & Verbeeten, B. (1988). Electromyographic and computed tomographic findings in five patients with monomelic spinal muscular atrophy. European Neurology, 28, 135–138. Fu, Y., Fan, D. S., Zhang, J., Pei, X. L., Han, H. B., & Kang, D. X. (2007). Clinical features and dynamics of cervical magnetic resonance imaging in Hirayama disease. Beijing Da Xue Xue Bao, 39, 189–192. Gourie-Devi, M. (2007). Monomelic amyotrophy of upper or lower limbs. In A. A. Eisen, P. J. Shaw (Eds.), Handbook of clinical neurology (pp. 207–227). Amsterdam, Netherlands: Elsevier, BV. Gourie-Devi, M., Gururaj, G., Vasisth, S., & Subbakrishna, D. K. (1993). Risk factors in monomelic amyotrophy — a case control study. NIMHANS Journal, 11, 79–87. Gourie-Devi, M., & Nalini A. (2001). Sympathetic skin response in monomelic amyotrophy. Acta Neurologica Scandinavica, 104, 162–166. Gourie-Devi, M., & Nalini, A. (2003). Long-term follow-up of 44 patients with brachial monomelic amyotrophy. Acta Neurologica Scandinavica, 107, 215–220. Gourie-Devi, M., Rao, C. J., & Suresh, T. G. (1992). Computed tomographic myelography in monomelic amyotrophy. Journal of Tropical and Geographical Neurology, 2, 32–37. Hirayama, K. (1991). Non-progressive juvenile spinal muscular atrophy of the distal upper limb (Hirayama disease). In J. M. de Jong (Ed.), Diseases of the motor system (pp. 107–120). Amsterdam, Netherlands: Elsevier Science Publishers BV.

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Hirayama, K., & Tokumaru, Y. (2000). Cervical dural sac and spinal cord in juvenile muscular atrophy of distal upper extremity. Neurology, 54, 1922–1926. Hirayama, K., Tomonaga, M., Kitano, K., Yamada, T., Kojima, S., & Arai, K. (1987). Focal cervical poliopathy causing juvenile muscular atrophy of distal upper extremity: A pathological study. Journal of Neurology, Neurosurgery, & Psychiatry, 50, 285–290. Hirayama, K., Toyukura, Y., & Tsubaki, T. (1959). Juvenile muscular atrophy of unilateral upper extremity: A new clinical entity. Psychiatry Neurology Japan, 61, 2190–2197. Kao, K. P., Liu, W. T., Wang, S. J., & Chern, C. M. (1993). Lack of serum neutralizing antibody against poliovirus in patients with juvenile distal spinal muscular atrophy of upper extremities. Brain & Development, 15, 219–221. Kao, K. P., Wu, Z. A., & Chern, C. M. (1993). Juvenile lower cervical spinal muscular atrophy in Taiwan: Report of 27 Chinese cases. Neuroepidemiology, 12, 331–335. Metcalf, J. C., Wood, J. B., & Bertorini, T. E. (1987). Benign focal amyotrophy: Metrizamide CT evidence of cord atrophy. Case report. Muscle Nerve, 10, 338–345. Mukai, E., Matsuo, T., Muto, T., Takahashi, A., & Sobue, I. (1987). Magnetic resonance imaging of juvenile–type distal and segmental muscular atrophy of upper extremities. Clinical Neurology (Japan), 27, 99–107. Pal, P. K., Atchayaram, N., Goel, G., Geulah, E. (2008). Central motor conduction in brachial monomelic amyotrophy. Neurology India, 56(4), 438–443. Pradhan, S., & Gupta, R. K. (1997). Magnetic resonance imaging in juvenile asymmetric segmental spinal muscular atrophy. Journal of the Neurological Sciences, 146, 133–138. Serratrice, G., Pellissier, J. P., & Pouget, J. (1987). Etude nosologique de 25 cas d’amyotrophie monomelique chronique. Revue Neurologique (Paris), 143, 201–210. Sethi, P. K., Khandelwal, D., Thukral, R., Torgovnick, J. (2006). Neuroimage: Monomelic amyotrophy. European Neurology, 56(4), 261

MOYAMOYA’S DISEASE DESCRIPTION

Moyamoya’s disease (MD) is a rare cerebrovascular disease of unknown etiology; it was given this name because moyamoya, a Japanese word that means ‘‘puff of smoke,’’ accurately describes the characteristic feature of the vascular network that is

seen on cerebral angiograms in the diagnosis of the disease (Suzuki & Takaku, 1969). The highest prevalence rates are found in Asia, with an 8:1 male-tofemale ratio. Age of onset tends to be around age 5 or in the 40s (Wakai et al., 1997). Although no specific infectious pathogens have been identified, infection of the head and neck has been implicated (Yamada et al., 1997). An inherited polygenic or autosomal dominant role with low penetrance has also been suggested (Mineharu et al., 2008). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Progressive occlusion of the internal carotid arteries, along with its main branches in the circle of Willis, leads to the formation of a fine vascular network (moyamoya vessels) that functions as collateral pathways for blood supply (Fukui, 1997). Childhood onset typically leads to transient ischemic attacks (TIA) or cerebral infarction, while adult patients are more likely to develop intracranial bleeding in addition to TIA and cerebral infarction (Fukui et al., 2000). Familial occurrences account for about 15% of cases (Yamauchi, Houkin, Tada, & Abe, 1997) and are characterized by a higher female to male ratio, younger age of onset, and earlier presentation of symptoms (Nanba et al., 2006). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Preoperative IQ is strongly correlated with patient’s age and cerebral blood flow, with older patients displaying significantly lower IQ (Ishii, Takeuchi, Ibayashi, & Tanaka, 1984). Performance IQ increased the most postoperatively. Neuropsychological findings, based on small samples, include decreases in IQ and motor functions over the course of 15 years (Kurokawa et al., 1985), and widespread neurocognitive and motor impairment preoperatively, with improvements noted at 1 and 3 years postoperatively (Bowen, Marks, & Steinberg, 1998). Matsushima, Aoyagi, Nariai, Takada, and Hirakawa (1997) found 80% of patients’ IQ scores remained in the average range at 9.5 years postsurgical intervention. MDrelated cerebrovascular accidents tend to result in deficits characteristic of the site of the cerebrovascular accident (CVA) (Jefferson, Glosser, Detre, Sinson, & Liebeskind, 2006). DIAGNOSIS

Cerebral angiography is considered the gold standard of diagnosis (Kuroda & Houkin, 2008). Diagnostic

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criteria include: (1) stenosis or occlusion of the terminal portions of the internal carotid arteries and proximal portions of the anterior and/or middle cerebral arteries; (2) abnormal vascular networks in the arterial phase in the vicinity of arterial occlusion; and (3) bilateral involvement (Fukui et al., 2000). Unilateral involvement is termed a ‘‘probable case,’’ which tends to progress to bilateral involvement in children but not in adults (Fukui et al., 2000). Six stages of angiographic changes have been described (Kuroda & Houkin, 2008; Suzuki & Kodama, 1983): (1) narrowing of the carotid fork; (2) initiation of basal moyamoya; (3) intensification of moyamoya along with defects of the middle and anterior cerebral arteries; (4) moyamoya minimizes, while posterior cerebral arteries become defective; (5) further reduction in moyamoya; (6) disappearance of moyamoya, with cerebral blood flow supplied only from the external carotid artery. CSF abnormalities have also been described, including increased concentrations of certain growth factors and cytokines (Malek, Connors, Robertson, Folkman, & Scott, 1997). TREATMENT

Surgical revascularization is the only effective treatment for MD. Direct bypass methods are effective for improving brain hemodynamics and resolving ischemic attacks immediately after surgery, and involve anastomosis of the superior temporal artery and the middle cerebral artery (Karasawa, Kikuchi, Furuse, Kawamura, & Sakaki, 1978). Indirect methods induce spontaneous angiogenesis between the brain surface and vascularized donor tissue (Ishii, 1986; Karasawa, Kikuchi, Furuse, Sakaki, & Yoshida, 1977; Kawaguchi et al., 1996; Kinugasa, Mandai, Kamata, Sugiu, & Ohmoto, 1993). Following treatment with encephaloduroarteriosynangiosis, cognitive outcome has been shown to be very poor in those younger than 2 years of age, with a more positive outcome if the operation is performed within 3 months of MD onset (Matsushima et al., 1992). Shane S. Bush Thomas E. Myers Bowen, M., Marks, M. P., & Steinberg, G. K. (1998). Neuropsychological recovery from childhood moyamoya disease. Brain and Development, 20, 119–123. Fukui, M. (1997). Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis (‘‘moyamoya’’ disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya disease)

of the Ministry of Health and Welfare, Japan. Clinical Neurology and Neurosurgery, 99, S238–S240. Fukui, M., Kono, S., Sueishi, K., & Ikezaki, K. (2000). Moyamoya disease. Neuropathology, 20, S61–S64. Ishii, R. (1986). Surgical treatment of moyamoya disease. No Shinkei Geka, 14, 1059–68 (in Japanese). Ishii, R., Takeuchi, S., Ibayashi, K., & Tanaka, R. (1984) Intelligence in children with moyamoya disease: Evaluation after surgical treatments with special reference to changes in cerebral blood flow. Stroke, 15, 873–877. Jefferson, A. L., Glosser, G., Detre, J. A., Sinson, G., & Liebeskind, D. S. (2006). Neuropsychological and perfusion MR imaging correlates of revascularization in a case of moyamoya syndrome. American Journal of Neuroradiology, 27, 98–100. Karasawa, J., Kikuchi, H., Furuse, S., Kawamura, J., & Sakaki, T. (1978). Treatment of moyamoya disease with STA-MCA anastomosis. Journal of Neurosurgery, 49, 679–88. Karasawa, J., Kikuchi, H., Furuse, S., Sakaki, T., & Yoshida, Y. (1977). A surgical treatment of ‘‘moyamoya’’ disease ‘‘encephalo-myo-synangiosis’’. Neurologia MedicoChirurfica (Tokyo), 17, 29–37. Kawaguchi, T., Fujita, S., Hosoda, K., Shibata, Y., Komatsu, H., & Tamaki, N. (1996). Multiple burr-hole operation for adult moyamoya disease. Journal of Neurosurgery, 84, 468–476. Kinugasa, K., Mandai, S., Kamata, I., Sugiu, K., & Ohmoto, T. (1993). Surgical treatment of moyamoya disease: Operative technique for encephalo-duro-arterio-myosynangiosis, its follow-up, clinical results, and angiograms. Neurosurgery, 32, 527–531. Kurokawa, T., Tomita, S., Ueda, K., Narazaki, O., Hanai, T., Hasuo, K., et al. (1985). Prognosis of occlusive disease of the circle of Willis (Moyamoya disease) in children. Pediatric Neurology, 1, 274–277. Kuroda, S., & Houkin, K. (2008). Moyamoya disease: Current concepts and future perspectives. Lancet Neurology, 7, 1056–1066. Malek, A. M., Connors, S., Robertson, R. L., Folkman, J., & Scott, R. M. (1997). Elevation of cerebrospinal fluid levels of basic fibroblast growth factor in moyamoya and central nervous system disorders. Pediatric Neurosurgery, 27, 182–189. Matsushima, Y., Aoyagi, M., Nariai, T., Takada, Y., & Hirakawa, K. (1997). Long-term intelligence outcome of post-encephalo-duro-arterio-synangiosis childhood Moyamoya patients. Clinical Neurology and Neurosurgery, 99(S2), S147–S150. Matsushima, T., Inoue, T., Suzuki, S. O., Fujii, K., Fukui, M., & Hasuo, K. (1992). Surgical treatment of moyamoya disease in pediatric patients-comparison between the results of indirect and direct revascularization procedures. Neurosurgery, 31, 401–405.

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Mineharu, Y., Liu, W., Inoue, K., Matsuura, N., Inoue, S., Takenaka, K., et al. (2008). Autosomal dominant moyamoya disease maps to chromosome 17q25.3 Neurology, 70, 2357–2363. Nanba, R, Kuroda, S., Tada, M., Ishikawa, T., Houkin, K., & Iwasaki, Y. (2006). Clinical features of familial moyamoya disease. Child’s Nervous System 22(3), 258–262. Suzuki, J., & Takaku, A. (1969). Cerebrovascular ‘‘moyamoya’’ disease. Disease showing abnormal net-like vessels in base of brain. Archives of Neurology, 20, 288–299. Suzuki, J., & Kodama, N. (1983) Moyamoya disease — A review. Stroke, 14, 104–109. Wakai, K., Tamakoshi, A., Ikezaki, K., Fukui, M., Kawamura, T., Aoki, R., et al. (1997). Epidemiological features of moyamoya disease in Japan: Findings from a nationwide survey. Clinical Neurology and Neurosurgery, 99, S1–S5. Yamada, H., Deguchi, K., Tanigawara, T., Takenaka, K., Nishimura, Y., Shinoda, J., et al. (1997). The relationship between moyamoya disease and bacterial infection. Clinical Neurology and Neurosurgery, 99, S221–S224. Yamauchi, T., Houkin, K., Tada, M., & Abe, H. (1997). Familial occurrence of moyamoya disease. Neurology and Neurosurgery, 99, S162–S167.

MUCOPOLYSACCHARIDOSES DESCRIPTION

Mucopolysaccharidoses (MPS) are a family of seven inherited metabolic disorders characterized by lysosomal enzyme deficiencies. Impaired or absent production of these enzymes leads to decreased degradation of glycosaminoglycans (GAGs). Intralysosomal GAG accumulations occur and interfere with normal cellular functioning. These diseases cause various forms of progressive neurologic and somatic dysfunction. Their manifestations vary based on the type and extent of enzyme dysfunction. The overall frequency of MPS is between 1.5 and 3.5 per 100,000 live births (Spranger, 2006). MPS I is classified into three separate disorders based on the severity of the clinical manifestations. Pfaundler–Hurler disease, or simply Hurler’s disease (MPS I-H), is the most severe disease process, whereas Schiene’s disease (MPS I-S) has a milder clinical presentation. Hurler–Schiene’s disease (MPS I-H/S) falls somewhere in the middle. The incidence of MPS I is 1:100,000 (Orchard et al., 2007). MPS II, or Hunter’s disease, is the only nonautosomal-recessive MPS disorder. It has an

X-linked recessive inheritance pattern. As a result, this is an almost exclusively male disease. However, it can be seen in certain females with skewed inactivation of X chromosomes (Pyeritz, 2007). MPS III, also known as Sanfilippo’s disease, is a category of four separate lysosomal enzyme deficiencies, designated A–D that all result in the buildup of heparan sulfate (Fraser et al., 2005). MPS IV, known as Moquiro’s disease, is divided into two categories, MPS IVA and MPS IVB, which designate two different enzyme defects. However, both diseases cause an increased accumulation of both keratan sulfate and chondroitin sulfate. MPS IVA typically presents as a more severe disease than MPS IVB (Spranger, 2007). MPS VI, referred to as Maroteaux–Lamy disease, is a rare disease with an incidence of 1:235,000 (Orchard et al., 2007). MPS VII, also known as Sly syndrome, is caused by a defect in beta-galactosidase, which causes pathologic accumulation of dermatan sulfate and heparan sulfate. The accumulated storage products are dermatan sulfate and heparan sulfate (Maertens & Dyken, 2007). MPS IX, known as hyaluronidase deficiency, or Natowicz syndrome, is a defect in hyaluronidase 1. There is only one reported case of MPS IX (Spranger, 2006). Multiple sulfatase deficiency is also a recognized rare form of MPS. This occurs with defective arylsulfatase A, B, and C enzymes and leads to the storage of dermatan sulfate and heparan sulfate. (Maertens & Dyken, 2007). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The pathophysiology and neuropathology of the MPS disorders relates to the specific type of enzyme deficiency. MPS I is characterized by a deficiency in alpha-Liduronidase that results from a mutation of the IUA gene In MPS I, radiological studies show a characteristic skeletal dysplasia, diosmosis multiplex. This is often seen on X-rays as thickened ribs and ovoid vertebral bodies. Enlarged, coarsely trabeculated diaphyses and irregular epiphysis and metaphysis can also be seen. Thickened calvarium, premature closure of the lamboid and sagittal sutures, shallow orbits and enlarged J-shaped sellas are often seen as well. In Hurler’s syndrome, macrocephaly, communicating hydrocephalus with progressive ventricular enlargement and increased intracranial pressure (ICP) are common findings on MRI. White matter lesions are

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more prominent in MPS I-H than MPS I-H/S or MPS I-S (Vedolin et al., 2007). MPS II (Hunter’s disease) results from a mutation involving iduronate sulfate sulfatase, which is encoded on chromosome Xq28. Point mutations are the most common type and appear in over 80% of MPS II patients. However, major deletions or rearrangements have also been detected and result in more severe pathology. The accumulated proteins are dermatan sulfate and heparan sulfate (Spranger, 2006). Brain MRI demonstrates decreased cerebral volume, brain atrophy, and white matter lesions (Vedolin et al., 2007). The four enzymes deficient in MPS III are heparan-N-sulfatase (Type A), alpha-N-glucosaminidase (Type B), acetylcoenzyme A, alpha-glucosaminide acetyltransferase (Type C), and N-acetyl glucosamine 6-sulfase (Type D), result in slowly progressive central nervous system (CNS) degeneration with mild somatic disease (Fraser et al., 2005). Disproportionate neurological involvement compared with somatic symptoms is unique to MPS III (Spranger, 2006). In MPS IVA, the gene encoding N-acetylgalactosamine-6-sulfatase has been mapped to chromosome 16q24.3. A W273L mutation of the GLB1 gene at 3p21.33 causes MSIVB. GLB1 encodes for beta-galactosidase. In both MSIVA and MSIVB, the product of accumulation is keratan sulfate (Wraith, 1995). MPS VI is caused by mutations of the ARB gene on chromosome 5q11-13. This gene encodes N-acetylgalactosamine-4-sulfatase, also called arylsulfatase B (Spranger, 2006). Brain MRI demonstrates white matter lesions and hydrocephaly to the same degree as is found in other MPS disorders. This is unexpected, as clinical findings typically show little neurological compromise (Vedolin et al., 2007). MP VII is caused by the mutation of the GUSB gene, located on chromosome 7q21.11. This results in a deficiency of beta-glucuronide and intracellular storage of GAG fragments. Ultrasound can be used to detect lethal nonimmune hydrops fetalis in utero. Peripheral blood smear demonstrates coarse granulocytic inclusions. Occasionally, the less severe disease presentations can be discovered incidentally based on the peripheral blood smear findings (Spranger, 2006). The mutation of the HYAL1 gene on chromosome 3p21.2-21.2 causes MPS IX. This gene is responsible for encoding 1 of 3 hyaluronidase. Radiographic studies show small erosions in both acetabulae.

there is considerable overlap in the resulting sequelae of each subtype. All subtypes of MPS result in a buildup of mucopolysaccharides in cellular lysosomes making the brain a primary storage site. As a consequence, CNS involvement is seen in all forms as the most common functional outcome. Somatic dysplasia, insidious decline of mentation, and a progressive decline in motor control are all commonly observed (Maertens & Dykens, 2007). Mental retardation is a prominent feature in all subtypes. In MPS I, although infants may appear to develop normally, by 6 months of age facial abnormalities, hepatosplenomegaly, and umbilical and inguinal hernias become apparent. Otis media and visual defects are also commonly seen. Developmentally, though initial motor development may seem on time, these skills are soon lost and severe mental retardation develops. Type 2 of this variant is associated with less severe symptoms. Individuals are generally undersized and have severe joint defects. Hepatosplenomegaly is often observed. While mental deficits are observed, they are less severe, commonly presenting as just mild mental retardation. Finally, Type 3 may present with any of the features observed in MPS I and MPS II, but in milder forms. In MPS II, two variants are described. Both may demonstrate facial anomalies similar to those observed in MPS I variants. Types 1 and 2 are both associated with a skin rash, commonly presenting on the extremities. The primary differences functionally between the two types of MPS II is that Type 1 is associated with severe mental retardation whereas Type 2 is not. MPS III has four variants. All are associated with manifestation of clinical symptoms developing around 2 years of age after an apparent period of normal development. At that point in time, an array of cognitive and behavioral symptoms may develop including aggression, hyperactivity, and speech deficits. Mental retardation is seen with progressive deterioration. Motor dysfunction also presents in relation to a progressive deterioration impeding children’s ability to walk. Physical features may be similar to those observed in MPS I and MPS II. MPS IV has two variants. As with the other subtypes, the first type is more severe than the second. Compression of the spinal cord and brainstem may result in neurological features. The majority of other features are muscoskeletal based.

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

DIAGNOSIS

Although variability may be seen across presentations in terms of their specific enzyme deficiency, as a group

All MPS disorders can be diagnosed using enzyme assays. Enzyme levels can be measured via serum

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leukocytes or cultured fibroblasts using commercially available or radio-labeled substrate. Semiquantitative spot test for increased urinary GAG excretion are quick and inexpensive initial evaluation methods. However, they are limited by false positive and negative rates. Quantifying total urinary excretion of GAGs can be done via chemical quantification of uronic acid containing substances. Though this will demonstrate the mucopolysacchariduria, tandem mass spectrometry is necessary to determine type-specific profiles. Patients with Moquiro’s syndrome can be diagnosed by urine reactive to monoclonal antibodies. Radiographs of the chest, spine, pelvis, and hands may demonstrate signs of dystosis multiplex (Spranger, 2006). Prenatal diagnosis is available for all MPS diseases and can be undertaken using cell cultures from amniocentesis or chorionic villus biopsy or enzyme assay. Directly measuring GAGs in amniotic fluid is unreliable. There are currently no neonatal screening tests for MPS (Spranger, 2006). TREATMENT

Hematopoetic cell therapy (HCT), including bone marrow or umbilical cord blood transplantation demonstrates clinical improvement in children with MPS I, MPS II, and MPS VI. Significant improvements in somatic disease and increased life expectancy have been reported. Improvement or resolution of growth failure, hepatosplenomegaly, joint stiffness, facial appearance, sleep apnea, heart disease, communicating hydrocephalus, and hearing loss have also been documented. Enzyme activity in serum and urinary GAG excretion may normalize. In general, anticipated decline in cognitive function arrests with HCT. However, if patients with baseline mental development index greater than 70 receive transplants before 2 years of age, they have improved long-term neurological outcomes. Though storage material diminishes in the myocardium and coronary arteries, valvular thickening has not been shown to resolve with treatment. In addition, evidence is still unclear as to the efficacy of HCT in improving orthopedic complications (Orchard et al., 2007). Overall results of HCT are more promising when using related, rather than random HLA matched donors. Major limiting factors include, graft failure, which occurs in up to 30% of patients, and transplant-related deaths (Spranger, 2006). Enzyme replacement therapy for patients is now available for patients with MPS I, MPS VI, and in clinical trials for treatment of MPS II, MPS IVB, and MPS VII (Wenger, Coppola, & Liu, 2003 and Spranger,

2007). For MPS I, laronidase (Aldurazyme) infusions every 2 weeks for 1 year in adolescent and adult patients reduced hepatosplenomegaly and improved pulmonary function, sleep apnea, and joint mobility. For MPS VI, galsulfase (Naglazyme) has been approved to reduce somatic manifestations of disease (Pyertiz, 2007). Since these enzymes do not cross the blood–brain barrier, they do not prevent neurocognitive or CNS complications. Enzyme replacement is recommended in young patients to stabilize somatic disease manifestations prior to transplant therapy (Spranger, 2006). Care for medical complications of MPS is also necessary. This typically involves assembling a multidisciplinary team. For patients with hydrocephalus, ventricular-peritoneal shunting may be necessary. Behavioral disturbances can be managed with behavioral or medication therapy. Disturbed sleep-wake cycles most commonly seen in MPS III best respond to melatonin therapy (Fraser et al., 2005). Patients with atlanto-axial instability benefit from upper cervical fusion. Anticonvulsants have been effective in treating MPS-related seizures. Ophthalmologic surgery can improve corneal opacities and retinal degeneration (Spranger, 2006). Rebecca Durkin Chad A. Noggle Fraser, A., Gason, A., Wraith, J. E., & Delatycki, M. B. (2005). Sleep disturbance in Sanfilippo syndrome: A parental questionnaire study. Archives of Disease in Childhood, 90, 1239–1242. Maertens, P., & Dyken, R. (2007). Lipoidoses. In C. G. Goetz (Ed.), Textbook of clinical neurology (pp. 616–625). Philadelphia, PA: Saunders. Orchard, P. J., Blazar, B. R., Wagner, J., Charnas, L., Kivit, W., & Tolar, J. (2007). Hematopoetic cell therapy for metabolic disease. Journal of Pediatrics, 151, 340–346. Pyeritz, R. E. (2007). Inherited diseases of connective tissue. In L. Goldman & D. Ausiello (Eds.), Cecil medicine (23rd ed.). Philadelphia, PA: Elsevier. Spranger, J. (2006). The mucopolysaccharidoses. In D. L. Rimoin, J.M. Connor, R. E. Pyeritz, & B. R. Korf (Eds.) Emery and Rimoin’s principles and practice of medical genetics (5th ed., pp. 1797–1806). New York: Churchill Livingstone. Vedolin, L., Schwartz, I. V. D., Komlos, M., Schuch, A., Azevedo, A. C., Viera, T., et al. (2007). Brain MRI in mucopolysaccharidosis: Effect of aging and correlation with biochemical findings. Neurology, 69, 917–924. Wenger, D. A., Coppola, S., & Liu, S. (2003). Insight into the diagnosis and treatment of lysosomal storage diseases. Archives of Neurology, 60, 322–328.

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Wraith, J. E. (1995). The mucopolysaccharidoses: A clinical review and guide to management. Archives of Disease in Childhood, 72, 263–267.

this sensory demyelination occurs in the absence of significant clinical findings.

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MULTIFOCAL MOTOR NEUROPATHY DESCRIPTION

Multifocal motor neuropathy (MMN) is a progressive neurological disorder that affects primarily motor neurons. It is rare, affecting approximately 1–2 per 100,000 individuals (Misulis & Head, 2007). It is an incurable, but treatable, disease that is more prevalent in men than women (approximately a 3:1 ratio). Furthermore, MMN most commonly affects young adults with approximately two-thirds of individuals suffering from MMN being less than 45 years of age. Consequently, the mean age of onset is approximately 40. However, it is rare in children. It is often mistaken for other neurological disorders, such as amyotrophic demyelinating polyneuropathy lateral sclerosis (ALS) and chronic inflammatory demyelinating polyneuropathy (CIDP).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

Although the exact cause of MMN is unknown, it is believed that the etiology involves an autoimmune cell-mediated process. Immunoglobulin M antibodies are believed to erroneously target ganglioside GM1 cells of affected individual’s nerve cells as foreign: GM1, GM2, and possibly glycolipids (Nobile-Orazio, Cappellari, & Priori, 2006). This immune response destroys neuronal tissue, including the myelin sheath, which encapsulates nerve cells. This destruction causes nerve cells to undergo demyelination, which invariably causes conduction deceleration, leading ultimately to partial or complete motor nerve blockade, termed as conduction block (CB; Bradley, Daroff, Fenichel, & Jankovic, 2008; Delmont et al., 2008; Filo, Szodkowska, Hosiec, & Bogucki, 2008; Lewis, 2007). This demyelination occurs predominantly in motor nerves. Focal motor CB ultimately causes denervation of motor neurons. Due to denervation of motor neurons, individuals who suffer from MMN commonly suffer from progressive paresis and muscle weakness across common terminal motor neurons (NobileOrazio, 2008). Sensory nerves are commonly spared; however, some studies suggest that some sensory involvement may occur (Filo et al., 2008). However,

The Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society define MMN as a ‘‘slowly progressive or stepwise progressive, asymmetrical limb weakness, or motor involvement having a motor nerve distribution in at least two nerves, for more than 1 month and no objective sensory abnormalities except for minor vibration sense abnormalities in the lower extremities’’ (van Schaik et al., 2006). A common initial clinical presentation is an inability or weakness in extending fingers (Donaghy, 1999; Misulis & Head, 2007). This is a common early first sign. It is hypothesized that one of the early nerves implicated in this disorder is the posterior interosseous nerve. The onset is usually insidious; however, once muscle weakness begins, it is progressive. Individuals may also complain of muscle cramps, as well as fasciculations. Common sites include a peripheral nerve distribution in areas such as the radial nerve in the upper extremity and the peroneal nerve, resulting in wrist drop and foot drop, respectively (Misulis & Head, 2007). This is usually an asymmetric presentation. Reflexes are usually normal initially; however, there may be a slight reduction or slowing in distal reflexes initially. As the disease process progresses, reflexes may diminish completely and individuals develop muscle wasting. In addition, individuals often complain of paresthesias, numbness, or tingling in the affected areas. DIAGNOSIS

Nerve conduction studies are essential in diagnosing MMN. EMG studies demonstrate focal motor conduction blockade. In greater than 50% of the cases, you would observe a reduction in amplitude of muscle-evoked response (Olney, Lewis, Putnam, & Campellone, 2003). Some conduction studies and electromyography show diffuse innervation without significant conduction abnormalities. Anti-GM ganglioside antibodies are measured using ELISA. This is considered to be elevated with IgM titer of greater than 1:400. Although nonspecific, assays for antiganglioside antibodies are positive in 25% to 80% of the cases. However, individuals who suffer from ALS also have elevated immunoglobulin M antiganglioside antibodies in 15% of the cases.

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A comprehensive physical examination is also important. Physical examination findings include weakness and decreased muscle size as a result of muscle wasting. Usually, upper extremities are affected greater than lower extremities. You will also notice muscle twitching. Deep tendon reflexes are often decreased. Cranial nerve involvement is usually rare; if present, it usually involves areas on the face or tongue, including the ocular, fascicular, and hypoglossal nerves. Although the cerebral spinal fluid is commonly unaffected, up to one-third of individuals who suffer from MMN have elevated proteins in their cerebral spinal fluids. In differentiating MMN, it is important to include in the differential diagnosis CIDP and ALS. CIDP is another autoimmune disease that has a similar presentation to Guillain–Barre´. This is also a cellmediated immune response affecting myelin, causing demyelination. In this condition, decreased motor nerve conduction is common. This may progress to complete CBs. You would also have elevated cerebral spinal fluid protein, as well as muscle weakness; however, muscle weakness is often symmetrical in CIDP (asymmetrical in MMN). Nerve damage is usually proximal (versus distal in MMN) and sensory deficits are common. With CIDP, it is common to have sural nerve demyelination with a characteristic onionbulb formation and inflammatory infiltrates histologically. Eighty percent of individuals who suffer from CIDP fully recover from this illness. Another disorder to consider in the differential diagnosis is ALS. This disorder is common in the central nervous system as well as the peripheral nervous system. This disorder is progressive and invariably fatal. It affects the anterior horn cells of the spinal cord and cranial nerve nuclei, with a propensity toward the brainstem. This causes muscle atrophy, fasciculation, and spasticity. The cause of this disorder is unknown, but we do know that it has a familial predisposition and occurs in 5% to 10% of individuals with similarly affected family members. Age of onset is in the 50s–60s. TREATMENT

Historically, the treatment of MMN has been wrought with controversy (Nobile-Orazio et al., 2006). Initially it was believed that treatments such as prednisone and plasma exchange are efficacious in treating other neurological disorders like CIDP. However, it was discovered that these treatments are ineffective in the treatment of MMN and, in some instances,

potentially exacerbate progressive muscle weakness and CB. At the present time the standard treatment of choice for MMN is the use of intravenous immunoglobulin (IVIg; Harbo et al., 2009; Nobile-Orazio et al., 2002; van Schaik et al., 2006). It is believed that this treatment helps to attenuate the cell-mediated autoimmune response caused by anti-GM antibodies. The impact of IVIg is ultimately to counteract the overactive immune response and to increase muscle strength and conduction velocity. The usual dosage is 2 g/kg per day for 2–5 days followed by maintenance treatment (Terenghi et al., 2004). Maintenance treatment may entail weekly to monthly injections. Early in course of illness, in which muscle weakness is present in the absence of CB, treatment may be plausible. However, with the progression of the disorder usually comes varying levels of disability. It is during this course of the illness that IVIg is indicated. In some instances, if individuals are refractory to IVIg, other immunosuppressant drugs may be beneficial, such as cyclophosphamide, interferon, or azathioprine (van Schaik et al., 2006) Due to risk of toxicity, cyclophosphamide is a suboptimal alternative. With progression of MMN, individuals may develop physical disability and comorbid psychological/psychiatric disorders. This includes clinical depression, anxiety, substance use, and other compromised coping behaviors. Standard treatments of these disorders, including biological modalities and therapy, are indicated. Stephen Robinson Bradley, W., Daroff, R., Fenichel, G., & Jankovic, J. (2008). Multifocal motor neuropathy with conduction block. In Neurology in clinical practice (5th ed., Vol. 2, pp. 2300–2302). Amsterdam: Elsevier. Delmont, E., Azulay, J., Giorgi, R., Attarian, S., Verschueren, A., Uzenot, D., et al. (2008). Multifocal motor neuropathy with and without conduction block a single entity? Neurology, 67, 592–596. Donaghy, M. (1999). Classification and clinical features of motor neuron diseases and motor neuropathies in adults. Journal of Neurology, 246, 331–333. Filo, M., Szodkowska I., Hosiec, T., & Bogucki, A. (2008). Multifocal motor neuropathy with conduction block with sensory fibre involvement in a diabentic patient. Case report. Neurologia I Neurochirurgia Polska, 42(3), 267–273. Harbo, T., Andersen, H., Hess, A., Hansen, K., Sindrup, S., & Jakobsen, J. (2009). Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy: A

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randomized, single-blinded cross-over trial. European Journal of Neurology, 16, 631–638. Lewis, R. (2007). Neuropathies associated with conduction block. Current Opinion in Neurology, 20, 525–530. Misulis, K., & Head, T. (2007). Multifocal motor neuropathy. Netter’s Concise Neurology, 340–341. Nobile-Orazio, E. (2008). What’s new in multifocal motor neuropathy in 2007–2008? Journal of the Peripheral Nervous System, 13, 261–263. Nobile-Orazio, E., Cappellari, A., Meucci, N., Carpo, M., Terenghi, F., Bersano, A., et al. (2002). Multifocal motor neuropathy: Clinical and immunological features and response to IVIg in relation to the presence and degree of motor conduction block. Journal of Neurology Neurosurgery & Psychiatry, 72, 761–766. Nobile-Orazio, E., Cappellari, A., & Priori, A. (2006). Multifocal motor neuropathy: Current concepts and controversies. Muscle and Nerve, 31, 663–680. Olney, R., Lewis, R., Putnam, T., & Campellone, J., Jr. (2003). Consensus criteria for the diagnosis of multifocal motor neuropathy. Muscle & Nerve, 27, 117–121. Terenghi, F., Cappellari, A., Bersano, A., Carpo, M., Barbieri, S., & Nobile-Orazio, E. (2004). How long is IVIg effective in multifocal motor neuropathy? Neurology, 62, 666–668. van Schaik, I. N., Bouche, P., Illa, I., Leger, J.-M., Van den Bergh, P., Cornblath, D. R., et al. (2006). European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Journal of the Peripheral Nervous System, 11, 1–8.

MULTI-INFARCT DEMENTIA DESCRIPTION

Multi-infarct dementia (MID) is a disorder characterized by a stepwise deterioration of cognitive functioning associated with strokes or accumulated transient ischemic attacks. The term ‘‘multi-infarct dementia’’ was coined by Hachinski, Lassen, and Marshall (1974) when they described the relationship between atherosclerosis and mental deterioration. They explained that dementia is not directly caused by atherosclerosis, rather it may lead to recurring small infarcts which can cause mental deterioration. Additional risk factors for MID include hypertension, cardiovascular disease, high cholesterol, diabetes mellitus, and cigarette smoking. The disease is more prevalent in males than females. Along with cognitive deficits, individuals with MID may suffer from

psychological symptoms and motor impairments. The disorder is irreversible, though pharmacological treatment and management of risk factors may be helpful in preventing further progression. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Computed tomography (CT) and magnetic resonance imaging (MRI) can be used to identify infarcts in individuals with suspected MID. Infarcts may occur in cortical or subcortical structures. Affected brain functions may vary among individuals with MID depending on the site, size, and number of lesions; however, some widespread pathological radiographic findings have been generally observed. For example, MRI scans have shown that individuals with MID have a smaller genu area of the corpus callosum than healthy controls (Lyoo, Satlin, Lee, & Renshaw, 1997). PET findings reveal individuals with MID have lower cerebral glucose metabolism rates in gray matter compared to healthy controls, and lower cerebral metabolic rates in gray matter are associated with more severe intellectual impairment (Meguro et al., 1991). PET scans of persons with MID demonstrate decreased cerebral blood flow and lower cerebral oxygen metabolism in the cerebral cortex, basal ganglia, and thalamus (De Reuck et al., 1998). Also, longer P300 latencies of event-related potentials have been associated with MID and decreased cognitive functioning, as assessed by WAIS scores (Neshige, Barrett, & Shibasaki, 1988). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Symptoms of MID include confusion, memory deficits, motor impairments, hemiparesis, sleep disturbances, gait abnormalities, speech impairments, somatic complaints, and psychological symptoms, including depression and anxiety as well as psychosis. Speech deficits in individuals with MID are typically characterized by impairment in speech mechanics, including articulation, prosody, pitch, and rate. Individuals with MID may also display deficits in narrative writing and writing to dictation. Furthermore, failure to follow complex instructions, reduced phrase length, and poorer performance on word list generation tasks are also associated with more severe cognitive impairments (Powell, Cummings, Hill, & Benson, 1988). ‘‘Extensor plantar response, pseudobulbar palsy, gait abnormalities, exaggeration of deep tendon reflexes, or weakness of an extremity’’ (p.158) may be displayed by individuals with MID (American Psychiatric Association [APA], 2000). Within each

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individual, MID differentially affects various neuropsychological functions. The presence and severity of deficits depend on a variety of factors including the location, magnitude, and number of infarctions. DIAGNOSIS

MID was included in the Diagnostic and Statistical Manual of Mental Disorders-Third Edition, Revised (DSM-III-R). Criteria for MID included stepwise progression of cognitive decline with acquired differential deficits among various functions; focal neurological deficits; and evidence of an association between cerebrovascular disease and the dementia (APA, 1987). In the DSM-IV (APA, 1994), the term ‘‘multiinfarct dementia’’ was replaced with ‘‘vascular dementia.’’ Diagnostic criteria for vascular dementia, as defined in the current DSM-IV-TR, include memory impairments and aphasia, apraxia, agnosia, and/or executive functioning deficits that result in social or occupational impairments as well as focal neurological signs and symptoms or laboratory findings of cerebrovascular disease, the cause of the dementia (APA, 2000). More recently ‘‘vascular cognitive impairment’’ has been proposed to replace the term ‘‘vascular dementia’’ (Bowler, 2007), to allow the inclusion of persons with symptomatic vascular disease that have not yet crossed the threshold for a dementia diagnosis. Vascular dementia and vascular cognitive impairment are more comprehensive concepts than MID because they include dementias resulting from various other circulatory etiologies in addition to multiple cerebral infarctions. MID and Alzheimer disease (AD) are often difficult to differentiate. Accurate diagnosis is even more challenging because these disorders are not mutually exclusive. Generally, AD is associated with a more gradual course than MID. Like AD, memory impairment is associated with MID; however, memory deficits resulting from MID are typically not as severe as deficits resulting from AD. For example, a comparison of neuropsychological performance between individuals with AD to individuals with MID found that while individuals in both groups showed broad impairments, those with AD obtained significantly lower overall mean scores on the neuropsychological battery. The largest differences between the groups were on measures of memory and learning, including orientation, paragraph recall, picture recognition memory, and face-name learning, on which individuals with AD performed more poorly. Psychomotor deficits, however, may be more pronounced in individuals with MID (Taylor, Gilleard, & McGuire, 1996), and individuals with MID may also demonstrate

poorer performance on measures of executive function and speech mechanics than individuals with AD (Looi & Sachdev, 1999; Powell et al., 1998). While individuals with AD show poverty of content of speech, individuals with MID produce shorter utterances with less grammatical complexity. Sultzer, Levin, Mahler, High, and Cummings (1993) found that individuals with MID displayed greater levels of psychopathology than individuals with AD. In the same study, psychopathology was not correlated with cognitive impairments in individuals with MID, but more severe psychiatric symptoms have been associated with greater dementia severity in individuals with AD (Sultzer et al., 1993; Sultzer, Levin, Mahler, High, & Cummings, 1992). Overall neuropsychological presentation is not very useful in distinguishing between individuals with MID and AD, as variability among individuals within these groups is more salient than differences between groups. The Ischemic Score, developed by Hachinski et al. (1975), has demonstrated utility in differentiating individuals with MID and AD. The scale is comprised 13 features characteristic of MID. Abrupt onset, fluctuating course, history of stroke, focal neurological symptoms, and focal neurological signs have a point value of 2, and stepwise deterioration, nocturnal confusion, relative preservation of personality, depression, somatic complaints, emotional incontinence, history or presence of hypertension, and evidence of associated atherosclerosis have a point value of 1. Total scores range from 0 to 18. Scores above 6 are indicative of MID, while scores below 5 are indicative of AD. Rosen, Terry, Fuld, Katzman, and Peck (1980) confirmed the utility of the Ischemic Score in differentiating individuals with AD from individuals with MID or both MID and AD; however, they suggested an abbreviated revision of scale that would only include eight features, namely, abrupt onset, stepwise deterioration, somatic complaints, emotional incontinence, history or presence of hypertension, history of strokes, and focal neurological signs and symptoms. TREATMENT

Generally, MID is chronic and irreversible. However, pharmacological approaches are available to treat symptomology and prevent further decline. Heparin-induced extracorporeal LDL/fibrinogen precipitation (HELP) has been found to ameliorate the pathologic hemorheologic state associated with MID (Walzl, 2000). Also, rivastigmine has been shown to be more effective than nimodipine in improving behavioral symptoms associated with MID, including hallucinations, aberrant behavior, sleep disturbances, and anxiety disorders. Individuals with MID who are

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treated with rivastigmine also show a reduced reliance on other medications, including neuroleptics and benzodiazepines (Moretti, Torre, Antonello, Cazzato, & Pizzolato, 2008). The effectiveness of vinpocetine has also been investigated. In a clinical trial, individuals who received this medication demonstrated preserved scores on the digit span backward test after 3 months (Kemeny, Molnar, Andrejkovics, Makai, & Csiba, 2005). When five individuals with MID were treated with physostigmine, results revealed reduced P300 latencies and significant increases in the WAIS scores of four of the participants (Neshige et al., 1988). Treatment of MID also involves the management of various risk factors, including cardiovascular disease, high cholesterol, diabetes mellitus, and hypertension. Alyse Barker Mandi Musso William Drew Gouvier American Psychiatric Association. (1987). Diagnostic and statistical manual of mental disorders (3rd ed., rev.). Washington, DC: Author. American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC: Author. Bowler, J. V. (2007). Modern concept of vascular cognitive impairment. British Medical Bulletin, 83, 291–305. De Reuck, J., Decoo, D., Marchau, M., Santens, P., Lemahieu, I., & Strijckmans, K. (1998). Positron emission tomography in vascular dementia. Journal of Neurological Sciences, 154, 55–61. Hachinski, V. C., Iliff, L. D., Zilhka, E., Duboulay, G. H., McAllister, V. L., Marshall, J., et al. (1975). Cerebral blood-flow in dementia. Archives of Neurology, 32(9), 632–637. Hachinski, V. C., Lassen, N. A., & Marshall, J. (1974). Multiinfarct dementia: A cause of mental deterioration in the elderly. The Lancet, 304(7874), 207–209. Kemeny, V., Molnar, S., Andrejkovics, M., Makai, A., & Csiba, L. (2005). Acute and chronic effects of vinpocetine on cerebral hemodynamics and neuropsychological performance in multi-infarct patients. Journal of Clinical Pharmacology, 45, 1048–1054. Looi, J. C. L., & Sachdev, P. S. (1999). Differentiation of vascular dementia from AD on neuropsychological tests. Neurology, 53, 670–678. Lyoo, I. K., Satlin, A., Lee, C. K., & Renshaw, P. F. (1997). Regional atrophy of the corpus callosum in subjects

with Alzheimer’s disease and multi-infarct dementia. Psychiatric Research: Neuroimaging Section, 74, 63–72. Meguro, K., Doi, C., Ueda, M., Yamaguchi, T., Matsui, H., Kinomura, S., et al. (1991). Decreased cerebral glucose metabolism associated with mental deterioration in multi-infarct dementia. Neuroradiology, 33, 305–309. Moretti, R., Torre, P., Antonello, R. M., Cazzato, G., & Pizzolato, G. (2008). Different responses to rivastigmine in subcortical dementia and multi-infarct dementia. American Journal of Alzheimer’s Disease & Other Dementias, 23(2), 167–176. Neshige, R., Barrett, G., & Shibasaki, H. (1988). Auditory long latency event-related potentials in Alzheimer’s disease and multi-infarct dementia. Journal of Neurology, Neurosurgery, and Psychiatry, 51, 1120–1125. Powell, A. L., Cummings, J. L., Hill, M. A., & Benson, D. F. (1988). Speech and language alterations in multi-infarct dementia. Neurology, 38, 717–719. Rosen, W. G., Terry, R. D., Fuld, P. A., Katzman, R., & Peck, A. (1980). Pathological verification of ischemic score in differentiation of dementias. Annals of Neurology, 7, 486–488. Sultzer, D. L., Levin, H. S., Mahler, M. E., High, W. M., & Cummings, J. L. (1992). Assessment of cognitive, psychiatric, and behavioral disturbances in patients with dementia: the Neurobehavioral Rating Scale. Journal of the American Geriatrics Society, 40(6), 549–555. Sultzer, D. L., Levin, H. S., Mahler, M. E., High, W. M., & Cummings, J. L. (1993). A comparison of psychiatric symptoms in vascular dementia and Alzheimer’s disease. American Journal of Psychiatry, 150(12), 1806–1812. Taylor, R., Gilleard, C. J., & McGuire, R. J. (1996). Patterns of neuropsychological impairment in dementia of the Alzheimer type and multi-infarct dementia. Archives of Gerontology and Geriatrics, 23, 13–26. Walzl, M. (2000). A promising approach to the treatment of multi-infarct dementia. Neurobiology of Aging, 21, 283–287.

MULTIPLE SCLEROSIS DESCRIPTION

Multiple sclerosis (MS) is a degenerative and autoimmune condition that affects 100–130 per 100,000 people in the United States (Kurtzke & Wallin, 2000). Currently, MS is considered one of the most prevalent chronic neurological disorders in young and middle adulthood, with a peak incidence in the third decade and the highest prevalence within 40–59

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years of age. Women present a higher tendency to develop MS with an average ratio of 2.6:1. The clinical presentation of MS is caused primarily by demyelination (destruction of the myelin sheath), with associated inflammation and visible white matter lesions in magnetic resonance studies being a prominent feature. Etiological causes of MS are still unknown; however, the interaction of genetic and environmental factors has been postulated as most important susceptibility agents (Ebers, 2008). There is a latitudinal variation in the prevalence of MS, being reportedly more frequent in areas more distant from the Equator and mounting evidence between the inverse relation between sun exposure and the development of MS (MacLean & Freedman, 2009). MS presentation is characterized by episodes of focal deficits of the optic nerves, and spinal cord and brain injury that usually require medical attention and that might remit and recur sporadically for years. Clinical symptoms in MS include motor weakness, paraparesis (motor weakness on lower extremities), vision changes, diplopia, nystagmus, dysarthria, intention tremor, ataxia, somatosensory changes (paresthesias), and bladder dysfunction. Other important and common, but sometimes underreported, symptoms include cognitive and affective changes (Haase, Tinnefeld, Lieneman, Ganz, & Faustmann, 2003). Diagnosis in MS is difficult due to the relapsing and remitting pattern, the subtle nature of symptoms and the apparent similarity with other diseases especially autoimmune ones. MS subtypes have been identified as relapsing–remitting MS (RRMS), progressive relapsing, primary progressive, and secondary progressive. The most aggressive and likely type to produce morbidity is primary progressive. Another important clinical category within the MS spectrum is the clinically isolated syndrome (CIS) an isolated CNS syndrome (optic neuritis, incomplete transverse myelitis, brainstem or cerebellar lesion), which is often the first MS attack (Thrower, 2007). The use of MRI has enlightened our knowledge of this disease and has replaced other studies used in the past to aid in the diagnosis of MS. Earlier diagnosis is now possible with its routine use (Bakshi, Hutton, Miller, & Radue, 2004). Treatment methods in MS aim to decrease the possibility of new clinical relapses or slowing of the progression of the disease by MRI. The first method of treatment is through interferons, which are naturally occurring antiviral proteins. Glatiramer acetate, which acts in the immune system to spare myelin from further attack, has shown to alter the natural history of RRMS. Natalizumab, and chemotherapeutic agents are used in secondary progressive MS, and other less conventional therapies are intravenous corticosteroids

intravenous immunoglobulin or plasma exchange. In MS, neuropsychology presents an important bridge between the physical (e.g., brain lesions) and cognitive and emotional (e.g., memory and depression) areas. In doing so, the Cartesian dualism is hinged to form one continuum. The end result of neuropsychological assessment is heightened understanding and advanced treatment of the patient with MS. NEUROPATHOLOGY/PATHOPHYSIOLOGY

MS is largely an inflammatory demyelinating autoimmune disease that is thought to develop by a combination of genetic and environmental factors. Pathologic damage is caused by T lymphocytes that become activated and gain entrance to the blood– brain barrier. This entrance causes an inflammatory response that in turn attacks the myelin. During the disease process, only central myelin produced by oligodendrocytes is affected, which causes astrocytes to respond by forming a glial scar. These patches of demyelination in the white matter of the brain or spinal cord disrupt central nerve transmission. Pathologic studies along with more advanced neuroimaging techniques indicate axonal damage and neuronal loss that eventually lead to brain atrophy. Axon loss is the major cause of irreversible disability in patients with MS (Dutta & Trapp, 2007). Antibody- and complement-mediated myelin phagocytosis (macrophages engulfing cellular debris), in this case myelin, is also a pathophysiological process occurring later in the degenerative process of this disease (Dhib-Jalbut, 2007). These disease processes have been well documented in postmortem specimens of MS patients. Neurobiological Markers

Many biological markers have been studied in MS, and the most widely used markers are those obtained through a spinal tap from the CSF like myelin basic protein (MBP), immunoglobulin (IgG) index, and oligoclonal bands (OGCB). The genetic region most clearly associated with MS susceptibility is the human leukocyte antigen (HLA) locus on the short arm of chromosome 6 (6p21) (De Jager et al., 2008). In various studies, the HLA region has been estimated to confer somewhere between 10% and 50% of the inheritability of MS. In Caucasian MS populations of northern European descent, the critical MS-associated genetic region is thought to reside near the class II *locus and is comprised of a group of genes with specific alleles that tend to occur in certain fixed combinations termed haplotypes. In molecular terms, the

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‘‘DR2’’ haplotype is designated as HLA-DRB1*1501, DQA1*0102, and DQB1*0602. These DR molecules are comprised of alpha and beta chains (encoded by A and B genes, respectively), and the polymorphisms are predominantly present in the beta chain. Of the more than 100 beta-chain sequence variations identified in humans, only one (1501, also designated as DR2) is associated with MS, and the DR2 gene is the most important genetic contributor to MS susceptibility identified to date.

Table 1 INFORMATION PROVIDED BY MRI Techniques T1

Gadolinium-enhancing lesions detect blood–brain barrier leakage, inflammatory disturbances, and recent (  6 weeks) activity, with lesion formation. Hypointense lesions (black holes) reflect more severe tissue pathology, including axon loss and correlates with disability.

Neuroimaging Techniques

MRI can be used to demonstrate dissemination in space and time within the brain and spinal cord, which has led to its common use as a paraclinical measure for diagnosis of MS including diagnosing patients with CIS. In addition, MRI is used to monitor the progress of disease in patients with clinically definite MS, including assessment of lesions and atrophy (Bakshi et al., 2004). Several MRI techniques can be used to study MS (Table 1). The most important ones, required for diagnosis are T2-weighted images (showing areas of demyelination and edema) and gadolinium-enhanced (T1) images (indicating the presence of acute inflammation). T1 images also help to determine the presence of ‘‘black holes’’ or axonal damage. On T2 and FLAIR, MS lesions are seen as hyperintense, ovoid-shaped, periventricular white matter lesions oriented perpendicular to the ventricular surface (known as Dawson’s fingers). They also commonly appear as corpus callosal, juxtacortical, and infratentorial lesions involving the posterior fossa and spinal cord. Not widely available but useful in the evaluation of MS patients is the functional MRI that helps to evaluate neuronal circuits needed for diverse brain functions. It measures critical circuitry involved in response to injury, activation, loss of function, and recovery of function. Magnetic resonance spectroscopy (MRS) is another MRI technique that has gained much interest in recent years because it can be used to detect early abnormalities even in otherwise normalappearing brain tissue. Studies have shown that decreased N-acetyl aspartate (NAA) levels reflect axon damage that is an important cause of disability. NAA is a biochemical found in neurons considered an index of axonal integrity and functional activity. In 2003, Cristodoulou et al. found a correlation between neuropsychological symptoms and NAA/Cr ratios on the brain central ventricular areas, with a higher correlation on the right hemisphere. Some researchers hypothesize that the cognitive and emotional symptoms observed at early stages of the disease could be

Importance

T2

Hyperintense lesions provide total burden of disease measure, including reversible and irreversible pathologies. Most predictive of disease course in early MS. Hyperintense T2 lesions can reflect a variety of pathologic processes in addition to demyelination, such as inflammation, edema, axonal loss, and remyelination

Diffusion-weighted

Detects abnormalities in both lesions and normal-appearing CNS tissue. Detects white matter changes.

Flair (fluid attenuated inversion recovery)

Hyperintense lesions

more related to early biochemical changes than to structural damage caused by lesions and inflammation (Benedict, Weinstock-Guttman, Fishman, Sharma, & Tjoa, 2004). Magnetic Resonance Spectroscopy in MS

MRS is a noninvasive neuroimaging technique that allows the in vivo quantification of brain neurochemistry by measuring concentration of key metabolites (Stanley, 2002) like NAA, mio-inositol, choline, and Cr. Over the past 20 years, MRS has been used to study the pathological mechanisms of neurological and psychiatric disorders, monitor long-term changes, identify differences among diagnostic groups, and study cognitive dysfunction on these disorders (Ross & Sachdev, 2004). The relative quantity or amount of these metabolites is usually determined by comparing their resonance peaks. Other methods like eventrelated potentials, brain size volume, cerebral metabolic rate, and cerebral blood flow have not been

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found to be strongly associated with cognitive functions, and due to cerebral plasticity measures of neural integrity such as MRS, should be the most sensitive to the neuropathology that leads to cognitive decline (Zivadinoff & Bakshi, 2004). Interestingly, in MS these lowered levels of NAA do not correlate with the total amount of lesions (Fillipi et al., 2003), which are critical in the diagnosis of MS criteria (McDonald, Compston, & Edan, 2001). This represents an important finding and might support the cognitive/ neuropsychological deficits that have been observed in MS patients in early stages of the disease. Diffusion Weighted Imaging and Diffusion-Tensor Imaging in MS

The magnetic resonance signal is intrinsically sensitive to motion at the molecular level. Two complementing MRI techniques known as diffusion-weighted and diffusion tensor-imaging (DWI and DTI) are capable of measuring water diffusion1 and diffusion anisotropy2. Of particular relevance for the study of MS neuropathology is the fact that these diffusion-based MRI techniques are capable of characterizing white matter integrity and the orientation of white matter fiber bundles. Increased water diffusion serves as a marker for cell membrane disruption. Moderate correlations have been found for DTI diffusivity and fractional anisotropy (FA) and cognitive functions on normal appearing gray matter and normal appearing white matter (Rovaris et al., 2002). Moreover, longitudinal studies using DTI3 and mean diffusivity have found progressive microstructural changes after 18 months in the normal appearing matter that do not correlate with lesions and atrophy (Ojera et al., 2005). Water diffusion is restricted within intact white matter fibers. It is inferred that the more anisotropic the water diffusion is in a particular region of the brain, the more restricted it is and the higher the probability that it is constrained within intact tissue. By measuring the degree of directional anisotropy of diffusion, the DTI technique probes tissue integrity on a microscopic scale that is not possible to achieve using conventional anatomical MRI techniques such as those used for clinical diagnosis of MS. The most recent DTI data on MS patients have shown that normal appearing white matter showed

significant increased diffusivity as measured by the Apparent Diffusion Coefficient (ADC) and reduced FA compared with controls, whereas ADC had a stronger association to clinical disability than lesion load (Vrenken et al., 2006). Another recent study, with 23 early onset MS patients, showed decreased FA on normal-appearing white matter, which confirms occult tissue damage (Tortorella et al., 2006). In view of the most recent studies and metabolite quantification with MRS, DTI seems to be, for the moment, one of the most promising neuroimaging techniques available for the study of diffuse white matter degeneration. DTI is susceptible to subtle global tissue degeneration at a microscopic scale in otherwise normal appearing white matter using conventional anatomical MRI techniques, and it could become a potential diagnostic marker for MS at preclinical or early clinical stages (Table 1). Spinal Tap

Spinal tap is a relatively easy procedure that can be done in MS patients to exclude any other infectious or inflammatory process that could mimic MS. CSF is taken for analysis that includes markers that aid in the diagnosis of the disease (Table 2). Evoked Potentials

Evoked potentials (EPs) are electrodiagnostic studies that aid in the diagnosis of MS when history, clinical findings, or imaging studies do not confirm it and more evidence is needed. EPs evaluate processing pathways of sensory nerve tracts in the spinal cord,

Table 2 CSF DISEASE MARKERS IN MS Marker Oligoclonal bands (OGCB)

OGCB are produced by the overrepresentation of particular antibodies. They are typical of the CSF of MS patients, but not exclusive to it.

Intrathecal immunoglobulin production (IgG, IgM)

Immunoglobulins are produced by plasma cells and are integral in adaptive immune responses. Polyclonal increases of IgG occur in chronic infection and inflammation.

Myelin basic protein (MBP)

A major component of myelin, MBP is increased in the CSF of some, but not all, MS patients following a demyelinating episode.

1

Diffusion with tissue integrity in a microscopic scale. Diffusion anisotropy, associated with restricted diffusion. 3 DTI, using directionally selective diffusion measurements, is used to determine the degree of anisotropy in the diffusion of water. 2

Description

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thalamus, and sensory cortex, auditory pathways in the brainstem and optic nerve function. These studies help to determine whether there has been an otherwise silent demyelinating lesion to the CNS. Among the evoked potential studies, the highest yield for diagnosis in people with probable M S a r e t h e s o m a t o sensory EPs, followed by the visual EPs. As a group, their use has declined due to the advent of MRI as a tool for diagnosis. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

MS is a chronic recurrent inflammatory neurological disease in which immune-mediated events contribute to subsequent neurologic impairment and disability. It is a complex and frequently active disease process that involves diverse pathological and clinical features. Based mostly in studies of the natural history of the MS disease, some clinical subtypes have been defined (Table 3). It is known that the majority of individuals followed in natural history studies develop progressive disability over long periods of time. Also later stages of the disease are marked by reduced relapses but continued worsening and progressive deterioration. The clinical presentation and course of MS is variable and sometimes unpredictable as it is influenced by brain pathology and the individual

disease course in each patient. Similarly, the neuropsychological symptoms can vary within subtypes at different stages of the disease (Patti, Amato, Trojano, Lijoi, & Bastianello, 2008). Although MS subtypes have been identified based on severity and progression, the clinical neuropsychological presentation within subtypes is quite unpredictable and overlaps with motor/neuromuscular and affective domains. However, despite the difficulties in establishing a neuropsychological profile in MS, some variables including the area of the lesions, progression of disease, number of years from initial diagnosis, mood/depression, and fatigue mediate the neuropsychological symptoms in each patient (Amato, Zipoli, & Portaccio, 2006). Recently, some researchers have established that neuropsychological symptoms are one of the most disabling yet poorly understood and measured features of the disease and have been documented in 40% to 60% of the patients (Huijbregts et al., 2004; Rao et al., 1991). Also, these symptoms can predict performance on simple and complex activities of daily living (Gaudino et al., 2006) needed for occupational tasks and independent living. Comprehensive neuropsychological assessments evidence that in MS these symptoms may be broadly subdivided into two broad categories that include mood and cognitive functioning difficulties (Feinstein, 2004). Although they vary in severity, cognitive symptoms in MS involve deficits on visuospatial skills, memory, speed of processing, visuospatial abilities, sensorimotor functions, executive functions, concept formation, abstract reasoning, and verbal fluency

Table 3 CLINICAL SUBTYPES OF MULTIPLE SCLEROSIS (MS) Relapsing-remitting MS

This is the major MS subtype. Approximately 66–85% of patients with a diagnosis of MS start out with relapsing MS, but after 10 years, only half are still relapsing. Relapsing MS patients show a high rate of inflammatory lesion activity (gadolinium-enhancing lesions).

Primary progressive MS

This subtype accounts for 10–15% of MS. Patients show gradual worsening from onset, without disease attacks. These patients tend to be older and often present with a spinal cord dysfunction without obvious brain involvement. This subtype is the least likely to show inflammatory lesion activity on MRI (gadolinium-enhancing). Unlike the other subtypes of MS, men are as likely as women to develop primary progressive MS.

Progressive relapsing MS

This subtype accounts for about 5% of MS. Patients show slow worsening from onset, with superimposed attacks. Recent studies suggest these patients are similar to primary progressive patients. This is the major progressive subtype and accounts for approximately 30% of MS. About half of the relapsing MS patients usually transition to secondary progressive disease. They show gradual worsening, with or without superimposed relapses. Natural history studies of untreated relapsing MS indicate 50% of patients will be secondary progressive at 10 years and almost 90% by 25 years. This form of MS shows a lower rate of inflammatory lesion activity than relapsing MS, yet the total burden of disease continues to increase. This most likely reflects ongoing axonal loss.

Secondary progressive MS

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(Schulthesis, Garay, & DeLuca, 2001). Cognitive symptoms have been found to be a good predictor of distress and disability (Rao et al., 1991), as well as occupational, social, and overall impairment (Bagert, Camplair, & Bourdette, 2002; Rao et al., 1991). Although no consensus has been established neuropsychological impairment in MS seems to increase and overlap with physical disability and progression (Bobholz & Rao, 2003). Cognitive deficiencies tend to be more prevalent in the later stages (Beatty, Goodkin, Monson, Beatty, & Hertsgaard, 1998; Heaton, Nelson, Thompson, Burks, & Franklin, 1985), although in some cases they may be detectable at an early phase of the disease (Bagert et al., 2002; Grant, McDonald, Trimble, Smith, & Reed, 1984; Lyon-Caen et al., 1986). Earlier symptoms can involve information processing speed and verbal fluency (Arango-Laspirilla, DeLuca, & Chiaravalloti, 2007). The later symptoms may involve deficits in memory, conceptual/abstract reasoning, attention, moderate to severe decrease in the speed of information processing, and visuospatial functions (Bagert et al., 2002; Rao, 1986; Ron, Callanan, & Warrington, 1991). A recent study with 416 relapsing–remitting patients found that processing speed seems to be the most significant cognitive symptom in RRMS (Nocentini et al., 2006). Sensorimotor Functions

As discussed earlier, MS primary symptoms involve sensorimotor dysfunction; however, presentations are different and therefore the severity and the pattern of dysfunction may vary in each case. Visual impairment is a cardinal symptom in optic neuritis. Motor output sequences become slower due to demyelization and the degeneration characteristic of MS. In MS, motor impairment can be evident with tests that involve different aspects of gross and fine motor output, motor speed, and perceptual skills. In fact, many of the most current cognitive batteries recommended for MS have tried to control for sensory motor effects like the Paced Auditory Serial Addition Test (PASAT), the oral Symbol Digit Modalities Test (SDMT), the Rao’s Brief Repeatable Battery (BRB), and the Stroop Color Word Task in order to assess more complex cognitive skills. Visuospatial Skills, Visuocostructive Abilities

Visuospatial and visuoperceptual abilities are complex procedures that include sensorimotor, executive, and perceptual abilities. In general, these appear to be impaired in approximately 20% of patients with MS (Prakash, Snoook, Lewis, Motl, & Kramer, 2008).

Taking into consideration that patients might experience significant visuospatial, visuoperceptual, and visuoconstructive abilities, cognitive evaluation should be specific and take into account the perceptual deficits that might interfere with other cognitive domains. The Benton Visual Orientation Tests are helpful in determining visuospatial and visuoperceptual difficulties. Clinical treatment and recommendations for MS patients should be supported with a minimal screening of visual functions since the quality of life and safety of a patient might change (e.g., driving) as a direct consequence of visuospatial impairment. Memory

Performance in memory measures of MS might be in part influenced by the attention and psychomotor speed difficulties that these patients experience; therefore, measures used to evaluate different aspects of a patient’s memory should control for the above, for example, visuoperceptual deficits and processing speed. Short-term memory and working memory (WM) studies in MS have found that arithmetic seems to be more impaired in patients with MS suggesting that WM deficits tend to be more pervasive as they involve processing simultaneous information. In addition to evaluating processing speed, the PASAT evaluates verbal WM. Consistently, studies have found that 20% to 25% of MS patients tend to present significant impairment on the PASAT as compared with controls (Demaree, DeLuca, Gaudino, & Diamond, 1999; Rao, Leo, Bernardin, & Unverzagt, 1991). Other studies using newer experimental procedures such as the N-back Test that RRMS patients present impairment relative to complexity after taking simple motor speed into account (Parmenter, Shucard, Benedict, & Shucard, 2006; Parmenter, Shucard, & Shucard, 2007). WM deficits seem to be directly related to the course and severity of the disease and primary progressive patients seemed to be more impaired in WM (Zakanis, 2000). Similarly, De Luca establishes that the fundamental difficulties in WM are directly related to processing speed. (DeLuca et al., 2004). Long-term memory performance seems to be associated with WM and processing speed; however, MS patients tend to maintain an adequate capacity to learn new information (DeLuca, Barbieri-Berger, & Johnson, 1994) and learning trials of lists evidence that the learning slope remains intact (DeLuca et al., 2004; Prakash et al., 2008). Long-term declarative memory impairment also seems to be mediated by impairment in retrieval of information, whereas storage and consolidation of memory seem to be relatively preserved where recognition trials seem to

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improve retrieval and represent the learning and consolidation processes (Randolph, Arnett, & Higginson, 2001). Difficulties in long-term memory in MS seem to be related to poor encoding, semantic clustering, reduction of semantic categorization, and interference (Arnett et al., 1997). Speed of Processing

Processing speed deficits seem to be the most evident and fundamental deficit in MS (DeLuca et al., 2004; Parmenter et al., 2007). Due to the white matter abnormalities of MS and lack of myelin in nerve conduction, processing speed difficulties are identified in many patients with MS (DeLuca et al., 2004). However, the differences in the Trail Making Test are not that evident (Arnett et al., 1997). Understanding the challenges of conducting assessments accurately, Rao (1990) developed the PASAT to specifically evaluate the processing capacities without the visual and motor interference that might be present in the disease. The PASAT has been translated and adapted to many languages and has become part of the official National Multiple Sclerosis Society recommended cognitive screening. Executive Functions

The Wisconsin Card Sorting Test (WCST) and the Halstead Category Test (HCT) are the most commonly used assessments for evaluating executive functions in terms of planning, flexibility, and inhibition. On both measures, MS patients seem to present moderate to severe deficits that are in part mediated by processing speed difficulties (Arnett et al., 1997). Executive deficits in MS have been associated with depressed mood. However, it seems that nonspeeded tax index using the Tower of London (TOL) (as measured by the TOLmoves per trial) indicated a deficient nonspeeded central executive skill secondary to the slow information processing deficits (Arnett, Higginson, & Randolph, 2001). Also, deficits in executive functions may be evident in clinical observations and everyday quality of life questionnaires. Language/Verbal Fluency

Studies of neuropsychological measures of language functioning in MS have found that verbal fluency tends to be affected even at early stages of the disease (Beatty, 2002; Prakash et al., 2008). In contrast, confrontational naming seems to be more preserved (Vlaar & Wade, 2003). However, in the areas of verbal comprehension and overall verbal IQ (Wechsler Adult Intelligence Scale [WAIS]), MS patients have exhibited

mild difficulties (Matotek, Saling, Gates, & Sedal, 2001; Prakash et al., 2008), although deficits seem to be associated with time and severity of the disease (Drake, Allegri, & Carra´, 2002). Intellectual Abilities

As a consequence of sensory motor difficulties observed in MS, general intelligence measures like the Wechsler’s Intelligence Scale reveal that MS patients tend to have difficulties in performance subtests and perceptual reasoning indexes (Prakash et al., 2008). However, when comparing performance within the MS samples, performance IQ seems to be more impaired than verbal IQ even in patients with no physical disability as measured with Expanded Disability Status Scale (EDSS) (Prakash et al., 2008). Nonetheless, intelligence as a general measure depends on lower hierarchy functions like speed of processing, sensory, and motor functions, which are all consistently negatively affected in patients with MS. In conclusion, neuropsychological assessments adapted for MS should always be considered as alternate and supplemental instruments rather than the traditional batteries of intelligence. Affective and Emotional Symptoms

Cognitive difficulties can be confounded by the emotional symptoms and psychiatric manifestations that accompany this disorder. In contrast, some researchers support that the cognitive symptoms observed in MS patients lack motor and physical impairment, whereas others observe a connection between physical disability and cognitive symptoms (Van Den Burg et al., 1987). The emotional disturbances most commonly associated with MS are depression and anxiety (Randolph, Arnett, & Freeske, 2004). However, findings support that depression is the most prominent emotional disturbance identified in MS (Arnett, 2005). Proper identification of depression in MS might be difficult since the cardinal symptoms of MS are very similar and overlap with the fiscal disability. Further, in some tests such as the Beck Depression Inventory, many items such as the ones involving fatigue could be specific symptoms more associated with MS than symptoms of depression. For example, concentration difficulties, psychomotor retardation, and sexual dysfunction in MS patients can be considered symptoms of depression, but they can also be a pathophysiological manifestation of MS (Voss et al., 2001). In 2001, Voss and colleagues discovered that physical

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disability and fatigue were indirectly predictive of depressed mood via recreational functioning. However, fatigue was directly related to depressed mood in MS. Another study conducted by Arnett and Randolph in 2006 using the Beck Depression Inventory and the Chicago Multiscale Depression Inventory (CMDI) Evaluative Symptoms and the CMDI-Vegetative Symptoms assessed different symptom clusters of mood (negative evaluative and neurovegetative) and its relation to active coping strategies in MS. Interestingly, they found that although the lifetime prevalence of depression seems to be very high, the mood symptoms tend to be more variable over long periods of time than negative or neurovegetative symptoms, and increased use of active coping strategies tended to decrease depressed mood longitudinally (Arnett & Randolph, 2006). Also, they found that MS patients that use Beta interferon tended to present a higher risk for depression. Other studies of MS and depression have focused on exploring what affective and cognitive factors contribute to the presence of depression symptoms. One of these studies found that objective executive difficulties contributed to depression; however, the authors found depressive attitudes and depression treatment also mediated memory complaints (Memory Functioning Questionnaire [MFQ]). The authors concluded that interventions for depression might improve the patient’s self-perceptions and quality of life (Randolph et al., 2004). Fatigue in MS

In MS patients experience unpredictable fluctuations in their energy and mood that result in physical, psychological, and social deficits. Some research has shown that in MS patients, fatigue was a direct effect of a patient’s mood state (Voss et al., 2001). Nevertheless, fatigue in MS can be distinguished from fatigue related to traditional symptoms of depression, based on the fact that fatigue in MS is aggravated by heat, is often alleviated by sleep, and lasts for only a few hours compared with the more persistent fatigue associated with depression (Patten & Metz, 2002). Alternative treatments such as yoga have been reported to improve fatigue symptoms; other pharmacological treatments such as modafinil have presented mixed results. Assessing each patient’s individual symptoms of fatigue is crucial in determining best treatment options. DIAGNOSIS

Current diagnosis of MS requires a more specific set of criteria requiring the evidence of recurrent

neurological deficits, which typically consist of sensory disturbances, optic neuritis, diplopia, limb weakness, clumsiness, and gait ataxia. The diagnosis of MS since its original descriptions has been one based mostly on history and clinical findings. Recurrent neurological deficits disseminated in space and time are basic requirements for diagnosis. These deficits can include sensory disturbances, optic neuritis, diplopia, limb weakness, clumsiness, and gait ataxia. Different diagnostic criteria have been developed over time, and currently MRI has been recognized as an essential tool to exclude other possible diagnosis, to give uniformity to a disease that has such variable presentations, and to account that there was progression of disease. In 2001, the McDonald International Panel proposed a new diagnostic scheme for diagnosis, which replaced previous criteria, incorporated MRI findings (Table 4) and paraclinical studies such as CSF and visual EPs with neurological history and examination. These criteria were revised in 2005. Diagnosis of MS according to McDonald criteria requires either clinical or radiographic evidence of one or more ‘‘attacks’’ with dissemination in time in conjunction with objective evidence by clinical examination or MRI of lesions with dissemination in space. Revised MRI criteria for dissemination in time requires either gadolinium-enhancing lesion(s) at least 3 months after onset of a clinical event but not corresponding to the site associated with the event or detection at any time of a new T2 lesion that was not present on a reference scan performed at least 30 days after an initial event. Despite evolving MS diagnostic criteria, for an accurate diagnosis, there is no substitute for careful consideration of the patient’s history, neurological examination, imaging results, laboratory tests, CSF analysis, EPs, and testing that excludes other possible diagnosis. Clinically Isolated Syndrome

This refers to patients who present with an isolated CNS syndrome (optic neuritis, incomplete transverse myelitis, brainstem or cerebellar lesion), which is often the first MS attack. Clinical, MRI, and CSF studies indicate that such patients with normal brain MRI and CSF have a low risk of developing MS. In contrast, those with abnormal MRI have a high risk of developing MS (Tintore´ et al., 2003). In patients with CIS suggestive of demyelination, evidence for dissemination in time and space could be provided by MRI alone. Dissemination in space can be identified by meeting three of four MRI criteria, or, alternatively, by showing at least two lesions plus the presence of OGCB (or elevated IgG index) in

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Table 4 MRI EVIDENCE OF DISSEMINATION IN SPACE BY MCDONALD CRITERIA 3 of the following (one spinal cord lesion can be substituted for one brain lesion): & One gadolinium-enhancing lesion or 9 T2 hyperintense lesions &

One or more juxtacortical lesions

&

One or more infratentorial lesions

&

Three or more periventricular lesions

Common &

Sensory problems (numbness or tingling of a body part)

&

Weakness

&

Difficulty walking

&

Monocular decreased vision

&

Poor coordination

Examples

Vascular diseases

Vasculitis, antiphospholipid antibody syndrome, CADASIL, cerebrovascular disease, Susac syndrome

Infectious diseases

Bacterial (Lyme disease, syphilis, Whipple’s disease), viral (HIV infection, human T-lymphotrophic virus Type-1 infection, herpes viruses, progressive multifocal leukoencephalopathy, JC virus)

Neoplastic diseases

Primary brain tumor (i.e., CNS lymphoma), metastatic tumors, paraneoplastic syndromes

Structural or compressive conditions

Cervical spondylosis, degenerative disc disease, Chiari malformation, dural arteriovenous fistulas, syrinx

Inflammatory diseases

Collagen vascular diseases (SLE, Sjogren’s syndrome), neurosarcoidosis, Bechet’s disease

Genetic conditions

Leukodystrophies (adrenoleukodystrophy, adrenomyeloneuropathy), lysosomal storage diseases, Fabry’s disease, mitochondrial diseases

Metabolic diseases

Vitamin B12 deficiency, acquired copper deficiency, folate deficiency, hyperhomocysteinemia, vitamin E deficiency Conversion disorder, depression, anxiety

Uncommon &

Bladder problems

&

Bowel problems

&

Sexual dysfunction

&

Cognitive difficulties

&

Pain

Brain Lesions

Spinal Cord Lesions

High signal on T2-weighted and FLAIR MRI sequences

1 or 2 vertebral segments in length

When actively inflamed, often enhanced with gadolinium contrast

Generally incomplete crosssectional involvement (dorsolateral common)

Position abutting ventricles (often perpendicular)

Less likely to enhance with gadolinium contrast

Juxtacortical position (gray–white junction)

No cord swelling

Involvement of brainstem, cerebellum, or corpus callosum

Disease Categories

Better seen with STIR MRI sequences

CSF. In a multicenter study, it was shown that if Barkhof/Tintore´ criteria are fulfilled the likelihood for conversion to clinically definite MS is much higher and the time much shorter than if criteria are not fulfilled (Korteweg et al., 2006). Early, routine, and yearly assessment of neurological symptoms in MS patients is a critical aspect required in the careful monitoring of a patient’s disease progression, response to treatment, and overall quality of life. Despite the evidence that cognitive and emotional symptoms have a significant impact on the patient’s quality of life, a study revealed that in 2002, MS clinics and neurological practices did not routinely conduct neuropsychological assessments. This may have been attributed to a lack of consensus

Psychogenic conditions

in the field about the right way to evaluate MS (Benedict et al., 2002). As a result of the discrepancy, a group of neurologists and neuropsychologists from the United States, Canada, the United Kingdom, and Australia met together and agreed that the new standard for diagnosing MS would require a minimal neuropsychological assessment. These experts developed the Minimal Assessment of Cognitive Function in MS (MACFIMS). The MACFIMS is a 90 min battery composed of seven neuropsychological tests that evaluate the domains of processing speed, WM, learning and memory, executive function, visuospatial processing, word retrieval, and provides recommendations for evaluation of sensorimotor functions, fatigue, and depression (Benedict et al.,

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2002). Some of the tests that have proven to be effective with MS patients are Rao’s BRB, MS Neuropsychological Screening Questionnaire, PASAT, SMDT (Smith, 1982), California Verbal Learning Test, and the Brief Visuospatial Memory Test.

TREATMENT

Today there are many innovative disease-modifying treatments for MS that aim to decrease the possibility of new clinical relapses or slow the progression of the disease by MRI. The first method of treatment is through interferons, which are naturally occurring antiviral proteins. Interferon beta-1a low dose (Avonex) and high dose (Rebif) as well as interferon beta-1b (Betaseron) have been shown to alter the natural history of RRMS. The interferon treatments have been shown to decrease the number of exacerbations and may slow the progression of the physical disability. These medications vary in their dose and frequency and are thought to work by modifying the effects of endogenous interferons on the immune system. Other treatment available is glatiramer acetate (Copaxone), which consists of a mixture of peptide fragments thought to act as a decoy for the immune system to spare myelin from further attack. All of the above treatments are injected subcutaneously with the exception of interferon beta-1a low dose which is injected intramuscularly. Current therapeutic treatments have been shown to work best in the more active inflammatory phases early in the disease. Natalizumab is a monoclonal antibody given intravenously once per month for patients who have been on the above medications with poor response or have eventually failed treatment. Chemotherapeutic agents such as mitoxantrone are being used as an alternative form of treatment for more aggressive progression like in the case of secondary progressive MS. The chemotherapeutic form of treatment is more a last resort because of the amount of undesirable side effects it causes. Newer therapies are currently under study including oral medications to avoid relapses. Unfortunately, none of the existing pharmaceutical interventions ‘‘cure’’ the disease. In addition, the markers for success are typically MRI lesions, which, as indicated earlier, do not appear to have a strong correlation with functional and cognitive limitations. For acute exacerbations, intravenous corticosteroids are the treatment of choice that is frequently used for the purpose of hastening recovery in a patient who has already had a relapse. These antiinflammatory agents suppress cell migration into the CNS, reducing inflammation around active

plaques. They are usually administered for 3–5 days and then rapidly tapered down or discontinued. Less conventional therapies that can be used at times, in more aggressive cases, are intravenous immunoglobulin or plasma exchange. Symptomatic therapy includes treatment for associated spasticity, pain, bladder dysfunction, tremors, or fatigue. It is very important for the clinician to assess symptoms that can be secondary to fatigue, heat, lack of rest, or inadequate diet since these can mimic an acute relapse associated with a worsening of previous deficits. The addition of nonmedical interventions may be as critical, if not more, than the previously discussed interventions. These would include but not be limited to temperature regulation, fatigue control, massage, controlled exercise, vocational intervention, and psychotherapy. The course of this disease is quite variable in each patient. Relapses may have measurable and lasting impact causing disability at a later time. Subtle clinical symptoms can be related to active inflammatory activity that can go unnoticed in the absence of careful evaluation. It is thought that roughly 15% of MS patients will never have a relapse and that most MS patients will eventually develop the secondary progressive form of MS. Factors that have been associated with poorer prognosis are frequent relapses in the first 2 years, primary progressive onset, male sex, the presence of multiple MRI lesions, and early motor or cerebellar findings. EDSS is the most widely used scale for assessing level of disability in MS patients (Kurtzke, 1983). This rating system is frequently used for classifying and standardizing the condition of people with MS; it is also an important tool in clinical trials (can be used as inclusion/exclusion criteria and to compare results). The score is based on a clinical neurological examination and consists of a number scale from 0 to 10 where the range from 0.0 to 4.5 includes patients who are ambulatory and the range from 5.0 to 9.5 is defined by impairment of ambulation. Although it provides an objective measure, there is an apparent discrepancy between conventional lesions in MRI and clinical disability as measured by this scale (Li et al., 2006) since it places emphasis on the ability to walk and it may not be able to detect the extensive clinical changes that patients can experience. In general, the course and manifestation of symptoms in MS are quite variable in each patient. Relapses may have measurable and lasting impact causing disability at a later time. Subtle clinical symptoms can be related to active inflammatory activity that can go unnoticed in the absence of careful evaluation. It is thought that roughly 10% of patients

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have benign MS and that 70% will become secondary progressive. Liza San Miguel-Montes Brenda Deliz-Rolda´n Kriste Treftz-Puente

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Ross, A. J., & Sachdev, P. (2004). Magnetic resonance spectroscopy in cognitive research. Brain Research Reviews, 44, 83–102. Rovaris, M., Inannucci, G., Falautano, M., Possa, F., Martinelli, V., Comi, G., & Fillipi, M. (2002). Cognitive dysfunction in patients with mildly disabling relapsing– remitting multiple sclerosis: an exploratory study with diffusion tensor MR imaging. Journal of the Neurological Sciences, 195(2), 103–109. Schulthesis, M. T., Garay, E., & DeLuca, J. (2001). The influence of cognitive impairment on driving performance in multiple sclerosis. Neurology, 56, 1089–1094. Smith, A. (1982). The symbol digit modalities test manual: Revised. Los Angeles: Western Psychological Services. Stanley, J. A. (2002). In vivo magnetic resonance spectroscopy and its implications to neuropsychiatric disorder. Canadian Journal of Psychiatry, 47, 315–326. Thrower, B. W. (2007). Clinically isolated syndromes: Predicting and delaying multiple sclerosis. Neurology, 68(24, Suppl. 4), S12–S15. Tintore´, M., Rovira, A., Rı´o, M., Nos, C., Grive´, E., SastreGarriga, J., et al. (2003). New diagnostic criteria for multiple sclerosis: Application in first demyelinating episode. Neurology, 60(1), 27–30. Tong, B., Yip, J., Mc Lee, T., & Li, L. (2002). Frontal fluency and memory functioning among multiple sclerosis patients in Hong Kong. Brain Injury, 16(11), 987–995. Tortorella, P., Rocca, M. A., Mezzapesa, D., Ghezzi, A., Lamanthia, L., Comi, G., et al. (2006). MRI quantification of gray and white matter damage in patients with early onset multiple sclerosis. Journal of Neurology, 253(7), 903–907. Van den Burg, W., van Zomeren, A. H., Minderhoud, J. M., Prange, A. J., & Meijer, N. S. (1987). Cognitive impairment in patients with multiple sclerosis and mild physical disability. Archives of Neurology, 44, 49–501. Vlaar, A. M., & Wade, D. T. (2003). Verbal fluency assessment of patients with multiple sclerosis: Test–retest and inter-observer reliability. Clinical Rehabilitation, 17, 756–764. Voss, W. D., Arnett, P. A., Higginson, C. I., Randolph, J. J., Campos, M. D., & Dyck, D. G. (2001). Contributing factors to depressed mood in multiple sclerosis. Archives of Clinical Neuropsychology, 17, 113–115. Vrenken, H., Pouwels, P. J., Geurts, J. J., Knol, D. L., Polman, C. H., Barkhof, F., et al. (2006). Altered diffusion tensor in multiple sclerosis normal-appearing brain tissue: Cortical diffusion changes seem related to clinical deterioration. Journal of Magnetic Resonance Imaging, 23(5), 628–636. Zakanis, K. K. (2000). Distinct neurocognitive profiles in multiple sclerosis subtypes. Archives of Clinical Neuropsychology, 15(2), 115–136.

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In 1960, Dr. Milton Shy at the National Institutes of Health and Dr. Glen Drager at Baylor College of Medicine first identified and named Shy-Drager syndrome, currently known as multi-system atrophy with orthostatic hypotension (Shy & Drager, 1960). Other terms used for this syndrome include livopontocerebellar atrophy, striatonagral degeneration, and Parkinson’s plus (Bannister & Oppenheimer, 1972). The etiology remains unknown, yet autoimmune dysfunction or neurotoxins have been proposed to play some role in its composition (Bensimon, Ludolph, Agid, Vidailhet, Payan, & Leigh, 2008). The disorder is progressive and is characterized by an excessive drop in blood pressure when standing, also referred to as supine hypotension, that often leads to sensations of dizziness or fainting. Not all cases of multi-system atrophy exhibit hypotension; however, such cases are rare. Still, as a result, multisystem atrophy is often classified as with or without orthostatic hypotension. Other symptoms of multisystem atrophy with orthostatic hypotension include urinary incontinence, constipation, sexual impotence in men, generalized weakness, visual disturbances (i.e., diplopia), difficulty breathing and swallowing, sleep disturbances, decreased sweating, and movement symptoms (Watanabe et al., 2002). These generalized symptoms may often be misdiagnosed as other disorders with similar presentations (i.e., autoimmune disorders, movement disorders, autonomic dysfunction disorders, etc.), especially in the formative stages of the disease process and considering how blood pressure is often monitored in a seated position. Prevalence of multi-system atrophy is approximately 46 per 1,000,000 with typical age of onset in the late 50s early 60s with 55% of cases being male (Bensimon et al., 2008). The course of the disease is 7 to 10 years with respiratory failure as the primary cause of mortality (Watanabe et al., 2002). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Regarding the pathophysiology, initially it was believed that damage to gray matter was paramount;

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however, with understanding of glial cells, it became apparent that white matter involvement is actually more important (Burn & Jaros, 2001). Thus, the glial involvement and accompanying demyelination play a distinct role in the pathogenesis of multi-system atrophy with orthostatic hypotension. The etiology for the cell loss is unknown and there is little evidence to confirm autoimmune and toxic (i.e., saxitoxin) agents as contributory; neither is there evidence to suggest a genetic cause (Daniel, 1992). The pathophysiology of multi-system atrophy with orthostatic hypotension is attributed to progressive neuronal and oligodendroglial loss in various neuroanatomic regions with symptoms correlating to the areas involved (Wenning, Colosimo, Geser, & Poewe, 2004). For example, orthostatic hypotension and urinary incontinence are the result of preganglionic damage of the intermediolateral cell columns; cerebellar ataxia, nystagmus, and dysarthria are due to damage in the cerebellar cortex, pontine nuclei, and inferior olives, respectively and motor abnormalities, akinesia, and rigidity are secondary to cortical motor areas and basal ganglia, globus pallidus, and putamen, respectively (Wenning et al., 2004). The degeneration of Onuf’s nucleus that is the sacral anterior horn cells is associated with urinary, sexual, and anorectal impairments (Vodusek, 2001). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The clinical presentation of multi-system atrophy with orthostatic hypotension is characterized by autonomic dysfunction, parkinsonian symptoms, and ataxia (Bannister & Oppenheimer, 1972). Common preliminary symptoms includes an "akinetic-rigid syndrome" (characterized by diminished initiation speed and bradykinetic movements), with less common symptoms including balance problems often with falls, genitourinary problems (including incontinence and retention), and erectile dysfunction (Geser & Wenning, 2006). Progression of the disease is marked by increased parkinsonism, cerebellar dysfunction, and autonomic dysfunction. Clinical evaluation will reveal bradykinesia and rigidity, poor balance (i.e., dizziness or fainting when standing up) and coordination, and impaired parasympathetic body functions (Watanabe et al., 2002). The latter consists of urinary incontinence, impotence, constipation, dry mouth or skin, difficulties with regulating body temperature, and abnormal breathing especially during sleep. Cognitive functions are generally normal, yet confusion and dysarthria

may also be present especially later in the disease progression (Watanabe et al., 2002). DIAGNOSIS

Multi-system atrophy with orthostatic hypotension was classically divided into three types; however, recent changes have elucidated a four-domain classification system: autonomic failure/urinary dysfunction, parkinsonism, cerebellar ataxia, and corticalspinal dysfunction (Gilman et al., 1998). Diagnosis is confirmed upon autopsy; however, certain tests exist that inform the differential. Brain imaging may be normal or demonstrate cerebellar atrophy and striatonigral degeneration (i.e.. putaminal lesions) (Burn & Jaros, 2001). Other tests include scintigraphy, positron emission tomography (PET), autonomic function test, and sphincter electromyography (Colosimo, Tiple, & Wenning, 2005). Differential diagnoses are numerous and include chorea, cortical basal ganglionic degeneration, Hallervorden-Spatz disease, idiopathic orthostatic hypotension, mitochondrial cytopathies, multiple sclerosis, neuroacanthocytosis, neurosarcoidosis, neurosyphillis, olivopontocerebellar atrophy, Parkinson’s disease, Parkinson plus syndromes, and Pelizaeus-Merzbacher disease (Geser & Wenning, 2006). Differentiation of Parkinson’s from multi-system atrophy tends to be difficult, yet is possible when impairments are rapid, there is a poor response to levadopa (i.e., confusion), autonomic dysfunction (i.e., urinary problems or orthostatic hypotension) is prominent, rigidity and bradykinesia are more pronounced than tremor, speech is dysarthric, there are falls and an absence of dementia, and abnormal breathing patterns are noted (Burn, Sawle, & Brooks, 1994). Another common differential with multi-system atrophy is pure autonomic failure, which may be difficult to differentially diagnose in the early stages. Unlike pure autonomic failure, which is a result of peripheral impairments, multi-system atrophy is secondary to central impairments (Geser & Wenning, 2006). Additionally, the progression of pure autonomic failure is slower than multi-system atrophy, and pure autonomic failure has low plasma norepinepherine levels (Geser & Wenning, 2006). Multi-system atrophy may be differentially diagnosed from progressive supranuclear palsy by analysis of horizontal and vertical ocularmotor movements that demonstrate that the latter maintain slowing of the saccades (Burn et al., 1994). Those with progressive supranuclear palsy often demonstrate different physiologic responses to autonomic function tests, and cardiovascular dysfunction is exclusionary

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to this diagnosis (Burn et al., 1994). Multi-system atrophy may be differentially diagnosed from corticobasal ganglionic degeneration in that the onset of the former is typically characterized by unilateral rigidity and dystonia. Unlike multi-system atrophy, apraxia is focused in the cortex (Geser & Wenning, 2006). Cerebrovascular etiologies are ruled out through imaging. TREATMENT

There is no cure for multiple system atrophy with orthostatic hypotension, and the goal of interventions is to control symptoms. Anti-Parkinson medication, such as carbidopa-levodopa (Sinemet), may be utilized, as well as pharmaceutical agents to manipulate blood pressure (Colosimo et al., 2005). As the disease progresses, artificial feeding tubes, breathing assistance, and/or surgery may all be required to address more severe problems such as bradycardia and dysphagia among others (Colosimo et al., 2005). In addition to the multiple pharmacological treatments for multi-system atrophy, nonpharmacologic treatments may include specific mechanical maneuvers and clothing to address orthostatic hypotension, diet alteration, catheterization, speech therapy for improvements in dysphagia and communication, and physical therapy to prevent deconditioning (Colosimo et al., 2005). Javan Horwitz Natalie Horwitz Chad A. Noggle Bannister, R., & Oppenheimer, D. (1972). Degenerative diseases of the nervous system associated with autonomic failure. Brain, 95(3), 457–474. Bensimon, G., Ludolph, A., Agid, Y., Vidailhet, M., Payan, C., & Leigh, P. (2008). Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study. Brain, 132, 156. Burn, D., & Jaros, E. (2001). Multiple system atrophy: Cellular and molecular pathology. Molecular Pathology, 54(6), 419–426. Burn, D., Sawle, G., & Brooks, D. (1994). Differential diagnosis of Parkinson’s disease, multiple system atrophy, and Steele-Richardson-Olszewski syndrome: Discriminant analysis of striatal 18F-dopa PET data. Journal of Neurology, Neurosurgery and Psychiatry, 57(3), 278–284. Colosimo, C., Tiple, D., & Wenning, G. (2005). Management of multiple system atrophy: State of the art. Journal of Neural Transmission, 112(12), 1695–1704. Daniel, S. (1992). The neuropathology and neurochemistry of multiple system atrophy. In R. Bannister & C. Mathias (Eds.), Autonomic failure: A textbook of clinical

disorders (3rd ed., pp. 564–585). Oxford, England: Oxford University Press. Geser, F., & Wenning, G. (2006). The diagnosis of multiple system atrophy. Journal of Neurology, 253, 3–15. Gilman, S., Low, P., Quinn, N., Albanese, A., Ben-Shlomo, Y., Fowler, C., . . . Wenning, G. (1998). Consensus statement on the diagnosis of multiple system atrophy. American Autonomic Society and American Academy of Neurology. Clinical Autonomic Research, 8(6), 359–362. Shy, G., & Drager, G. (1960). A neurological syndrome associated with orthostatic hypotension: A clinical-pathologic study. Archives of Neurology, 2, 511–527. Vodusek, D. (2001). Sphincter electromyography and differential diagnosis of multiple system atrophy. Movement Disorders, 16, 600–607. Watanabe, H., Saito, Y., Terao, S., Ando, T., Kachi, T., Mukai, E., . . . Sobue, G. (2002). Progression and prognosis in multiple system atrophy: An analysis of 230 Japanese patients. Brain, 125, 1070–1083. Wenning, G., Colosimo, C., Geser, F., & Poewe, W. (2004). Multiple system atrophy. Lancet Neurology, 3, 93–103.

MUSCULAR DYSTROPHY DESCRIPTION

The muscular dystrophies (MDs) describe a group of genetic and inherited diseases in which specific genes that control muscle function are found to be defective (Emery, 2008). This group of genetic diseases is marked by the progressive and increasing weakness and degeneration of the skeletal or voluntary muscles, which control movement. In general, incorrect and missing genetic information in patients with MD prevents their bodies from correctly producing proteins that are used in building and maintaining muscles. Although such characteristics may appear to be pervasive in all patients with MD, it is important to recognize that over 30 subtypes of MD have been identified. Characteristics of MDs that are not specific to a particular subtype include the effects of the disease on striated, voluntary muscles. In many subtypes of MD, the disease affects both sides of the body in a symmetrical manner, from the bottom up (i.e., loss of lower extremity or torso control precedes loss of hand function), and maturation of MD occurs before deterioration (flaccid paralysis), although the individual does not always appear to be getting worse. For many subtypes of MD, the disease further affects the body and the related cause of death includes respiratory infection (problems immobilizing secretions) or

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heart attack, which typically occurs in the late teens or early 20s. Still, other MDs do not become evident until adulthood (i.e., oculopharyngeal muscular dystrophy) (Emery, 2008). The most common MD in children is Duchenne’s muscular dystrophy (DMD), which occurs in 1 in every 3,300 live male births (Iannacome, 1992). The diagnosis for DMD is based on physical characteristics, as well as medical history and testing results. Typically, children with DMD present motor delays such as abnormal walking patterns, waddling, and frequent falling (Iannacome, 1992). Another physical indication of this disorder is the decreased muscle size in the calves or any muscle group. A deficiency of the membrane protein, dystrophin, causes the progressive deterioration of muscle fibers (Van Deutekom, 2005). Mutations in the DMD gene cause the disorder (Lalic et al., 2005). Becker’s muscular dystrophy (BMD) is another more common subtype that often resembles DMD. BMD is caused by the same gene mutations that also cause DMD, but in individuals with BMD, protein produced is abnormal despite the mutant gene’s normal synthesis of dystrophin (Emery, 2008). Though individuals with BMD display similar symptoms to those with DMD (i.e., symmetrical weakness — weakness in lower limbs, followed by upper limb weakness), these individuals tend to have a later onset (in their teens and 20s), and may have relatively mild weakness compared with those with DMD. Although MDs are, in general, fairly rare, specific subtypes of the disease appear to occur at higher incidences than others. Besides DMD and BMD (which are considered higher incidence MD subtypes), some of the more common forms of MD include Emery–Dreifuss’ muscular dystrophy, limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, distal muscular dystrophy, oculopharyngeal muscular dystrophy, congenital muscular dystrophies, and myotonic dystrophy. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Because MD is a genetic disorder, a primary pathological characteristic is defects in the gene’s ability to produce or contain a specific protein. Gene abnormalities differ based on the specific diagnosed subtype of MD (Emery, 2008). As mentioned previously, DMD is the most commonly occurring form of MD. Symptoms associated with DMD (the weakening of muscles) can be explained by the absence of the dystrophin protein within the gene. Mutations in the dystrophin gene are identified in more than 75% of patients with DMD or BMD. Along with other related proteins,

dystrophin retains the structure of a muscle fiber membrane. Mutations in mRNA produce a truncated dystrophin molecule in which carboxy terminus is missing thereby inhibiting proper binding with dystrophin-associated proteins at the point of the cell membrane and thus resulting in the dystrophin deficiency in the DMD type (Siddique, Sufit, & Siddique, 2007). Because individuals with DMD lack this protein, the membrane breaks down and allows leakage, thus allowing substances and molecules within the fiber to leak into the blood stream. One particular substance that leaks from the fiber is creatine kinase (CK), a muscle enzyme that is necessary for muscle contractions (Iannacome, 1992). BMD is characterized by preserved carboxy terminus, producing milder symptoms associated with this type (Matsumura et al., 1993). Besides genetic mutations present in patients with MD, some hypotheses exist regarding the effects of such deficiencies (i.e., the absence of dystrophin) on the brain. In addition to motor impairment, differences in intellectual functioning (slightly lower IQ) may be present in patients with MD. Specifically, children with DMD appear to have more difficulties in verbal IQ in comparison with performance IQ (Yiu & Kornberg, 2008). For impairments in verbal IQ, such as problems with poor long-term and working verbal memory or poor reading and expressive skills, it has been hypothesized that such difficulties are not due to structure abnormalities within the brain, but cellular abnormalities as a result of the lack of dystrophin in the brain (Hinton, De Vivo, Nereo, Goldstein, & Stern, 2001). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The primary clinical features of MD include motor delays, impairments, and/or abnormal gait. In those with DMD, children present with difficulties getting up from the ground (i.e., using hands to ‘‘crawl’’ up their legs), running, and jumping, or may display frequent falling or toe-walking, which is typically observed between 3 and 5 years (Yiu & Kornberg, 2008). Further motor impairments may be observed through proximal muscle weakness, in which the lower extremities are affected prior to the upper extremities. Patients with MD may be described as having a ‘‘waddling’’ gait, enlarged calves, and are often wheelchairbound during early adolescence (Siddique et al., 2007). Besides motor deficits evident in patients with MD, cardiovascular and respiratory complications may occur. For example, atrial and ventrical

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arrhythmias and ventricular dysfunction may develop in later childhood due to lack of physical activity, despite a high frequency of cardiac involvement (Yiu & Kornberg, 2008). Furthermore, chronic respiratory complications are typically present in patients with MD. Such individuals may develop restrictive lung disease, in which respiratory vital capacity increases, followed by an increased risk of death. In addition to the aforementioned complications associated with MD, some impairments in intellectual functioning may occur at a rate higher than that of the general population. For example, intellectual disability is observed in 30% of males with DMD, with a mean IQ of 85 (Yiu & Kornberg, 2008). Such individuals also display a higher incidence of attention deficit hyperactivity disorder. DIAGNOSIS

When developing an understanding of MD, it is imperative for individuals to consider the diagnostic measures that are taken. The diagnosis for MD is based on physical characteristics as well as medical history and testing results. Again, physical indications as mentioned in the description of the clinical presentation are useful in diagnosing MD. For example, children with DMD present with motor delays such as abnormal walking patterns, waddling, and frequent falling (Iannacome, 1992). Another physical indication of this disorder is the decreased muscle size in the calves or any muscle group. In addition to the observation of physical characteristics associated with MD, several genetic analyses are likely to be employed, including genetic counseling, prognostications, and antenatal diagnostics (Kakulas, 2008). As mentioned, patients with DMD have abnormally high levels of CK, approximately 10 times higher than normal. By examining both the physical symptoms and the CK levels, physicians have a fair indication for the diagnosis of DMD. Three diagnostic tests typically used to identify MD include blood tests, electromyography, and a muscle biopsy. Two blood tests are conducted in order to measure the levels of CK and to examine DNA mutations. An electromyography is a test that is conducted in order to measure the electrical activity of a muscle fiber, also known as an action potential. Patients with MD tend to have small measures of action potentials. The third diagnostic test, a muscle biopsy, is a crucial aspect in the diagnosis because it allows direct examination of muscle tissue. In a muscle biopsy, one must search for the dystrophin content. If dystrophin is absent from the patient’s

muscle, a diagnosis of DMD is typically appropriate. If dystrophin is present in abnormal amounts, the individual may have BMD. When interpreting the prognosis for DMD, the mean age at which the patient is no longer ambulatory is 11 years (Iannacome, 1992). Common complications of DMD include orthopedic deformities, respiratory problems, heart failure, as well as psychological needs (academic, emotional, and behavioral needs). In other subtypes of MD, however, symptoms do not appear until adulthood (i.e., oculopharyngeal muscular dystrophy). TREATMENT

While the disease progresses, it is important that physicians implement strategies to manage the complications of MD. When considering management of the disorder, the patient’s mobility and quality of life should remain the most important goal (Iannacome, 1992; Siddique, Sufit, & Siddique, 2007). In order to assist in orthopedic insufficiencies, physical therapists may work with patients and their families by introducing motion exercises that can be performed at home. Occasionally, surgical procedures are considered to correct deformities. One example of an orthopedic deformity is the presence of scoliosis, which progresses once the patient becomes wheelchair bound. Another obstacle to which an individual with MD is bound is the respiratory deficiency due to weakness in truncal muscles. Although the immune system and lung tissue is normal in MD patients, they may lack the ability to clear the airway and improve ventilation. To prevent pneumonia and respiratory failure, physicians may recommend pressure ventilation during sleep to improve oxygenation and endurance during the day. In later stages of the disease, the individual and the family may be required to decide whether they want to use artificial ventilation as a means of prolonging the life of the patient with MD. During examination of management strategies for patients with MD, physicians often consider the emotional aspects of the patients’ disorder. Families often benefit from some form of counseling during a grieving phase after a diagnosis is made. Clinical depression in patients usually results from family discord, loss of function, and fear of dying (Iannacome, 1992). Specialists may assist in dealing with the coming to terms with these aspects of MD. Although there is, unfortunately, no cure for MD, there are a variety of treatments. However, many of these treatments continue to be experimental procedures. Corticosteroids are the most commonly

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employed form of treatment, showing some efficacy in delaying motor deterioration (Siddique, Sufit, & Siddique, 2007). Although this is the most common treatment, it involves side effects that cause controversy. For example, the side effects of prednisone do not enable the trial to be truly double blind. Also, it is safer for lower doses of prednisone to be dispersed due to the side effects of steroids. Physicians must consider the fact that once an individual is nonambulatory, prednisone is no longer effective. Another treatment for MD is myoblast transfer therapy, most commonly applied to the Duchenne subtype. Here, normal muscle precursor cells (myoblasts) are introduced to muscles that are deficient of the dystrophin gene. Ideally, cells derived from other skeletal muscles will be used to genetically correct these cells and be used as a source of replacement myoblasts (Lee-Pullen & Grounds, 2005). Unfortunately, myoblast transfer may be painful due to several myoblast injections as well as repeated biopsies that evaluate the results of the treatment. An additional proposed treatment is gene therapy. For gene therapy to be effective, genetic material must somehow enter every muscle fiber in order to reverse the dystrophic process. Although these treatments have been helpful in prolonging the lives of MD patients, research continues to be done to further the potential of finding a cure. Sarah C. Connolly Chad A. Noggle Emery, A. E. H. (2008). Muscular dystrophy (3rd ed.). New York: Oxford University Press. Hinton, V. J., De Vivo, D. C., Nereo, N. E., Goldstein, E., & Stern, Y. (2001). Selective deficits in verbal working memory associated with a known genetic etiology: The neuropsychological profile of Duchenne muscular dystrophy. Journal of the International Neuropsychological Society, 7, 45–54. Iannacome, S. T. (1992). Current status of Duchenne muscular dystrophy. In J. B. Bodensteiner (Ed.), The pediatric clinics of North America — pediatric neurology (39th ed., Vol. 4, pp. 879–894). Philadelphia: W.B. Saunders Company. Kakulas, B. A. (2008). A brief history of muscular dystrophy research: A personal perspective. Neurology India, 3(56), 231–235. Lalic, T., Vossen, R. H., Coffa, J., Schouten, J. P., Guc-Scekic, M., & Radivojevic, D. (2005). Deletion and duplication screening in the DMD gene. European Journal of Human Genetics, 13, 1231–1234. Lee-Pullen, T. F., & Grounds, M. D. (2005). Muscle-derived stem cells: Implications for effective myoblast. Life, 57(11), 731–736.

Matsumara, K., Tome, F. M., Ianaescu, V., Ervasti, J. M., Anderson, R. D., Romero, N. B., et al., (1993). Deficiency of dystrophin-associated proteins in Duchenne muscular dystrophy patients lacking the COOH-terminal domains of dystrophin. Journal of Clinical Investigation, 92, 866–871. Siddique, N., Sufit, R., & Siddique, T. (2007). In C.G. Goetz (Ed.) Textbook of clinical neurology (3rd ed. pp. 781–812) Philadelphia: Saunders Elsevier. Van Deutekom, J. C. (2005). The ‘Pro-sense’ approach to Duchenne muscular dystrophy. Journal of Human Genetics, 13, 518–519. Yiu, E. M., & Kornberg, A. J. (2008). Duchenne muscular dystrophy. Neurology India, 56(3), 236–247.

MYASTHENIA GRAVIS DESCRIPTION

Myasthenia gravis (MG) is a chronic autoimmune disease that demonstrates preferential targeting and impairment of neuromuscular functioning leading to fluctuating degrees of muscle weakness and fatigability. Current estimates suggest MG has a relative prevalence of 1 out of 2,500–5,000 (Mantegazza, Baggi, Antozzi, et al., 2003; Vincent, Palace, & Hilton-Jones, 2001). It is most commonly seen in women under 40 years of age as well as men and women between the age of 50 and 70. The presentation originates from an altering, blockade, and/or destruction of acetylcholine receptors by antibodies. Clinically, weakness of eye and facial muscles are often the first symptoms. Dysphagia and dysarthria may also manifest. Peripheral involvement of the extremities may also be observed with symptoms varying based on severity. After a time of rest, symptoms usually remit. Given the presentation originates from degradation of acetylcholine receptors, thereby diminishing the levels of the neurotransmitter within the system, medicinal treatment with cholinesterase inhibitors in combination with immunosuppressants is the most common intervention. In some instances, surgical intervention is employed. With treatment, patients live fairly normal lives. NEUROPATHOLOGY/PATHOPHYSIOLOGY

MG occurs secondary to a degradation of acetylcholinesterase receptors in the neuromuscular junction by buildup of immunoglobulin G antibodies. Idiopathic in nature, no pathogenic cause has been noted.

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However, increased risk of MG has been linked with other presentations including diabetes mellitus Type I, rheumatoid arthritis, and lupus. In addition, a high portion of patients present with abnormalities of the thymus, particularly thymomas. This significant correlation is related to the thymus’ role in producing T cells that bind to the acetylcholinesterase receptors. These T cells convert B cells into plasma cells, and it is from these plasma cells that the antibodies that block the acetylcholinesterase receptors originate (Richman & Agius, 1994). This reduces the amount of sodium ions that are essential to depolarizing muscle cells and opening sodium channels eventually leading to a release of calcium. The strength of the muscular contraction is dependent upon the amount of calcium present within the muscle cells. Consequently, the hallmark histological features of MG includes decreased numbers of acetylcholine receptors, simplification of the postsynaptic cleft, and widening of the synaptic space in the presence of a normal presynaptic nerve terminal (Drachman, 1994). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The classic clinical feature of MG is pronounced muscle weakness and increased fatigability. Facial muscles are commonly, but not always, involved. Limb, axial, and respiratory muscles may also be involved. Variability is seen across cases in terms of muscles involved and severity of symptoms (ContiFine, Milani, & Kaminski, 2006; Vincent et al., 2001). In some instances, it can be just localized to the eye muscles or simply present as ptosis of either one eye or both. Dysarthria and dysphagia can occur. The severity of symptoms may be classified across five levels. At the mildest level (Class I), only eye weakness is observed. As you move through Classes 2–4, eye muscle weakness may be seen of any severity, but the involvement and severity of other muscle symptoms increases, usually being divided into subclasses based on whether limb and axial muscles are involved or bulbar or respiratory muscles are involved. In Class 5, the weaknesses are of such severity that intubation is needed to maintain integrity of the airway. Although the presentation is most commonly noted in adults, variations are seen in childhood and adolescence. Neonatal MG occurs when an affected mother passes the problematic antibodies to her unborn child via the placenta. It represents a transient disorder with symptom onset a few days after birth and resolving a few weeks later. Juvenile MG has a similar physiological basis as the adult form but presents unusually early. These variations are

distinguished from congenital myasthenia in that the latter is not caused by an autoimmune process. (For more details see the article on Congenital and Childhood Myasthenias.) DIAGNOSIS

Diagnostic consideration of MG starts with the symptom onset. Given the high prevalence of thymomas MRIs are commonly performed to determine the presence of such tumors. Repeated nerve stimulation tests can be utilized to determine the relative fatigability of muscles. In addition, performance-based assessments may be carried out including tasks such as climbing stairs, doing squats, sustained diverted gaze, and so forth. Single fiber electromyography is frequently used to determine the relative voltage of muscle impulse transmission (Rostedt, Padua, & Stalberg, 2005). A common differential diagnosis is Lambert– Eaton syndrome in which a chest X-ray is often employed to rule out. Stool samples should be evaluated to determine if there is presence of botulinum toxin which may suggest Botulism as the cause of the symptoms (Bartt & Topel, 2007). TREATMENT

The treatment of MG is largely based on the underlying cause. Given the presentation arises from a relative deficiency of acetylcholine, due to receptor blockade or destruction cholinesterase inhibitors are used with success. This is done in combination with immunosuppressant treatment to prevent the production of the abnormal antibodies. Intravenous immunoglobulins (IVIGs) have been used to target and bind to circulating antibodies (Diaz-Manera, Rojas-Garcı´a, & Illa, 2009; Gold & Schneider-Gold, 2008; Manfredi, Fasulo, Fulgaro, & Sabbatani, 2008). In those patients who present with an abnormal thymus gland, such as in the case of thymomas, surgical removal of the gland (i.e., thymectomy) may relieve symptoms (Gronseth & Barhon, 2000; Mantegazza, Baggi, Bernasconi, et al., 2003). In severe cases, plasmapheresis may be considered as a means of removing the abnormal antibodies from the blood. Chad A. Noggle Amy R. Steiner Bartt, R. E., & Topel, J. L. (2007). Autoimmune and inflammatory disorders. In C. G. Goetz (Ed.) Textbook of clinical neurology (3rd ed., pp. 1155–1184). Philadelphia, PA: Saunders Elsevier.

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Conti-Fine, B. M., Milani, M., & Kaminski, H. J. (2006). Myasthenia gravis: Past, present, and future. Journal of Clinical Investigation, 116, 2843–2854. Diaz-Manera, J., Rojas-Garcı´a, R., & Illa, I. (2009). Treatment strategies for myasthenia gravis. Expert Opinion on Pharmacotherapy, 10(8), 1329–1342. Drachman, D. B. (1994). Myasthenia gravis. New England Journal of Medicine, 330, 1797–1810. Gold, R., & Schneider-Gold, C. (2008). Current and future standards in treatment of myasthenia gravis. Neurotherapeutics, 5(4), 535–541. Gronseth, G. S., & Barhon, R. J. (2000). Practice parameter: Thymectomy for autoimmune myasthenia gravis (an evidence-based review): Report of the quality standards subcommittee of the American Academy of Neurology. Neurology, 55, 7–15. Manfredi, R., Fasulo, G., Fulgaro, C., & Sabbatani, S. (2008). Associated thyreoiditis, myasthenia gravis, thymectomy, Chron’s disease, and erythema nodosum: Pathogenetic and clinical correlations, immune system involvement, and systemic infectious complications. Rheumatology International, 28(11), 1173–1175. Mantegazza, R., Baggi, F., Antozzi, C., Confalonieri, P., Morandi, L., Bernasconi, P., et al. (2003a). Myasthenia gravis (MG): Epidemiological data and prognostic factors. Annals of the New York Academy of Sciences, 998, 413–423. Mantegazza, R., Baggi, F., Bernasconi, P., Antozzi, C., Confalonieri, P., Novellino, L., et al. (2003b). Video-assisted thoracoscopic extended thymectomy and extended transsternal thymectomy (T-3b) in nonthymomatous myasthenia gravis patients: Remission after 6 years of follow-up. Journal of the Neurological Sciences, 212, 31–36. Richman, D. P., & Agius, M. A. (1994). Myasthenia gravis: Pathogenesis and treatment. Seminars in Neurology, 14, 106–110. Rostedt, A., Padua, L., & Stalberg, E. V. (2005). Correlation between a patient-derived functional questionnaire and abnormal neuromuscular transmission in myasthenia gravis patients. Clinical Neurophysiology, 116, 2058–2064. Vincent, A., Palace, J., & Hilton-Jones, D. (2001). Myasthenia gravis. Lancet, 357, 2122–2128.

MYOCLONUS DESCRIPTION

Myoclonus is defined as a sudden, rapid, involuntary jerking of a muscle or a group of muscles (Factor & Weiner, 2004) and is observed as a presenting symptom of a variety of disorders, often termed hyperkinetic movement disorders or dyskinesias,

which may be described as positive or negative suggesting their underlying cause. Specifically, positive myoclonus is caused by muscular contraction whereas negative myoclonus is caused by muscular inhibitions. These jerks or twitches are unable to be controlled by the patient and can be the result of voluntary movement or a simple response to an external event. Due to the sporadic and unpredictable nature of myoclonic jerks, it is often difficult to determine true triggers for their occurrence. Myoclonus is a symptom that is often classified in a variety of ways. However, due to the great number of situations in which myoclonus presents, it is often difficult to classify in simple terms. The most clear-cut definition of myoclonus is a brief muscle twitch, followed by relaxation. Some common forms of myoclonus are present in patients with multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, Creutzfeldt–Jakob’s disease, epilepsy, and certain sleep disorders (National Institute of Neurological Disorders and Stroke [NINDS], 2000). NEUROPATHOLOGY/PATHOPHYSIOLOGY

According to research done by the NINDS, there are specific locations in the brain, particularly in the brainstem, that create myoclonic responses. For example, rhythmical myoclonus has been most commonly associated with segmental lesions of the brainstem and spinal cord. These may be the direct result of an injury or they may be genetically influenced. In the case of injury to the brain, one case study reported patients had functional impairment (difficulty holding a cup, tremors in the hands) after the injury, following otherwise normal cognitive and physical development (Balci, Utku, & Cobanoglu, 2007). Similarly, some types of peripheral myoclonus may be related to localized injury to those nerves causing transient inhibition or activation of those corresponding muscles. In most other cases, it is believed that generalized impairment of the central nervous system is the cause of myoclonus. Beyond the brainstem, high-amplitude somatosensory evoked potentials with cortical spikes have been linked with cortical reflexive myoclonus (Fahn, 2007). On a more general level, myoclonus is related to hyperexcitability of neurons causing either sudden muscular contraction or inhibition. Although it is evident that there is a link between the brain and myoclonus, there also appears to be recent research of types of myoclonus linking to specific genes, especially in regard to myoclonic epilepsy (Striano et al., 2004). Research done in Europe and Japan on autosomal-dominant myoclonus and epilepsy have also corroborated this familial link

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(Guerrini, Bonanni, & Patrignani, 2001; Laubage et al., 2002; Uyama, Fu, & Ptacek, 2005, Van Rootselaar et al., 2005) NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

As mentioned, there are many disorders in which myoclonus is observed and many ways in which it may present clinically. Simple, nonpathological forms of myoclonus, such as a hiccup or a sudden jerk immediately upon falling asleep, occur in many individuals and are not problematic. However, more severe forms of myoclonus may involve repetitive twitches, several times a minute, that may start in one area of the body and either remain isolated or spread to other muscles (NINDS, 2000). This form of myoclonus may significantly inhibit the patient’s gross and fine motor skills, including the ability to walk, eat, write, or talk. In clinical assessments, the individual may have difficulty completing pencil and paper tasks, have abnormal gait, or slurred speech due to these myoclonic jerks. Patients may report these symptoms to occur very frequently (several times a minute), or infrequently (several times a day). Triggers to the myoclonic jerks may be undetectable to the patient or may be in direct response to certain stimuli, such as bright light, certain sounds, or touch (NINDS, 2000). Often, if triggers are undetectable to the patient, they may be identified with an electroencephalogram (EEG), as they could be the result of low oxygen to the brain (postanoxic myoclonus). They may also report distinguishing patterns or circular movements, or sporadic, isolated events, which are all common presentations of myoclonus. As is evident, the majority of presenting problems with myoclonus are related to sensorimotor challenges. Striano et al. (2004) looked at cognitive abilities with relation to myoclonic epilepsy and found no significance. They also examined the developmental processes of their small sample and found no link to developmental difficulties with late-onset symptomology. Depending on the severity and time of onset of symptomology, emotional or psychological factors may manifest as a result of difficulties in social and interpersonal situations due to myoclonus. DIAGNOSIS

Diagnosis of myoclonus can be very difficult due to the great number of similar presenting behaviors. It often requires the use of more sophisticated neuroimaging techniques to differentiate with other

disorders. Terminology to describe the outward signs of myoclonus such as tremors, twitches, jerks, tics, and/or seizures are all used by clinicians, further complicating the diagnostic process (Gilbert, 2006). In fact, at times, clinicians may mistake myoclonus for simple seizures, making specific diagnostic criteria a necessity. It appears the simplest way to diagnose myoclonus is to better understand the various classifications, which may then lead to better understanding of etiology and treatment. The following is a brief description of several ways to classify myoclonus. Location

Cortical reflex myoclonus originates in the cerebral cortex and usually manifests in one part of the body and may be worsened when voluntary movements are attempted. Spinal or segmental myoclonus, also reticular reflex myoclonus, originates around the spinal cord and brainstem, often causing more severe jerks, affecting the entire body. Palatal myclonus is a form of segmental myoclonus identified as a twitching or contraction of the soft palate, which may also include other muscles in the face, throat, or mouth, causing repetitive sounds in the ear, often eliciting minor complaints from the individual. Parts of the Body Involved

Focal myoclonus involves only one part of the body, and multifocal myoclonus involves many parts of the body simultaneously. If only one segment of the body is affected, it is considered segmental myoclonus, and if the entire body is involved it is considered generalized myoclonus. Muscle Response

Myoclonus can be classified as either a muscle contraction, positive myoclonus, or by the muscle relaxation, negative myoclonus. These are often observed and identified by neuroimaging techniques, such as EEG. Related Cause

Some common types of myoclonus, as mentioned, are physiological in nature and are experienced by almost everyone, including the startle response, initial sleep jerks, and hiccups. Others may be classified as primary myoclonus, as they are not the direct effect of some other medical cause. These forms of myoclonus can be inherited, such as essential myoclonus and generally remain stable over time. Secondary myoclonus is the

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most common form, as this is the case when it is the symptom of a disorder, brain injury, or a reaction to a medication or intervention.

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The best possible treatment for myoclonus is inherent in identification of the cause of the symptom. Treatment is usually an attempt to decrease or eliminate the twitches and typically involves medication such as clonazepam, or similar types of tranquilizers. When epilepsy is identified as the cause, treatment may involve medications specific to the epileptic symptoms, such as certain barbiturates. If peripheral myoclonus is identified, surgical techniques may be used to decompress the injured area. Due to the varying etiology of myclonus, it may require multiple trials of medications, or multiple medications for symptoms to subside.

Striano, P., Chifari, R., Striano, S., de Fusco, M., Elia, M., Guerrini, R., et al. (2004). A new benign adult familial myoclonic epilepsy (BAFME) pedigree suggesting linkage to chromosome. Epilepsia, 45, 190–192. Uyama, M. D., Fu, Y. H., & Ptacek, L. (2005). Familial adult myoclonic epilepsy (FAME). In A. V. Delgado-Escueta, R. Guerrini, M. T. Medina, P. Genton, & M. Bureau (Eds.), Advances in neurology. Myoclonic epilepsies (Vol. 95, Chap. 22, pp. 281–288). Philadelphia, PA: Lippincott Williams & Wilkins. Van Rootselaar, A. F., van Schaik, I. N., van den Maagdenberg, A. M., Koelman, J. H., Callenbach, P., & Tijssen, M. (2005). Familial cortical myoclonic tremor with epilepsy: A single syndromic classification for a group of pedigrees bearing common features. Movement Disorders, 20, 665–673.

MYOPATHY

Beth Trammell Raymond S. Dean DESCRIPTION Balci, K., Utku, U., & Cobanoglu, S. (2007). Two patients with tremor caused by cortical lesions. European Neurology, 57, 36–38. Factor, S. A., & Weiner, W. J. (2004). Hyperkinetic movement disorders. In W. J. Weiner & C. Goetz (Eds.), Neurology for the non-neurologist (5th ed., pp. 155–204). Philadelphia, PA: Lippincott, Williams, & Wilkins. Fahn, S. (2007). Hypokinesia and hyperkinesias. In C. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 289–306). Philadelphia, PA: Saunders Elsevier. Gilbert, D. (2006). Treatment of children and adolescents with tics and Tourette syndrome. Journal of Child Neurology, 21, 690–700. Guerrini, R., Bonanni, P., & Patrignani, A. (2001). Autosomal dominant cortical myoclonus and epilepsy (ADCME) with complex partial seizures and generalized seizures: A newly recognized epilepsy syndrome with linkage to chromosome. Brain, 124, 2459–2475. Laubage, P., Amer, L. O., Simonetta-Moreau, M., Attane, F., Tannier, C., Clanet, M., et al. (2002). Absence of linkage to 8q24 in a European family with familial adult myoclonic epilepsy (FAME). Neurology, 58, 941–944. Martens, P., & Dyken, R. (2007). Storage diseases: Neuronal ceroid-lipofuscinoses, lipidoses, glycogenoses, and leukodystrophies. In C. Goetz (Ed.), Textbook of clinical neurology (pp. 612–639). Philadelphia, PA: Saunders Elsevier. National Institute of Neurological Disorders and Stroke. (2000). NINDS myoclonus information page. Retrieved March 8, 2009, from http://www.ninds.nih.gov/ disorders/myoclonus/myoclonus.htm

The term ‘‘myopathy’’ can be used to define any disease or syndrome in which the patient’s symptoms and/or physical signs can be attributed to pathological, biochemical, or electrophysiological changes that are occurring in the muscle fibers (or muscular interstitial tissues) for which there is no evidence that the symptoms are entirely secondary to the disordered function of the central or peripheral nervous system. This group of diseases includes many disorders that are genetically determined, as well as others of metabolic origin, and still others in which the disease process is inflammatory. Common disorders classified under myopathy would include certain muscular dystrophies, such as Duchenne’s dystrophy, congenital myopathies, and mitochondrial myopathies. In general, muscular myopathies are characterized by patterns of proximal shoulder and hip girdle weakness with preservation of distal strength, reduction of reflexes proportionate to reduced strength, and lack of sensory abnormalities (Hammerstaad, 2007). NEUROPATHOLOGY/PATHOPHYSIOLOGY

It would be impossible to offer a concise discussion of the underlying pathophysiology of the myopathies as it encompasses such a wide variety of disorders. In all cases, the pathological basis corresponds with a disruption of the integrity of muscle fibers. For specifics regarding the individual presentations that fall

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under this umbrella, readers are recommended to see the respective articles within this text, including Congenital Myopathy, Mitochondrial Myopathies, Mitochondrial Cardiomyopathy, Muscular Dystrophy. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Patients with some form of myopathy often present with an uncommon syndrome of benign exertional muscle pain for which no cause has been identified (Ropper & Brown, 2005, chapter 51). Atrophy may occur but develops slowly over the years in relation to reduced usage. As previously noted, in general, the myopathies are characterized by patterns of proximal shoulder and hip girdle weakness with preservation of distal strength, reduction of reflexes proportionate to reduced strength, and lack of sensory abnormalities (Eisenchenk, Triggs, Pearl, & Rojiani, 2001; Hammerstaad, 2007; Hund et al., 1997). Ptosis, open mouth expression, and reduced facial mobility are seen at higher rates across the myopathies (Hammerstaad, 2007). DIAGNOSIS

Clinical data, an electromyogram (EMG), and a muscle biopsy are used in conjunction when a diagnosis of muscle disease is made. None of the three approaches is entirely adequate by itself, but their combined use yields the correct diagnosis in a very high proportion of cases (Eisenchenk et al., 2001; Spuler et al., 2008). Within the clinical data, the genetic history, history of the illness, symptoms of muscle diseases, and the clinical examination are important considerations. The patient’s genetic history is relevant to diagnosis as well as knowledge regarding the muscular dystrophies, congenital myopathies, and inherited metabolic myopathies (Kataeva, Krasik, & Komandenko, 1992). A negative family history, however, does not exclude autosomal recessive inheritance or a new mutation. In autosomal dominant disorders, a negative family history needs to be validated by examination of both parents. The clinical examination of biochemical tests may help in detecting a heterozygote in autosomal recessive or X-linked recessive diseases. Upon examination of the history of the illness, one should pay particular attention to age of onset, duration, and rate of progression of symptoms. Most benign congenital myopathies, congenital muscular dystrophies, and inherited metabolic myopathies present in infancy. Duchenne’s dystrophy usually presents in early childhood. Most inherited myopathies

present in childhood or early adult life. Muscle weakness that evolves over a few hours suggests an exogenous intoxication (i.e., poisoning), whereas an abrupt onset of symptoms indicates defects with neuromuscular transmission. Relatively few symptoms are associated with diverse muscle diseases; these include weakness, decrease of muscle bulk, increased fatigability, muscle pain, cramps, stiffness, and discoloration of urine caused by myoglobinuria. Vague complaints, such as constant fatigue and exhaustion, as well as weakness of the cranial, cervical, torso, and limb muscles present stereotypically. In evaluating abnormal fatigability, it is important to define the duration and intensity of the exercise that provokes fatigue. In patients with defects of neuromuscular transmission, even mild exercise can induce fatigue. The clinical examination should include inspection and manual muscle testing. Inspection can reveal muscle atrophy, hypertrophy, contractures, fasciculations, and winging of scapulas (Eisencehnk et al., 2001; Hund et al., 1997; Spuler et al., 2008). Inspection provides information on the distribution of weakness, which is confirmed by detailed manual muscle testing. The manual muscle testing part of the examination requires knowledge of the origin, insertion, action, and innervation of the muscles tested, a consistent technique, and a generally accepted rating scale (Ropper & Brown, 2005). This evaluation helps determine the distribution of the weakness and aids in diagnosis because increasing weakness in proximal versus distal muscles suggests a myopathy rather than a neuropathy. EMG is a test that consists of the analysis of spontaneous, evoked, and voluntarily generated potentials from nerve and muscle. This procedure is useful in distinguishing between broad categories of disease, such as myopathy versus neuropathy. The final approach, the muscle biopsy, makes use of biopsy specimens for light microscopic, ultrastructural, and biochemical studies. Typically, muscles showing mild to moderate weakness are biopsied. TREATMENT

Because of the nature and diversity of the causes of muscular weakness and wasting, no single suggested medical treatment is viable. Depending upon the specific characteristics and features of the myopathy, numerous treatments may be employed. Unfortunately, no drug has any influence upon the course of the disease, though complications such as respiratory and urinary infections may demand antibiotics. Physical exercise appears to delay the continued

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weakness and onset of contractures; a regular exercise program of activities may be started under the supervision of a skilled physiotherapist and subsequently continued at home. Such exercise would include regular passive stretching of those tendons that show a tendency to shorten. In certain cases, operative procedures for the control of scoliosis may be justified, whereas in select cases, surgical lengthening of shortened tendons is advised. However, immobilization or prolonged bed rest resulting from surgery must be avoided as these inevitably cause rapid deterioration. The additional burden of obesity or excess weight should be avoided and caloric requirements are likely to be less than normal. Physicians working with patients diagnosed with muscle diseases are familiar with harsh complaints of diffuse muscular pain that is induced by minimal effort and greatly restricts activity but for which no physical or biochemical cause has presently been determined. Some individuals are of obsessional and introspective temperament; it is likely that some of their symptoms may have an emotional origin. Treatment with tranquillizing drugs is rarely helpful. Treatment with analgesic and relaxant drugs is often of little if any benefit, and symptoms may prove to be both persistent and disabling. Occasionally, a reflex contraction indicative of myopathies will be accentuated or evoked by anxiety in the patient. Genetic counseling has been suggested as a treatment option such that the heredity nature of many myopathies can be recognized. Genetic counseling should be no different from counseling by a physician for any other illness. The facts should be clearly presented to all concerned family members so a rational decision about further pregnancies can be made. Information should be presented simply as patients often misunderstand and misinterpret genetic information during counseling sessions. Follow-up visits and written communications are usually helpful. Psychological management demands considerable patience and understanding on the part of parents and/or family members, doctors, nurses, and social workers. Support, optimism, and encouragement are of great importance in the face of continuing deterioration. Patients and families can be referred for genetic counseling and support counseling by physicians and health care personnel. Patients and families should be made aware of early diagnosis, carrier detection, and prevention. Matthew Holcombe Raymond S. Dean Chad A. Noggle

Eisenchenk, S., Triggs, W. J., Pearl, G. S., & Rojiani, A. M. (2001). Proximal myotonic myopathy: Clinical, neurpathologic, and molecular genetic features, Annals of Clinical & Laboratory Science, 31(2), 140–146. Hammerstaad, J. P. (2007). In C. Goetz (Ed.) Textbook of clinical neurology (3rd ed., pp. 243–288). Philadelphia: Saunders Elsevier. Hund, E., Jansen, O., Kock, M. C., Ricker, K., Fogel, W., Neidermaier, N., et al. (1997). Proximal myotonic myopathy with MRI white matter abnormalities of the brain. Neurology, 48, 33–37. Kataeva, N., Krasik, E., & Komandenko, N. (1992). Neuropsychic syndromes in hereditary neuromuscular pathology. Zhurnal Nevropatologii i Psikhiatrii imeni S.S. Korsakova, 92(4), 31–35. Ropper, A. H. & Brown, R. H. (2005). Adams and Victor’s principles of neurology (8th ed., Ch. 51, pp. 1230–1243). New York: McGraw-Hill. Spuler, S., Carl, M., Zabojszcza, J., Straub, V., Bushby, K., Moore, S., et al. (2008). Dysferlin-deficient muscular dystrophy features amyloidosis. Annals of Neurology, 63(3), 323–328.

MYOTONIA DESCRIPTION

Myotonia is an intrinsic disorder of muscle caused by defects in either ion channel or muscle membrane function. Clinically, myotonia in the individual muscle fibers summates to produce a prolonged time for relaxation after voluntary muscle contraction and external mechanical stimulation (Hudson, Ebers, & Bulman, 1995). Patients with myotonia may report painless muscle stiffness immediately upon initiating muscle activity after a period of rest, for example, trouble climbing stairs after a period of sitting. Myotonia may be demonstrated by asking the patient to make tight fists and then to quickly open the hands or inability to release hand grip after a strong handshake. The patient may have a lag in opening the eyes after initial tight eyelid closure. It may be induced by striking the thenar eminence with a percussion hammer, and it may be detected by watching the involuntary drawing of the thumb across the palm. Myotonia may also be demonstrated in the tongue by pressing the edge of the wooden tongue blade against its dorsal surface and by observing the deep furrow that disappears slowly. Myotonia improves with

MYOTONIA & 511

muscle exercise or repeated efforts, the so-called ‘‘warm-up phenomenon.’’ Another phenomenon known as paramyotonia, is also a painless muscle stiffness that is associated with exercise rather than improving with exercise, that is, there is no warming-up phenomenon. It is usually not difficult to distinguish them from muscle cramps that present with a sudden and painful focal muscle contracture. Myotonic disorders are classified into dystrophic myotonias (DM) and nondystrophic myotonias (Figure 1).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

Both myotonia and paramyotonia are associated with myotonic discharge on electromyogram (EMG). The classical myotonic EMG shows spontaneous runs of motor unit potentials with a characteristic waxing and waning of both amplitude and frequency, producing a sound often reminiscent of a World War II dive

bomber or a motor cycle engine when audio-amplified. By definition, myotonic discharges last 500 ms or longer and should be identified in at least three areas of an individual muscle outside of an endplate region (Streib, 1987). Although most patients with myotonia have myotonic dystrophy, myotonia is not specific for this disease and occurs in several rarer conditions. The differential diagnosis may be divided on the basis of presence of electrical myotonia and the clinical picture (myotonia/paramyotonia/both absent) (Miller, 2008). The myotonia is seen in myotonic dystrophies and myotonia congenita. The paramyotonia is seen in paramyotonia congenita (Miller, 2008). Only electrical myotonia without clinical myotonia is seen in acid maltase deficiency (Miller, 2008). Schwartz– Jampel’s syndrome (chondrodystrophia myotonia), McArdle’s disease (glycogenosis Type 5), Hoffman’s disease (myotonia in hypothyroidism), Brody’s disease (sarcoplasmic reticulum — Ca2þATPase deficiency), neuromyotonia, neuroleptic malignant syndromes, and tetanus may mimic clinical myotonia, but they

Figure 1 Classification of myotonic disorders DM 1 Paramyotonia Congenita Myotonic Dystrophies (DM)

Hyperkalemic Periodic Paralysis with Paramyotonia

DM 2

Myotoniafluctuans DM 3

Hyperkalemic Periodic Paralysis with myotonia

PotassiumAggravated Myotonias

Myotonic Disordess

Myotonia Permanens

Sodium Channelopathie

Acetazolamide Responsive Myotonia

Nondystrophic Myotonias Becker’s Myotonia

Chloride Channelopathies (Myotonia Congenta) Thomsen’s Myotonia

Source: Adapted from (Heatwole & Moxley, 2007).

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lack characteristic electrodiagnostic features (pseudomyotonia) (Heatwole & Moxley, 2007; Trip, Drost, van Engelen, & Faber, 2006). DM is inherited as an autosomal-dominant trait. It often exhibits a pattern of anticipation in which each successive generation has a tendency to be more severely involved (Kliegman, Stanton, Geme, Schor, & Behrman, 2007). DM Types 1 and 2 have RNAmediated disease mechanism. DM Type 1 is caused by cytosine-thymine-guanosine (CTG) trinucleotide repeat expansion on chromosome 19q13.3 in the 3 0 untranslated region in the dystrophia myotonica protein kinase (DMPK) gene (Brook et al., 1992). DM Type 2 is caused by cytosine-cytosine-thymine-guanosine repeat expansion in the first intron in zinc finger protein 9 gene on chromosome 3q21 (Liquori et al., 2001). The expanded repeat is transcribed in RNA and forms discrete inclusions in the nucleus. Mutant RNA sequesters MBNL1, a splice regulator protein and depletes MBNL1 from the nucleoplasm. The loss of MBNL1 results in altered splicing of CIC-1 mRNA. Altered splice products do not encode functional CIC-1 protein. This defect causes loss of chloride conductance in the muscle membranes leading to myotonia. The nondystrophic myotonias are pure skeletal muscle diseases without the involvement of other organ systems. They are ion channel disorders caused by mutations/deletions in the genes encoding chloride (CIC-1) or sodium (SCN4A) channels expressed exclusively in skeletal muscles (Koch et al., 1992; McClatchey et al., 1992; Ptacek et al., 1992, 1994). There are two forms of chloride channel disorders: autosomal recessive myotonia congenita (Becker’s disease) and autosomal-dominant myotonia congenita (Thomsen’s disease). They are discussed in detail in another article entitled Myotonia Congenita. Sodium channel disorders are all autosomal-dominantly inherited or sporadic. The exact prevalence of sodium channel diseases is not known although the prevalence of paramyotonia congenita has been estimated at 1 per 356,000 (Trip et al., 2006). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

DM 1 commonly presents between 20 and 40 years of age, whereas DM 2 commonly presents between 30 and 40 years of age. Severe congenital form is seen in a minority of cases and to date have had the DM 1 form only (Kliegman et al., 2007). Clinical diagnosis can be easily made by the combination of myotonia and the characteristic pattern of muscle wasting and weakness that include weakness of superficial facial muscle, levator palpebrae superioris, temporalis,

masseter and palate with resultant ptosis, dysarthria and hatchet face. DM 1 has a prominent distal distribution of myopathy while DM 2 has predominant proximal distribution involving limb girdles, the socalled proximal myotonic myopathy. DM causes dysfunction in multiple organ systems. Not only is the striated muscle severely affected but smooth muscle of the alimentary tract and uterus are also involved; cardiac function is altered; and patients have multiple variable endocrinopathies, immunologic deficiencies, cataracts (characteristic Christmas tree–like appearance), dysmorphic facies, frontal balding, and other neurologic abnormalities (Kliegman et al., 2007). About half of the patients with DM are intellectually impaired, but severe mental retardation is unusual. Cognitive impairment may be due to accumulation of mutant DMPK mRNA and aberrant alternative splicing in the neurons (Kliegman et al., 2007). As noted, the nondystrophic myotonias are pure musculoskeletal diseases without the involvement of other organ systems. The myotonic disorder without progressive weakness, wasting, and dystrophic histopathology fall into this category. Figure 1 shows the classification of nondystrophic myotonias. Nondystrophic myotonia can be dramatic and sometimes disabling. Emotional surprises, cold exposure, potassium ingestion, or exercise are potential triggers of nondystrophic myotonia. DIAGNOSIS

The primary diagnostic test of DM is a DNA analysis of blood to demonstrate the abnormal expansion of the CTG repeat. The muscle biopsy specimen may be useful in older children, which revels prominent pyknotic nuclear clumps, increased internal nuclei, variable muscle fiber size, muscle fiber atrophy involving Type 1 fiber in DM 1 and Type 2 fiber in DM 2. There is an absence of fibrosis, necrosis, and regeneration. Muscle biopsy is not usually required for diagnosis, which in typical cases can be based on the clinical manifestation. Diagnosis of nondystrophic myotonia is mostly based on clinical presentation, which includes history and physical examination. Ancillary tests such as EMG and nerve conduction studies may be helpful. Clinical response to cold exposure or exercise testing can help in classification, and it is useful to inquire about these responses before undertaking electrodiagnostic testing. Cold frequently worsens myotonia in paramyotonia congenita and acetazolamide-responsive myotonia (Russell & Hirsch, 1994). Gene tests are usually not required to make the diagnosis, and there is an absence of significant histopathology in the muscle

MYOTONIA CONGENITA & 513

biopsy. Clinically, the nondystrophic myotonias can usually be differentiated based on their inheritance pattern, response to stimuli/triggers, electrodiagnostic features, muscle histology, genetic mutations, and myotonia characteristic (Hudson et al., 1995). TREATMENT

Myotonia is rarely disabling in DM. Patients often do not require specific medical therapy for myotonia. Sodium channel blockers (procainamide, phenytoin, and mexiletine), tricyclic antidepressive drugs, benzodiazepines, calcium-antagonists, taurine, and prednisone may be of use in reducing myotonia (Trip et al., 2006). To date, we do not have any medication to open chloride channels of the skeletal muscles. Due to insufficient good quality data and lack of randomized studies, it is impossible to determine whether drug treatment is safe and effective in the treatment of myotonia. Small single studies give an indication that clomipramine and imipramine have a short-term beneficial effect and that taurine has a long-term beneficial effect on myotonia (Trip et al., 2006). Management of DM remains at best supportive comprehensive care including patient education, genetic counseling, regular monitoring of cardiac rhythm, early detection of respiratory and swallowing problems, avoidance of anesthesia-related complications, cataract surgery, and provision of physical therapy, occupational therapy, speech and swallowing therapy, and community outreach social welfare programs (Mankodi, 2008). Myotonia and other symptoms are easily manageable by activity modifications, avoiding certain triggers, and pharmacological therapies (as discussed above). Prognosis is generally excellent. Gaurav Jain Sarita Singhal Chad A. Noggle Brook, J. D., McCurrach, M. E., Harley, H. G., Buckler, A. J., Church, D., Aburatani, H., et al. (1992). Molecular basis of myotonic dystrophy: Expansion of trinucleotide repeat at the 3’ end of the transcript encoding at protein kinase family member. Cell, 68, 799–808. Heatwole, C. R., & Moxley, R. T., III. (2007). The nondystrophic myotonias. Neurotherapeutics, IV, 238–251. Hudson, A. J., Ebers, G. C., & Bulman, D. E. (1995). The skeletal muscle sodium and chloride channel diseases. Brain, 118, 547–563. Kliegman, R. M., Stanton, B. M. D., Geme, J. S., Schor, N., & Behrman, R. E. (Eds.). (2007). Nelson textbook of pediatrics (18th ed., pp. 2544–2546). Philadelphia: Saunders Elsevier.

Koch, M. C., Steinmeyer, K., Lorenz, C., Ricker, K., Wolf, F., Otto, M., et al. (1992). The skeletal muscle chloride channel in dominant and recessive human myotonia. Science, 257, 797–800. Liquori, C. L., Ricker, K., Moseley, M. L., Jacobsen, J. F., Kress, W., Naylor, S. L., et al. (2001). Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science, 293, 864–867. Mankodi, A. (2008). Myotonic disorders. Neurology India, 56(3), 298–304. McClatchey, A. I., Van den Bergh, P., Pericak-Vance, M. A., Raskind, W., Verellen, C., McKenna-Yasek, D., et al. (1992). Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita. Cell, 68, 769–774. Miller, T. M. (2008). Differential diagnosis of myotonic disorders. Muscle and Nerve, 37, 293–299. Ptacek, L. J., George, A. L. Jr., Barchi, R. L., Griggs, R. C., Riggs, J. E., Robertson, M., et al. (1992). Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita. Neuron, 8, 891–897. Ptacek, L. J., Tawil, R., Griggs, R. C., Meola, G., McManis, P., Barohn, R. J., et al. (1994). Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Neurology, 44, 1500–1503. Russell, S. H., & Hirsch, N. P. (1994). Anaesthesia and myotonia. British Journal of anaesthesia, 72, 210–216. Streib, E. W. (1987). Differential diagnosis of mytonic syndromes. Muscle Nerve, 10, 603–615. Trip, J., Drost, G., van Engelen, B. G., & Faber, C. G. (2006). Drug treatment for myotonia. Cochrane Database of Systematic Reviews, (1), CD004762.

MYOTONIA CONGENITA DESCRIPTION

Myotonia congenita was first described by Thomsen in 1876, whose family, including Thomsen himself, suffered with the disease (Lossin & George, 2008). It is a nondystrophic type of myotonia (see Figure 1 on p. 511) that includes Thomsen’s myotonia congenita and Becker’s myotonia congenita. The two additional variants of Thomsen’s disease are myotonia levior and fluctuating myotonia congenita (Hudson, Ebers, & Bulman, 1995). All forms of myotonia congenita are caused by mutations that result in impaired functioning of the skeletal muscle chloride channel (ClC-1) that leads to

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an increase in sarcolemmal excitability that clinically presents as delayed muscular relaxation (myotonia) (Cannon, 2006). The disorder may be transmitted as either an autosomal-dominant or recessive trait with close to 130 currently known mutations (Lossin & George, 2008). They are pure skeletal muscle diseases without multisystem involvement. The estimated worldwide prevalence of myotonia congenita is approximately 1:100,000 (Emery, 1991). NEUROPATHOLOGY/PATHOPHYSIOLOGY

All forms of myotonia congenita have dysfunction of chloride conductance and have mutations affecting the skeletal muscle voltage-gated chloride channel gene (CLCN1) at its chromosome 7q locus (Shapiro & Ruff, 2002). The responsible mutations of CLCN1 alter the skeletal muscle chloride channel protein, ClC-1 (Lehmann-Horn & Rudel, 1995). A reduction in chloride conductance occurs and leads to membrane hyperexcitability. Myotonia results due to reduced chloride conductance across the transverse tubular system (Shapiro & Ruff, 2002). In normal muscle, a high chloride conductance allows for fast repolarization of the t-tubules, largely eliminating recurrent depolarization. In myotonia congenita, depolarization results in repetitive firing of the muscle fiber and subsequent myotonia. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The affected individuals describe muscular stiffness upon initiating movements. The stiffness remits with several repetitions of the same movements, giving rise to so called warm-up phenomenon. (Refer to the article on mytonia for further details about myotonia.) Thomsen’s disease is dominantly inherited and is usually evident during early infancy. The first symptom may be delayed relaxation of the eyelids after forceful closure following sneezing or crying (von Graefe’s sign or lid lag) (Wakeman, Babu, Tarleton, & Macdonald, 2008). The predominant features of Thomsen’s disease are a painless, transient, muscle stiffness with a predilection for both the upper extremity and the facial muscles (Davies & Hanna, 1999). It can vary in severity from mild to moderate. There are no central nervous system manifestations. Social and cognitive regression does not occur, nor does significant occupational limitation (Gutmann & Phillips, 1991). However, a psychiatric burden can be evident, especially in young males where muscular hypertrophy is obvious, mockery and misunderstanding by peers on account of poor physical performance and ‘‘clumsiness’’ can be

problematic (Lossin & George, 2008). Life expectancy is normal, and the affected individual can lead a satisfying and successful life. Becker’s disease, or recessive generalized myotonia, is an autosomal recessive form of myotonia congenita (Lossin & George, 2008). Compared with Thomsen’s disease, Becker’s disease is more common, more insidious, and has later onset (Heatwole & Moxley, 2007). It is characterized by moderate to severe myotonia with associated transient weakness (typically lasting seconds to minutes), slowly progressive weakness (more common in lower extremities), and eventual wasting in some patients or more pronounced lower extremity hypertrophy in others. Overall, the prognosis is good in Becker’s disease, with no reduction in life expectancy (Gutmann & Phillips, 1991). Cognitive regression does not occur. However, some may develop a crippling disability from their lack of strength (Gutmann & Phillips, 1991; Shapiro & Ruff, 2002). Two additional forms of myotonia congenita have been described: myotonia levior and fluctuating myotonia congenita (Heatwole & Moxley, 2007). Whether these two entities are truly distinct disorders is under debate, and some propose that they are variants of Thomsen’s disease (Hudson, Ebers, & Bulman, 1995). The clinical and diagnostic features of the chloride channel nondystrophic myotonias are summarized in Table 1 (Heatwole & Moxley, 2007; Lossin & George, 2008; Mankodi, 2008). DIAGNOSIS

The diagnosis of myotonia congenita is mostly based on clinical presentation including a careful history and physical examination (Mankodi, 2008). A family history of myotonia is helpful for distinguishing subtypes in some, but not all, cases, owing to variable expressivity (Lossin & George, 2008). Ancillary tests such as electromyography (EMG) and nerve conduction studies may be helpful. The EMG reveals typically myotonic discharges in many muscles. Motor unit potentials are normal in morphology. Sensory and motor conduction studies are normal. Repetitive nerve stimulation and short exercise test may show decline in compound muscle action potential (larger decline in Becker’s subtype). Long exercise tests may reveal a small decrement in Becker’s disease but is not a feature of Thomsen’s disease (Heatwole & Moxley, 2007). Laboratory tests show a trend toward more pronounced elevation in serum creative phosphokinase in Becker’s subtype than in Thomsen’s disease (Lossin & George, 2008). Genetic testing usually

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Table 1 CLINICAL SUBTYPES OF MYOTONIA CONGENITA

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Thomsen’s Disease Variants Thomsen’s Disease

Fluctuating Myotonia Congenita

Myotonia Levior

Becker’s Disease

Inheritance chromosome

Dominant 7q

Dominant 7q

Dominant 7q

Recessive 7q

Age of onset

Early first decade

Late first decade

First decade to early second decade

Late first decade

Muscles involved

Upper extremity and face > lower extremity

Lower extremity, ocular and masticatory muscles

Predominantly grip

Lower extremity > upper extremity

Severity

Moderate

Mild to moderate (fluctuating)

Mild to moderate

Moderate to severe

Muscle hypertrophy

Yes

No

No

Yes (mostly at lower extremity)

Pain

No

Yes

No

Rare

Movement after rest, cold, pregnancy, fasting state, emotional stress

Movement after rest or maintenance of posture

Provocative stimuli

Movement after prolonged rest, cold, pregnancy, emotional surprise

Movement after rest or maintenance of posture, cold

Nerve conduction studies

Normal; repetitive stimulation may see moderate decremental response

Normal

Normal

Decremental response to repetitive stimulation

Treatment

Mexiletine, quinine, procainamide, acetazolamide

Mexiletine, quinine, procainamide, acetazolamide

Mexiletine, quinine, procainamide, acetazolamide

Mexiletine

confirms the diagnosis. Genetic analysis of CLCN1 is now commercially available. TREATMENT

Many individuals with myotonia congenita do not require any pharmacological intervention. Mostly symptoms are easily manageable by activity modifications, relaxation techniques, and avoiding certain triggers. When these maneuvers are insufficient, drugs that reduce the excitability of the sarcolemma can be used. Historically, quinidine and quinine were used as antimyotonic agents (Lossin & George, 2008). They are usually well tolerated in low doses and for short intervals. However, long-term use is not recommended because of side effects that include cinchonism, gastrointestinal upsets, visual and auditory problems. Other drugs that have been used in treating myotonia with varying levels of success include procaine, tocainide, mexiletine, carbamazepine, lithium, and phenytoin (Lossin & George, 2008). All of these

drugs act by use-dependent block of voltage-gated sodium channels. The other approach for ameliorating myotonia due to chloride channel defects is to pharmacologically increase the chloride conductance of skeletal muscle. Taurine and the R (þ) isomer of clofibric acid produce modest increase in resting chloride conductance but not sufficient to prevent myotonia (Conte-Camerino et al., 1989; Conte-Camerino, Tortorella, Ferranini, & Bryant, 1984). Anesthesia should be administered cautiously to patients of myotonia congenita as there is an increased risk for a malignant hyperthermia syndrome. Gene therapy is currently under research for treatment of myotonia congenita. A major challenge to successful gene therapy remains the great difficulty in systemically targeting skeletal muscle with a gene delivery vector (Lossin & George, 2008). Gaurav Jain Sarita Singhal Chad A. Noggle

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Cannon, S. C. (2006). Pathomechanisms in channelopathies of skeletal muscle and brain. Annual Review Neuroscience, 29, 387–415. Conte-Camerino, D., De Luca, A., Mambrini, M., Ferrannini, E., Farconi, F., Giotti, A., et al. (1989). The effects of taurine on pharmacologically induced myotonia. Muscle Nerve, 12, 898–904. Conte-Camerino, D., Tortorella, V., Ferranini, E., & Bryant, S. H. (1984). The toxic effects of clofibrate and its metabolite on mammalian skeletal muscle: An electrophysiological study. Archives of Toxicology (Suppl. 7), 482–484. Davies, N. P., & Hanna, M. G. (1999). Neurological channelopathies: Diagnosis and therapy in the new millennium. Annals of Medicine, 31, 406–420. Emery, A. E. (1991). Population frequencies of inherited neuromuscular diseases — a world survey. Neuromuscular Discorders, 1, 19–29. Gutmann, L., & Phillips, L. H., II. (1991). Myotonia congenita. Seminars in Neurology, 11, 244–248. Heatwole, C. R., & Moxley, R. T., III. (2007). The nondystrophic myotonias. Neurotherapeutics, 4(2), 238–251.

Hudson, A. J., Ebers, G. C., & Bulman, D. E. (1995). The skeletal muscle sodium and chloride channel diseases. Brain, 118, 547–563. Lehmann-Horn, F., & Rudel, R. (1995). Hereditary nondystrophic myotonias and periodic paralysis. Current Opinion in Neurology, 8, 402–410. Lossin, C., & George, A. L. (2008). Myotonia congenita. Advances in Genetics, 63, 25–55. Mankodi, A. (2008). Myotonic disorders. Neurology India, 56(3), 298–304. Shapiro, B., & Ruff, R. (2002). Disorders of skeletal muscle membrane excitability: Myotonia congenita, paramyotonia congenita, periodic paralysis, and related disorders. In B. Katirji, H. J. Kaminski, D. C. Preston, R. L. Ruff, & B. E. Shapiro (Eds.), Neuromuscular disorders in clinical practice (pp. 987–1020). Boston: Butterworth-Heinemann. Wakeman, B., Babu, D., Tarleton, J., & Macdonald, I. M. (2008). Extraocular muscle hypertrophy in myotonia congenita. Journal of the American Academy of Pediatric Ophthalmology, 12, 294–296.

N NARCOLEPSY

symptoms is a medical condition or neurological disorder (AASM, 2005). NEUROPATHOLOGY/PATHOPHYSIOLOGY

DESCRIPTION

In 1880, French neurologist Jean-Baptiste Gelineau first coined the term ‘‘narcolepsie’’ to describe a disease (Williams, Karacan, & Moore, 1988). This disorder is now more commonly known as ‘‘narcolepsy,’’ but is also referred to as Gelineau’s syndrome. Narcolepsy is a chronic neurological disorder caused by the brain’s inability to regulate sleep–wake cycles normally (National Institute of Neurological Disorders and Stroke [NINDS], 2008). Narcolepsy is a chronic and potentially disabling disorder that affects approximately 1 in 2,000 individuals (Longstreth, Koepsell, Ton, Hendrickson, & van Belle, 2007). The main symptoms of narcolepsy include uncontrollable, excessive sleep, regardless of the time of day or whether the person had enough sleep the previous night (Swanson, 1999). The International Classification of Sleep Disorders (ICSD-2) has recognized three forms of narcolepsy: narcolepsy with cataplexy, narcolepsy without cataplexy, and narcolepsy due to a medical condition (American Academy of Sleep Medicine [AASM], 2005). Narcolepsy with cataplexy includes a sudden episode of loss of muscle function, ranging from slight weakness (such as limpness at the neck or knees, to sagging facial muscles, or inability to speak clearly) to complete body collapse (Swanson, 1999). Narcolepsy without cataplexy is characterized by excessive daytime sleepiness (EDS), naps that are typically refreshing, normal or moderately disturbed nocturnal sleep, and an abnormal tendency for inappropriate transition into rapid eye movement (REM) sleep (AASM, 2005). Narcolepsy without cataplexy is thought to represent between 10% and 50% of all narcolepsy cases, but the precise prevalence is unknown (Billiard, 2008). Narcolepsy due to a medical condition is also known as a secondary or symptomatic narcolepsy, and is diagnosed when the direct cause of the

According to the NINDS (2008), narcolepsy may be secondary to a disease effecting brain mechanisms that regulate REM sleep. For normal sleepers, a typical sleep cycle is about 100–110 min long, beginning with non-REM sleep and transitioning to REM sleep after 80–100 min. People with narcolepsy frequently enter REM sleep within a few minutes of falling asleep (NINDS, 2008). The pathophysiology of narcolepsy is not confined to REM sleep, but also involves wakefulness and non-REM sleep. During wakefulness, sleep attacks occur often at intervals of 90–120 min similar to the nocturnal non-REM/REM cycle and to the ultraradian sleep–wake cycle of normal newborns (Culebras, 2000). In both wakefulness and sleep, features of the different states of being (wakefulness and REM and non-REM sleep) can intermingle and give rise to such clinical phenomena as sleepwalking, REM sleep-behavior disorder, sleep paralysis, cataplexy, and hallucinations. Narcolepsy therefore appears to represent a disorder of state boundary control (Broughton et al., 1986). Whether or not narcoleptic symptoms represent an exaggeration of normal sleep mechanisms related to insufficient maturation of arousal or to non-REM-sleep mechanisms remains controversial (Culebras, 2000). A number of variant forms (alleles) of genes located in a region of chromosome 6, known as the HLA complex, have proved to be strongly, although not invariably, associated with narcolepsy (NINDS, 2008). The majority of people diagnosed with narcolepsy are known to have specific variants in certain HLA genes (NINDS, 2008). Current evidence strongly supports the pathogenic role of selective loss of hypocretin-containing neurons in the hypothalamus of individuals with narcolepsy with cataplexy (Scammell, 2003). Scientists have found that brains from humans with narcolepsy often contain greatly

518 & NARCOLEPSY

reduced numbers of hypocretin-producing neurons (NINDS, 2008).

N

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

In most cases, symptoms first appear in individuals between the ages of 10 and 25, but narcolepsy can become clinically apparent at virtually any age (NINDS, 2008). According to Reite, Ruddy, and Nagel (1997), the presenting complaints of narcolepsy include EDS, episodes of irresistible sleepiness, paroxysmal muscle weakness that is often elicited by emotion or surprise (cataplexy), temporary inability to initiate motor movement before sleep on awakening (sleep paralysis), hypnagogic hallucinations, automatic behavior, and disturbed nocturnal sleep. If left undiagnosed and untreated, narcolepsy can pose special problems for children and adolescents, interfering with their psychological, social, and cognitive development, and undermining the ability to succeed at school (NINDS, 2008). Experts have begun to recognize that narcolepsy sometimes contributes to certain childhood behavioral problems, such as ADHD, and must be addressed before the behavioral problem can be resolved (NINDS, 2008). DIAGNOSIS

The diagnostic criteria for narcolepsy according to the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association [APA], 2000) includes: (1) irresistible attacks of refreshing sleep that occur daily over at least 3 months; (2) the presence of one or both of the following: (i) cataplexy, (ii) recurrent intrusions of elements of REM sleep into the transition between sleep and wakefulness, as manifested by either hypnopompic or hypnagogic hallucinations or sleep paralysis at the beginning or end of sleep episodes; and (3) the disturbance is not due to physiological effects of a substance (e.g., drug of abuse and medication) or other general medical condition. A clinical examination and exhaustive medical history are essential for diagnosis and treatment (NINDS, 2008). A battery of specialized tests, which can be performed in a sleep disorders clinic, is usually required before a diagnosis can be established (NINDS, 2008). Two tests in particular are considered essential in confirming a diagnosis of narcolepsy: the polysomnogram (PSG) and the multiple sleep latency test (MSLT; NINDS, 2008). A PSG is an overnight test that takes continuous measurements while a patient is asleep and can help reveal whether REM sleep occurs at abnormal times in the sleep cycle (NINDS, 2008).

MSLT measures the amount of time it takes a person to fall asleep. Ten minutes or longer is considered a normal amount of time for a person to fall asleep. A latency period of 5 min or less is considered suggestive of narcolepsy (NINDS, 2008). Rare cases of narcolepsy are known to result from traumatic injuries to parts of the brain involved in REM sleep or from tumor growth and other disease processes in the same regions. Infections, exposure to toxins, dietary factors, stress, hormonal changes (such as those occurring during puberty or menopause), and alterations in a person’s sleep schedule are just a few of the many factors that may exert direct or indirect effects on the brain, thereby possibly contributing to disease symptoms (NINDS, 2008). TREATMENT

Treatment approaches for narcolepsy include behavioral and pharmacological interventions. Behavioral approaches include maximal sleep hygiene, scheduled naps, and education for patient, family, teachers, and employers (Reite et al., 1997). Several recent studies provide evidence that modafinil and sodium oxybate are effective for treatment of hypersomnia due to narcolepsy (Wise, Arand, Auger, Brooks, & Watson, 2007). Despite significant advances in understanding the pathophysiology of narcolepsy, there is still not an identified ideal treatment to restore full and sustained alertness (Wise et al., 2007). New approaches currently being developed include: symptomatic neurotransmitters and endocrine therapy, hypocretin-based therapies, immune-based therapies, and skin warming or cooling (Billiard, 2008). Within the Federal government, NINDS, a component of the National Institutes of Health (NIH), has primary responsibility for sponsoring research on neurological disorders. As part of its mission, the NINDS supports research on narcolepsy and other sleep disorders with a neurological basis through grants to major medical institutions across the country (NINDS, 2008). Justin Boseck Raymond S. Dean American Academy of Sleep Medicine. (2005). The international classification of sleep disorders: Diagnostic & coding manual (2nd ed.). Westchester, IL: Author. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text revision). Arlington, VA: Author. Billiard, M. (2008). Narcolepsy: Current treatment options and future approaches. Neuropsychiatric Disease and Treatment, 4(3), 557–566.

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Broughton, R., Valley, V., Aguirre, M., Roberts, J., Suwalski, W., & Dunham, W. (1986). Excessive daytime sleepiness and the pathophysiology of narcolepsy-cataplexy: A laboratory perspective. Sleep, 9, 205–215. Culebras, A. (Ed.). (2000). Sleep disorders and neurological disease. New York: Marcel Decker. Longstreth, W. T., Koepsell, T. D., Jr., Ton, T. G., Hendrickson, A. F., & van Belle, G. (2007). The epidemiology of narcolepsy. Sleep, 30, 13–26. National Institute of Neurological Disorders and Stroke. (2008, September). Narcolepsy fact sheet. Retrieved January 19, 2011, from National Institutes of Neurological Disorders and Stroke via: http://www.ninds.nih. gov/disorders/narcolepsy/narcolepsy.htm Reite, M., Ruddy, J., & Nagel, K. (1997). Evaluation and management of sleep disorders (2nd ed.). Washington, DC: American Psychiatric Press. Scammel, T. E. (2003). The neurobiology, diagnosis, and treatment of narcolepsy. Annals of Neurology, 53, 154–166. Swanson, J. (Ed.). (1999). Sleep disorders sourcebook. Detroit, MI: Omnigraphics. Williams, R. L., Karacan, I., & Moore, C. A. (1988). Sleep disorders: Diagnosis and treatment. New York: WileyInterscience Publications. Wise, M. S., Arand, D. L., Auger, R. R., Brooks, S. N., & Watson, N. F. (2007). Treatment of narcolepsy and other hypersomnias of central origin. Sleep, 30(12), 1712–1727.

NEUROCANTHOCYTOSIS DESCRIPTION

Neuroacanthocytosis (NA) is a homogeneous, neurodegenerative disease that refers to a group of conditions first discovered in the 1960s (Bruneau, Lesperance, Chouinard, 2003). The disease presents with acanthocytosis (spiny red blood cells) and neurological features without any lipid abnormalities (Dobson-Stone et al., 2002; Nicholl et al., 2004). The core conditions included in NA are chorea-acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington disease-like 2 (HDL2), and pantothenate kinaseassociated neurodegeneration (PKAN) (Danek & Walker, 2005). Symptoms associated with NA include chorea, neuroanatomical atrophy, muscle atrophy and weakness, and cognitive impairments. NA may be more prevalent among men (Balhara, Varghese, & Kayal, 2006). The average life expectancy for a patient with the disease is 5–10 years (Robinson, Smith, & Reddy, 2004). Treatment can only assess the psychological and physiological symptoms; NA is fatal.

NEUROPATHOLOGY/PATHOPHYSIOLOGY

NA is an autosomal recessive disease (Bruneau et al., 2003). The cause of NA appears to be mutations of the CHAC gene on chromosome 9q21 (Chowdhury, Saward, & Erber, 2005). In the disease, the red blood cell membrane (erythrocyte membrane) is dysfunctional, which causes the appearance of coarse and irregularly shaped red blood cells, called acanthocytosis (Raina, Salazar, & Micheli, 2007). NA conditions can be divided into two groups based on the occurrence of acanthocytosis. Whereas acanthocytosis is common in ChAc and MLS, it is less prevalent in HDL2 and PKAN. Acanthocytosis occurs only in 10% of patients with PKAN (Schneider, Walker, & Bhatia, 2007). The cause for the erythrocyte membrane dysfunction is relatively unknown. Neurological dysfunction has to be present to diagnose NA; movement disorders are characteristics of NA. ChAc, MLS, HDL2, and late-onset PKAN present with chorea, parkinsonism, or dystonia. Dysarthia, dystonia, and rigidity are more common in early onset PKAN (Danek & Walker, 2005; Schneider et al., 2007). Neuroimaging has shown general cerebral atrophy in patients with NA (Nicholls et al., 2004). However, the basal ganglia (caudate, putamen, and globus pallidus) is especially affected by atrophy (Robinson et al., 2004). Hypometabolism has been observed in the striatum, but not in the general cerebral cortex (Schneider et al., 2007). A previous study found a reduced glucose metabolism of 60–70% in patients with NA (Hallett, Levey, & Di Chiro, 1989). Neurochemical changes are present in NA. Decreased levels of dopamine have been found in greater parts of the brain; decreased levels of serotonin have been reported in the caudate nucleus and substantia nigra, while increased levels of norephedrine have been found in globus pallidus and putamen (Balhara et al., 2006). Clinical features include peripheral neuropathy, muscle weakness, reduced motor speed, general seizures, involuntary facial movements, and the eye condition retinitis pigmentosa (Rowland & Merritt, 2005; Dotti, Supple, Danek, & Lawden, 2004). The involuntary facial movements, orofacial dyskinesia, are a key feature of NA and can lead to difficulty swallowing and self-mutilation of the tongue, inside of cheeks, and lips. Orofacial dyskinesia often occurs with lingual dystonia, painful muscle contractions of the tongue (Dykstra, Adams, & Jog, 2007). The neurogeneaology involved in NA differs for the separate conditions. The VPS13A gene that encodes the protein chorein has been implemented in ChAc. ChAc patients have reduced amounts of chorein in their tissue (Danek & Walker, 2005).

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The function of chorein is unknown. In MLS, absence of Kx red blood cell antigens and the production of weak Kell antigens due to a mutation on the XK gene create a carrier susceptible to the MLS NA condition (Danek & Walker, 2005; Danek, & Frey, 2007). The junctophilin 3 gene, involved in the formation of junction membrane structures and located on chromosome 16q24.3, has been associated with HDL2. Forty, or more, CAG/CTG repeat expansions at the junctophilin 3 gene locus cause HDL2 (Holmes et al., 2001). Mutations of the PKAN2 gene give rise to PKAN. The PKAN2 gene is located on chromosome 20p13 (Freeman et al., 2007). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Due to the nonspecific nature of NA, it is important to consider all neuropsychological symptoms that the patient displays when diagnosing the disease. Neuropsychological symptoms tend to be the first symptoms to appear in patients with NA. Behavioral problems due to executive dysfunction such as impulsivity, compulsivity, progressive apathy, irritability, loss of initiative, and impulsiveness are common. Personality changes are often reported by the person’s family. Behavioral observations may include adapted behavior due to peripheral neuropathology (burning sensations, numbness, paralysis, or sensitivity to touch) or due to muscle weakness (stiffness and spasms) (National Institute of Neurological Disorders and Stroke [NINDS], 2008). Constant biting on the lips or tongue, muscle twitches in the face, and loud grunting indicate orofacial dyskinesia, which is irreversible (Kobayashi, 1976). Psychiatric manifestations include anxiety, depression, loss of insight, apathy, and psychosis (Balhara et al., 2006; Kartsounis & Hardie, 1996). Psychotic behavior may also manifest in the form of paranoid delusions in NA (Kartsounis & Hardie 1996). A decline of general intelligence can be expected in patients with NA and speech production impairments are common symptoms. The pattern of cognitive decline and memory disturbances that are present from the beginning of the disease’s onset are consistent with cognitive symptoms in subcortical dementias. However, visuoperceptual and some language abilities generally remain preserved (Kartsounis & Hardie, 1996). DIAGNOSIS

A blood smear has to be performed on peripheral blood in order to diagnose NA and findings of greater than 3% acanthocytosis indicate presence of the

disease. Lipoprotein profiles should present as normal, whereas serum creatine kinase-levels should be increased. Electro/echocardiography, muscle biopsy, neuroimagery, and neuropsychological testing should be included in diagnosing NA (Bruneau et al., 2003). Genetic testing should be done to distinguish MLS, PKAN, and HDL2, but genetic testing can be less helpful in diagnosing ChAc since there are several different types of mutations present in this condition (Danek & Walter, 2005). Another finding that can assist in the process of diagnostic narrowing is to measure the creatine-kinase levels, which are elevated in MLS and ChAc. Liver enzymes are also elevated in MLS and ChAc, although when testing, Wilson’s disease has to be excluded. By using specific antibodies, the phenotype of the Kell erythrocyte antigens can be identified providing for a diagnosis of MLS (Danek & Walker, 2005). Iron accumulation in the medial globus pallidus lead to a diagnosis of PKAN. It is through the ‘‘eye of the tiger’’ sign on an MRI that the iron accumulation is found (Danek, 2004). Behavioral observations may include choreiform movements, tics, mood changes, paralysis, stiffness, seizures, and abnormal gait. Slow speech rate and decreased speech intelligibility could be signs of lingual dystonia; presence of lingual dystonia is indicative of NA. (Dykstra et al., 2007). Self-neglect is common among patients with NA; therefore, the patient may arrive at the appointment appearing inappropriately dressed or groomed. Weight loss may be due to impairment ability to swallow, which is indicative of NA and can differentiate the disease from Huntington’s disease (Kartsounis & Hardie, 1996). In contrast from Huntington’s disease, there are also few pathological findings in the cerebral cortex and the locus coeruleus. Age of onset is another factor that is important to consider. The different NA conditions have different ages of onset: MLS: 40–60 years; ChAc: 20–30 years; PKAN: childhood; HDL2: 30–40 years (Schneider et al., 2007). It is important to consider the lack of research that has been conducted for investigating psychosis in NA. It is therefore difficult to differentiate between psychosis and tardive dyskinesia in schizophrenia, and psychosis with a primary movement disorder such as in NA. TREATMENT

Treatment of NA is limited to treating the symptoms. Psychopharmacology, such as selective serotonin reuptake-inhibitors in addition to mood stabilizers, can relieve depression, anxiety, or psychosis (Danek & Walker, 2005). Atypical antipsychotics may impact

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movement disorders and psychosis (Danek & Walker, 2005; Kobayashi, 1976). PKAN has been treated successfully by surgically attaching tiny electrodes to the globus pallidus (pallidotomy) and/or by delivering muscle relaxants directly into the spinal fluid (intrathecal baclofen) (Danek & Walker, 2005). Baclofen can also diminish symptoms of dystonia in NA (Burton, 2000). It is important to bank autologous blood when considering operations on a patient with MLS because blood transfusion reactions can occur. A change in heart rate or weakness of the cardiac muscle can occur; it is therefore important to monitor the person closely. This can potentially be a concern in ChAc (Walker, Saiki, Irvine, Danek, & Hallett, 2008). Therapy can educate the patient about the symptoms and teach the patient how to deal with them. It is important that the patient understand the prognosis and potential developments in the disease. Maintaining proper nutrition is important for a patient with NA, but as the difficulty swallowing progresses, a feeding tube may be needed (Robinson et al., 2004). Motor speed impairments may affect the person’s speech, or even make them lose the ability to speak. Speech therapy, or in extreme cases, a computerassisted speech system may be necessary (Danek & Walker, 2005). Furthermore, dementia, motor neuron disease, and parkinsonism can also evolve from NA which may addressed by symptom-targeted intervention. Potential causes of death include emaciation due to progressive weakness, dysphagia, and tracheobronchial aspiration (Robinson et al., 2004). Beyond those steps previously noted, therapy may also serve to educate the patient’s family about the disease, allowing them to assume a supportive role. Lena M. F. Prinzi Charles Golden Balhara, Y. P. S., Varghese, S. T., & Kayal, M. (2006). Neurocanthocytosis: Presenting with depression. Journal of Neuropsychiatry and Clinical Neurosciences, 18, 426. Bruneau, M.-A., Lesperance, P., & Chouinard, S. (2003). Schizophrenia-like presentation of neurocanthocytosis. The Journal of Neuropsychiatry and Clinical Neurosciences, 15, 378–380. Burton, L. S. (2000). Evaluation and treatment of dystonia. Southern Medical Journal, 93, 746–751. Chowdhury, F., Saward, R., & Erber, W. (2005). Neurocanthocytosis. British Journal of Haematology, 131, 285. Danek, A. (Ed.). (2004). Neuroacanthocytosis syndromes. New York: Springer. Reviewed January 2, 2009. Danek, A., & Walker, R. (2005). Neurocanthocytosis. Current Opinion in Neurology, 18, 386–392. Dobson-Stone, C., Danek, A., Rampoldi, L., Hardie, R. J., Chalmers, R. M., Wood, N. W., et al. (2002). Mutational

spectrum of the CHAC gene in patients with choreaacanthocytosis. European Journal of Human genetics, 10, 773–780. Dykstra, A. D., Adams, S. G., & Jog, M. (2007). The effect of botulinum toxin type A on speech intelligibility in lingual dystonia. Journal of Medical Speech-Language Pathology, 15, 173–186. Freeman, K., Gregory, A., Turner, A., Blasco, P., Hogarth, P., & Hayflick, S. (2007). Intellectual and adaptive behaviour functioning in pantothenate kinase-associated neurodegeneration. Journal of Intellectual Disability Research, 51, 417–426. Holmes, S. E., O’Hearn, E., Rosenblatt, A., Callahan, C., Hwang, H. S., Ingersoll-Ashworth, R. G., (2001). A repeat expansion in the gene encoding of junctophilin-3 is associated with Huntington’s disease-like 2. Natures Genetics, 29, 377–378. Kartsounis, L. D., & Hardie, R. J. (1996). The pattern of cognitive impairment in neurocanthocytosis: A subcortical dementia. Archives of Neurology, 53, 77–80. Kobayashi, R. M. (1976). Orofacial dyskinesia. The Western Journal of Medicine, 125, 277–288. National Institute of Neurological Disorders and Stroke. (2008). Peripheral neuropathy fact sheet. National Institute of Health Publication No. 04-4853. Reviewed January 2, 2009, from http://www.ninds.nih.gov/disorders/ peripheralneuropathy/detail_peripheralneuropathy.htm Nicholl, D., Sutton, I., Dotti, M., Supple, S., Danek, A., & Lawden, M. (2004). White matter abnormalities on MRI in neurocanthocytosis. Journal of Neurology, Neurosurgery, and Psychiatry, 75, 1200–1207. Robinson, D., Smith, M., & Reddy, R. (2004). Neurocanthocytosis. American Journal of Psychiatry, 161, 1716. Rowland, L. P., & Merritt, H. H. (2005). Merritt’s neurology: Integrating the physical exam and echocardiography. Philadelphia: Lippincott Williams & Wilkins. Schneider, S. A., Walker, R. H., & Bhatia, K. P. (2007). The Huntington’s disease-like syndromes: What to consider in patients with a negative Huntington’s disease gene test. Nature Clinical Practice: Neurology, 3, 517–525. Walker, R. H., Saiki, S., Irvine, G., Danek, A., & Hallett, M. (2008). Neuroacanthocytosis Syndromes II. New York: Springer.

NEURODEGENERATION WITH BRAIN IRON ACCUMULATION DESCRIPTION

Neurodegeneration with brain iron accumulation (NBIA) or pantothenate kinase associate neurodegeneration, previously termed Hallervorden–Spatz

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disease, is a rare, progressive, and fatal autosomal recessive disease affecting both adults and children. Although sporadic cases have also been cited within the literature, this is extremely rare. NBIA is characterized by excessive iron accumulation and discoloration of the medial globus pallidus and substantia nigra. Clinical features are noted to include extrapyramidal signs (dystonia, rigidity, parkinsonism, dysarthria), corticospinal tract involvement, pyramidal motor symptoms, optic atrophy, retinal pigmentation, psychiatric manifestations, cognitive deficits, dementia later in the course of the disease, and eventually death. NBIA was first identified in 1922 by Julius Hallervorden and Hugo Spatz. The pair witnessed pigmentation of the basal ganglia in five siblings with progressive dysarthria and dementia. The preferred name, NBIA, evolved from moral concerns raised regarding Hallervorden’s involvement in euthanasia during World War II (Hinkelbein, Kalenka, & Alb, 2006). One hallmark feature of NBIA is the ‘‘eye of the tiger’’ sign observed on T2-weighted MRI due to bilateral low-signal intensities within the globus pallidus and hyperintensity within the central or anteriomedial areas of the pallidum associated with iron accumulation (Hinkelbein et al., 2006). These high-signal intensities have also been attributed to spongiosis and neuronal vacuolization (Bindu, Desai, Shehanaz, Nethravathy, & Pal, 2006; Hinkelbein et al., 2006). The incidence of NBIA worldwide is estimated to be between one and three per one million population (Freeman et al., 2007; Hinklebein et al., 2006). NBIA appears to affect both genders equally. Although NBIA has been reported in all races, the frequency is unknown because it is quite rare (Hinkelbein et al., 2006). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Mutations in the pantothenate-kinase 2 gene (PANK2) on chromosome 20p13 have been identified as a pathological basis of the presentation (Bindu et al., 2006; Matarin, Singleton, & Houlden, 2006). Deficiency of pantothenate kinase may lead to accumulation of cysteine, which in the presence of iron leads to a cytotoxic event causing free radical production (Mendez & Cummings, 2003; Hinkelbein et al., 2006). Postmortem findings reveal cerebral atrophy, pigmentation, and iron accumulation in the globus pallidus and substantia nigra (Freeman et al., 2007). This accumulation occurs both extracellularly and intracellularly although it is primarily found in astrocytes, microglia, and neurons (Jankovic, 2007). Iron-containing pigment granules, axonal swelling, neuronal loss, gliosis, and demyelination within affected tissues have also been reported (Hinkelbein et al., 2006; Mendez &

Cummings, 2003). Large spheroid bodies are commonly present in the medial globus pallidus, substantia nigra, cortex, and subthalamic nucleus (Pellecchia et al., 2005).

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Heterogeneity in clinical presentation has been well established, particularly within same-age subtypes. However, literature involving neuropsychological and clinical features of the disease has been limited as NBIA is extremely rare and small sample sizes and case studies predominate within the literature. The disease course is usually 10–15 years with onset typically occurring during the first or second decade, though in rare cases may occur up to the seventh decade (Freeman et al., 2006; Mendez & Cummings, 2003). Although variations between classification systems exist, three variants of NBIA have been identified: (1) early-onset childhood type with onset between 1 and 3 years of age (neuroaxonal dystrophy), (2) classic juvenile type with onset between 7 and 12 years of age, and (3) the more rare adult type (Mendez & Cummings, 2003). Among the early-onset childhood type, one study discovered primary motor developmental delays among all participants (n ¼ 10) followed by cognitive decline. The juvenile type displayed more variability in presentation, including more behavioral features (e.g., verbal aggression and depression) in addition to extrapyramidal motor signs but without developmental delay (Bindu et al., 2006). Neuropsychological assessment findings in NBIA has suggested age of onset appears to correlate with disease severity, degree of intellectual impairment, and adaptive functioning, with earlier onset having a poorer prognosis (Bindu et al., 2006; Freeman et al., 2007). Furthermore, diversity in symptom expression has made it difficult to capture a clear picture of neuropsychological presentation in patients with NBIA (Freeman et al., 2007). Slowed processing speed is common with deficits in visuospatial abilities and memory reported; language may be affected later in the course of the disease (Loring, Sethi, Lee, & Meador, 1990). General intellectual functioning often varies between intact to markedly impaired and is often dependent upon disease progression (Freeman et al., 2007). Within the literature, the presence of dysarthria, neuro-ophthalmologic and motor signs almost universally impact formal neuropsychological assessment procedures making nonstandard administration imperative.

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Later in the course of the disease, psychiatric manifestations may develop, though one case study of prodromal behavioral symptoms (e.g., anxiety, depression, irritability, mood lability, and verbal aggression) has been identified. These psychiatric manifestations all occurred before the onset of extrapyramidal and pyramidal motor signs, and behavioral symptoms eventually progressed to paranoid delusions that responded well to antipsychotic medications (Panas et al., 2007). DIAGNOSIS

Prior to advancements in neuroimaging capabilities, confirmation of NBIA was typically given upon autopsy based on the aforementioned iron accumulation and discoloration within the brain in combination with the noted clinical presentation. Neurodiagnostic imaging with T-2 weighted MRI scans may prove useful in the diagnosis of NBIA, although the hallmark ‘‘eye of the tiger’’ sign may be absent in a very small group of NBIA patients. Most recently, identifying the defect on the arm of chromosome 20 has led to positive diagnosis as have pathological results of an affected sibling. Based on prominent gait disturbance and extrapyramidal signs, differential diagnosis of NBIA includes dementia with Lewy bodies, Parkinsonplus syndromes, progressive supranuclear palsy, Wilson’s disease, normal pressure hydrocephalus, and Huntington’s disease. In summary, clinical features including progressive course and neuroophthalmologic findings, molecular testing, and MRI findings all remain important in the diagnosis of NBIA, with genetic markers being the most recent advancement in differential diagnosis. TREATMENT

There is no cure for NBIA and no specific treatments exist. Current pharmacological treatments include muscle relaxants, spasticity agents, and dopaminergic medications to control motor symptoms. Within the literature, stereotactic procedures of pallidotomy, thalamotomy, and bilateral pallidothalamotomy have been reported but only in a very small number of patients, and relief appears to be temporary in nature (Hinkelbein et al., 2006; Mendez & Cummings, 2003). Additional treatments are supportive in focus. Physical, occupational, and speech therapies may be utilized to assist in addressing developing deficits that occur with disease progression and to assist in maintaining independent functionality as long as possible. Individualized educational plans can be essential for children with the disease. As the disease progresses, regular modifications are essential. Therapeutic

services may be helpful for both patients and their families to aid them in coping with and adjusting to the disease from an emotional and psychosocial standpoint. Michelle R. Pagoria Chad A. Noggle Bindu, P. S., Desai, S., Shehanaz, K. E., Nethravathy, M., & Pal, P. K. (2006). Clinical heterogeneity of HallervordenSpatz syndrome: A clinicoradiological study in 13 patients from South India. Brain and Development, 28, 343–347. Freeman, K., Gregory, A., Turner, A., Blasco, P., Hogarth, P., & Hayflick, S. (2007). Intellectual and adaptive behaviour functioning in pantothenate kinase-associated neurodegeneration. Journal of Intellectual Disability Research, 51, 417–426. Hinkelbein, J., Kalenka, A., & Alb, M. (2006). Anesthesia for patients with pantothenate-kinase-associated neurodegeneration (Hallervorden-Spatz disease) — A literature review. Acta Neuropsychiatrica, 18, 168–172. Jankovic, J. (2007). Movement disorders. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed.). Philadelphia: Saunders Elsevier. Loring, D. W., Sethi, K. D., Lee, G. P., & Meador, K. J. (1990). Neuropsychological performance in HallervordenSpatz syndrome: A report of two cases. Neuropsychology, 4, 191–199. Matarin, M. M., Singleton, A. B., & Houlden, H. (2006). PANK2 gene analysis confirms genetic heterogeneity in neurodegeneration with brain iron accumulation (NBIA) but mutations are rare in other types of adult neurodegenerative disease. Neuroscience Letters, 407, 162–165. Mendez, M. F., & Cummings, J. L. (2003). Dementia: A clinical approach (3rd ed.). Philadelphia: ButterworthHeinemann. Panas, M., Spengos, K., Koutsis, G., Tsivgoulis, G., Sfagos, K., Kalfakis, N., et al. (2007). Psychosis as presenting symptom in adult-onset Hallervorden-Spatz syndrome. Acta Neuropsychiatrica, 19, 122–124. Pellecchia, M. T., Valente, E. M., Cif, L., Salvi, S., Albanese, A., Scarano, V., et al. (2005). The diverse phenotype and genotype of pantothenate kinase associated neurodegeneration. Neurology, 64, 1810–1812.

NEUROFIBROMATOSIS DESCRIPTION

Neurofibromatosis (NF) is an umbrella term encompassing a group of presentations characterized by

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neurocutaneous lesions. Individual distinction of the different variants is based on the clinicopathological manifestations of each including various types and distributions of lesions. To date, eight different variants are described; however, only NF-1 and NF-2 are definitely recognized by all as falling in this group, as they demonstrate overlapping genetics at a molecular level. Consequently, only these two forms are discussed at this time. Both NF-1 and NF-2 are autosomal-dominant syndromes characterized by the formation of neural tumors. NF-1 is far more common with a relative prevalence of 1 in 3,000, whereas NF-2 presents in only 1 out of every 40,000–50,000 (MacCollin, 1995). The disorders correspond to abnormalities in the development of neural crest cells producing hypoplasia, neoplasia, and dysplasia of the neuroectodermal elements and their supporting structures (Berg, 2007). NF-1 presents with multiple cafe´-au-lait spots, multiple peripheral neurofibromas or plexiform, optic gliomas, axillary freckling, and osseous lesions (Riccardi, 1992). Lisch nodules and dysplasias of the skull and spine as well as the extremities are common in adults (Jackson, 1995). NF-2 is commonly characterized by neoplasms of the central nervous system (CNS) and hallmarked by schwannomas in the region of the eighth cranial nerve bilaterally. Neurofibromas, meningiomas, gliomas, and cerebral calcifications are also quite common (Lantos et al., 2005).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

NF-1 is associated with a number of tumors of the nervous system. These include plexiform neurofibroma, which is the hallmark of NF-1, multiple neurofibromas of other systemic areas including paraspinal neurofibromas, optic gliomas, paraspinal schwannomas, pilocytic astrocytomas of the third ventricle and cerebellum, and astrocytomas of the brain and spinal cord (Russell & Rubenstein, 1989). Hyperintensities of the globus pallidus are often noted on T1-weighted images; basal ganglia, brainstem, and cerebellum hyperintensities are noted on T2 imaging (Truhan et al., 1993). The NF-1 gene mutations are localized to the 17q11.2 chromosome, which encodes neurofribromin, an amino acid protein that is expressed in most tissues thus explaining the widespread manifestations of the disorder (von Deimling et al., 1995). In the nervous system, neurofribromin is present in oligodendrocytes, Schwann cells, and smooth endoplasmic reticulum of neuronal populations (Nordlund et al., 1993).

NF-2 is most often associated with vestibular schwannomas and the potential of other CNS neoplasms, schwannomas, and meningiomas being the most common. Beyond this, additional neurological features, as seen in NF-1, are not associated with NF-2 (Truhan et al., 1993). Meningioangiomatosis may present in the cortex, meninges, and/or subcortical white matter. It appears as hyperdense lesions with internal calcifications and edema of the adjacent white matter (Aizpuru et al., 1991). Gliomas and microhamartomas may also manifest with the latter more often arising in the basal ganglia, thalamus, cerebellum, and deeper layers of the cerebral cortex and the prior more commonly developing in the spinal cord. The NF-2 gene mutations are located on chromosome 22q11.1922q13.1. The gene aids in the production of cytoskeletal associated proteins and acts as a tumor suppressor (Louis et al., 1995). Macrocephaly presents in 10% to 40% of individuals, the middle fossa may be ‘‘ballooned,’’ and there may be seen an enlarged or J-shaped sella and dysplastic changes of the sphenoid (Berg, 2007). These features are noted across both types of NF. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

NF-1 presents with cutaneous pigmentation, multiple tumors within both the central and peripheral nervous systems, and lesions of the vascular and other organ systems (Riccardi & Eichner, 1986). As discussed, cafe´au-lait spots are associated with presentation, arising at birth and becoming more apparent as individuals age. However, cafe´-au-lait spots are not definitive of the presentation as they may arise in other disorders or in isolation. In actuality, for diagnosis of NF-1 more than six spots must be observed. Fibroma molluscum, which are soft or firm papules developing just under the skin, may also occur, as well as Lisch nodules and optic gliomas. Peripheral neurofibromas can present anywhere. CNS tumors most commonly involve meningiomas and gliomas. Their locality corresponds with neurological symptoms that manifest. Schwannomas may also develop affecting the cranial nerves with the noted dysfunction corresponding with specific cranial nerve affected. Individuals with NF-2 often become symptomatic in the second or third decade of life. As previously noted, individuals may present with unilateral or bilateral masses of the eighth cranial nerve as well as neurofibromas, meningiomas, gliomas, schwannomas, or posterior subcapsular lenticular opacity (Berg,

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2007). Bilateral acoustic neuromas manifest in nearly all patients (>95%). As a result of the latter, tinnitus and hearing loss are common complaints. Cafe´-au-lait spots present in NF-2 as they do in NF-1. In both forms of NF, mental retardation and seizures can occur. Specifically, approximately 80% of individuals with NF will present with moderate to severe impairments of neurocognition corresponding with the locality of the intracranial tumors (Hyman et al., 2005). These researchers also reported that roughly 50% of individuals demonstrated deficits in reading, spelling, and mathematics, although only 20% meet diagnostic criteria of a specific learning disability. DIAGNOSIS

Diagnostic practices in NF are multifaceted. CT and MRI are useful evaluations, with preference given to the latter if not contraindicated. They permit evaluation of neurofibromas’ locality and infiltration. Imaging should be focused on the peripheral system and internal organs, including the abdomen and chest. MRI is essential in the evaluation of intracranial masses. As suggested previously, additional neuroanatomical findings may also be observed, particularly in NF-1, including hyperintensities. However, calcifications associated with NF-2 may also be evaluated through these means. In some of these instances, MRI is necessary as CT with contrast has not demonstrated great enough sensitivity to offer full appreciation of some of these lesions (Berg, 2007). Beyond the brain, imaging of the spine is also important in individuals with NF-1. In individuals with NF-2, gadolinium should be used to best evaluate the cerebellopontine region and for acoustic neuromas. Electroencephalogram may be used to document potential seizure activity. Measurement of neurotransmitter metabolites has also been recommended (Berg, 2007). Neuropsychological assessment should be comprehensive as no pure profile of NF exists. TREATMENT

Treatment of NF is nonspecific. Rather it is symptombased and supportive. Neurosurgical intervention is utilized to address intracranial and spinal masses. Radiation may also be used. Although most tumors are not malignant, chemotherapy may still be used. Chemotherapy may be employed in cases of optic gliomas that become overly problematic or concerning. However, chemotherapy and/or surgery are only used to treat optic gliomas when absolutely necessary, as demonstrated by documented progression on serial

MRIs (Imes & Hoyt, 1986). In fact, for most tumors that present centrally or in the peripheral system, surgery or other means of intervention are only employed when necessary as determined by charted growth rates or locality of presentation. Peripheral neurofibromas rarely require removal unless rapid growth is demonstrated, repeated trauma has been experienced, or for cosmetic reasons. The latter reason is the primary basis for plexiform neuromas to be removed. Pain medications may be employed to control irritation due to the region of neurofibromas, although often in these instances surgery may be undertaken. Antiepileptic drugs are used to control seizure activity if it remains following surgical removal of the intracranial mass causing the symptoms. Neuropsychological assessment is an important aspect of treatment, as it permits documentation of the nature and extent of any neurocognitive or learning deficits. Based on findings, appropriate interventions should be enacted. Special education services may be warranted in cases of learning deficits. Chad A. Noggle Aizpuru, R. N., Quencer, R. M., Norenberg, M., et al. (1991). Meningioangiomatosis: clinical, radiological, and histopathologic correlation. Radiology, 179, 819–821. Berg, B (2007). Chromosomal Abnormalities and Neurocutaneous Disorders. In Goetz, C., Textbook of clinical neurology (pp. 683-697). Philadelphia: Saunders. Hyman, S. L., Shores, A., North, K. N. (2005). The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology, 65, 1037–1044. Imes, R. K., Hoyt, W. F. (1986) Childhood chiasmal gliomas: Update on the fate of patients in the 1969 San Francisco study. British Journal of Ophthalmology, 70, 179–182. Jackson, I. T. (1995) Neurofibromatosis of the skill base. Clinics in Plastic Surgery, 22, 513–530. Lantos, P. L., Vandenberg, S. R., & Kleihues, P. (2005). Tumours of the nervous system. In D.I. Graham & P.L. Lantos (Eds.) Greenfield’s neuropathology (6th ed., vol. 2, pp. 583–879). London: Arnold. Louis, D. N., Ramesh, V., & Gusella, J. F. (1995). Neuropathology and molecular genetics of neurofibromatosis 2 and related tumors. Brain Pathology, 5, 163–172. MacCollin, M. (1995). CNS Young Investigator Award Lectures: molecular analysis of the neurofibromatosis 2 tumor suppressor. Brain & Development, 17, 231–238. Nordlund, M., Gu, X., Shipley, M. T., Rater, N. (1993). Neurofibromin is enriched in the endoplasmic reticulum of CNS neurons. Journal of Neuroscience, 13, 1588–1600. Riccardi, V. M. (1992). Neurofibromatosis: Phenotype, natural history, and pathogenesis, (pp. 1–450). Baltimore: Johns Hopkins University Press.

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Riccardi, V. M., & Eichner, J. E. (1986). NeurofibromatosisPhenotype, natural history and pathogenesis. Baltimore: Johns Hopkins University Press. Russell, D. S., Rubenstein, L. J. (1989). Pathology of tumours of the nervous system (5th ed). London: Edward Arnold. Truhan, A. P., Filipek, P. A. (1993). Magnetic resonance imaging: Its role in the neuroradiologic evaluation of neurofibromatosis, tuberous sclerosis, and SturgeWeber syndrome. Archives of Dermatology, 129, 219–226. von Diemling, A., Krone, W., Menon, A. G. (1995). Neurofibromatosis type 1: pathology, clinical features and molecular genetics. Brain Pathology, 5: 153–163.

NEUROLEPTIC MALIGNANT SYNDROME DESCRIPTION

Neuroleptic malignant syndrome (NMS) is a potentially fatal, adverse reaction to antipsychotic medication, typically characterized by muscle rigidity, hyperthermia (pyrexia), alterations in mental status, and autonomic disturbance (Guzofski & Peralta, 2006; Haddad & Dursun, 2008; Susman, 2001). NMS normally occurs 4–11 days after starting an antipsychotic or increasing its dosage (Guzofski & Peralta, 2006). Though less common, NMS cases involving other drugs, including lithium and antidepressants, have been reported (Kohen, 2004). In two-thirds of cases, onset occurs in the first week; however, there are reports of symptoms starting abruptly long after the offending medication was prescribed without changes in dosage. Upon discontinuation of the offending agent, NMS typically resolves in 7–10 days (Guzofski & Peralta, 2006; Kohen, 2004). There is considerable disparity in the literature regarding incidence rates of NMS. Reported rates have varied from 0.007% to 3.23%, with 0.2% being the most widely accepted estimate (Caroff, 2005; Kohen, 2004). The mortality rate of NMS is also unclear, but it is estimated to be around 10% (Caroff, 2005). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The pathophysiology of NMS is not yet known; however, the most prevalent theory is that it is related to reduced dopaminergic activity subsequent to neuroleptic blockade of dopamine receptors (Caroff, 2005; Kohen, 2004). Hyperthermia is thought to be related to antagonized dopamine receptors of the anterior hypothalamus, an area associated with

thermoregulation (Kohen, 2004; Susman, 2001). Dopaminergic blockade of the nigrostriatal pathway is believed to produce muscle rigidity, a contributor to hyperthermia (Guzofski & Peralta, 2006; Kohen, 2004). Changes in state of consciousness may be related to reduced dopaminergic activity in the reticular activating system (Guzofski & Peralta, 2006). NMS symptoms of mutism, akinesia, and decreased arousal could be subsequent to decreased dopamine input to the anterior cingulate-medial orbitofrontal circuit (Kohen, 2004). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

There are a number of symptoms that tend to appear early in the course of NMS. Unexpected changes in mental status often develop such as delirium and obtundation (Caroff, 2005). Early on, such changes in consciousness may take the form of mild confusion and can be difficult to discriminate from existing psychiatric illness and the sedating affects of antipsychotic medication (Kohen, 2004; Pelonero, Levenson, & Pandurangi, 1998). Other common early symptoms include fever, new onset catatonia, tachycardia, diaphoresis, drooling, incontinence, extrapyramidal symptoms refractory to standard treatment, dysphagia, dysarthria, and elevated creatinine phosphokinase (CPK) levels. In a review of the literature, it was found that in 80% of cases (n ¼ 79) of NMS, the initial symptoms were changes in mental status and rigidity. Yet, early symptoms are not always helpful in identification, as the course and presentation of NMS are often idiosyncratic, and in rare cases, it can develop abruptly (Caroff, 2005). The clinical picture is further obscured, as symptoms can fluctuate over hours or days and can temporarily remiss completely (Haddad & Dursun, 2008). DIAGNOSIS

The diagnostic criteria of NMS have proven to be a topic of debate, due to NMS’s heterogeneous clinical presentation and variability in severity. The Diagnostic Statistic Manual IV-TR outlines criteria for NMS; however, many researchers have proposed their own (Addonizio, Susman, & Roth, 1986; American Psychiatric Association [APA], 2000; Caroff, 2005; Caroff & Mann, 1993; Levenson, 1985; Nierenberg et al., 1991; Pope, Keck, & McElroy, 1986; Sachdev, Mason, & Hadzi-Pavlovic, 1997). No set of criteria has received consensus; thus, much of the diagnostic responsibility relies on a high index of clinician suspicion (Seitz, 2005).

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NMS is considered a diagnosis of exclusion, making differential diagnosis essential in the identification of the disorder (Strawn, Keck, & Caroff, 2007; Susman, 2001). Types of ailments most commonly confused with NMS are benign extrapyramidal symptoms, agitated delirium, and infections (Strawn et al., 2007). One condition that can have an identical presentation to NMS is lethal catatonia. In fact, some researchers consider NMS to be a drug-induced iatrogenic form of lethal catatonia (Kohen, 2004; Strawn et al., 2007). The course of lethal catatonia seems to differ from NMS in that it typically begins with psychotic excitement and progresses to exhaustion, as opposed to NMS, which often starts with muscular rigidity (Kohen, 2004; Pelonero et al., 1998). Another condition that is extremely difficult to discern from NMS is serotonin syndrome. The core features of serotonin syndrome are changes in mental status, autonomic instability, and neuromuscular hyperactivity (Haddad & Durnsun, 2007). It differs from NMS in that it has a rapid onset of about 24 hr, and myoclonus and restlessness is prominent, compared to akinesia and rigidity found in NMS. Also, gastrointestinal symptoms (i.e., nausea, vomiting, and diarrhea) are common in serotonin syndrome unlike NMS. As its name implies, serotonin syndrome normally is induced by medications that increase serotonergic transmission (Guzofski & Peralta, 2006; Haddad & Durnsun, 2007; Kohen, 2004). Patient medication history, behavioral prodrome, and the chronology of symptom presentation are essentials for distinguishing it from NMS (Guzofski & Peralta, 2006). Other conditions that can mimic NMS are anticholinergic delirium and heat stroke. Like NMS, pyrexia and confusion are symptoms of anticholinergic delirium. However, an individual with anticholinergic delirium will lack rigidity, and their skin will appear dry, in contrast to the sweating that is often observed in NMS (Haddad & Durnsun, 2007; Kohen, 2004). Heat stroke can also look like NMS in that an individual may present with confusion, hyperthermia, agitation, tachycardia, and tachypnea. It differs from NMS in that the skin of the individual will appear red, hot, and dry and typically muscle flaccidity is present (Haddad & Durnsun, 2007; Kohen, 2004; Strawn et al., 2007). For a comprehensive listing of differential diagnoses for consideration, see Strawn et al. (2007). TREATMENT

Once NMS is suspected, neuroleptic medications should be immediately discontinued, along with

other psychotropic medications such as antidepressants and lithium. Withdrawal of anticholinergics should also be considered. A complete medical and neurologic work-up is necessary and supportive treatments should begin promptly. Pulse, blood pressure, and temperature should be evaluated every 2 hours (Kohen, 2004), and monitoring of pulse-oximetry and electrolyte levels should also be conducted regularly. CPK levels should be quickly established and examined daily for the 1st week and every 2 days after that, until returning to normal (Guzofski & Peralta, 2006; Kohen, 2004; Strawn et al., 2007). Rehydration may be required; laryngeal dystonia, dysphagia, respiratory distress, and delirium can impede oral fluid intake; thus, intravenous administration of fluids may be necessary. Electrolyte abnormalities may also require normalization. If hyperthermia is evident, treatment with a cooling blanket is indicated. Chest wall rigidity can impair respiration and may require intubation and ventilator support (Guzofski & Peralta, 2006; Pelonero et al., 1998). While pharmacological treatment is recommended for NMS, there are conflicting reports regarding the effectiveness of such interventions. Due to the absence of controlled studies of drug therapy, there are no definitive pharmacological guidelines (Pelonero et al., 1998). Nevertheless, potentially beneficial treatment must not be withheld in cases when severity warrants drug therapy. Benzodiazepines are a firstline treatment for catatonia and are also useful for decreasing agitation, and may treat fever and rigidity as well. A 1–2 mg starting dose is recommended. Consistent with the theorized pathophysiology of NMS, a dopamine agonist of amantadine or bromocriptine is suggested. Amantadine can be initiated at 200–400 mg per day, or bromocriptine at 2.5 mg 2–3 times a day (not to exceed 45 mg per day). Bromocriptine can potentially worsen psychosis and hypotension, and should be used cautiously in patients with risk of aspiration, as it may induce vomiting. In addition, the muscle relaxant dantrolene can be used. To start, dantrolene should be administered intravenously at 1–2.5 mg/kg of body weight. If rapid recession of fever and rigidity are observed, it should be continued at 1 mg/kg every 6 hr and then tapered or switched to its oral version after a few days. Dantrolene may be used with both benzodiazepines and dopamine agonists; however, to prevent risk of cardiovascular collapse it should not be used with calcium channel blockers (Strawn et al., 2007). In cases where NMS symptoms are refractory to supportive and pharmacological therapies after 48 hrs, ECT should be considered. For acute NMS, 6–10 treatments with bilateral electrode placement are standard (Strawn et al., 2007).

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The nature of NMS dictates that most patients with the syndrome will have a diagnosis of severe mental illness, a diagnosis often exacerbated upon its onset. Withdrawal of antipsychotics mandated by treatment generally causes a worsening of psychotic symptoms. Thus, resumption of psychotropic medication upon NMS conclusion is frequently required (Kohen, 2004). Due to the rarity of NMS, there are few studies that have investigated pharmacological rechallenge. This, along with the idiosyncratic nature of the syndrome, makes it difficult to identify predictors for NMS relapse. Nevertheless, antipsychotics (and other psychotropics) can be safely resumed for most patients, if precautions are taken. Psychoactive medications should not be resumed until at least 2 weeks after the NMS episode has resolved. During that time, the costs and benefits of rechallenge should be evaluated and alternatives treatments considered. Once the necessity of antipsychotic treatment has been established, an antipsychotic with a different pharmacodynamic profile than the offending medication should be used. A low-potency typical or atypical (preferably atypical) antipsychotic is recommended, though it should be started at a low dose and titrated slowly (Guzofski & Peralta, 2006; Kohen, 2004; Pelonero et al., 1998). At this time, the patient must be monitored for signs of re-emerging NMS. Assessment for fever, autonomic instability, changes in mental status, extrapyramidal symptoms, dehydration, and monitor temperature, pulse, and blood pressure are important at this time. CPK measurements and white blood cell counts may also be warranted (Guzofski & Peralta, 2006; Kohen, 2004). If agitation is observed, treat promptly with benzodiazepine, as it is a risk factor of NMS (Guzofski & Peralta, 2006). For a comprehensive review of the NMS literature, visit the Neuroleptic Malignant Syndrome Information Service at http://www.nmsis.org/ that also provides a toll-free hotline for consultation regarding suspected cases of NMS.

www.nmsis.org/content.asp?type ¼ education&src ¼ pages/NMS_OnlineProgram.asp&title ¼ NMSþOnlineþ ProgramþOverview Caroff, S. N., & Mann, S. C. (1993). Neuroleptic malignant syndrome. Medical Clinics of North America, 77, 185–202. Guzofski, S., & Peralta, R. (2006). Neuroleptic malignant syndrome, with attention to its occurrence with atypical antipsychotic medication: A review. Jefferson Journal of Psychiatry, 20(1), 53–61. Haddad, P. M., & Dursun, S. M. (2008). Neurological complications of psychiatric drugs: Clinical features and management. Human Psychopharmacology: Clinical and Experimental, 23, 15–26. Kohen, D. (2004). Neuroleptic malignant syndrome. In P. Haddad, S. Dursun, & B. Deakin (Eds.), Adverse syndromes and psychiatric drugs: A clinical guide (pp. 21–36). USA: Oxford University Press. Levenson, J. L. (1985). Neuroleptic malignant syndrome. American Journal of Psychiatry, 142, 1137–1145. Nierenberg, D., Disch, M., Manheimer, E., Patterson, J., Ross, J., Sivestri, G., et al. (1991). Facilitating prompt diagnosis and treatment of the neuroleptic malignant syndrome. Clinical Pharmacology and Therapeutics, 50, 580–586. Pelonero, A. L, Levenson, J. L., & Pandurangi, A. K. (1998). Neuroleptic malignant syndrome: A review. Psychiatric Services, 49, 1163–1172. Pope, H. G., Jr., Keck, P. E., & McElroy, S. L., Jr. (1986). Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. American Journal of Psychiatry, 143, 1227–1232. Sachdev, P., Mason, C., & Hadzi-Pavlovic, D. (1997). Casecontrol study of neuroleptic malignant syndrome. American Journal of Psychiatry, 154, 1156–1158. Seitz, D. P. (2005). Diagnostic uncertainty in a case of neuroleptic malignant syndrome. Canadian Journal of Emergency Medicine, 7, 266–272. Strawn, J. R., Keck, P. E., Jr., & Caroff, S. N. (2007). Neuroleptic malignant syndrome. American Journal of Psychiatry, 164, 870–876. Susman, V. L. (2001). Clinical management of neuroleptic malignant syndrome. Psychiatric Quarterly, 72, 325–336.

Brian Schmitt Raymond S. Dean

NEURONAL CEROID LIPOFUSCINOSES Addonizio, G., Susman, V. L., & Roth, S. D. (1986). Symptoms of neuroleptic malignant syndrome in 82 consecutive inpatients. American Journal of Psychiatry, 143, 1587–1590. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text revision). Washington, DC: Author. Caroff, S. N. (2005). Neuroleptic malignant syndrome: An online presentation [Flash Program]. Retrieved from http://

DESCRIPTION

Neuronal ceroid lipofuscinoses (NCLs) represent a group of autosomal recessive neurodegenerative diseases. Often NCLs and Batten’s disease are used interchangeably, which is inaccurate. In reality, Batten’s disease represents only one of the NCLs (i.e.,

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NCL 3), albeit the classic variant that is the chronic juvenile form. Defects in lysosomal enzymes or transporters cause accumulation of proteins within the lysosome. The incidence of disease is 1:100,000 live births worldwide but increases to 1:12,500 in the United States and Scandinavia (Pierret, Morrison, & Kirk, 2008). NCL diseases can be categorized by the type of genetic mutation or by the clinical course of the disease. There are 10 genetic subtypes of NCLs, designated CLN1-10. The five major clinical forms are based on the age of onset: congenital (CNCL), infantile (INCL), late infantile (LINCL), juvenile (JNCL) and adults (Kuf’s disease or ANCL). All NCLs share a clinical picture consistent with neurologic degeneration, including blindness, motor disturbances, development regression, seizures, and premature death (Jalanko & Braulke, 2009). NEUROPATHOLOGY/PATHOPHYSIOLOGY

CLN1 is associated with the clinical picture of INCL. It is caused by a mutation on chromosome 1p32 encoding palmitoyl protein thioesterase-1 (PPT1). Over 45 separate mutations have been described; however, missense mutations are the most common. The exact pathophysiological process is not known. It has been theorized that PPT1 may be involved with endocytosis, vesicular trafficking, synaptic function, lipid metabolism, and apoptotic signaling (Jalanko & Braulke, 2009). The proteins accumulated are two types of sphingolipid activator proteins (saposins) A and D. T2-weighted MRI shows decreased signal intensity from the basal ganglia to the thalami. MRI also shows increased intensity on periventricular white matter (Williams et al., 2006). Screening blood tests can be used for CLN1 diagnosis, and blood samples may show slight changes in calcium concentration (Williams et al., 2006). Changes in electroencephalogram (EEG) correspond with progressing disease. The first finding is decreased reactivity to eye movements, later sleep spindles are lost, and at 3 years of age EEGs become isoelectric. On electron microscopy (EM) of skeletal muscle fibers there are characteristic granular lipopigments, seen only in CLN1 and rare cases of adult type NCL. These are referred to as granular osmiophilic deposits or GRODs (Jalanko & Braulke, 2009). GRODs are typically associated with saposin A and D protein accumulations (Haltia, 2006). CLN2 encodes the serine protease, tripeptidyl peptidase protein 1 (TTP1) (Ramirez, Rothberg, & Pearce, 2006). This cleaves tripeptides from the amino-termini of partially unfolded proteins. The major components of stored material include mitochondrial adenosine triphosphate (ATP) synthase

subunit C and minimal amounts of saposins A and D (Ramirez et al., 2006). Preliminary studies show that CLN2 mutations cause decreased TPP1 activity and hinder processing of mature size peptidase. This results in protein retention in the endoplasmic reticulum (Steinfeld, Steinke, Isbrandt, Kohlschutter, & Gartner, 2004). On EM of neuronal tissue, intraneuronal GRODs characterized by a pure curvilinear patter of lipopigmentation can be seen. These are pathognomonic for CLN2. MRI demonstrates severe cerebellar atrophy that is typical of CLN2 (Jalanko & Braulke, 2009). The CLN3 protein, referred to as battenin, is an intrinsic membrane protein that has been localized to the lysosome. However, its role in the pathophysiology of the disease remains unknown. Diagnosis of this variant is considered if EM tissue samples demonstrate the characteristic fingerprint ultrastructure of lipopigments within lyosomal vacuoles (Haltia et al., 2006). CLN4 is the adult variant of NCL. The chromosome, gene, and gene product remain unknown. However, the stored protein is believed to be the subunit c of mitochondrial ATP synthase. The ultrastructural appearance of intraneuronal storage bodies demonstrates fingerprint bodies and granules (Haltia, 2006). CLN5 has been localized to chromosome 13q21q32. In 94% of cases, a 2bp deletion in exon 4 results in a stop codon at Tyr392. CLN5 represents a Finnish variant of NCL. The function of the CLN5 protein has not yet been identified. EEGs of subjects demonstrate posterior spikes to low frequency photic stimulation and giant somatosensory-evoked potentials. Decreased signal intensity of the thalami and increased signal intensity of the periventricular white matter and posterior limbs of the internal capsule are seen on T2-weighted MRI. (Williams et al., 2006). EM demonstrates CLN5 avacuolar fingerprint body lipopigments in rectilinear profiles, curvilinear profiles, and fingerprint bodies (Haltia, 2006). CLN6 is located on chromosome 15q23. The CLN6 protein encoded by this gene is found in the endoplasmic reticulum (ER) and is involved in ER retention signals. It is still unknown how this affects lysosomal function. Autopsy studies demonstrate neuronal loss in layer V of the cerebral cortex (Jalanko & Braulke, 2009). Like CLN5, CLN6 is also associated with avacuolar fingerprint-containing lipopigments and rectilinear and curvilinear profiles (Williams et al., 2006). CLN7 is located on chromosome 4q28.1-q28.2. CLN7 protein belongs to the large major facilitator super family of transporter proteins. The specific role of CLN7 is unknown. CLN7 is also associated

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with avacuolar fingerprint-containing lipopigments (Williams et al., 2006). CLN8 is on chromosome 8p23. CLN8 protein is localized in the ER but may travel between the ER and Golgi intermediate complex. It is hypothesized that it may be involved in biosynthesis, metabolism, transport, and detection of lipids (Jalanko & Braulke, 2009). The CLN9 gene remains unknown. However, fibroblasts from CLN9 patients do show rapid growth, sensitivity to apoptosis, a specific cell adhesion defect, and reduced levels of ceramide, dihydroceramide, and sphingomyelin (Haltia, 2006). CLN10 is localized to chromosome 11p15.5 and encodes for major lysosomal aspartic protease cathepsin D(CTSD). CTSD is involved in selective, rather than bulk proteolysis and cleaves prosaposin into saposins A, B, C, and D. CTSD is thought to be involved in cell proliferation, antigen processing, apoptosis, and regulation of plasma HDL cholesterol. Overall, MRI shows decreased signal intensity from the thalami to the basal ganglia on T2-weighted images and generalized cerebral atrophy (Williams et al., 2006). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Though all NCLs share a common presentation of progressive neurological deterioration, each clinical profile is unique and disease specific. CLN1, Santavuori’s disease, most commonly causes INCL. However, there are rare cases in which CLN1 resulted in other phenotypes. INCL is characterized by early and severe onset. The age at first presentation is usually 6–12 months. At birth, children appear normal and prior to 6 months will meet normal developmental milestones. At 6 months of age, deceleration of head growth and muscular hypotonia are detectable. In progressing to the 2nd year of life, children display ataxia, sleep disturbance, visual difficulties, and irritability. Hyperkinesias are common. By 2–3 years of age, patients are usually blind and have lost all social interest. They display with increasing frequency spasticity, seizures, and myoclonic activity. The average age of death is 13 years old (Williams et al., 2006). CLN2, Bielschowsky’s disease, mutations result in late infantile NCL. At birth and during the first 3 years of life, patients appear healthy. However, after 3 years of age, psychomotor delay is common, as is sudden onset epilepsy. Usually, seizures are of a severe myoclonic type and can be resistant to drug treatment. Retinal degeneration is also characteristic. With

appropriate supportive care, children may live up to 10 years (Williams et al., 2006). CLN3, Batten’s disease, mutations cause JNCL. There is a wide variety of clinical presentations associated with this specific type of mutation. However, the first signs of illness are vision failure from retinal degeneration, which typically occur around 5–10 years of age (Jalanko & Brakle, 2009). Epileptic seizures usually begin at approximately 10 years of age. In addition, mental retardation develops slowly over the course of the illness. JNCL patients may also display aggressive behavior, depression, and sleep disorders. Death usually occurs around 20–30 years old (Jalanko & Braulke, 2009). CLN4, also known as Kuf’s disease, represents the adult form of NCL. Symptom onset usually occurs prior to age 40 and is marked by progressive dementia. This endmark is preceded by one of two clinical presentations. In one group of individuals, dementia is preceded by late onset myoclonic epilepsy whereas motor functioning is spared (Berkovic, Carpenter, Andermann, Andermann, & Wolfe, 1988). Another group does not commonly manifest seizures, at least in the initial stages. Rather, their presentation is characterized by predominant motor dysfunction most commonly involving cerebellar ataxia or progressive rigidity and parkinsonism (Burneo et al., 2003). CLN5 is the Finnish variant of LINCL. The first symptoms of disease begin with motor clumsiness, progressive visual failure, myoclonia, and seizures around 4–9 years of age. Death occurs between the second and fourth decades of life (Jalanko & Braulke, 2009). CLN6, Lake’s disease, is another variant of LINCL and is most commonly found in people of Eastern European, Pakistani, or Portuguese heritage. In 65% of patients, seizures begin before reaching 5 years old. The age of onset is between 18 months and 8 years. Deterioration is rapid after diagnosis, and most children die between 5 and 12 years old. CLN7 is the Turkish variant of LINCL. The age of onset ranges from 2 to 7 years old. The most common presenting symptom is severe epilepsy. CLN8 is another variant of LINCL and has been reported in Finnish, Turkish, Italian, and Israeli patients. Epileptic symptoms begin at ages 5–10. All patients have generalized tonic-clonic seizures. Progressive mental deterioration and motor problems, as well as more frequent seizure episodes occur during puberty. Patients may survive to between 50 and 60 years of age. Historically, only four patients in total have been diagnosed with CLN9. Symptoms reported are identical to CLN3 patients (Jalanko & Braulke, 2009).

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Only 10 cases of CLN10, also called congenital NCL, have been described. These result in infants that present with congenital microcephaly, respiratory distress, and status epilepticus. Death occurs within the first few weeks of life (Williams et al., 2006). DIAGNOSIS

There is a screening test for CLN1 and CLN2 in which TPP1 or PPT1 levels can be measured using a fluorescent substrate enzymatic assay. Samples can be taken as fresh blood, dried blood spots, saliva, or cultured fibroblasts from a skin biopsy. The level of activity of PPT1 or TPP1 is measured. CLN3 can be suspected in the cases of clinical NCL disease and unremarkable PPT1 and TPP1 assays. Presence of vacuolated lymphocytes in the peripheral smear suggests a CLN3 diagnosis as well. Final confirmation of this diagnosis can be performed using CLN3 genetic mutation analysis (Williams et al., 2006). More extensive genetic screening may be merited if the patient has a clinical picture of an NCL disorder, with normal levels of TTP1 or PPT1 and without vacuolated lymphocytes in the peripheral smear. In this case, CLN5-CLN10, mutation analysis can be performed. The patient’s ethnicity and clinical picture can provide a basis for which CLN5-CLN10 testing is necessary. However, not all genetic mutations have been identified, and, as a result, genetic analysis does not detect all NCL disorders (Williams et al., 2006). Prenatal diagnosis is available and performed using a combination of mutation analysis and enzymatic assays. If necessary, this diagnosis can be confirmed using chorionic biopsies (Williams et al., 2006). TREATMENT

There are no treatment options available for reversing, slowing, or preventing the neurodegeneration that occurs in NCL disorders. Supportive measures are the mainstay of treatment. This includes effective treatment with anticonvulsants, if necessary. Valproate has been successful in this. It has been suggested that treatment with antioxidants and vitamin D may delay loss of motor function and help to reduce seizure frequency and severity as well. Behavior modification techniques may be useful as well (Maertens & Dyken, 2007). There are a number of treatment methods being researched at present. One option being considered is enzyme replacement therapy (ERT), which has shown encouraging results in other lysosomal storage disease. However, these exogenous enzymes do not

pass through the blood–brain barrier, making ERT less successful in resolving the central nervous system (CNS) pathology of lysosomal storage diseases. Gene therapy is another treatment option being explored. Virus-associated delivery of human PPT1 has shown promising results in mouse models. Clinical trials of human neuronal stem cell injection into children with CLN3 began in 2006. In terms of pharmacologic treatment, cysteamine and N-acetylcystiene combination therapies are in phase II trials (Pierret et al., 2008). Rebecca Durkin Chad A. Noggle Berkovic, S. F., Carpenter, S., Andermann, F., Andermann, E., & Wolfe, L. S. (1988). Kufs’ disease: A critical reappraisal. Brain, 111, 27–62. Burneo, J. G., Arnold, T., Palmer, C. A., Kuzniecky, R. I., Oh, S. J., & Faught, E. (2003). Adult-onset neuronal ceroid lipofuscinosis with autosomal dominant inheritance in Alabama. Epilepsia, 44, 841–846. Haltia, M. (2006). The neuronal ceroid-lipofuscinoses: From past to present. Molecular Basis of Disease, 1762(10), 850–856. Jalanko, A., & Braulke, T. (2009). Neuronal ceroid-lipofuscinoses. Biochimica et Biophysica Acta, 1793, 697–709. Martens, P., & Dyken, R. (2007) Lipoidoses. In C. Goetz (Ed.), Textbook of Clinical Neurology (pp. 616–625). Philadelphia, PA: Saunders. Pierret, C., Morrison, J. A., & Kirk, M. D. (2008). Treatment of lysosomal storage disorders: Focus on the neuronal ceroid-lipofuscinoses. Acta Neurobiologiae Experimentalis, 68, 429–442. Ramirez, M., Rothberg, P. G., & Pearce, D. A. (2006). Another disorder finds its gene. Brain, 129, 1351–1356. Steinfeld, R., Steinke, H. B., Isbrandt, D., Kohlschutter, A., & Gartner, J. (2004). Mutations in classical late infantile neuronal ceroid lipofuscinosis disrupt transport of tripeptidyl-peptidase I to lysosomes. Human Molecular Genetics, 13, 2483–2491. Williams, R. E., Aberg, L., Autti, T., Goebel, H. H., Kohlschutter, A., & Lonnqvist, T. (2006). Diagnosis of neuronal ceroid lipofuscinoses: An update. Biochimica et Biophysica Acta, 1762, 865–872.

NEUROPATHY DESCRIPTION

Neuropathy is a neurodegenerative disorder characterized by damage to one or more peripheral nerves.

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The peripheral nervous system (PNS) transmits information from the CNS to limbs and organs. Central neuropathy refers to damage sustained by the brain or the spinal cord, both of which are encompassed by the CNS. Though neuropathies may originate in the CNS, the majority originate in the PNS (Uzun, Uluduz, Mikla, & Aydin, 2006). Damage to peripheral nerves causes distortion of information transmitted to and from the body and extremities (i.e., anything beyond the brain and spinal cord), resulting in symptoms ranging from temporary numbness to paralysis and organ or gland dysfunction. There are several types of neuropathies, each distinguishable by the extent and location of the nerve damage (Andreoli, 2007). When disturbance in function occurs in one nerve, the neuropathy is classified as a mononeuropathy simplex. Mononeuropathy multiplex indicates involvement of several nonadjacent peripheral nerves. Polyneuropathies are more common, concurrently affecting the function of numerous peripheral nerves. The subclassifications of polyneuropathies include axonal neuropathies, principally affecting the axons, demyelinating neuropathies, involving the myelin sheath surrounding the axons, and neuronopathies, involving neurons of the PNS. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Neuropathy may be acquired or inherited. Idiopathic inflammatory neuropathies are a classification of acquired neuropathies. They are caused by inflammation from activities of the immune system and include acute idiopathic polyneuropathy (Guillain–Barre´ syndrome) and chronic inflammatory demelinating polyneuropathy (see the entries on Guillain-Barre´ syndrome and Chronic Inflammatory Demyelinating Polyneuropathy for further review). Metabolic and nutritional neuropathies can be caused by diabetes, uremia, liver disease, vitamin B12 deficiency, and other endocrinopathies including hypothyroidism and acromegaly. Vitamin B12 is an essential element of healthy nerve function, with a deficiency leading to widespread nerve tissue damage. Peripheral neuropathy is the most common complication of diabetes. Mild neuropathies accompanied by sensory abnormalities are found in up to 70% of diabetic patients, whereas symptomatic neuropathies affect an additional 5–10% (Andreoli, 2007). The clinical form of neuropathy most diabetic patients present with is symmetric polyneuropathy associated with rapid physiologic dysfunction and hyperglycemia. Infective and granulomatous neuropathies have a variety of causes including AIDS, diphtheria, leprosy,

sarcoidosis, sepsis, and multiorgan failure. Though diphtheria and leprosy are rare, Lyme disease is more common and can cause a rapidly developing polyneuropathy. Mixed connective tissue disease, polyarteritis nodosa, rheumatoid arthritis, and systemic lupus erythematosus are known causes of vasculitic neuropathies. Certain connective tissue disorders, including polyarteritis nodosa and rheumatoid arthritis, may cause mononeuropathy multiplex or even polyneuropathy. Neoplastic and paraproteinemic neuropathies are caused by compression and infiltration resulting from a tumor, paraneoplastic syndromes, paraproteinemias, and amyloidosis. Neurofibromatoses, genetic diseases involving tumors growing directly on nerve tissue, are often associated with polyneuropathies. Drug-induced and toxic neuropathies are caused by alcohol, organic compounds such as hexacarbons, and organophosphates, heavy metals such as arsenic, gold, lead, platinum, thallium, and tryptophan. Thiamine deficiency is a common problem associated with alcoholism and can cause neuropathy of the extremities. Excessive alcohol consumption alone may directly cause damage to the peripheral nerves. Peripheral nerve damage is also a side effect of longterm use of anticancer drugs, anticonvulsants, and antibiotics. Finally, hereditary neuropathies of an idiopathic nature may be caused by Friedreich ataxia and familial amyloidosis, whereas hereditary neuropathies of a metabolic nature may be caused by porphyria, metachromatic leukodystrophy, Krabbe’s disease, abetalipoproteinemia, Tangier’s disease, Refsum’s disease, and Fabry’s disease. Hereditary neuropathies result from genetic code errors or new genetic mutations and may begin in infancy in severe cases or in early adulthood for milder forms (Dyck & Thomas, 2005). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Proper operation of the axon and its myelin sheath is vital for the normal functioning of myelinated nerve fibers. When the axon begins to degenerate as a result of a variety of metabolic, toxic, and heritable causes, the myelin also begins to break down. Axonal degeneration of long nerve fibers is usually the underlying cause of polyneuropathies. When demyelination occurs in peripheral nerves as a result of demyelinating neuropathies, functional deficits identical to those resulting from axonal degeneration are produced. Demyelinating neuropathies are largely caused by inherited disorders of myelin, autoimmune attacks

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on myelin, and mechanical, toxic, and physical injuries to the nerve (Dyck & Thomas, 2005). Clinical presentation of the neuropathies depends upon the associated pathophysiologic mechanisms and the anatomical location of the nerve damage. Peripheral nerves have highly specialized functions, leading to a wide array of symptoms when the nerves are damaged. The most common symptom of damage to peripheral motor nerves is muscle weakness, whereas other symptoms may include cramps, muscle loss, bone degeneration, and fasciculations (Andreoli, 2007). Sensory nerve damage generally results in impaired and abnormal sensations and numbness. When involvement of peripheral nerve fibers of a certain size is selective, dissociated sensory loss may occur. In such cases, certain sensory modalities are impaired while others are preserved. Additional sensory and reflex changes associated with the motor neuron deficits suggest peripheral nerve damage. When small fibers within nerves are affected by the neuropathy, pain is a prominent symptom. Pain is an established symptom of neuropathies related to alcohol use, and diabetes may also be a feature of entrapment neuropathies. Patients with diabetic polyneuropathies generally present with autonomic dysfunction, spontaneous sensations of neuropathic pain including dysesthesias, and reduced pain sensibility. Diabetic neuropathy occurs most often in patients with insulin-requiring long-standing diabetes, and a diagnosis can be confirmed with electrodiagnostic studies. In a study conducted by Turcot, Allet, and Golay (2009), participants with diabetic neuropathy also presented with greater postural instability than control participants. L-periaxin is a protein involved in the stabilization of mature myelin in peripheral nerves. Lawlor, Richards, and De Vries (2002) report the presence of anti-L-periaxin antibodies in patients with diabetes-associated peripheral neuropathy, resulting in morphologic abnormalities of the sensory nerves. When the neural pathways that mediate reflexes are interrupted, tendon reflexes may be impaired or lost. Patients with polyneuropathies generally experience loss of ankle reflexes first, followed by additional tendon reflex loss. Symptoms associated with Guillain–Barre´ syndrome and diabetic neuropathies or those caused by amyloidosis include coldness of extremities, bladder and bowel function disturbances, impotence, and postural hypotension. Along with being an additional symptom of amyloidosis, enlarged peripheral nerves may be an indication of hereditary motor and sensory neuropathies and neuropathies associated with leprosy, Refsum’s disease, and acromegaly. Again,

the interested reader is recommended to review these entries within this text. DIAGNOSIS

Due to high symptom variability, diagnosis of neuropathy can be challenging. Symptoms of a sensory nature are often the first clue of peripheral nerve involvement. Acute development of symptoms usually relates to an inflammatory polyneuropathy, whereas gradual evolution of symptoms is an indication of hereditary or metabolic polyneuropathies. Mononeuropathies with acute symptom presentation generally result from traumatic causes. Symptoms caused by minor traumatic injuries and entrapment of nerves are more likely indications of mononeuropathies of gradual onset. Along with drug and alcohol history, occupational history should also be considered during patient evaluation as certain industrial substances may lead to peripheral neuropathy. When a diagnosis of neuropathy is suspected, EMG may be used to determine location of denervation. Nerve conduction velocity tests are used to determine whether nerve damage is the result of myelin sheath or axon degeneration. Demyelinating and axonal neuropathies may be differentiated using electrodiagnostic or histopathologic studies. Nerve biopsies may also be conducted to determine the degree of nerve damage. When a diagnosis of peripheral neuropathy is confirmed electrodiagnostically, additional laboratory studies including blood glucose levels, serum vitamin B12, and liver and thyroid function blood tests should be conducted. MRI can detect nerve damage caused by compression and can provide data on muscle size and quality. Abnormal antibodies associated with neuropathies can be identified during examination of CSF, and simple tests to evaluation ability to register sensations may reveal the size of sensory nerve fibers affected. TREATMENT

Though treatments of inherited forms of neuropathy are limited, depending on classification, acquired neuropathies may be treated in several ways. Generally, the underlying cause of the neuropathy is treated first to limit progression of the symptoms or even reverse the neuropathy itself before symptomatic treatment is initiated. Adopting a healthy lifestyle, avoiding exposure to toxins, limiting alcohol consumption, correcting vitamin deficiencies, and eating a balanced diet are all helpful strategies to reduce the physical symptoms of many neuropathies. Regular exercise may help in

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reducing cramps associated with certain neuropathies and improve muscle strength, a vital component of avoiding muscle wasting associated with limb paralysis. Plasmapheresis shortens recovery time associated with Guillain–Barre´ syndrome, whereas intravenous immunoglobulin in high doses is an equally effective treatment. Careful monitoring of respiratory function in patients with Guillain–Barre´ syndrome, diphtheritic neuropathy, and other idiopathic inflammatory neuropathies is essential to effective treatment. Correction of blood glucose levels is important for preventing and reducing neuropathic symptoms associated with diabetic neuropathy. Anticonvulsants and tricyclic antidepressants have also been found to reduce the painful symptoms of diabetic neuropathy. J. T. Hutton Rachel Rock O. J. Vidal Antonio E. Puente Andreoli, T. E. (2007). Cecil essentials of medicine (7th ed.). Philadelphia: Saunders Elsevier. Dyck, P. J., & Thomas, P. K. (2005). Peripheral neuropathy (4th ed.). Philadelphia: Saunders Elsevier. Lawlor, M. W., Richards, M. P., & De Vries, G. H. (2002). Antibodies to L-periaxin in sera of patients with peripheral neuropathy produce experimental sensory nerve conduction deficits. Journal of Neurochemistry, 83, 592–600. Turcot, K., Allet, L., & Golay, A. (2009). Investigation of standing balance in diabetic patients with and without peripheral neuropathy using accelerometers. Clinical Biomechanics, 24(9), 716–721. Uzun, N., Uluduz, D., Mikla, S., & Aydin, A. (2006). Evaluation of asymptomatic central neuropathy in type I diabetes mellitus. Electromyography and Clinical Neurophysiology, 46(3), 131–137.

NEUROSARCOIDOSIS DESCRIPTION

Sarcoidosis is a multisystem immune system disorder of unknown etiology characterized by granulomas typically presenting in the lymphatic system and lungs. In rare cases, the central nervous system (CNS) is involved and this is referred to as neurosarcoidosis. Signs of neurologic involvement are usually seen in patients known to have active disease in other systems of the body, occurring in 5% of these patients.

Isolated neurosarcoidosis, without systemic disease, is particularly rare, occurring in only 1% or less of all cases (Burns, 2003; Joseph & Scolding, 2007). The exact cause of sarcoidosis is not known. The disease is associated with an abnormal immune response, but what triggers this response is uncertain. The mechanism of spreading from one system of the body to another is also unclear. Review articles highlight the protean effects of sarcoidosis on the CNS including potential involvement of the meninges, brain parenchyma, cranial nerves, and peripheral nerves (Burns, 2003; Joseph & Scolding, 2007; Nowak & Wideka, 2001). Because of its typical location near the base of the brain, symptoms are variable but can include seizures, endocrine abnormalities, gait and balance disturbance, vision deficits, amnestic syndromes, cranial nerve abnormalities, and neuropathies. The prevalence of sarcoidosis varies widely according to various demographic groups, but the general incidence rate is 20 per 100,000 persons. Less than 10% of the cases with systemic sarcoid will have neurological involvement, typically occurring later in the disease course, resulting in an incidence rate of less than 2 per 100,000. This prevalence drops significantly for cases of isolated neurosarcoidosis with no other systemic disease occurring in less than 1% of all cases with an incidence rate of less than 0.2 per 100,000 (Nowak & Widenka, 2001). The disease is more common in young adults (20–40 years of age) with predominance in African Americans and slightly greater frequency in women (Joseph & Scolding, 2007; Nowak & Widenka, 2001). Neurosarcoidosis is uncommon in children, particularly those under the age of 9. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Histologically, neurosarcoidosis is characterized by the formation of granulomas in the CNS. The lesion consists of lymphocytes and mononuclear phagocytes surrounding a noncaseating epithelioid cell granuloma. These granulomas represent an autoimmune response to CNS tissues (Joseph & Scolding, 2007). As described earlier, the presentation of neurosarcoidosis is quite variable with several areas showing vulnerability. Colover (1948), in his clinical case review, found that the optic nerves and retina; the facial, glossopharyngeal, and vagus nerves; the pars intermedia of the pituitary gland and pituitary stalk; and the peripheral nerves are particularly likely to be affected by neurosarcoisosis. This review also found that the CNS may develop meningoencephalitis or meningomyelitis, may exhibit localized infiltration by sarcoid tissue, or may be affected by tumor-like masses in the dura

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mater. As outlined in more recent review papers, later studies also confirmed these findings (Burns, 2003; Joseph & Scolding, 2007; Nowak & Widenka, 2001). These reviews highlight the frequent involvement of the cranial nerves, particularly the optic nerve. Additionally, manifestations of tubular-like sarcoid granulomas and intracranial masses in a variety of neurologic areas including intraparenchymal, extraaxial, and diffuse leptomeningeal lesions are also described. The involvement of spinal cord, peripheral nerves and roots, and muscle are less frequent. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Like most space-occupying focal lesions, the clinical symptoms of neurosarcoidosis are dependent on the location of the lesion. Signs and symptoms may mimic those seen in meningitis, brain neoplasm, subarachnoid hemorrhage, cerebrovascular ischemia, cranial nerve palsy, hydrocephalus, or other focal neurologic conditions. According to the review of Nowak and Widenka (2001), the most common general clinical signs and symptoms of neurosarcoidosis include cranial nerve palsies (50%), headache (30%), seizures (10%), pituitary dysfunction (10%), sensory and motor deficits (10%), neuropsychological deficits (10%), cerebellar symptoms (10%), hydrocephalus (5%), and signs and symptoms of meningitis (5%). As outlined by Joseph and Scolding (2007), specific clinical symptoms are associated with the location of the lesion. Some of the more common specific symptoms include reduced facial motor and sensory functioning due to facial nerve involvement, and reduced visual perception due to optic nerve involvement. Besides, other vision problems are also caused due to obstruction of the normal cerebrospinal fluid (CSF) flow by granulomas. Granulomas in the pituitary gland result in endocrine disturbance including amenorrhoea, diabetes insipidus, hypothyroidism, or hypocortisolism. Meningeal presentations result in headache, nuchal rigidity, and other symptoms of meningitis. If the granulomas are large and tumor-like, a mass effect may occur causing headache, increased risk of seizures, and obstruction of the flow of CSF, which results in increased risk of raised intracranial pressure and hydrocephalus. Focal parenchymal lesions result in abnormalities in the function associated with their presenting location. The involvement of the spinal cord is rare, but when present leads to abnormal sensation or weakness in one or more limbs or cauda equina syndrome. Neuropsychological deficits are variable and consistent with the site of the lesion. As a result, there is no

defined neuropsychological profile for neurosarcoidosis. However, general attention and concentration deficits are common in acute presentations as expected in any acute inflammatory process. Psychiatric problems occur in approximately 20% of the cases. These include various psychiatric signs and symptoms including depression and, in rare cases, acute psychosis in cases with temporal lobe infiltration (Joseph & Scolding, 2007). DIAGNOSIS

Because of its nonspecific clinical presentation and neuroradiological imaging characteristics, intracranial neurosarcoidosis remains a very difficult diagnosis, particularly in the absence of extracranial signs of the disease (Nowak & Widenka, 2001). Due to the wide spectrum of neuroradiological findings, intracranial sarcoid granulomas can be mistaken for primary brain tumors such as glioma, meningioma, and other masses, as well as an infectious state of the CNS (Nowak & Widenka, 2001). MRI with administration of Gd-Gd-DTPA has been shown to be sensitive in detecting intracranial abnormalities due to neurosarcoidosis, particularly when pathological enhancement of the brain parenchyma and leptomeninges and evidence of periventricular and white matter disease are noted (Zajicek et al., 1999). MRI helps narrow the diagnostic possibilities, but is not conclusive in identifying neurosarcoidosis. Research regarding the usefulness of CSF and other laboratory analysis in the differential diagnosis of neurosarcoidosis has not been promising (Nowak & Widenka, 2001). A definitive diagnosis for neurosarcoidosis can only be made by biopsy (Burns, 2003; Joseph & Scolding, 2007; Nowak & Wideka, 2001). This would demonstrate granulomas rich in epithelioid cells and surrounded by other immune system cells. According to a classification system developed by Zajicek and colleagues (1999), definite neurosarcoidosis is diagnosed by plausible symptoms, a positive biopsy, and no other possible causes for the symptoms. Probable neurosarcoidosis is diagnosed if the symptoms are suggestive, there is evidence of CNS inflammation, and other diagnoses have been excluded. A diagnosis of systemic sarcoidosis is not essential. Possible neurosarcoidosis may be diagnosed if there are symptoms not due to other conditions, but other criteria are not fulfilled. TREATMENT

There have been no controlled prospective studies to identify useful therapeutic options for neurosarcoidosis

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(Nowak & Widenka, 2001). Corticosteroids are the treatment of choice as they usually suppress inflammation and may relieve acute symptoms. CNS mass lesions may be especially responsive to corticosteroid therapy (Nowak & Widenka, 2001; Zajicek et al., 1999). Whether corticosteroids change the natural course of neurosarcoidosis is unclear. When corticosteroids provide limited benefit, immunosuppressive agents are the next option, although limited research is available regarding the efficacy of these interventions (Nowak & Widenka, 2001). In addition to these treatments, symptom-specific therapies are commonly used to minimize the impact of the disease. In patients unresponsive to medical treatment, radiotherapy may be required. Additionally, if the granulomatous tissue causes obstruction or mass effect, neurosurgical intervention is sometimes necessary to minimize the effects of hydrocephalus and increased intracranial pressure (Joseph & Scolding, 2007). Mark T. Barisa Burns, T. M. (2003). Neurosarcoidosis. Archives of Neurology, 60, 1166–1168. Colover, J. (1948). Sarcoidosis with involvement of the nervous system. Brain, 71, 451–475. Joseph, F. G., & Scolding, N. J. (2007). Sarcoidosis of the nervous system. Practical Neurology, 7, 234–244. Nowak, D. A., & Widenka, D. C. (2001). Neurosarcoidosis: A review of its intracranial manifestation. Journal of Neurology, 248, 363–372. Zajicek, J. P., Scolding, N. J., Foster, O., Rovaris, M., Evanson, J., Moseley, I. F., et al. (1999). Central nervous system sarcoidosis — Diagnosis and management. Quarterly Journal of Medicine, 92, 103–117.

NEUROSYPHILIS DESCRIPTION

Neurosyphilis refers to the syphilitic infection of the CNS caused by Treponema pallidum (Conde-Sendin, Hernandez-Fleta, Cardenes-Santana, & Amela-Peris, 2002). It is a medically important and frequently encountered sexually transmitted disease (Vieira Santos, Matias, Saraiva, & Goulano, 2005). Much of what we know about neurosyphilis is based on case reports, small series reports, and retrospective reviews (Marra, 2009). Timely intervention is important to help prevent the progression of the disease (Lee,

Lin, Lu, & Liu, 2009). If left untreated, 4–9% of patients go on to develop symptomatic neurosyphilis (Verma & Solbrig, 2006). Neurosyphilis can occur in the secondary stage of the disease process, sometimes called ‘‘early neurosyphilis’’ (O’Donnell & Emery, 2005). Early neurosyphilis can impact the CSF, meninges, and cerebral vasculature (Marra, 2009; O’Donnell & Emery, 2005). Approximately one-third of patients develop tertiary stage or ‘‘late neurosyphilis.’’ Late neurosyphilis is a slowly progressive inflammatory disease, which can impact the brain or spinal cord parenchyma (Marra, 2009; O’Donnell & Emery, 2005). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Identifying the radiological appearance of neurosyphilis is important so that clinical testing and treatment may be initiated (Santos et al., 2005). Russouw, Roberts, Emsley, and Truter (1997) performed MRI on 20 newly diagnosed patients with neurosyphilis, 13 of whom showed radiological abnormalities including generalized atrophy and foci of increased signal intensity on T2-weighted images. They found that frontal lesions were significantly associated with the degree of psychiatric morbidity, suggesting that the location for the burden of lesions may help to determine psychiatric symptoms that frequently accompany the disease process (Russouw et al., 1997). Santos and colleagues (2005) emphasized that imaging findings in neurosyphilis can be similar to those in other conditions that impact the limbic system, such as herpes encephalitis. Pavlovic´ and Milovic´ (1999) found that CT and MRI findings evidenced cortical and subcortical atrophy in the brain parenchyma in four (57%) patients, and multi-ischemic changes in two (29%) patients (seven patients were studied retrospectively). At least 16 patients with medial temporal lobe involvement on neuroimaging findings have been documented in the literature (Lee, Wilck, & Venna, 2005). EEG findings can show generalized periodic epileptiform discharges similar to what is seen in Creutzfeldt–Jacob disease (Anghinah, Camargo, Braga, Waksman, & Nitrini, 2006). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Neurosyphilis can have a wide array of clinical symptoms, which often mimics better-known neurological conditions (Conde-Sendin, Hernandez-Flet, Cardenes-Santan, & Amela-Peris, 2002). To start, individuals can be asymptomatic or symptomatic. In regard to the former, it is marked by abnormal CSF evaluation with mild lymphocytic or mononuclear

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pleocytosis, and elevated protein concentration, and a reactive CSF-venereal disease research laboratory (CSF-VDRL) test (CDC, 2007). When individuals are acutely symptomatic, the most common features are that of headache, nausea, stiff neck, and occasional papilledema. Cranial nerves II, III, VI, and VII are most affected, as observed in studies conducted during the pre-antibiotic area (Merritt, Adams, & Solomon, 1946). Beyond the acute phases, neurosyphilis often resembles psychiatric disorders (Russouw et al., 1997). Personality changes, irritability, depression, and psychosis can occur (O’Donnell & Emery, 2005). The course of the disease can be long and result in a progressive impairment in mental abilities. Very specific deficits can occur due to focal lesions related to the disease (Lezak, 2004); memory loss and concentration difficulties are not uncommon (O’Donnell & Emery, 2005). General paresis is the encephalitic form of neurosyphilis and can result in progressive dementia 15–20 years after the initial infection (range, 5–50 years) (Verma & Solbring, 2004). The clinical manifestation may include dysarthria, delusions, apathy, intention tremor, seizures, myclonus, hyperreflexia, and Argyll Robertson pupils (Verma & Solbring, 2004). Dementia can be a manifestation of late syphilis with associated cognitive and behavioral symptoms (Vargas, Carod-Arfal, Del Negro, & Rodriguez, 2000). Neurosyphilis can also be the cause of epileptic seizures (Anghinah et al., 2006). The clinical findings consistent with neurosyphilis are not clearly defined by the Centers for Disease Control and Prevention (CDC) (Marra, 2009) but in a survey of 49 cases, clinical findings included auditory disease, acute meningitis, stroke, ocular disease, headache, altered mental status, and cranial nerve dysfunction (Wharton, Chorba, Vogt, Morse, & Buehler, 1990). Pavlovic and Milovic (1999) found gait disturbance in five (71%) of seven patients. DIAGNOSIS

Neurosyphilis can be difficult to diagnose, and it is often further complicated by the co-occurrence of HIV infection (O’Donnell & Emery, 1995). The CDC outlines criteria for ‘‘confirmed’’ and ‘‘presumptive’’ neurosyphilis (Wharton et.al., 1990). Confirmed neurosyphilis is (1) any syphilis stage and (2) a reactive CSF-VDRL. Presumptive neurosyphilis is (1) any syphilis stage, (2) a nonreactive CSF-VDRL, (3) elevated CSF protein or white blood cell count without any other known causes for these abnormalities, and (4) clinical signs or symptoms consistent with neurosyphilis without other known causes for

these abnormalities. Although serologic tests are important in diagnosing syphilis, they can be difficult to interpret. For example, Lyme neuroborreliosis or Borrelia burgdorferi is a well-established confound on serologic tests (Scheid, 2006). TREATMENT

Penicillin is the drug of choice for the treatment of syphilis during all stages, but ceftriaxone is considered a reasonable alternative for those who are allergic to penicillin (Marra, 2009). Efficacious treatment is considered as normalized CSF (which may take longer when HIV is present) and resolution of clinical abnormalities, although these abnormalities may persist, especially if there is tissue damage (Marra, 2009). Amy R. Steiner Chad A. Noggle Amanda R. W. Steiner Centers for Disease Control and Prevention (CDC). (2007). Symptomatic early neurosyphilis among HIV-positive men who have sex with men — four cities, United States, January 2002–June 2004. MMWR. Morbidity and Mortality Weekly Report, 56, 625–628. Conde-Sendı´n, M. A., Herna´ndez-Fleta, J. L., Ca´rdenesSantana, M. A., & Amela-Peris, R. (2002). Neurosyphilis: Forms of presentation and clinical management. Revista de Neurologia, 35(4), 380–386. Lee, C. H., Lin, W. C., Lu, C. H., & Liu, J.W. (2009). Initially unrecognized dementia in a young man with neurosyphilis. Neurologist, 15(2), 95–97. Lee, J. W., Wilck, M., & Venna, N. (2005). Dementia due to neurosyphilis with persistently negative CSF VDRL. Neurology, 65, 1838. Marra, C. (2009). Update on neurosyphilis. Current Infectious Disease Reports, 11, 127–134. Merritt, H. H., Adams, R. D., & Solomon, H.C. (1946). Neurosyphilis. New York: Oxford University Press. O’Donnell, J. A., & Emery, C. L. (2005). Neurosyphilis: A current review. Current Infectious Disease Reports, 7, 277–284. Pavlovic´, D. M., & Milovic´, A. M. (1999). Clinical characteristics and therapy of neurosyphilis in patients who are negative for human immunodeficiency virus. Srpski Arhiv za Celokupno Lekarstvo, 127(7–8), 236–240. Russouw, H. G., Roberts, M. C., Emsley, R. A., & Truter, R. (1997). Psychiatric manifestations and magnetic resonance imaging in HIV-negative neurosyphilis. Biological Psychiatry, 41(4), 467–473. Scheid, R. (2006). Differential diagnosis of mesiotemporal lesions: Case report of neurosyphilis. Neuroradiology, 48, 506.

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Verma, A., & Solbrig, M. V. (2006). Infections of the nervous system. In W. G. Bradley, R. B. Daroff, G. M. Fenichel, & J. Jankovic (Eds.), Neurology in clinical practice: Principles of diagnosis and management (Vol. 2, 4th ed., pp. 1496–1498). Philadelphia: Elsevier. Vieira Santos, A., Matias, S., Saraiva, P., & Goula˜o, A. (2005). Differential diagnosis of mesiotemporal lesions: Case report of neurosyphilis. Neuroradiology, 47, 664–667. Wharton, M., Chorba, T. L., Vogt., R. L., Morse, D. L., & Buehler, J. W. (1990). Case definitions for public health surveillance. MMWE. Recommendations and Reports, 39, 1–43.

NEUROTOXICITY DESCRIPTION

Neurotoxicant exposure has been associated with an array of deleterious effects on cerebral structures and functions. The range of substances that has been described as ‘‘neurotoxic’’ is considerable, and includes substances that naturally develop and are esoteric such as mold, solvents, metals and pesticides, chemicals prescribed for therapeutic purposes (e.g., chemotherapy), and alcohol and illicit drug use. The nature and extent of empirical support for direct CNS effects of these ‘‘toxins’’ vary considerably. The presentation of behavioral and cognitive dysfunction depends on numerous factors, including the substance ingested, route of exposure (i.e., inhalation, ingestion, dermal, and injection), tissue absorption levels, time frames of absorption (i.e., exposure duration), personality traits, and litigation status. The need to discern both acute and long-term ‘‘subclinical’’ toxin-related neuropsychological dysfunctions and to distinguish such dysfunction from non-CNS etiologies is a critical issue for neuropsychologists. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Some potentially toxic agents may provoke edema, atrophy, demyelination, infarctions, calcifications, hemorrhages, or changes of perfusion, metabolism, or receptor density (Lang, 2000). The specific pathophysiology seems to depend to some extent on the specific toxin. Solvents, for example, target lipid-rich locations, such as white matter tracts, resulting in demyelination and axonal loss (Rutchik, 2006). With solvent exposure, neuroimaging results are often normal, but have been found to reveal atrophy, particularly volume loss involving the white matter more than gray matter, as well as occasional focal involvement of the temporal

lobes, frontal lobes, basal ganglia, thalamus, and cerebellum (Rutchik, 2006). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Presenting clinical concerns suggestive of CNS dysfunction tend to be changes in personality, memory disturbance, and attentional difficulties (Morrow, Kamis, & Hodgson, 1993; Morrow, Robin, Hodgson, & Kamis, 1992). For most substances, the effects of acute exposure can be distinguished from the more enduring influences of chronic exposure (Morrow, 2006). For example, acute exposure to solvent neurotoxicants tends to produce a constellation of symptoms including headaches and dizziness, easy fatigability, skin rash, nausea, and mental confusion or feeling intoxicated (Morrow, RoBards, Saxton, & Methany, 2008). In contrast, more chronic exposure to these substances, which include chemicals used in cleaning fluids and paints, can appear neuropsychologically as involving deficits in attention and memory, and slowing of responses (Anger, 1992), as well as reduced information-processing capacity (Morrow et al., 1992). Although the threshold values have been established for certain individual solvents and toxins (e.g., lead), it is difficult to precisely determine the dose that causes impairment in any particular person due to many factors such as chemical half-life and individual physiological differences including rates of absorption and clearance (Proctor, Hughes, & Fischman, 1988). Following exposure, neuropsychological dysfunction tends to be diffusely present, with alterations described on tests of memory and learning, attention, visuospatial and motor functioning and executive capacity (Morrow et al., 2008). Research on causally related cognitive deficits has also produced inconsistent results with methodological problems, perhaps contributing most to the ambiguous interpretations concerning the relationship between toxic exposure and cognitive dysfunction (Lees-Haley & Williams, 1997; Wood & Liossi, 2005). While certain neurotoxic substances have been studied and are known to have adverse neuropsychological effects (e.g., lead, CO, and mercury), opinions concerning the causation of dysfunction stemming from other substances (e.g., mycotoxins) are speculative and are not grounded in the scientific literature (Lees-Haley, 2003). DIAGNOSIS

Blood and urine assay can provide an objective source for appreciating body burden (e.g., body exposure index), but these data are rarely available, which leaves the clinical interview as the primary means

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by which information concerning exposure can be gathered. Although neurotoxins exert their impact on a molecular level, their cumulative effect of some toxins on the CNS can be sufficient for detection through neuroimaging at various stages of disease progression (Arora et al., 2008). However, functional and structural imaging techniques have not revealed a consistent pattern of findings that can be applied with diagnostic confidence (Rutchik, 2006). Similarly, EMG and NCS studies have produced mixed and inconsistent results. The neuropsychological diagnosis of persons reporting problems associated with exposure to a toxic substance typically relies heavily on (1) examinee’s self-report of exposure to a substance that in the right amount or for a prolonged period of time can result in compromised CNS functioning; (2) examinee’s self-report of symptoms; and (3) deficits on neuropsychological tests. Challenges arise because exposure intensity and duration may not be objectively established, neuropsychological symptoms are nonspecific, deficits on neuropsychological instruments can result from many factors other than neurological damage, and known patterns of neuropsychological performance associated with exposure to various toxins may lack adequate scientific support. The possibility of psychogenic disturbance or dissimulation should be included in the differential diagnosis, with the presence of clear biological markers of high toxicity helping to support a neurological cause or contribution (Greve et al., 2006). TREATMENT

If symptoms do not subside after the person is no longer exposed to the offending agent, therapeutic efforts should target neurocognitive deficits and both acute and long-standing psychological problems. Approaches to the treatment of persons with toxicantrelated neuropsychological changes utilize cognitive rehabilitation techniques, psychotherapy, and psychopharmacologic interventions to reduce symptoms and promote resumption of roles and routines within home, work, and community settings (Rutchik, 2006).

Greve, K. W., Bianchini, K. J., Black, F. W., Heinly, M. T., Love, J. M., Swift, D. A., & Ciota, M. (2006). The prevalence of cognitive malingering in persons reporting exposure to occupational and environmental substances. Neurotoxicology, 27, 940–950. Lang, C. J. (2000). The use of neuroimaging techniques for clinical detection of neurotoxicity: A review. Neurotoxicology, 21, 847–855. Lees-Haley, P. R. (2003). Toxic mold and mycotoxins in neurotoxicity cases: Stachybotrys, fusarium, trichoderma, aspergillus, penicillium, cladosporium, alternaria, trichothecenes. Psychological Reports, 93, 561–584. Lees-Haley, P. R., & Williams, C. W. (1997). The implications of limitations in hydrocarbon research for neuropsychological assessment. Archives of Clinical Neuropsychology, 12, 207–222. Morrow, L. A. (2006). Neurotoxicology. In P. J. Snyder & P. D. Nussbaum (Eds.), Clinical neuropsychology: A pocket handbook for assessment (2nd ed.). Washington, DC: American Psychological Association. Morrow, L. A., Kamis, H., & Hodgson, M. J. (1993). Psychiatric symptomatology in persons with organic solvent exposure. Journal of Consulting and Clinical Psychology, 61, 171–174. Morrow, L. A., RoBards, M., Saxton, J. A., & Methany, K. (2008). Toxins in the CNS: Alcohol, illicit drugs, heavy metals, solvents and related exposure. In J. E. Morgan & J. H. Ricker (Eds.), Textbook of clinical neuropsychology (pp. 588–598). New York NY: Taylor & Francis. Morrow, L. A., Robin, N., Hodgson, M. J., & Kamis, H. (1992). Assessment of attention and memory efficiency in persons with solvent neurotoxicity. Neuropsychologia, 30, 911–922. Proctor, N. H., Hughes, J. P., & Fischman, M. L. (1988). Chemical hazards of the workplace (2nd ed.). Philadelphia PA: Lippincott. Rutchik, J. S. (2006). Organic solvents. Retrieved October 10, 2009 from http://emedicine.medscape.com/article/ 1174981-overview Wood, R. L., & Liossi, C. (2005). Long-term neuropsychological impact of brief occupational exposure to organic solvents. Archives of Clinical Neuropsychology, 20, 655–665.

Shane S. Bush Mark A. Sandberg

NIEMANN–PICK DISEASE Anger, W. K. (1992). Assessment of neurotoxicity in humans. In H. Tilson & C. Mitchell (Eds.), Neurotoxicology (pp. 363–386). New York NY: Raven Press. Arora, A., Neema, M., Stankiewicz, J., Guss, Z. D., Prockop, L., & Bakshi, R. (2008). Neuroimaging of toxic and metabolic disorders. Seminars in Neurology, 28, 495–510

DESCRIPTION

Niemann–Pick disease (NPD) refers to a group of disorders that impair the body’s ability to metabolize sphingolipids, resulting in fatal levels of these lipids

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within various organs of the body. These sphingolipidoses are part of a larger classification of disorders referred to as lysomal storage diseases. Although as many as six types of NPDs have been described based on presentation and affected organs (Fotoulaki et al., 2007), the following three types of NPDs are most widely referenced in current practice: &

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NPD Type A is a severe neurodegenerative form of NPD that presents in infancy and typically results in death by the age of 3 years (Takahashi, Suchi, Desnick, Takada, & Schuchman, 1992). NPD Type B is characterized by the pathological involvement of the lungs and visceral organs, absent or minimal neurological impairment, and survival into adulthood (McGovern et al., 2008). NPD Type C includes both visceral and neurological involvement with varying life expectancy that is related to the age of onset (Sevin et al., 2007).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

The NPD types can be further conceptualized as belonging to one of two categories based on etiology. NPD Types A and B are sometimes referred to as Type I NPD because they both result from an inherited deficiency of the enzyme acid sphingomyelinase (ASM). This deficiency prevents the effective metabolization of sphingomyelin, subsequently accumulating in the major body organs. Although the prevalence of NPD Types A and B have been estimated to be 0.5–1 per 100,000 live births, this number is thought to be under-representative of the true incidence within the general population (Schuchman, 2007). NPD Type A has demonstrated a higher rate of prevalence amongst the Ashkenazi Jewish population. NPD Type C, or Type II NPD, results from defective trafficking of lysosomal cholesterol at the intracellular level (Griffin, Gong, Verot, & Mellon, 2004) and is not secondary to an ASM deficiency. These trafficking errors result in excessive accumulation of lysosomal cholesterol and other lipids within the body organs. The prevalence of NPD Type C is estimated to be 1 in 150,000 in Western Europe, although certain populations (i.e., the French Acadians of Nova Scotia and the Spanish-Americans of southern Colorado and New Mexico) demonstrate a much higher incidence (Sun et al., 2001). A fourth type of NPD (NPD Type D) has been used to describe individuals with NPD Type C who are of Nova Scotian descent. However, current research suggests that the etiology and progression of the two types of NPD are the same, making this distinction unnecessary.

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

1. NPD Type A presents during infancy and is characterized by a general failure to thrive, psychomotor retardation, hepatosplenomegaly, and neurological deterioration leading to death by 3 years of age (Takahashi et al., 1992). 2. NPD Type B is typically diagnosed during childhood and is characterized by hepatosplenomegaly, respiratory involvement, and absent or minimal neurological involvement. Although progression and severity of NPD Type B is variable, affected individuals typically survive into adulthood and may live into middle age (Levran, Desnick, & Schuchman, 1991). 3. NPD Type C has a highly variable presentation and includes an acute infantile form that rapidly leads to death, a progressive adolescent form resulting in death in the 2nd or 3rd decade, and a rare adult form with a generally slow progression (Battisti et al., 2003). Physical manifestations are equally diverse and include hepatosplenomegaly, pulmonary distress, neurological deterioration, or psychiatric features. Almost all patients with NPD Type C will eventually develop neurological or psychiatric symptoms, which may include dementia, supranuclear gaze palsy, ataxia, dysarthria, dysphagia, and dystonia (Patterson, Porter, Vaurio, & Brown, 2009; Sevin et al., 2007). DIAGNOSIS

Diagnosis of NPD is based on the observation of the clinical features associated with each type, with hepatosplenomegaly often being the first visible indicator. Diagnosis of NPD Types A and B is confirmed via fluid and tissue cultures that reveal deficient ASM activity (Takahashi et al., 1992). Similarly, the presence of NPD Type C is confirmed by studying cultured fibroblasts and their ability to transport and store lysosomal cholesterol. Advances in DNA analysis also allow for observation of the characteristic mutations in the genes associated with the different types of NPD (Griffin et al., 2004; Schuchman, 2007). TREATMENT

At the present time, no therapies have been shown to be effective in the treatment of any of the three types of NPDs (Griffin et al., 2004; McGovern, Aron, Brodie, Desnick, & Wasserstein, 2006). Experimental treatments have included the use of enzyme replacement therapies and stem cell transplantation. Treatment is

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therefore largely supportive and it may help to manage the psychiatric features and loss of cognitive functions that may be present. Counseling may prove beneficial for patients and family members coping with the stress associated with a terminal illness. Jacob T. Lutz Raymond S. Dean Battisti, C., Tarugi, P., Dotti, M. T., De Stefano, N., Vattimo, A., Chierichetti, F., et al. (2003). Adult-Onset NiemannPick type C disease: A clinical, neuroimaging, and molecular genetic study. Movement Disorders, 18(11), 1405–1409. Fotoulaki, M., Schuchman, E. H., Simonaro, C. M., Augoustides-Savvopoulou, P., Michelakakis, H., Panagopoulou, P., et al. (2007). Acid sphingomyelinasedeficient Niemann-Pick disease: Novel findings in a Greek child. Journal of Inherited Metabolic Disease, 30, 986. doi: 10.1007/s10545-007-0557-3 Griffin, L. D., Gong, W., Verot, L., & Mellon, S. H. (2004). Niemann-Pick disease type C involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nature Medicine, 10(7). doi: 10.1038/nm1073 Levran, O., Desnick, R. J., & Schuchman, E. H. (1991). Niemann-Pick type B disease [Electronic edition]. The Journal of Clinical Investigation, 88, 806–810. McGovern, M. M., Aron, A., Brodie, S. E., Desnick, R. J., & Wasserstein, M. P. (2006). Natural history of type A Niemann-Pick disease. Neurology, 66, 228–232. McGovern, M. M., Wasserstein, M. P., Giugliani, R., Bembi, B., Vanier, M. T., Mengel, E., et al. (2008). A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B. Pediatrics, 122(2). doi: 10.1542/peds.2007-3016 Patterson, M., Porter, F., Vaurio, R., & Brown, T. (2009). Longitudinal study of cognition in subjects with Niemann-Pick disease, type C. Molecular Genetics and Metabolism, 96(2), S34. doi: 10.1016/j.ymgme. 2008.11.102 Schuchman, E. H. (2007). The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. Journal of Inherited Metabolic Disease, 30,654–663. doi: 10.1007/s10545-007-0632-9 Sevin, M., Lesca, G., Baumann, N., Millat, G., Lyon-Caen, O., Vanier, M. T., et al. (2007). The adult form of NiemannPick disease type C. Brain, 130, 120–133. doi: 10.1093/ brain/awl260 Sun, X., Marks, D. L., Park, W. D., Wheatley, C. L., Vishwajeet, P., O’Brien, J. F., et al. (2001). Niemann-Pick C variant detection by altered sphingolipid trafficking and correlations with mutations within a specific domain of NPC1 [Electronic version]. The American Journal of Human Genetics, 68(6), 1361–1372.

Takahashi, T., Suchi, M., Desnick, R. J., Takada, G., & Schuchman, E. H. (1992). Identification and expression of five mutations in the human acid sphingomyelinase gene causing types A and B Niemann-Pick disease [Electronic version]. The Journal of Biological Chemistry, 267(18), 12552–12558.

NONVERBAL LEARNING DISABILITY DESCRIPTION

Nonverbal learning disability (NLD) is a syndrome characterized by neuropsychological deficits in visuospatial-organizational, tactile-perceptual, complex psychomotor, and nonverbal problem-solving skills that coexist with relative strengths in rote verbal learning, phoneme-grapheme matching, verbal output, and verbal classification (Rourke, 1989, 1995b). Neuropsychological deficits may appear at birth or shortly thereafter or may be caused by significant craniocerebral trauma, such as brain diseases, disorders, and injuries following a period of normal development (Rourke, 1989). NLD syndrome is usually perceived as a subtype of a learning disorder, but does not appear in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (Daley, 2004). Contrary to learning disorders that are more language/ phonological based, some language functioning in children with NLD (e.g., word recognition and verbal output) is often well developed, whereas other important language functions (e.g., pragmatics and prosody) are often severely impaired. The capacity to process information delivered through the auditory modality is the principal neuropsychological strength of children who exhibit the NLD syndrome. Within school settings, the neuropsychological strengths of children with NLD often lead to academic strengths in word decoding, spelling, and verbatim memory, while the neuropsychological deficits usually lead to academic deficits in reading comprehension, mechanical arithmetic, mathematics, and science. Children with NLD often exhibit difficulty participating in social situations and reading signs of affective and nonverbal communication (Pelletier, Ahmad, & Rourke, 2001). They desire social connection but often lack the ability to self-reflect, make attribution, or monitor their behavior (Forrest, 2004). They are prone to psychosocial dysfunction as they mature (Pelletier et al., 2001) and often develop affective disorders, such as anxiety and depression (Ingalls & Goldstein, 1999). In addition, children with learning

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disabilities who had well-developed rote verbal skills are very successful using rote repetition to memorize discrete information like vocabulary words or geographic places (Harnadek & Rourke, 1994), which often lead to appearance as a ‘‘human encyclopedia.’’ As a result, they often experienced social rejection (Forrest, 2004) and were more likely to exhibit psychopathology than children without NLD (Tsatsanis, Fuerst, & Rourke, 1997). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The right hemisphere is believed to have a higher concentration of white matter than the left and a greater capacity to integrate complex information and process several models of representation within a single cognitive task (Goldberg-Costa, 1981; Filley, 2001). Based on this theory, Rourke (1989) suggested that NLD represents a manifestation of white matter dysfunction, which compromises the functioning of right hemisphere systems more so than the left hemisphere systems. Extending from this concept, Rourke (1989,1995a) hypothesized that the presentation of the deficits in children with NLD is dependent upon the severity of white-matter involvement and the age at which the damage is sustained. Severe or widespread white-matter disturbance occurring very early in life would be expected to result in deficiencies in virtually all skills and abilities, while mild degrees and extents of dysfunction occurring later in life would be expected to result in a milder impact on a child’s neuropsychological abilities. Functions that have been reasonably developed will be less likely affected by white-matter disturbance. In addition, neuropsychological strengths and deficits of children with NLD change over the course of development (Casey et al., 1991). Progressive deterioration in skills is expected and will become more apparent and more debilitating as individuals approach adulthood (Rourke, 1989; Rourke, van der Vlugt, & Rourke, 2002). Although NLD syndrome is thought mostly to be congenital, it is also seen in individuals with acquired neurological diseases and disorders, including general deterioration or significant destruction of neuronal white matter (long myelinated fibers) within the right cerebral hemisphere, destruction of access to neuronal intercommunication (e.g., callosal agenesis), head injuries, and some types of hydrocephalus. Filley (2001) suggested that demyelination of white matter or other abnormalities in white matter volume have been associated with manifestations of emotional dysfunction, often resulting in the development of depression, mania, and psychosis. This

association between dysfunctional white matter and affective disorders provides an explanation for the increased risk of emotional and social dysfunction of children with NLD. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Deriving from his extensive research on NLDs, Rourke outlined the principal clinical manifestations of the NLD syndrome as follows: 1. Well-developed rote verbal capacities, with very well-developed rote verbal-memory skills. 2. Bilateral tactile-perceptual deficits, most noticeably on the left side of the body. 3. Bilateral psychomotor coordination deficiencies, most noticeably on the left side of the body. 4. Considerable deficiencies in visuospatial-organizational abilities. 5. Severe deficits in nonverbal problem solving, concept formation, hypothesis testing, and the ability to benefit from positive and negative informational feedback in various situations. 6. Serious difficulties with cause–effect relationships and deficiencies in the appreciation of incongruities. 7. Significant difficulty adapting to novel and complex situations with overreliance on prosaic, rote behaviors. 8. Deficiencies in mechanical arithmetic despite proficiencies in word decoding/recognition and spelling. 9. Phonetically accurate misspellings. 10. Excessive use of words in a repetitive, rote nature, with poor psycholinguistic pragmatics and little, if any, speech prosody. 11. Reliance on language for social relations, information collection, and anxiety relief. 12. Severe deficits in social perception, judgment, and interaction skills. DIAGNOSIS

Compared to children without disabilities and children with a phonological-processing subtype of disabilities (e.g., reading and spelling), children with NLD tend to perform more poorly on neuropsychological measures involving visual-perceptualorganizational skills, psychomotor coordination, complex tactile-perceptual skills, and conceptual and problem-solving skills. Clinicians considering making a diagnosis of possible NLD and developing treatment programs should devote attention to children’s performance within these realms.

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Pelletier et al. (2001) established the following rules for classification of children (ages 9–15) as NLD with the percentage of children classified as having NLD who exhibit each feature (in parentheses): 1. Less than two errors on simple tactile perception and suppression versus finger agnosia, finger dysgraphesthesia, and astereognosis composite greater than 1 SD below the mean (90.9%) 2. WRAT standard score for reading is at least eight points greater than arithmetic (85.7%) 3. Two of WISC/WISC-R vocabulary, similarities, and information are the highest of the verbal scales (77.9%) 4. Two of the WISC/WISC-R block design, object assembly, and coding subtests are the lowest of the performance scales (76.6%) 5. Target test at least 1 SD below the mean (63.6%) 6. Grip strength within 1 SD of the mean or above versus grooved pegboard test greater than 1 SD below the mean (63.6%) 7. Tactual performance test right, left, and both hand times become progressively worse vis-a`-vis the norms (59.7%) 8. WISC/WISC-R VIQ exceeds PIQ by at least 10 points (27.3%) Pelletier et al. (2001) suggested that the 10-point difference between VIQ and PIQ rule may be eliminated from the list without compromising diagnostic accuracy given that it was present only in 27% of the individuals with NLD used to validate these criteria. In addition, it should be noted that many of the tests used to validate the criteria have been revised and are in need of refinement. Applying the above criteria to younger children (ages 7–8), Drummond, Ahmad, and Rourke (2005) delineated the following rules to identify younger children with NLD. The percentage of children classified as having NLD who exhibit each feature is indicated in parentheses: 1. Target test at least 1 SD below the mean (90.0%) 2. Two of the WISC block design, object assembly, and coding subtests are the lowest of the performance scales (90.0%) 3. Two of WISC vocabulary, similarities, and information are the highest of the verbal scales (80.0%) 4. Tactual performance test right, left, and both hand times become progressively worse vis-a`-vis the norms (77.8%) 5. Grip strength within 1 SD of the mean or above versus grooved pegboard test greater than 1 SD below the mean (70.0%) 6. WISC VIQ exceeds PIQ by at least 10 points (70.0%)

7. WRAT standard score for reading is at least eight points greater than arithmetic (60.0%) 8. Less than two errors on simple tactile perception and suppression versus finger agnosia, finger dysgraphesthesia, and astereognosis composite greater than 1 SD below the mean (10.0%) Drummond et al. (2005) noted that strict application of rules 1 through 3 should result in very few falsepositive identification of young children with NLD, and that eliminating rule 8 as a criterion should not affect the accuracy of classification. TREATMENT

The prognosis of individuals with NLD is limited by the neuropsychological deficits that become progressively more apparent and more debilitating as adulthood approaches (Rourke et al., 2002). Academic difficulties often lead to difficulty in securing and/ or sustaining employment in adulthood, and deficits in social information processing and emotional understanding are likely to interfere with opportunities to establish intimate, long-term relationships, both of which tend to increase susceptibility to depression and anxiety. However, early diagnosis with NLD is as critical as it is with other subtypes of learning disorders. An accurate early diagnosis along with an appropriate remedial program can improve the outcome for individuals suffering from the neuropsychological deficits of NLD (Marti, 2004). Following an accurate and reliable diagnosis, an appropriate remediation treatment plan should be established in the problem areas that may include deficits in social skills, prosody, spatial orientation, problem solving, recognition of nonverbal cues, complex motor skills, attention, initiation, organization, planning, and difficulty with mathematical concepts. A treatment plan should be individually tailored as patterns of specific strengths and weaknesses may not be identical for every individual with NLD. In addition, a treatment plan should be reevaluated and modified as needed to adapt to the problems with NLD that shift across the life span (Marti, 2004). Parents of children with NLD should teach their child coping, organizational, and problem-solving skills, as well as how to set up routines to deal with daily tasks and responsibilities and how to perform everyday tasks in an efficient manner. Taking the time to make sure that children with NLD master all of the daily living skills necessary to function independently can facilitate a sense of confidence and self-efficacy and may reduce susceptibility to psychiatric problems (e.g., depression and anxiety). Additionally, within the school environment, academic interventions

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should be provided in the areas of study skills, organizational skills, and how to find main points in reading, make reference, and apply learned skills and knowledge. Physical therapy, occupational therapy, and social skills training should also be beneficial for those with motor difficulties and problems with recognition and interpretation of verbal and nonverbal cues (Marti, 2004). Psychotherapy is useful when it focuses on helping the individual with NLD understand his/her areas of strengths and weaknesses and develop appropriate ways to manage them. Primary goals for therapy should emphasize coping skills, helping children and their families understand how NLD affects thinking, behavior, and perceptions, and learning how to work with deficits that may be pervasive (Marti, 2004). Moreover, medication is common in treating the emotional aspect of NLD symptoms because of their resemblance to those seen in a number of psychiatric disorders, such as mood disorders and anxiety disorders, including obsessive-compulsive disorder, social phobia, and panic disorder. Medication also can be prescribed for attention deficits. However, prescribing practitioners should be aware that those with NLD may have trouble processing the complex and multiple factors in the use of medicine; therefore, they should help patients understand the short- and long-term side effects of each prescribed medication. Finally, the combination of medication with behavioral interventions and training has shown to be a more effective longterm strategy in managing neurologically based disorders, including NLD (Marti, 2004). Mei Chang Andrew S. Davis Casey, J. E., Rourke, B. P., & Picard, E. M. (1991). Syndrome of nonverbal learning disabilities: Age differences in neuropsychological, academic, and socioemotional functioning. Development and Psychology, 3(3), 329–345. Daley, S. (2004). Nonverbal learning disabilities (NLD): Introduction (a disorder of cerebral white matter). Retrieved June 23, 2009, from http://gseacademic.harvard.edu/ ~daleysa/index.htm Drummond, C. R., Ahmad, S. A., & Rourke, B. P. (2005). Rules for the classification of younger children with nonverbal learning disabilities and basic phonological processing disabilities. Archives of Clinical Neuropsychology, 20(2), 171–182. Filley, C. M. (2001). The behavioral neurology of white matter. New York: Oxford University Press. Forrest, B. J. (2004). The utility of math difficulties, internalized psychopathology, and visual-spatial deficits to

identify children with the nonverbal learning disability syndrome: Evidence for a visualspatial disability. Child Neuropsychology, 10(2), 129–146. Goldberg, E., & Costa, L. D. (1981). Hemispheric differences in the acquisition and use of descriptive systems. Brain and Language, 14, 144–173. Harnadek, M., & Rourke, B. P. (1994). Principal identifying features of the syndrome of nonverbal learning disabilities in children. Journal of Learning Disabilities, 27(3), 144–154. Ingalls, S., & Goldstein, S. (1999). Learning disabilities. In S. Goldstein & C. R. Reynolds (Eds.), Handbook of neurodevelopmental and genetic disorders in children (pp. 101–153). New York: The Guilford Press. Marti, L. (2004). Helping children with nonverbal learning disability: What I have learned from living with nonverbal learning disability. Journal of Child Neurology, 19(10), 830–836. Pelletier, P. M., Ahmad, S. A., & Rourke, B. P. (2001). Classification rules for basic phonological processing disabilities and nonverbal learning disabilities: Formulation and external validity. Child Neuropsychology, 7(2), 84–98. Rourke, B. P. (1989). Nonverbal learning disabilities: The syndrome and the model. New York: Guilford Press. Rourke, B. P. (1995a). The NLD syndrome and the white matter model. In B. P. Rourke (Ed.), Syndrome of nonverbal learning disabilities (pp. 1–26). New York: Guilford Press. Rourke, B. P. (1995b). Syndrome of nonverbal learning disabilities: Neurodevelopmental manifestations. New York: Guilford Press. Rourke, B. P., Ahmad, S. A., Collins, D. W., Hayman-Abello, B. A., Hayman-Alello, S. E., & Warriner, E. M. (2002). Child clinical/pediatric neuropsychology: Some recent advances. Annual Review of Psychology, 53(1), 309–339. Rourke, B. P., van der Vlugt, H., & Rourke, S. B. (2002). Practice of child-clinical neuropsychology: An introduction. Lisse, The Netherlands: Swets & Zeitlinger. Tsatsanis, K. D., Fuerst, D. R., & Rourke, B. P. (1997). Psychological dimensions of learning disabilities: External validation and relationship with age and academic functioning. Journal of Learning Disabilities, 30, 490–502.

NORMAL PRESSURE HYDROCEPHALUS DESCRIPTION

Normal pressure hydrocephalus (NPH) is a central nervous system disorder involving interruption in cerebrospinal fluid (CSF) dynamics. Known as the

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only reversible dementia, NPH is estimated to represent approximately 6% of all dementias, and prevalence is broadly estimated between 0.5% and 1% (Clarfield, 2003, Trenkwalder et al., 1995; Vanneste, Augustiin, Dirven, Tan, & Goedhart, 1992). Clinical presentation typically occurs between the ages of 60 and 80 and is recognized by a classic triad of symptoms including gait ataxia, dementia, and urinary incontinence/urgency. In the presence of the classic triad, neuroradiologic evidence of ventriculomegaly has become a cardinal feature. Current nomenclature describes NPH according to etiology (idiopathic vs. secondary), intracranial pressure (high vs. low), and flow of CSF (communicating vs. obstructive). NEUROPATHOLOGY/PATHOPHYSIOLOGY

CSF is the protective, nourishing fluid surrounding the brain in the subarachnoid space and circulating through the cerebral ventricles and aqueducts. Healthy CSF dynamics entail the production, distribution, and reabsorption of CSF. By processes of diffusion and pinocytosis, CSF is produced primarily in the choroid plexus at a rate of 0. 2–0.7 mL/min, resulting in an average daily production of 500 mL. Through pulsation of the choroid plexus, CSF is transferred into the ventricular system and circulated via cilia motion of ependymal cells to the arachnoid villi where it is reabsorbed. NPH is a consequence of disruption in the natural flow and/or absorption of CSF. Instances of NPH resulting from known etiology, such as hemorrhage, infection, and/or head trauma, are branded ‘‘secondary NPH.’’ Conversely, many cases of NPH are of unknown etiology, and have been termed ‘‘idiopathic NPH’’ (iNPH). Disruption in CSF dynamics is typically classified according to locus of pathology. Disturbance due to the obstruction in the ventricular system is termed ‘‘noncommunicating’’ hydrocephalus. Alternatively, disruptions occurring in the subarachnoid space or in venous uptake result in ‘‘communicating’’ hydrocephalus. High and low intracranial pressure has been observed in NPH, suggesting that the name ‘‘normal pressure’’ hydrocephalus is a misnomer. Distinctions regarding the pathophysiology of secondary NPH are more easily made due to the presence of an identifiable precipitant, whereas the pathophysiology of idiopathic NPH remains poorly understood. Early hypotheses of iNPH, proposed a disparity between CSF production and absorption, with expansion of the cerebral ventricles in accommodation of elevated intracranial pressure. Expansion of the cerebral ventricles was considered a normalizing

response to elevated intracranial pressure and thought to explain the common finding of ‘‘normal pressure’’ in the CNS. Current mechanistic conceptualizations extend beyond purely hydrodynamic disruption to include hemodynamic pathologies, neurochemical alterations, or multifactorial combinations (Shprecher, Schwalb, & Kurlan, 2008). Secondary and idiopathic NPH share the neuroradiological finding of ventriculomegaly. Other common neuroradiological findings include bowing of the corpus callosum, flattened gyri, and periventricular hyperintensities (Gallia, Rigamonti, & Williams, 2005). The neuroanatomical changes observed in NPH, principally ventricular dilation, are theorized to produce the symptomatic triad by affecting neuroanatomical areas related to gait ataxia, dementia, and urge/incontinence. Gait disturbance in NPH has been described as ataxic, magnetic, slow, wide-based, shuffling, and parkinsonian. Disrupted gait is generally cited as the first symptom of the triad to present clinically, and the symptom most amenable to treatment. Originally, gait ataxia was attributed to effects on the primary pyramidal tract; however, current literature implicates extrapyramidal origins involving subcortical/frontal motor pathways. Specifically, the interference in projections from the substantia nigra and basal ganglia to the frontal lobes has been implicated. The hallmark cognitive disturbance in NPH is described as a subcortical dementia and involves slowed processing, impaired attention, apathy, and poor recall. The cognitive symptoms of NPH are heterogeneous, spanning a broad array of neurocognitive domains, and ranging in severity from mild to profound. The exact pathophysiology of NPH dementia is poorly understood, though the neuropathology appears similar to that of gait disturbance, in that the effects of enlarged ventricles on proximal subcortical projections, parenchyma, and vasculature are thought to underlie the cognitive disturbance. Urinary symptoms in NPH are ‘‘neurogenic’’ in nature and initiate as increased urgency/frequency, and worsen to incontinence as NPH progresses. While incontinence is considered a classic symptom of NPH, it is not clinically present in all cases and its absence does not rule out a diagnosis of NPH. Urinary urgency is the most common urologic symptom followed by infrequency, frequency, and frank incontinence. Urodynamic investigations cite increased activity of the bladder’s detrusor muscle as the cause of urinary symptoms. Detrusor hyperactivity is associated with supraspinal disruption, resulting from the effects of ventriculomegaly on surrounding parenchyma. Incontinence can also result from

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functional inability secondary to gait disturbance and/or dementia. Symptoms of the classic triad of NPH are generally attributable to the anatomic, neurochemical, and metabolic effects of ventriculomegaly. However, each of the cardinal symptoms is common among the elderly making diagnosis difficult. Moreover, the presence of each symptom in the triad is not required to consider a diagnosis of NPH. Thus, examination of each of the symptoms on a case-by-case basis is critical and the presence of alternative explanations serves as an important factor in diagnosing NPH. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The neurocognitive changes associated with NPH are characteristic of subcortical dementias. Clinical descriptions often include apathy, forgetfulness, and bradykinesia/phrenia. Neuropsychological assessment commonly exposes performance impairments across a variety of tasks (Devito et al., 2005). The elemental neurocognitive disturbance of NPH is impaired psychomotor speed; however, dysfunction in attention, memory, executive operations, and visuospatial tasks are also common. Poor attention and concentration often present on tasks such as digit span, letter number sequencing, and arithmetic. Visuospatial deficits are observed on tasks of spatial recognition, design copy, and block design. Impairment in both immediate and delayed verbal recall, with relatively sparred recognition, is an ordinary observation on memory measures. Broad deficits in executive functioning are not unusual; however, impairment on tasks involving initiation, cognitive flexibility, and/or verbal fluency is most typical. Because the features of NPH are a result of disruption in subcortical and frontostriatal systems, cortical functions such as naming are often unaffected. In addition, depression, mania, aggression, obsessive-compulsive behavior, disinhibition, and psychosis have also been reported. Notably, depression can be neurogenic in nature or a reaction to functional deficits. DIAGNOSIS

In the elderly population, suspicion of NPH is raised in the presence of the symptomatic triad; however, the entire triad need not be present to consider the diagnosis. Because of the heterogeneity of NPH symptoms and their common occurrence in the elderly,

differential diagnosis and rule out of other possible causes are required before offering a diagnosis of NPH. Diagnosis of secondary NPH differs from iNPH in that symptoms follow a known precipitant warrants investigation of NPH. Clinical guidelines for diagnosing iNPH incorporate historical, neuroradiological, clinical, and physiological information in categorizing the likelihood of NPH as ‘‘probable, possible and unlikely’’ (Relkin, Marmarou, Klinge, Bergsneider, & Black, 2005). Diagnosing NPH requires a minimum of gait disturbance plus one other symptom of the triad, neuroradiologic evidence of ventriculomegaly, and rule out of other etiologies. Ventriculomegaly is typically confirmed by an Evans’ Index greater than 0.3 (maximal width of frontal horn divided by transverse diameter of the skull). In the presence of the aforementioned criteria, NPH is typically confirmed through high volume lumbar puncture or external lumbar drain and subsequent observation of symptom reduction. Assessment of symptoms through neuropsychological testing, urodynamic analysis, gait assessment, functional neuroimaging, and other methods, have become common to assist in diagnosis, rule out of other causes, and prognosis. TREATMENT

Neurosurgical placement of a shunt is the only recognized intervention for NPH. Ventriculoperitoneal or ventriculoatrial shunting are the mainstays of intervention for NPH and involve the diversion of CSF from the ventricular system to a distal site where it can be reabsorbed. J. Forrest Sanders Jeffrey T. Barth Clarfield, A. M. (2003). The decreasing prevalence of reversible dementias: An updated meta-analysis. Archives of Internal Medicine, 163(18), 2219–2229. Devito, E. E., Pickard, J. D., Salmond, C. H., Iddon, J. L., Loveday, C., & Sahakian, B. J. (2005). The neuropsychology of normal pressure hydrocephalus (NPH). British Journal of Neurosurgery, 19(3), 217–224. Gallia, G. L., Rigamonti, D., & Williams, M. A. (2005). The diagnosis and treatment of idiopathic normal pressure hydrocephalus. Nature Clinical Practice Neurology, 2, 375–381. Relkin, N., Marmarou, A., Klinge, P., Bergsneider, M., & Black, P. M. (2005). Diagnosing idiopathic normalpressure hydrocephalus. Neurosurgery, 57, S4–S16

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Shprecher, D., Schwalb, J., & Kurlan, R. (2008). Normal pressure hydrocephalus: Diagnosis and treatment. Current Neurology and Neuroscience Reports, 8, 371–376. Trenkwalder, C., Schwarz, J., Gebhard, J., Ruland, D., Trenkwalder, P., Hense, H. W., et al. (1995). Starnberg trial on epidemiology of Parkinsonism and hypertension in the elderly. Prevalence of Parkinson’s disease

and related disorders assessed by a door-to-door survey of inhabitants older than 65 years. Archives of Neurology, 52(10), 1017–1022. Vanneste, J., Augustijn, P., Dirven, C., Tan, W. F., & Goedhart, Z. D. (1992). Shunting normal-pressure hydrocephalus: Do the benefits outweigh the risks? A multicenter study and literature review. Neurology, 42(1), 54–59.

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Occipital neuralgia is a form of headache that involves irritation of one or both of the occipital nerves emerging from between the bones of the spine in the upper neck and moving up into the scalp. The occipital nerves are two pairs of nerves that originate in the C2 and C3 vertebrae in the neck. These nerves supply the skin along the base of the skull, and although the nerves are not intertwined with the skull themselves, they are intertwined with other nerves outside of the skull and can affect any area through which any fibers or main nerves pass, forming a neural network. Occipital neuralgia may be either primary or secondary. Primary headaches do not have a clear cause (e.g., migraine and cluster headaches). Within this context, occipital neuralgia is often confused with migraine or cluster headaches. Secondary headaches are due to an underlying disease process, including trauma, tumor, infections, or hemorrhage. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Patients with occipital neuralgia can be divided into two groups: individuals with structural causes and individuals with idiopathic (unknown) causes. Structural causes may include trauma to the occipital nerves, compression to the occipital nerves or nerve roots (C2&C3), a cervical disc disease, or tumors on the nerve roots, infection, and diabetes. The greater occipital nerve is comprised of fibers from the C2 and C3 nerve roots. The third occipital nerve stems from the posterior area of the C3 nerve and may be involved in occipital neuralgia due to cervical spine changes. Compression of the C2 and C3 nerve roots may also lead to occipital neuralgia. Whiplash or hyperextension injuries are two ways in which this compression may occur. Localized infections, inflammation, diabetes, or gout may also be possible causes of occipital neuralgias. However, most patients fall into the area of ‘‘idiopathic’’ or unknown causes for the disorder.

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Patients present clinically with symptoms including burning, throbbing, and aching pain on one side of the head with intermittent shooting pain. The pain usually originates in the area below the occipital lobe of the brain and radiates to the back of the head or up to the scalp. Patients sometimes complain of pain behind the eyes, in the neck as well as over the temple, and regions of the frontal lobe. Pressure can amplify the pain. Doctors can sometimes find a positive tinel’s sign over the occipital nerve. A sensation of ‘‘pins and needles’’ may be apparent if the occipital nerve is tapped lightly. As previously suggested, patients may experience symptoms similar to migraine headaches or cluster headaches. Symptoms further associated with occipital neuralgia include dizziness, sensitivity to light, and burning or tingling in the back of the scalp. Chronic pain can result in a variety of psychological symptoms that include personality changes, irritability, attention problems, motivational issues, fatigue, and problems with complex, sustained higher cognitive tasks. There is often a debate on idiopathic cases as to whether the disorder has a true neurological cause or is a psychological disorder. Psychological symptoms often can be found with both forms of the disorder whether or not there is a clear physical etiology; hence, the presence of psychological symptoms alone does not rule out a physical cause.

DIAGNOSIS

Complete physical and neurologic exams are necessary in the diagnosis of occipital neuralgia. In this disorder, a diagnosis is typically based on the area of the pain. Finding extra sensitive areas to the pain also helps in determining a diagnosis. Clarification of whether the disorder is structural or idiopathic in nature is important to diagnosis. Structural causes are usually found with abnormal responses to a neurologic exam, in which case a CT scan or MRI may be prescribed for further information with focus placed on the cervical spine and head. If there is a history of

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arthritis or trauma, a full spine work-up is recommended. As previously noted, occipital neuralgia is a constant, burning, aching, shooting pain in occipital and posterior areas of the scalp, either unilaterally or bilaterally, and is usually worse with extension and rotation. Nevertheless, occipital neuralgia is often mistaken for migraine or other types of headaches. A migraine headache is unilateral and hemicranial with throbbing or pulsating pain, sensitivity to light and sound, as well as nausea. Migraines are neurovascular headaches associated with perivascular inflammation through the trigeminal nerve. In comparison, tension headaches are usually bilateral, with a dull, squeezing like pain. Sensitivity to light and sound may also occur. These typically affect frontal and fronto occipital areas. Cluster headaches involve excruciating, painful, drilling pain that is usually incredibly severe. Spain usually is accompanied by one autonomic sign such as lacrimation, nasal congestion, or miosis. Cervicogenic headaches have a similar presentation to occipital neuralgia, cluster, tension, and migraine headaches. Usually, these headaches are unilateral and are constant or intermittent. These headaches are rarely throbbing and are usually caused by neck or head movement. TREATMENT

If there is structural evidence to the cause of the occipital neuralgia, surgery may be necessary based on the source. However, most patients do not have clear structural causes, and therefore treatment becomes symptomatic. Occipital neuralgia may be difficult to manage due to it often being misconceived as other types of headaches. Nerve blocks, medications, implantation of stimulators, decompression, and/or lesioning are all types of treatment options for occipital neuralgias. Course of treatment usually starts with conservative methods including physical therapy acupuncture, massages, and application of heat. If response is not of a desirable level, conventional therapy involving medicinal interventions may be employed including nonsteroidal anti-inflammatory drugs, neuropathic medication, and sometimes opioids. Medications most often used include gabapentin (neurontin), carbamazepine (Tegretol), phenytoin (dilantin), valproic acid (Depakote), and baclofen (lioresal). Nerve blocks containing steroids and local anesthetics may also be used. An occipital nerve block is used for both diagnosis and treatment of occipital neuralgias. For the treatment of occipital neuralgia, 3– 5 mL of anesthetic is combined with steroids and injected. Anesthesia will typically occur in 10–20

min. Botulism toxin type A (Botox) has been an accepted treatment method for migraine headaches and thus may have a positive effect on occipital neuralgia. The clinical trials in migraines indicate that Botox decreases the duration, length, and severity of headaches and is generally well tolerated. Surgical options include electrical stimulation, neurolysis, and rhizotomies. Treatment through surgery has been found to be most successful in patients with microvascular nerve decompression. Another widely used treatment measure is radiofrequency thermocoagulation, which has resulted in significant pain relief in patients with occipital neuralgia. The final method of treatment for this disorder is an occipital nerve stimulator implantation. This method includes surgical implantation of an electrode under the skin on the C1–C3 nerve level and has been shown to significantly reduce pain in patients where other treatment methods have failed. Erin L. Tireman Charles Golden Anthony, M. (1992). Headache and the greater occipital nerve. Clinical Neurology and Neurosurgery, 94(4), 297–301. Kuhn, W. F., Kuhn, S. C., & Gilberstadt, H. (1997). Occipital neuralgias: Clinical recognition of a complicated headache. A case series and literature review. Journal of Orofacial Pain, 11(2), 158–165. Loder, E., & Biondi, D. (2002). Use of botulinum toxins for chronic headaches: A focused review. Clinical Journal of Pain, 18(6), S169–S176. Martelletti, P., & Suijlekom, H. V. (2004). Cervicogenic headache: Practical approaches to therapy. CNS Drugs, 11(18), 793–805. Stojanovic, M. (2001). Stimulation methods for neuropathic pain control. Current Pain and Headache Reports, 5, 130–137.

OHTAHARA’S SYNDROME DESCRIPTION

Ohtahara’s syndrome was first identified and described by Ohtahara and colleagues in 1976 (Pellock, Dodson, Bourgeois, Sankor, & Nordli, 2008). The disorder is also referred to as early infantile epileptic encephalopathy with suppression-bursts and is an age-dependent epileptic encephalopathy (Pellock et al., 2008). It is one of the earliest and

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most severe forms of epilepsy (Kato et al., 2007). Around 100 cases have been reported since the disorder was first identified (Jallon, 2003). It is the rarest of the age-dependent epileptic encephalopathies (Yamatogi & Ohtahara, 2002). There is no evidence of gender differences among those with the syndrome and no familial cases have been reported (Wyllie, Gupta, & Lachhwani 2004). The symptoms begin to appear within the first 10 days of life but could first appear as late as 3 months after birth (Cloherty, Eichenwald, & Stark, 2008). The prevalence of the disorder is very low, and 50% of infants with this disorder will not make it past 1 month of age (Niedermeyer & Lopes da Silva, 2004). The main type of seizure present in Ohtahara’s syndrome is a tonic spasm, an involuntary and abnormal contraction of muscles. Partial and generalized seizures can occur as well (Pellock et al., 2008). An infant may experience around 100–300 individual tonic spasms per day. The spasms may also happen in clusters (Binnie et al., 2003). Infants with this syndrome will show a suppression-burst EEG pattern (Pellock et al., 2008). Ohtahara’s syndrome often progresses into West’s syndrome (Pellock et al., 2008) and from West’s syndrome to Lennox–Gastaut’s syndrome (LSG) (Yamatogi & Ohtahara, 2002).

mental deterioration with the persistence of the seizures. There is a high mortality rate with the incidence of death occurring primarily in infancy but can occur up to adolescence (Pellock et al., 2008). Those who survive Ohtahara’s syndrome may suffer from severe mental retardation, may be quadriplegic and/or bedridden, and tend to have frequent infantile spasms (Cloherty et al., 2008; Pellock et al., 2008). Survivors also commonly experience psychomotor retardation (Shorvon, Fish, Pericca & Dodson, 2004). In about half of the cases reported, the seizures subside by school age, but the prognosis is still very poor (Jallon, 2003). DIAGNOSIS

Detailed neuroimaging is always necessary when Ohtahara’s syndrome is suspected (Wyllie et al., 2004). The syndrome is distinguished by tonic spasms, with or without clustering, that appear within the 1st months of life and a suppression-burst pattern in EEG (Yamatogi & Ohtahara, 2002). The suppression burst pattern shown through the EEG is vital to the diagnosis of the syndrome (Pellock et al., 2008). TREATMENT

NEUROPATHOLOGY/PATHOPHYSIOLOGY

The causes of the syndrome are heterogenous, though structural abnormalities in the form of brain malformations and/or lesions are commonly seen and lead to damage similar to that of cerebral palsy (Cloherty et al., 2008). CT and MRI tend to show irregular lesions and progressive brain atrophy. Other potential causes of Ohtahara’s syndrome are cerebral dysgenesis and anoxia (Pellock et al., 2008). Electroencephalogram (EEG) findings show a pattern of variant suppression-burst that occur for every 3–5 seconds and are characterized by increased voltage bursts that alternate with flat patterns (Pellock et al., 2008). These bursts are considered crucial to diagnosing the syndrome (Pellock et al., 2008). There is no sleep–wake cycling with the suppression-burst pattern. The tonic spasms associated with the syndrome occur during a period of suppression as opposed to bursts (Cloherty et al., 2008). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Ohtahara’s syndrome is an epileptic encephalopathy with the presence of a serious underlying disorder with frequent seizures, abnormal EEG patterns, and

With Ohtahara’s syndrome, the developmental prognosis is poor with profound physical and mental impairment being present. For survivors, the syndrome evolves into West’s syndrome and then to LSG (Pellock et al., 2008; Yamatogi & Ohtahara, 2002). Although the seizures are typically resistant to therapy, some with Ohtahara’s syndrome have been treated with adrenocorticotropic hormone (ACTH) therapy. ACTH therapy has been partially effective in some cases (Pellock et al., 2008). Other medications and vitamin therapies have been tried with little success (Pellock et al., 2008). Due to the difficulty of operating on young infants, very little research has examined the usefulness of surgical interventions for Ohtahara’s syndrome. Of the surgical cases presented, some evidence of seizure relief after surgery has been shown (Hmaimess et al., 2005). The seizures associated with the syndrome, for most cases, are resistant to therapy (Shorvon et al., 2004). Jessi H. Robbins Charles Golden Binnie, C., Cooper, R., Mauguiere, F., Osselton, J., Prior, P., & Tedman, B. (2003). Clinical neurophysiology: EEG, paediatric neurophysiology, special techniques and applications. Boston: Elsevier.

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Cloherty, J. P., Eichenwald, E. C., & Stark, A. R. (2008). Manual of neonatal care. Philadelphia: Lippincott Williams & Wilkins. Hmaimess, G., Raftopoulos, C., Kadhim, H., Nassogne, M., Ghariani, S., Tourtchaninoff, M., et al. (2005). Impact of early hemispherotomy in a case of Ohtahara syndrome with left parieto-occipital megalencephaly, Seizure, 14, 439–442. Jallon, P. (2003). Prognosis of epilepsies. Montreal: John Libbey Eurotext. Kato, M., Saitoh, S. Kamei, A., Shiraishi, H., Ueda, Y., Akasaka, M., et al. (2007). A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression burst pattern (Ohtahara syndrome), The American Journal of Human Genetics, 81, 361–366. Niedermeyer, E., & Lopes da Silva, F. (2004). Electroencephalography. Philadelphia: Lippincott Williams & Wilkins. Pellock, J., Dodson, W., Bourgeois, B., Sankar, B., & Nordli, D. (2008). Pediatric epilepsy. New York: Demos Medical Publishing. Shorvon, S., Fish, D., Perucca, E., & Dodson, W. (2004). The treatment of epilepsy. Malden, MA: Blackwell Publishing. Wyllie, E., Gupta, A., & Lachhwani, D. (2004). The treatment of epilepsy: Principles and practice. Philadelphia: Lippincott Williams & Wilkins. Yamatogi, Y., & Ohtahara, S. (2002). Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases, Brain and Development, 24, 13–23.

OLIVOPONTOCEREBELLAR ATROPHY DESCRIPTION

Dejerine and Thomas coined the term olivopontocerebellar atrophy (OPCA) to describe the pathology of a patient who presented with adult-onset progressive cerebellar ataxia. The use of the term OPCA was intended to describe the neuronal degeneration in the cerebellum, pontine nuclei, and inferior olivary nucleus. The patient described by Dejerine and Thomas was over 50 years of age and presented ataxia of gait, dysarthria, impassive face, hypertonia, hyperreflexia, and urinary incontinence. An autopsy revealed an advanced degeneration of the basis pontis, inferior olives, middle cerebellar peduncles, and inferior cerebellar peduncles. Severe atrophy of the Purkinje cells was also noted, with greater atrophy in the cerebellar hemispheres than in the vermis (see Berciano, Bosech, Perez-Ramos, & Wenning, 2006).

The disorder has no definitive treatment, and because motor disruption is a primary feature of OPCA, many of these patients eventually become confined to a bed or wheelchair (Caplan, 1984). The clinical presentation may include a number of different signs and symptoms, including dysphagia (Berciano, 1982; Testa, Tiranti, & Girotti, 2002), respiratory stridor from vocal cord paralysis (Comabella, Montalban, Serena, Lozano, & Codina, 1996; Kneisley & Rederich, 1990; Sundar, Sharma, Arekar, Vimal, & Yeolekar, 2003), dementia, especially later in the disease process (Berciano, 1982; Feher, Inbody, Nolan, & Pirozzolo, 1988), urinary incontinence (Berciano, 1982; Caplan, 1984), and sleep disturbances (Comabella et al., 1996; Kneisley & Rederich, 1990; Tachibana et al., 1995). The predominant signs include progressive gait and limb cerebellar ataxia and dysarthria (Berciano, 1982; Choi, Lee, Kim, & Choi, 1988; Manto, Godaux, Hildebrand, van Naemen, & Jacquy, 1997), with the extrapyramidal and cerebellar signs usually beginning in the lower extremities and subsequently progressing to the upper extremities (Adams & Victor, 1993). Pyramidal signs such as bilateral extensor plantar response, hyperactive deep tendon reflex, and spasticity due to pyramidal tract dysfunction are present early in the course of the disease (Berciano, 1982). Furthermore, position sense (Gatev, Thomas, Lou, Lim, & Hallett, 1996) and vibratory function (Uzunov, Kutchoukov, & Kolchev, 1991) are also reduced, likely secondary to neuropathy. Greenfield (1954) divided the pathology of ataxias into six different categories, which were aggregated into two different forms, including sporadic (Dejerine– Thomas type) and familial (Menzel type). The sporadic type is more common of the two forms and typically has a later age of onset (Adams & Victor, 1993). Also, the sporadic form does not typically present with nystagmus, optic atrophy, retinal degeneration, ophthalmoplegia, or urinary incontinence (Adams & Victor, 1993), although there are exceptions (Berciano, 1982). A number of other different nosologies have been proposed to subtype and differentiate the various forms of OPCA, each associated with advantages and disadvantages. Following a review of several nosological classifications, Berciano (1982) likened OPCA to a variable progressive cerebellar-plus syndrome, concluding that OPCA is a pathological label that is associated with lesions at all levels of the CNS. NEUROPATHOLOGY/PATHOPHYSIOLOGY

The term OPCA includes the common sporadic forms as well as the more uncommon genetic forms. Associations between the genetic forms and all three major inheritance patterns have been described in

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the literature, including autosomal dominant (Choi et al., 1988; Konigsmark & Weiner, 1970), autosomal recessive (Konigsmark & Weiner, 1970), and X-linked (Lutz, Bodensteiner, Schaefer, & Gay, 1989). The sporadic type of OPCA is considered by many to be a subgroup of multiple system atrophy (MSA; Gilman & Quinn, 1996; Penney, 1995; Rinne et al., 1995). Generally, the OPCAs are progressive neurodegenerative conditions. The typical age of onset for the familial form is 28 years and for the sporadic form, the age of onset is 49 years. The duration of OPCA is approximately 15 years for the familial form and 6 years for the sporadic form (Berciano, 1982). The etiology of OPCA is not well-known, but the sporadic forms have been shown to involve abnormalities of alphasynuclein (Jellinger, 2003; Yoshida, 2007). Also, specific genes have been identified in the familial form, but the precise manner in which these genes exert their influence is not well-known (Burk et al., 1996; Koeppen, 1998). As with other forms of MSA, the five histological features include glial cytoplasmic inclusions, neuronal cytoplasmic inclusions, neuronal nuclear inclusions, glial nuclear inclusions, and neuropil threads (Lowe, Lennox, & Leigh, 1997). Of these, glial cytoplasmic inclusions are the most relevant. Atrophy predominates in the cerebellum, middle cerebellar peduncles, and the pons. On autopsy, a graygreen discoloration of the putamen can be often seen along with general atrophy of this structure. Also seen is a loss of pigmentation in the substantia nigra and locus coeruleus (Lowe, Lennox, & Leigh, 1997). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

OPCA is primarily a motor-based dysfunction, characterized by cerebellar ataxia; research has also supported changes in memory, cognitive, and emotional functioning. However, the research regarding neuropsychological functioning in OPCA is far from equivocal. Some investigators have reported not only deficits in tasks with motor components but also mild deficits in cognitive functioning (Berent et al., 2002). Brandt, Leroi, O’Hearn, Rosenblatt, and Margolis (2004) reported that patients with cerebellar degeneration were impaired on tests of executive functioning. Similarly, Arroyo-Anllo and Botez-Marquard (1998) found that OPCA patients evidenced lower scores than normal controls on several tests purported to be sensitive to frontal lobe functioning, including hand sequencing, verbal reasoning, and proverb interpretation. Additional deficits were noted with visuoconstructional abilities and visuospatial immediate memory. Other investigators have also reported deficits with

memory and frontal lobe functioning in patients with OPCA (Kish et al., 1988). Botez-Marquard and Botez (1997) reported a pattern of neuropsychological deficits in patients with OPCA that resembles a ‘‘subcortical’’ pattern. Specifically, OPCA patients exhibited impaired executive functioning, slower speed of information processing, and difficulties with memory retrieval. Additional findings included deficits with visuospatial organization and working memory and difficulty with abstract thinking. Conversely, Moretti et al. (2002) found that OPCA patients, as compared with healthy controls, did not exhibit reduced abstraction, problem-solving abilities, or performance on memory tasks. Rather, they reported that OPCA patients evidenced impaired reading and writing execution. The reason for this discrepancy in research findings regarding the memory and cognitive functioning in OPCA patients is not entirely known. One possibility includes the emotional changes that may accompany this disease. Berent et al. (1990) found that OPCA patients experienced greater depression, anxiety, and subjective emotional distress than normal controls. When education and motor dysfunction were statistically controlled in the analyses, no differences were found between the OPCA patients and normal controls on measures of cognitive and intellectual functioning. Thus, these investigators concluded that OPCA patients may appear to have deficits with memory and cognitive functioning but that these deficits may be due to their motor and emotional functioning. However, it seems worth noting that depression also follows a classic ‘‘subcortical’’ pattern of findings on neuropsychological assessment. Further research will need to be conducted to determine whether the neuropsychological deficits seen in patients with OPCA are due to the neuropathological process of the disease or to emotional changes. This might be accomplished by using scores on measures of depression and anxiety as covariates in statistical analyses or by matching OPCA patients with healthy controls on these variables. DIAGNOSIS

A number of investigations have examined structural brain changes associated with OPCA. CT scans and MRI have emerged as important tools in identifying the brainstem and cerebellar atrophy that is characteristic of OPCA (Klockgether, Faiss, Poremba, & Dichgans, 1990; Ramos, Quintana, Diez, Leno, & Berciano, 1987; Savoiardo et al., 1990). Not surprisingly, typical findings from CT scans include atrophy of the cerebellum and pons (Garcı´a de la Rocha,

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Moreno Martı´nez, Garrido Carrio´n, Ferna´ndez, & Martı´n, 1988; Savoiardo et al., 1983). CT scans conducted in the first year following the onset of cerebellar symptoms may be read as normal, as serial scans are then required to detect infratentorial atrophy (Ormerod et al., 1994). Also, mild cerebellar and pontine atrophy may be necessary but not sufficient for a diagnosis of OPCA. However, the diagnosis becomes more definitive when combined with signal abnormalities in structures that are known to degenerate in OPCA (Savoiardo et al., 1997). Middle cerebellar peduncle diameter seems to be the most sensitive indicator to differentiate OPCA from cortical cerebellar atrophy (Okamoto et al., 2003; Wu¨llner, Klockgether, Petersen, Naegele, & Dichgans, 1993) and striatonigral degeneration (Naka et al., 2002). Typical findings from MRI investigations have included pancerebellar and brainstem atrophy, flattening of the pons, an enlarged fourth ventricle and cerebellopontine angle, and demyelination of the transverse pontine fibers (Berciano et al., 2006; Giuliani, Chiaramoni, Foschi, & Terziani, 1992; Huang, Tuason, Wu, & Plaitakis, 1993; Savoiardo et al., 1990; Sun, Tanaka, Kondo, Hirai, & Ishihara, 1994). A characteristic ‘‘hot cross bun’’ sign is also seen, resulting from the demyelination of the transverse pontine fibers (Berciano et al., 2006). Functional imaging may also assist in diagnostic determination. The PET scans of patients with OPCA evidence reduced glucose metabolism rate within the vermis, cerebellar hemispheres, and brainstem (Gilman et al., 1988), including the pons (Sun et al., 1994). Gilman et al. (1995) reported significantly reduced local cerebral blood flow in the cerebellum as well as decreased local cerebral glucose metabolism rate in the cerebellum, brainstem, cerebral cortex, basal ganglia, and thalamus. Other investigators have reported reduced cerebellar hemispheric blood flow and oxygen metabolism in patients with OPCA as compared with normal controls (Yamaguchi et al., 1994). TREATMENT

The treatment of OPCA largely comprises pharmacological intervention, although one investigation has reported successful treatment with electrostimulation of the spinal cord (Dooley, Sharkey, Keller, & Kasprak, 1978). A number of different medications have been used to treat OPCA. Botez et al. (1999) reported immediate and long-term benefits in motor functioning with amantadine hydrochloride. Subcutaneous lisuride infusion has also been reported to improve motor functioning in patients with OPCA (Heinz, Wo¨hrle, Scho¨ls, Klotz, Kuhn, & Przuntek, 1992). Carbidopa-levodopa was reported to provide

relief in a patient with OPCA who had developed respiratory distress and inspiratory stridor (Schiffman & Golbe, 1992). A recent review of the literature by Trujillo-Martı´n, Serrano-Aguilar, Monton-Alvarez, and Carrillo-Fumero (2009) supported the efficacy of 5-hydroxytryptophan in treating patients with OPCA. However, they also found a paucity of research regarding the effectiveness of physical rehabilitation and psychological interventions. However, Landers, Adams, Acosta, and Fox (2009) reported the case of a patient with OPCA who benefited from undergoing 12 weeks of gait and balance training. Certainly, given that these patients have been found to experience changes in mood and anxiety further research will need to be conducted to examine effective treatments for these behavioral symptoms. Furthermore, research regarding the effective treatment of mood and anxiety in OPCA patients will assist in determining whether the neuropsychological effects of OPCA are due more to the underlying neuropathological processes or to changes in mood and anxiety. Paul S. Foster Valeria Drago Adams, R. D., & Victor, M. (1993). Principles of neurology (5th ed.). New York: McGraw Hill. Arroyo-Anllo, E. M., & Botez-Marquard, T. (1998). Neurobehavioral dimensions of olivopontocerebellar atrophy. Journal of Clinical and Experimental Neuropsychology, 20, 52–59. Berciano, J. (1982). Olivopontocerebellar atrophy: A review of 117 cases. Journal of the Neurological Sciences, 53, 253–272. Berciano, J., Boesch, S., Perez-Ramos, J. M., & Wenning, G. K. (2006). Olivopontocerebellar atrophy: Toward a better nosological definition. Movement Disorders, 21, 1607– 1613. Berent, S., Giordani, B., Gilman, S., Junck, L., Lehtinen, S., Markel, D. S., et al. (1990). Neuropsychological changes in olivopontocerebellar atrophy. Archives of Neurology, 47, 997–1001. Berent, S., Giordani, B., Gilman, S., Trask, C. L., Little, R. J., Johanns, J. R., et al. (2002). Patterns of neuropsychological performance in multiple system atrophy compared to sporadic and hereditary olivopontocerebellar atrophy. Brain and Cognition, 50, 194–206. Botez, M. I., Botez-Marquard, T., Elie, R., Le Marec, N., Pedraza, O. L., & Lalonde, R. (1999). Amantadine hydrochloride treatment in olivopontocerebellar atrophy: A longterm follow-up study. European Neurology, 41, 212–215. Botez-Marquard, T., & Botez, M. I. (1997). Olivopontocerebellar atrophy and Friedreich’s ataxia: Neuropsychological consequences of bilateral versus unilateral cerebellar lesions. International Review of Neurobiology, 41, 387–410.

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Brandt, J., Leroi, I., O’Hearn, E., Rosenblatt, A., & Margolis, R. L. (2004). Cognitive impairments in cerebellar degeneration: A comparison with Huntington’s disease. Journal of Neuropsychiatry and Clinical Neurosciences, 16, 176–184. Burk, K., Abele, M., Fetter, M., Dichgans, J., Skalej, M., Laccone, F., et al. (1996). Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2, and SCA3. Brain, 119, 1497–1505. Caplan, L. R. (1984). Clinical features of sporadic (DejerineThomas) olivopontocerebellar atrophy. Advances in Neurology, 41, 21–-224. Choi, I. S., Lee, M. S., Kim, W. T., & Choi, K. K. (1988). Olivopontocerebellar atrophy. Yonsei Medical Journal, 29, 233–238. Comabella, M., Montalban, X., Serena, J., Lozano, M., & Codina, A. (1996). Early vocal cord paralysis in olivopontocerebellar atrophy. Journal of Neurology, 243, 670–671. Dooley, D. M., Sharkey, J., Keller, W., & Kasprak, M. (1978). Treatment of demyelinating and degenerative diseases by electro stimulation of the spinal cord. Medical Progress Through Technology, 13, 1–14. Feher, E. P., Inbody, S. B., Nolan, B., & Pirozzolo, F. J. (1988). Other neurologic diseases with dementia as a sequela. Clinics in Geriatric Medicine, 4, 799–814. Garcı´a de la Rocha, M. L., Moreno Martı´nez, J. M., Garrido Carrio´n, A., Ferna´ndez, P. M., & Martı´n Araguz, A. (1988). Present criteria for the diagnosis of in vivo of olivopontocerebellar atrophy. Acta Neurologica Scandinavica, 77, 234–238. Gatev, P., Thomas, S., Lou, J. S., Lim, M., & Hallett, M. (1996). Effects of diminished and conflicting sensory information on balance in patients with cerebellar deficits. Movement Disorders, 11, 654–664. Gilman, S., Markel, D. S., Koeppe, R. A., Junck, L., Kluin, K. J., Gebarski, S. S., et al. (1988). Cerebellar and brainstem hypometabolism in olivopontocerebellar atrophy detected with positron emission tomography. Annals of Neurology, 23, 223–230. Gilman, S., & Quinn, N. P. (1996). The relationship of multiple system atrophy to sporadic olivopontocerebellar atrophy and other forms of idiopathic late-onset cerebellar atrophy. Neurology, 46, 1197–1199. Gilman, S., St Laurent, R. T., Koeppe, R. A., Junck, L., Kluin, K. J., & Lohman, M. (1995). A comparison of cerebral blood flow and glucose metabolism in olivopontocerebellar atrophy using PET. Neurology, 45, 1345–1352. Giuliani, G., Chiaramoni, L., Foschi, N., & Terziani, S. (1992). The role of MRI in the diagnosis of olivopontocerebellar atrophy. Italian Journal of Neurological Sciences, 13, 151–156. Greenfield, J. G. (1954). The spinocerebellar degenerations. Oxford: Blackwell.

Heinz, A., Wo¨hrle, J., Scho¨ls, L., Klotz, P., Kuhn, W., & Przuntek, H. (1992). Continuous subcutaneous lisuride infusion in OPCA. Journal of Neural Transmission General Section, 90, 145–150. Huang, Y. P., Tuason, M. Y., Wu, T., & Plaitakis, A. (1993). MRI and CT features of cerebellar degeneration. Journal of the Formosan Medical Association, 92, 494–508. Jellinger, K. A. (2003). Neuropathological spectrum of synucleinopathies. Movement Disorders, 18, S2–S12. Kish, S. J., el-Awar, M., Schut, L., Leach, L., Oscar-Berman, M., & Freedman, M. (1988). Cognitive deficits in olivopontocerebellar atrophy: Implications for the cholinergic hypothesis of Alzheimer’s dementia. Annals of Neurology, 24, 200–206. Klockgether, T., Faiss, J., Poremba, M., & Dichgans, J. (1990). The development of infratentorial atrophy in patients with idiopathic cerebellar ataxia of late onset: A CT study. Journal of Neurology, 237, 420–423. Kneisley, L. W., & Rederich, G. J. (1990). Nocturnal stridor in olivopontocerebellar atrophy. Sleep, 13, 362–368. Koeppen, A. H. (1998). The hereditary ataxias. Journal of Neuropathology and Experimental Neurology, 57, 531–543. Konigsmark, B. W., & Weiner, L. P. (1970). The olivopontocerebellar atrophies: A review. Medicine (Baltimore), 49, 227–241. Landers, M., Adams, M., Acosta, K., & Fox, A. (2009). Challenge-oriented gait and balance training in sporadic olivopontocerebellar atrophy: A case study. Journal of Neurologic Physical Therapy, 33, 160–168. Lowe, J., Lennox, G., & Leigh, P. N. (1997). Disorders of movement and system degenerations. In D. I. Graham & P. L. Lantos (Eds.), Greenfield’s neuropsychology (6th ed.). New York: Oxford University Press. Lutz, R., Bodensteiner, J., Schaefer, B., & Gay, C. (1989). Xlinked olivopontocerebellar atrophy. Clinical Genetics, 35, 417–422. Manto, M., Godaux, E., Hildebrand, J., van Naemen, J., & Jacquy, J. (1997). Analysis of single-joint rapid movements in patients with sporadic olivopontocerebellar atrophy. Journal of the Neurological Sciences, 151, 169–176. Moretti, R., Torre, P., Antonello, R. M., Carraro, N., ZambitoMarsala, S., Ukmar, M. J., et al. (2002). Peculiar aspects of reading and writing performances in patients with olivopontocerebellar atrophy. Perceptual and Motor Skills, 94, 67–694. Naka, H., Ohshita, T., Murata, Y., Imon, Y., Mimori, Y., & Nakamura, S. (2002). Characteristic MRI findings in multiple system atrophy: Comparison of the three subtypes. Neuroradiology, 44, 204–209. Okamoto, K., Tokiguchi, S., Furusawa, T., Ishikawa, K., Quardery, A. F., Shinbo, S., et al. (2003). MR features of diseases involving bilateral middle cerebellar peduncles. American Journal of Neuroradiology, 24, 1946– 1954.

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Ormerod, I. E., Harding, A. E., Miller, D. H., Johnson, G., MacManus, D., du Boulay, E. P., et al. (1994). Magnetic resonance imaging in degenerative ataxic disorders. Journal of Neurology, Neurosurgery, and Psychiatry, 57, 51–57. Penney, J. B. (1995). Multiple system atrophy and nonfamilial olivopontocerebellar atrophy are the same disease. Annals of Neurology, 37, 553–554. Ramos, A., Quintana, F., Diez, C., Leno, C., & Berciano, J. (1987). CT findings in pinocerebellar degeneration. American Journal of Neuroradiology, 8, 635–640. Rinne, J. O., Burn, D. J., Mathias, C. J., Quinn, N. P., Marsden, C. D., & Brooks, D. J. (1995). Positron emission tomography studies on the dopaminergic system and striatal opioid binding in the olivopontocerebellar atrophy variant of multiple system atrophy. Annals of Neurology, 37, 568–573. Savoiardo, M., Bracchi, M., Passerini, A., Visciani, A., Di Donato, S., & Cocchini, F. (1983). Computed tomography of olivopontocerebellar degeneration. American Journal of Neuroradiology, 4, 509–512. Savoiardo, M., Grisoli, M., Girotti, F., Testa, D., & Caraceni, T. (1997). MRI in sporadic olivopontocerebellar atrophy and striatonigral degeneration. Neurology, 48, 790–791. Savioardo, M., Strada, L., Girotti, F., Zimmerman, R. A., Grisoli, M., Testa, D., & Petrillo, R. (1990). Olivopontocerebellar atrophy: MR diagnosis and relationship to multisystem atrophy. Radiology, 174, 693–696. Schiffman, P. L., & Golbe, L. I. (1992). Upper airway dysfunction in olivopontocerebellar atrophy. Chest, 102, 1291–1292. Sun, X., Tanaka, M., Kondo, S., Hirai, S., & Ishihara, T. (1994). Reduced cerebellar blood flow and oxygen metabolism in spinocerebellar degeneration: A combined PET and MRI study. Journal of Neurology, 241, 295–300. Sundar, U., Sharma, A., Arekar, M. A., Vimal, P., & Yeolekar, M. E. (2003). Olivopontocerebellar atrophy presenting with stridor. Journal of the Association of Physicians of India, 51, 813–815. Tachibana, N., Kimura, K., Kitajima, K., Nagamine, T., Kimura, J., & Shibasaki, H. (1995). REM sleep without atonia at early stage of sporadic olivopontocerebellar atrophy. Journal of the Neurological Sciences, 132, 28–34. Testa, D., Tiranti, V., & Girotti, F. (2002). Unusual association of sporadic olivopontocerebellar atrophy and motor neuron disease. Neurological Sciences, 23, 243–245. Trujillo-Martı´n, M. M., Serrano-Aguilar, P., MontonAlvarez, F., & Carrillo-Fumero, R. (2009). Effectiveness and safety of treatments for degenerative ataxias: A systematic review. Movement Disorders, 24, 1111– 1124. Uzunov, N., Kutchoukov, M., & Kolchev, C. (1991). CT scan and threshold vibrometry in the diagnosis of spinocerebellar degenerations. Italian Journal of the Neurological Sciences, 12, 175–179.

Wu¨llner, U., Klockgether, T., Petersen, D., Naegele, T., & Dichgans, J. (1993). Magnetic resonance imaging in hereditary and idiopathic ataxia. Neurology, 43, 318–325. Yamaguchi, S., Fukuyama, H., Ogawa, M., Yamauchi, H., Harada, K., Nakamura, S., et al. (1994). Olivopontocerebellar atrophy studied by positron emission tomography and magnetic resonance imaging. Journal of the Neurological Sciences, 125, 56–61. Yoshida, M. (2007). Multiple system atrophy: Alpha-synuclein and neuronal degeneration. Neuropathology, 27, 484–493.

OPSOCLONUS–MYOCLONUS SYNDROME DESCRIPTION

Opsoclonus–myoclonus syndrome (OMS) is a rare paraneoplastic syndrome most commonly observed in relation to viral infection affecting the brainstem. It has been noted across the life span, though it is most commonly discussed in pediatric populations with highest rates reported prior to age 2 (Rudnick et al., 2001). Although viral infection of the brainstem is the most common etiology for OMS, it has also been observed in relation to neuroblastomas. In fact, 50% of all children presenting with OMS have a neuroblastoma (Kramer & Pranzatelli, 2005; Rudnik et al., 2001) even though only 2% of children with neuroblastomas develop OMS. In adults, opsoclonus–myoclonus has been associated with breast and small cell lung carcinoma (Posner, 1991). OMS is associated with an acute onset of myoclonus (i.e., small, frequent, and multifocal jerks of the muscles), opsoclonus (rapid conjugate eye movements that are irregular and involuntary), and ataxia. In children, a rapid loss of motor control and speech, and regression from developmental milestones are commonly noted. Retrospective investigations have suggested that an increased irritability and severe disturbances of sleep precede the hallmark feature of myoclonus and opsoclonus. OMS has also been referred to as opsoclonus– myoclonus–ataxia, paraneoplastic opsoclonus– myoclonus–ataxia, myoclonic encephalopathy of infants, dancing eyes–dancing feet syndrome, and dancing eyes syndrome. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Neuropathological correlates of OMS vary. As previously suggested, the primary basis of the presentation is believed to be associated with an immune-mediated

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antitumor host response, which affects neural cells, with primary susceptibility of those in the cerebellum (Kramer & Pranzatelli, 2005). Some patients are relatively free of identifiable abnormalities, likely due to mild viral infection of the brainstem that is not yet causing anatomical or cellular changes (Ridley, Kennard, & Scholtz 1987). When alterations are seen, they are primarily noted in the cerebellum and brainstem. Loss of Purkinje cells, neuronal loss in the olivary neurons of the brainstem, astrogliosis, and inflammatory infiltration of the brainstem may all be observed (Posner, 1991; Ridley et al., 1987). An anti-Ri antibody with reactivity to proteins expressed in neuronal nuclei and primary tumor cells may be observed in the serum and CSF (Luque, Furneaux, & Ferzinger, 1991). Similarly, anti-Hu antibodies may also be observed in this same manner, but far less frequently. Anti-Ri antibodies are more commonly noted when the syndrome arises from breast carcinoma, although it has also been seen in gynecological neoplasms (Posner, 1991). Anti-Hu antibodies are often associated with small cell lung cancer. CSF B-cell expansion is a biomarker of disease activity and has been correlated with the presentations clinical severity (Pranzatelli et al., 2006). Still, others have failed to identify associated autoantibodies (Antunes et al., 2000; Blaes et al., 2005; Korfei et al., 2005; Pranzatelli et al., 2004). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The classic constellation of OMS comprises the subacute onset of jerky eye movements with involuntary, chaotic saccades, and arrhythmic-action myoclonus (Caviness, Forsyth, Layton, & McPhee, 1995). The opsoclonus presents as deficits in ocular motility characterized by spontaneous, arrhythmic, large-amplitude conjugate saccades occurring in all directions of gaze without saccadic interval (Pistoia, Conson, & Sara, 2010).The myoclonus presents as small, frequent, and multifocal jerks of the muscles. However, beyond these features, additional symptoms are known to present. Dysarthria, ataxia, and cortical dysfunction may develop (Pranzatelli, 1992). Other common symptoms include difficulties in ambulation, frequent falls, vertigo, nausea, vomiting, dizziness, blurry vision, and dysphasia (Pistoia et al., 2010). Over the long term, symptoms may persist, whether associated with neuroblastoma or a paraneoplastic origin (Hayward et al., 2001; Mitchell et al., 2005; Plantaz et al., 2000; Tate, Allison, Pranzatelli, & Verhulst, 2005). These studies as a collective group suggest that ataxia, speech and language

abnormalities, behavioral problems (e.g., irritability and explosiveness), sleep disturbances, inattention, and learning disabilities may remain over the long term without correlation to treatment response. Executive dysfunction, particularly planning, verbal fluency, and working memory, visuospatial organization, visuospatial memory, and personality changes may be seen (Levisohn, Cronin-Golomb, & Schmahmann, 2000; Riva & Giorgi, 2000; Schmahmann & Sherman, 1998). In all, roughly 60% have persisting cognitive deficits. Variability is seen across outcomes in terms of the percentage of children who demonstrate these residual deficits. What is consistently noted is that multiple relapses are associated with poorer clinical outcomes (Mitchell et al., 2005). In reality, only 12% to 38% of children experience complete recovery (Plantaz et al., 2000). DIAGNOSIS

Diagnosis is clinically based and corresponds with the symptom profiles exhibited by individuals. Review of medical history is also important given the relationship between the presentation and history of smallcell lung cancer, and, to a lesser extent, gynecological cancers. MRI of the brain is essential to evaluate for the presence of a neuroblastoma. PET-CT and bone scans may be employed to evaluate for potential metastatic disease related to a history of the small-cell lung cancer or gynecological cancer. CSF analysis may be undertaken to evaluate for the presence of anti-Ri and anti-Hu antibodies in the serum of the CSF (Luque, Furneaux, & Ferzinger, 1991; Posner, 1991). As previously noted, CSF B-cell expansion is a biomarker of disease activity; thus, its evaluation can be useful for diagnosis. Failure to find such autoantibodies does not rule out the presentation. TREATMENT

There are no standard protocols or guidelines for the treatment of OMS. In children with neuroblastoma, opsoclonus–myoclonus is approached with treatment of the tumor with chemotherapy and with prednisone, corticotropin, intravenous immunoglobulin (IVIg), and/or rituximab. However, these treatments themselves are associated with high toxicity and adverse event risks. In adults, paraneoplastic opsoclonus–myoclonus may be treated with IVIg and immunosuppression. Cyclophosphamide, methylprednisolone, and plasmapheresis have also demonstrated utility in this

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group as have some of the agents used in children (e.g., prednisone, corticotropin, and rituximab). Gabapentin has also shown some efficacy (Pistoia & Sara, 2009). Better neurological outcomes are seen with prompt tumor treatment. Patient with sleep disturbances may respond to trazodone. Children with OMS associated with neuroblastoma tend to have a better prognosis in terms of symptom resolution as the clinical features dissipate with treatment of the tumor (Telander, Smithson, & Groover, 1989). Chad A. Noggle

Antunes, N. L., Khakoo, Y., Matthay, K. K., Seeger, R. C., Stram, D. O., Gerstner, E., et al. (2000). Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonus-myoclonus. Journal of Pediatric Hematology/Oncology, 22, 315–320. Blaes, F., Fuhlhuber, V., Korfei, M., Tschernatsch, M., Behnisch, W., Rostasy, K., et al. (2005). Surface-binding autoantibodies to cerebellar neurons in opsoclonus syndrome. Annals of Neurology, 58, 313–317. Caviness, J. N., Forsyth, P. A., Layton, D. D., & McPhee, T. J. (1995). The movement disorder of adult opsoclonus. Movement Disorders, 10, 22–27. Hayward, K., Jeremy, R. J., Jenkins, S., Barkovich, A. J., Gultekin, S. H., Kramer, J., et al. (2001). Long-term neurobehavioral outcomes in children with neuroblastoma and opsoclonus-myoclonus-ataxia syndrome: Relationship to MRI findings and anti-neuronal antibodies. Journal of Pediatrics, 139, 552–559. Korfei, M., Fuhlhuber, V., Schmidt-Woll, T., Kaps, M., Preissner, K. T., & Blaes, F. (2005). Functional characterisation of autoantibodies from patients with pediatric opsoclonus-myoclonus-syndrome. Journal of Neuroimmunology, 170, 150–157. Kramer, K., & Pranzatelli, M. R. (2005). Management of neurologic complications. In N. K. V. Cheung & S. L. Cohn (Eds.), Neuroblastoma (pp. 213–222). Berlin: SpringerVerlag. Levisohn, L., Cronin-Golomb, A., & Schmahmann, J. D. (2000). Neuropsychological consequences of cerebellar tumour resection in children: Cerebellar cognitive affective syndrome in a paediatric population. Brain, 123, 1041–1050. Luque, F. A., Furneaux, H. M., Ferzinger, R. (1991). Anti-Ri: An antibody associated with paraneoplastic opsoclonus in breast cancer. Annals of Neurology, 29, 241–251. Mitchell, W. G., Brumm, V. L., Azen, C. G., Patterson, K. E., Aller, S. K., & Rodriguez, J. (2005). Longitudinal neurodevelopmental evaluation of children with opsoclonusataxia. Pediatrics, 116, 901–907.

Pistoia, F., Conson, M., Sara, M. (2010). Opsoclonusmyoclonus syndrome in patients with locked-in syndrome: a therapeutic porthole with gabapentin. Mayo Clinic Proceedings, 85(6), 527–531. Pistoia, K., & Sara, M. (2009). Gabapentin therapy for ocular opsoclonus-myoclonus restores eye movement communication in a patient with a locked-in syndrome. Neurorehabilitation and Neural Repair, 24, 493–494. Plantaz, D., Michon, J., Valteau-Couanet, D., Coze, C., Chastagner, P., Bergeron, C., et al. (2000). Opsoclonusmyoclonus syndrome associated with non-metastatic neuroblastoma. Long-term survival. Study of the French Society of Pediatric Oncologists. Archives of Pediatrics, 7, 621–628. Posner, J. B. (1991). Paraneoplastic syndromes. Neurology Clinics, 9, 919–936 Pranzatelli, M. R. (1992). The neurobiology of the opsoclonus-myoclonus syndrome. Clinical Neuropharmacology, 15, 186–228. Pranzatelli, M. R., Tate, E. D., Travelstead, A. L., Barbosa, J., Bergamini, R. A., Civitello, L., et al. (2006). Rituximab (anti-CD 20) adjunctive therapy for opsoclonus-myoclonus syndrome. Journal of Pediatric Hematology Oncology, 28, 585–593. Pranzatelli, M. R., Travelstead, A. L., Tate, E. D., Allison, T. J., Moticka, E. J., Franz, D. N., et al. (2004). B- and T-cell markers in opsoclonus-myoclonus syndrome: Immunophenotyping of CSF lymphocytes. Neurology, 62, 1526–1532. Ridley, A., Kennard, C., Scholtz, C. L. (1987). Omnipause neurons in two cases of opsoclonus associated with oat cell carcinoma of the lung. Brain, 110, 1699–1709. Riva, D., & Giorgi, C. (2000). The cerebellum contributes to higher functions during development: Evidence from a series of children surgically treated for posterior fossa tumours. Brain, 123, 1051–1061. Rudnick, E., Khakoo, Y., Antunes, N. L., Seeger, R. C., Brodeur, G. M., Shimada, H., et al. (2001). Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: Clinical outcome and antineuronal antibodies — a report from the Children’s Cancer Group Study. Medical and Pediatric Oncology, 36, 612–622 Schmahmann, J. D., & Sherman, J. C. (1998). The cerebellar cognitive affective syndrome. Brain, 121, 561–579. Tate, E. D., Allison, T. J., Pranzatelli, M. R., & Verhulst, S. J. (2005). Neuroepidemiologic trends in 105 US cases of pediatric opsoclonus-myoclonus syndrome. Journal of Pediatric Oncology Nursing, 22, 8–19. Telander, R. L., Smithson, W. A., Groover, R. V. (1989). Clinical outcome in children with cerebellar encephalopathy and neuroblastoma. Journal of Pediatric Surgery, 24, 11–14.

PARANEOPLASTIC SYNDROMES & 559

PARANEOPLASTIC SYNDROMES DESCRIPTION

Paraneoplastic syndromes represent a group of disorders that are varied in their functional impact and clinical presentation. They may affect all levels of the central and peripheral nervous systems. Paraneoplastic syndromes manifest as a result of the immune system’s detection and response to a tumor antigen that cross-reacts with similar antigens expressed by the nervous system (Baehering, Quant, & Hochberg, 2007). It is estimated that paraneoplastic syndromes affect up to 8% of patients with cancer (Baijens & Manni, 2006). Variability is seen based on the location of the onconeural antigen and thus the impact on the system. Based on the clinical features that arise, paraneoplastic syndromes can be divided into four categories: paraneoplastic endocrine syndromes, paraneoplastic hematologic syndromes, paraneoplastic dermatologic and rheumatologic syndromes, and paraneoplastic neurologic syndromes. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Again, paraneoplastic syndromes arise from an immune response to detected tumor antigens that cross-react with antigens within the nervous system. Individual discrepancies in physiology exist among the subtypes. As tumor cells invade the lymphatic system, this elicits the noted immune detection. Baehring et al. (2007) note that onconeural antigens are classified by their location, either on the cell surface or intracellular, in addition to their subcellular expression pattern. The underlying mechanism across presentations appears to be a serological immune response targeting intracellular antigens that activates cytotoxic T cells directed at peptide sequences arising from the intracellular antigen (Yu et al., 2001). Pathologically, paraneoplastic syndromes can correspond with neuronal loss that is fairly extensive and irreversible in combination with reactive gliosis, perivascular cuffing by lymphocytes, and meningeal infiltrates affecting the limbic system, brainstem, and spinal cord (Baehring et al., 2007). Again, variability is seen based on the syndrome type and its origin. Pelosof and Gerber (2010), in their review, offered a detailed synthesis of the literature in terms of the types of paraneoplastic syndromes that present, their features, pathology, diagnostic findings, and treatment options that have been adopted in Table 1.

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

There is no prototype of paraneoplastic syndromes. Various sites and systems can be affected throughout the system, and the manner in which they are affected corresponds with the clinical features that emerge. Table 1 gives for the main clinical/neuropsychological characteristics observed in conjunction with the various paraneoplastic syndromes. DIAGNOSIS

Diagnosis of paraneoplastic syndromes can be difficult and requires a synthesis of multiple sources of information including MRI and serological studies in addition to clinical evaluation. In many ways, diagnosis is dualistic in that identification of the paraneoplastic syndrome is important as is the identification of the underlying presentation (e.g., small cell lung cancer). The latter are outlined in Table 1 in terms of their link with specific paraneoplastic syndromes. MRI can aid in identifying anatomical alterations, including neuronal loss or regional enlargements. PET/CT scans can reveal areas of uptake throughout the body that may suggest cancerous origin/presence. EEG should be utilized in cases where seizures develop (e.g., syndrome of inappropriate secretion of antidiuretic hormone [SIADH]). Spinal tap with CSF analysis is often abnormal in a majority of patients; however, it does not differentiate among paraneoplastic syndromes. Serological studies can be coupled with CSF to narrow diagnostic focus. Specifically, the antibodies revealed on analysis can help direct diagnosis. For example, anti-CRMP-5, anti-Ma, anti-Ma2, and antiTr have each demonstrated capabilities in identifying specific cancerous presentations of various types (Bernal et al., 2003; Dalmau et al., 1999; Voltz et al., 1999; Yu et al., 2001). Diagnostic findings and studies based on the type of paraneoplastic syndrome are included in Table 1. TREATMENT

Treatment and management of paraneoplastic syndrome is often dualistic, requiring simultaneous treatment of the paraneoplastic syndrome itself while attempting to identify and/or treat the cancerous presentation. Plasmapheresis or intravenous immunoglobulin infusion can offer treatment of the paraneoplastic syndrome (Baehring et al., 2007). Immunosuppression with corticosteroids or cyclophosphamide can also be useful, but as noted by Baehring et al. (2007), this can be contraindicated in

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Diagnostic Findings

FEATURES

Breast, multiple myeloma, renal cell, squamous cell cancers (especially lung), lymphoma (including HTLV-associated lymphoma), ovarian, endometrial

Muscle weakness, peripheral edeSmall cell lung cancer, bronchial ma, hypertension, weight gain, carcinoid (neuroendocrine lung centripetal fat distribution tumors account for 50–60% of cases of paraneoplastic Cushing’s syndrome), thymoma, medullary thyroid cancer, GI, pancreatic, adrenal, ovarian

Hypercalcemia

Cushing’s syndrome

Altered mental status, weakness, ataxia, lethargy, hypertonia, renal failure, nausea/vomiting, hypertension, bradycardia

Smallcell lung cancer, mesothehoma, bladder, ureteral, endometrial, prostate, oropharyngeal, thymoma, lymphoma, Ewing’s sarcoma, brain, GI, breast, adrenal

Gait disturbance and falls, seizures, headache, nausea, fatigue, muscle cramps, anorexia, confusion, lethargy, respiratory depression, coma

Treatment

Hypokalemia (usually 29.0 mg/dL), normal to elevated midnight serum ACTH (>100 ng/L) not suppressed with dexamethasone

Hypercalcemia: mild, calcium 10.5–11.9 mg/dL; moderate, calcium 12.0–13.9 mg/dL; severe, calcium, 6 months) pattern of two or more of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms (American Psychiatric Association, 2001). In regard to schizophreniform, the potential features are largely consistent with that of schizophrenia except for the fact that active phase symptoms occur concurrently with episodes of mood disturbance. Furthermore, there must be a 2-week period in which psychotic features are seen outside the confines of mood disturbance. DIAGNOSIS

Diagnosis of the psychotic disorders remains dependent upon description of clinical features and their adherence to DSM-IV criteria. However, a neurological/physiological source should be ruled-out first. Particularly in those cases where symptom onset is reported as more rapid, neurological correlates must be evaluated. Some suggest an easy way of differentiating psychiatric from neurological in terms of hallucinations lies in whether there are auditory hallucinations present. Purely visual hallucinations have been reported in neurological presentations such as Lewy body dementia, peduncular hallucinosis, some seizure disorders, and so forth. In comparison, it is far more rare for auditory hallucinations to occur in association with anything but psychotic disorders. In presentations like temporal lobe epilepsy where Heschl’s gyrus is involved, some individuals will experience preictal auditory aura. Thus, clinical history should be very detailed outlining any or all symptoms and their features including experiences prior to and after their occurrence if such observations have been made. MRI and CT can be used to rule out specific structural

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abnormalities. EEG may be sought in instances where seizures/epilepsy is considered as part of the differential. Lumbar puncture with CSF analysis can aid in ruling-out an infectious or similar process. Many of these latter technologies are used for completeness sake.

TREATMENT

Treatment of psychotic disorders remains largely medicinally based. Although historically other methods such as psychosurgery were used, the prominent negative effects of these interventions, in combination with the advancement and effectiveness of modern day medicinal control, have limited such practices. Both typical and atypical antipsychotics are used today, although the prior is used on a very limited basis. Their mechanisms of action are slightly different, but in general, the term antipsychotic suggests an antagonistic effect on brain dopamine receptors (Ivanov & Charney, 2008). In the case of typical antipsychotic, they block dopamine D2 receptors (Surja, Tamas, & El-Mallakh, 2006). Although they are quite effective in controlling positive symptoms, they carry a significant adverse risk profile that includes akathisia, acute dystonias and dyskinesias, and gradually evolving parkinsonian bradykinesia as well as tardive dyskinesia and chronic dystonias (Gardner, Baldessarini, & Waraich, 2005). In comparison, atypical antipsychotics demonstrated equal, if not greater effectiveness in comparison to typical antipsychotics yet do not carry the same negative consequences. They differ from typical antipsychotics in that they demonstrate a mixed dopamine and serotonin blockade (Surja et al., 2006). Beyond medicinal treatment, there is a significant role of cognitive-behavioral interventions through a therapeutic modality. Neuropsychological assessment can identify strengths and from that define strategies for individual to compensate for cognitive weaknesses. The combination of these strategies can be essential to helping individuals maintain independence and success socially, educationally, and occupationally. Chad A. Noggle Akbarian, S., Vinuela, A., Kim, J. J., Potkin, S. G., Bunney, W. E. Jr., & Jones, E. G. (1993). Distorted distribution of nicotinamide-adenine dinucleotide phosphatediaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development. Archives of General Psychiatry, 50, 178–187.

American Psychiatric Association. (2001). Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition-Text Revision). Washington, D.C.: Author. Bartzokis, G. (2002). Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology, 27, 672–683. Bullmore, E. T., Frangou, S., & Murray, R. M. (1997). The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia. Schizophrenia Research, 28, 143–156. Gardner, D. M., Baldessarini, R. J., & Waraich, P. (2005). Modern antipsychotic drugs: A critical overview. Canadian Medical Association Journal, 172 (13), 1703–1711. Goldstein, J. M., Faraone, S., Chen, W., & Tsuang, M. (1995). Genetic heterogeneity may in part explain sex differences in the familial risk for schizophrenia. Biological Psychiatry, 38, 808–813. Gottesman, I. I., & Shields, J. (1982). The epigenetic puzzle. Cambridge, MA: Cambridge University Press. Harrison, P. J. (1999). The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain, 122, 593–624. Heinrichs, R. W. (2005). The primacy of cognition in schizophrenia. American Psychologist, 60, 229–242. Ivanov, I., & Charney, A. (2008). Treating pediatric patients with antipsychotic drugs: Balancing benefits and safety. Mount Sinai Journal of Medicine, 75, 276–286. Kendler, K. S., Gruenberg, A. M. & Tsuang, M. T. (1985). Psychiatric illness in first-degree relatives of schizophrenia and surgical control patients. Archives of General Psychiatry, 42, 770–779. Keshavan, M. S., Kennedy, J. L., & Murray, R. M. (2004). Neurodevelopment and schizophrenia. New York NY: Cambridge University Press. Kwon, J. S., O’Donnell, B. F., Wallenstein, G. V., Greene, R. W., Hirayasu, Y., Nestor, P. G., et al. (1999). Gamma frequency range abnormalities to auditory stimulation in schizophrenia. Archives of General Psychiatry, 56, 1001–1005. Marcopulos, B. A., Fuji, D., O’Grady, J., Shaver, G., Manley, J., & Aucone, E. (2008). Providing neuropsychological services for person with schizophrenia: A review of the literature and prescription for practice. In J. E. Morgan & J. H. Ricker (Eds.), Textbook of clinical neuropsychology (pp. 743–761). New York NY: Taylor & Francis. Mehler, C. & Warnke, A. (2002). Structural brain abnormalities specific to childhood-onset schizophrenia identified by neuroimaging techniques. Journal of Neural Transmission, 109, 219–234. Rajkowska, G., Selemon, L. D., & Goldman-Rakic, P. S. (1998). Neuronal and glial somal size in the prefrontal cortex: A postmortem morphometric study of schizophrenia and

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Japanese Society of Neuropathology Huntington disease. Archives of General Psychiatry, 55, 215–224. Seaton, B. E., Goldstein, G., & Allen, D. N. (2001). Sources of heterogeneity in schizophrenia: The role of neuropsychological functioning. Neuropsychology Review, 11, 45–67. Selemon, L. D., Rajkowska, G., & Goldman-Rakic, P. S. (1995). Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Archives of General Psychiatry, 52, 805–818. Spencer, K. M., Nestor, P. G., Perlmutter, R., Niznikiewicz, M. A., Klump, M. C., Frumin, M., et al. (2004). Neural synchrony indexes disordered perception and cognition in schizophrenia. Proceedings of the National Academic of Sciences of the United States of America, 101, 17288–17293.

Subuh Surja, A. A., Tamas, R. T., & El-Mallah, R. S. (2006). Antipsychotic medications in the treatment of bipolar disorder. Current Drug Targets, 7, 1217–1224 Weinberger, D. R. (1993). A connectionist approach to the prefrontal cortex. The Journal of Neuropsychiatry and Clinical Neurosciences, 5, 241–253. Weinberger, D. R., Lipska, B. K. (1995). Cortical maldevelopment, anti-psychotic drugs, and schizophrenia: A search for common ground. Schizophrenia Research, 16, 87–110. Zaidel, D. W., Esiri, M. M., & Harrison, P. J. (1997). Size, shape, and orientation of neurons in the left and right hippocampus: Investigation of normal asymmetries and alterations in schizophrenia. The American Journal of Psychiatry, 154, 812–818.

QR RASMUSSEN’S ENCEPHALITIS DESCRIPTION

Rasmussen’s encephalitis is a rare brain disorder that involves severe epileptic seizures, hemispheric atrophy, hemianopsia, hemiparesis, and aphasia if the left hemisphere is affected (Granata, 2003). The epileptic seizures in Rasmussen’s encephalitis are most commonly simple partial motor seizures, although tonic-clonic, complex partial, postural, and somatosensory seizures may be present as well (Bien et al., 2005). Very often, seizure activity progresses to epilepsia partialis continua (EPC) in children, which is defined as a persistent seizure involving consistent motor activity. EPC is often one of the first symptoms that inform clinicians of the presence of Rasmussen’s encephalitis. Rasmussen’s encephalitis has long been thought to be a disorder that solely affects children. However, recent advancements in the ability to diagnose and distinguish the presence of Rasmussen’s encephalitis has revealed that this disorder does primarily affect children, but can take an adult onset also (Bien et al., 2005). In children, Rasmussen’s encephalitis typically takes a predictable course, involving three proposed phases. The first phase of the disorder involves infrequent seizure activity and mild hemiparesis characterized as a weakness in one side of the body. This initial phase of the disorder typically lasts for about 8 months (Bien et al., 2005). The second phase is typified by much more frequent seizure activity, usually simple partial motor seizures, severe hemiparesis, and/or hemianopsia (i.e., blindness in one-half of the visual field of either one or both eyes). After an average of 8 months, the third chronic phase begins, which causes considerable cognitive deficits, as well as epileptic seizure activity (Bien et al., 2005). In contrast, adult onset Rasmussen’s encephalitis manifests itself in exactly the same way, though it exhibits milder seizure activity, usually occipital lobe seizures, and less cognitive deficits (Hart et al., 1997).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

There are several competing theories as to the etiology of this unusual condition, though there is currently no validated explanation. Debate persists as to the basis for Rasmussen’s encephalitis. Specifically, though some suggest Rasmussen’s encephalitis is caused by a viral infection that then leads to a localized immune response, there is also suggestion that the disorder is caused by an autoimmune deficiency that is unrelated to viral infection (Tran, Day, Eskin, Carney, & Maria, 2000). Most researchers agree that viral infection must be involved in the etiology due to many histopathological symptoms such as microglial nodules, and neuronophagia (neuronal death due to phagocytes), which are both common in central nervous system infection (Tran et al., 2000). Neuropathological findings indicate hemispheric atrophy occurs in Rasmussen’s encephalitis, and, more specifically, degeneration of the caudate nucleus is commonly seen. Further observation of the brain in Rasmussen’s encephalitis has revealed that often microglial nodules are present, which are nodules of necrotic tissue (Bien et al., 2005). In addition, significant brain inflammation has been found to be present, along with glial scarring, gyral necrosis, the presence of perivascular round cells, and neuronal death (Roger, Bureau, Genton, Tassinari, & Wolf, 2001). This significant brain inflammation is mainly caused by the infiltration of T cells and microglial cells. According to MRI studies, Rasmussen’s encephalitis begins by affecting the temporal or anterior parietal lobes, which leads to partial motor seizures (Deb et al., 2005). Robitaille and colleagues have suggested conceptualizing Rasmussen’s encephalitis pathology in four stages or steps. The most severe proposed stage of this chronic encephalitis is the ‘‘active disease’’ stage, which is defined as a stage of the disease causing glial scarring, the presence of perivascular cells, and nodules of necrotic brain tissue (Deb et al., 2005). The second stage, known as the ‘‘active and remote’’ stage is comprised of less microglial nodules than the former stage, round cell infiltration, and gyral necrosis (Deb et al., 2005). The third, known as the ‘‘remote stage’’ presents

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with still less glial scarring, some neuronal atrophy, and brain inflammation. Lastly, the ‘‘nonspecific change’’ stage is the most benign form of Rasmussen’s encephalitis with mild glial scarring, and mild neuronal damage (Deb et al., 2005). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Previous research has indicated that 90% of children with Rasmussen’s encephalitis maintain an average intelligence quotient before the onset of epileptic activity (Tran et al., 2000). The presence of focal seizures severely damages neuropsychological functioning and intellectually impairs 85% of individuals with the chronic encephalitis (Tran et al., 2000). Paralleling the rapid cognitive decline in Rasmussen’s encephalitis, are overt sensory and motor deficiencies such as hemianopsia. Due to the excessive neuronal damage among Rasmussen’s encephalitis patients, significant neuropsychological deficits are inevitable. Among children with this disorder, performance intelligence is commonly higher than verbal intelligence (Hennessy et al., 2001). This disparity between verbal and performance intelligence may be due to the temporal lobe focus of this disorder. As discussed previously, Rasmussen’s encephalitis often affects the temporal lobe specifically. Damage to the left temporal lobe may cause aphasia or dysphasia as delineated by neuropsychological testing (Deb et al., 2005). In addition, verbal comprehension may be impacted by focal temporal neuronal damage (Hennessy et al., 2001). Also, cases of memory loss, specifically short-term memory, and working memory have been reported due to hippocampal and parahippocampal damage (Hennessy et al., 2001). DIAGNOSIS

Diagnosing Rasmussen’s encephalitis is based on the clinical presence of seizures (especially EPC and by electroencephalocardiogram (EEG), MRI, or biopsy evaluation (Bien et al., 2005). Abnormal EEG patterns include an overwhelming amount of delta wave activity, and ictal discharge, which is indicative of seizure activity (Granata, 2003). MRI studies have contributed to the diagnosis of Rasmussen’s encephalitis by discovering several important MRI abnormalities in patients. First, the inner and outer cerebrospinal fluid compartment tends to be unilaterally enlarged (Bien et al., 2005). These studies have also provided evidence that cortical swelling occurs possibly due to viral infection. Lastly, in some cases, specific atrophy of the caudate nucleus can be seen in MRI scanning.

Brain biopsy is regarded as the last resort, or measure taken to appropriately diagnose the presence of Rasmussen’s encephalitis. Most commonly, frontal or temporal biopsies are performed due to the histopathological localization of affected tissue in these areas. The use of all four of these methods should be enough to derive the diagnosis of Rasmussen’s encephalitis. The activity of EPC seizures is probably the most useful indicator when assessing for Rasmussen’s encephalitis. When assessing for differential diagnoses, one must consider the possibility of other unilateral or unihemispheric neurological disorders such as Sturge– Weber’s syndrome (Bien et al., 2005). Secondly, other possibilities for the occurrence of EPC should be taken into account. For example, EPC is also seen in diabetes mellitus (Bien et al., 2005). Lastly, alternative diseases that cause brain inflammation such as multiple sclerosis should be considered (Bien et al., 2005). TREATMENT

Due to the persistent nature of the seizures in Rasmussen’s encephalitis, one of the major goals of treatment is to alleviate or eradicate seizure activity. One extreme way that this is done is by performing a functional hemispherectomy. This involves the removal of the temporal lobe of the affected hemisphere and surgically disabling the connection of one hemisphere to the other (Bien et al., 2005). This operation almost invariably ceases seizure activity, though causes many secondary symptoms such as significant cognitive decline, lack of interhemispheric tasks, and hemiparesis or hemiplegia. Current research offers disparate ideas about the implementation of the hemispherectomy, due to the significant cognitive impact that it can cause. The most common view is that a hemispherectomy should be avoided when dealing with individuals who have maintained average intelligence and cognitive functioning due to the degree of expected residuals that may themselves impede functioning and quality of life. In cases where cognition has already been detrimentally influenced, a hemispherectomy is generally recommended simply because of its ability to reduce seizure activity. Recently, the use of corticosteroids has increased in cases of Rasmussen’s encephalitis. These corticosteroids are thought to positively alter the course of the disorder by reducing epileptic activity and reducing brain inflammation (Tran et al., 2000). The use of steroids may be the first line of defense in treatment, because anticonvulsants alter the course of the disorder (Bien et al., 2005).

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Lastly, interferon therapy has been shown to alleviate Rasmussen’s encephalitis symptoms. Interferon therapy is applied intraventricularly and may reduce symptoms for several weeks. Previous research has provided evidence that interferon therapy reduces the frequency and severity of seizure activity (Bien et al., 2005). A major disadvantage of this treatment is the perpetual requirement of receiving this therapy every 3 weeks or so. This weakness in the treatment is what makes a functional hemispherectomy such a viable choice for many patients. Ryan Boddy Charles Golden Bien, C. G., Granata, T., Antozzi, C., Cross, J. H., Dulac, O., Kurthen, M., et al. (2005). Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: A European consensus statement. Brain, 128, 3, 454–471. Deb, P., Sharma, M. C., Gaikwad, S. M., Tripathi, P., Chandra, S., Jain, S., et al. (2005). Neuropathological spectrum of Rasmussen encephalitis. Neurology India, 53(2), 156–161. Granata, T. (2003). Rasmussen’s syndrome. Neurological Sciences, 4(24), 239–243. Hart, Y. M., Andermann, F., Fish, D. R., Dubeau, F., Robitaille, Y., Rasmussen, T., et al. (1997). Chronic encephalitis in adults and adolescents: A variant of Rasmussen’s syndrome? Neurology, 48, 418–424. Hennessy, M. J., Koutroumanadis, M., Dean, A. F., Jarosz, J., Elwes, R., Binnie, C. D., et al. (2001). Chronic encephalitis and temporal lobe epilepsy: A variant of Rasmussen’s syndrome? Neurology, 56, 678–681. Rasmussen, T., Olszwewski, J., & Lloyd-Smith, D. (1958). Focal seizures due to chronic localized encephalitis. Neurology, 8(6), 435–445. Roger, J., Bureau, M., Dravet, C., Genton, P., Tassinari, C., &Wolf, P. (2001). Epileptic syndromes in infancy, childhood and adolescence (3rd ed.). Montrouge, France: Eurotext. Tran, T., Day, J., Eskin, T., Carney, P. R., & Maria, B. L. (2000). Rasmussen’s syndrome: Aetiology, clinical features and treatment options.CNS Drugs, 14(5), 343–354.

READING DISORDERS DESCRIPTION

According to the American Psychiatric Association’s (APA) Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (APA, 2000), to meet criteria for Reading Disorder an individual’s

reading achievement (reading accuracy or comprehension) must be substantially below the expected level given the person’s age, age-appropriate education, and measured intelligence. Reading achievement must be measured via individually administered standardized tests, and the disturbance must significantly interfere with academic achievement or daily activities that require reading skills. An estimated 4% of school children meet criteria for Reading Disorder, and among those diagnosed, between 60% and 80% are male (APA, 2000). Though reading difficulties may be present as early as kindergarten (e.g., poor letter identification skills or poor association of letters with phonemes), formal reading instruction usually begins in the middle of first grade and, thus, Reading Disorder is rarely diagnosed prior to this point. When an individual with high IQ experiences Reading Disorder, symptoms may go undetected until the fourth grade or later. Early identification and intervention typically proves successful in a significant number of cases (APA, 2000). In 2001, the National Center for Education Statistics revealed that 37% of fourth-grade students are below the reading level necessary to work effectively at their grade level (Torgesen, 2002). Given that low reading achievement hinders vocabulary growth (Cunningham & Stanovich, 1998), negatively affects children’s motivation to read (Oka & Paris, 1986), and leads to diminished opportunities for developing comprehension strategies (Brown, Palincsar, & Purcell, 1986), early identification and early intervention is essential. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Neuroradiological findings have shown that specific types of brain activity are correlated with reading skills. Turkeltaub, Gareau, Flowers, Zeffiro, and Eden (2003) found that phonological awareness correlated with activity in the left posterior superior temporal cortex (grapheme-phoneme translation and phonology) and the inferior frontal gyrus (articulation). Further, activity in this network increased as a child’s phonological skill level increased. Cohen and Dehaene (2004) also found that the ‘‘visual word form area’’ becomes increasingly active as reading expertise develops. Simos et al. (2002) noted that children with developmental dyslexia demonstrate underactivation of phonological brain areas and that phonics-based interventions improve activation in these areas. They examined dyslexic children who had shown significant improvement following 80 hours of intensive phonological intervention. Prior to intervention, the children exhibited expected hypoactivation in the

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left temporoparietal regions (Goswami, 2008). Following intervention, a dramatic increase of activation in this area occurred, particularly in the left posterior superior temporal gyrus (which supports graphemephoneme coding in normally developing readers; Turkeltaub et al., 2003). Regarding the time course of neuronal activation and the development of reading skill (Goswami, 2008), Simos et al. (2005) found that individuals at high risk for reading difficulties were significantly slower in exhibiting neural activity in the occipitotemporal region when presented with both nonwords and letters in kindergarten. Further, the high-risk individuals demonstrated atypical activation in the left inferior frontal gyrus, as the onset of activity significantly increased from kindergarten to 1st grade. Typically, developing readers showed no such increase. Pennington, McGrath, and Smith (in press) note that researchers have identified candidate genes for dyslexia as these risk alleles have been linked to the development of poor neuronal connections. Functional neuroimaging studies reveal that reading involves the integration of several brain areas, including the anterior and posterior portions of the fusiform word area and language cortex. Given that integration is dependent upon connections between and within brain areas, malformations in neuronal connectivity produced by these risk alleles may cause interference with the integration of brain areas required for reading (Pennington, 2009). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Torgesen (2002) notes that in order to comprehend the meaning of text, an individual must have both of the following skills: general language comprehension and accurate and fluent identification of words in print. Fluent and accurate reading is preceded by an ability to implement accurate phonemic decoding skills, which then aid the child in acquiring specific memories for words, which is crucial in automatic recognition (Ehri, 1998). Weaknesses in phonemic awareness are found both in children of average intelligence and children of low intelligence. Children with low general oral language skills, such as those of lower socioeconomic status, present with an additional deficit as they are deficient in the critical language knowledge required for good reading comprehension (Gough, 1996; Whitehurst & Lonigan, 1998). Reading Disorder is highly comorbid with Attention Deficit Hyperactivity Disorder (Donfrancesco, Mugnaini, & Dell’Uomo, 2005). In addition to behavioral impulsivity, children with Reading Disorder

have demonstrated higher levels of cognitive impulsivity versus controls. Consequently, impulsivity assessments are useful when assessing children with Reading Disorder as such work enables one to devise a more specific rehabilitation program (Donfrancesco et al., 2005). Parents and teachers often view problematic behavior in the classroom as a factor that exacerbates academic struggle. What often goes unrecognized is that a mismatch between academic needs and instructional program can result in problematic behavior from the child. Such circumstances as excessive failure, frustration, and negative feedback from the teacher can exacerbate clinical concerns in the child. As such, it is imperative to properly assess a child’s academic performance in order to adequately assess a behavioral deficit (Noell, 2003). DIAGNOSIS

Children at risk for reading deficits can be identified in kindergarten through screeners that assess lettersound knowledge, phonemic awareness, and vocabulary. In order to reduce false negatives, Torgesen (2002) recommends screenings in kindergarten through third grade, three times per year. Minimal time can be used through implementation of measures such as the Test of Word Reading Efficiency (Torgesen, Wagner, & Rashotte, 1999), which requires 45 seconds to assess phonemic decoding efficiency and 45 seconds to measure sight word vocabulary growth. Another efficient assessment tool is called Dynamic Indicators of Basic Early Literacy Skill (DIBELS). DIBELS involves short (1 minute) standardized fluency measures that assess student alphabetic understanding, phonological awareness, and fluency. DIBELS is comprised of three subtests: Letter Naming Fluency, Initial Sound Fluency, and Phonemic Segmentation Fluency. These subtests have demonstrated reliability and have proven to be useful tools in identifying children with low reading achievement. Given its high levels of sensitivity, DIBELS is recommended as an initial screening tool. Subsequently, tests of higher specificity should be used with those positively identified in order to screen false positives (Hintze, Ryan, & Stoner, 2003). Though teacher referral (TR) is commonly used for identification of low-achieving children in the classroom, universal screening methods such as Problem Validation Screening (PVS) are currently available. VanDerHeyden and Witt (2005) compared TR with PVS and found that PVS maximizes the discovery of true positives. Further, though TR yields higher predictive power estimates in low-achieving

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classrooms, PVS outperformed TR as an identification tool in both high- and low-performing classrooms. TREATMENT

In 2004, the Individuals with Disabilities Education Act was reauthorized to allow schools to use response to intervention (RTI) to determine eligibility for learning disabled classification (Daly, Martens, Barnett, Witt, & Olson, 2007). RTI involves the continuous evaluation of a student’s response to evidence-based interventions. RTI models involve a three-tier, fixed sequence of delivery of type and strength of intervention (Daly et al., 2007). The first tier involves universal intervention that is delivered school and class-wide, ruling out inadequate instruction as a source of low performance and also serving as a universal screen (Gresham, 2004). In the second tier, children not adequately responding to the first tier are administered selected interventions. A third level provides more intensive intervention to children not responding the first two tiers. It is imperative that school-based intervention teams correctly adapt instruction to the student. The Instructional Hierarchy (IH) conceptualizes proficiency as progression through three steps: acquisition, fluency, and generalization (Daly, Lentz, & Boyer, 1996). The IH guides choice of intervention, and correct responses from the student are elicited through modeling, prompting, error correction, and feedback. Fluency is strengthened through repeated practice and reinforcement for meeting fluency goals. Gradually, assistance is withdrawn until the skill is performed not just accurately but also independently (Daly et al., 2007). Martens and Eckert (2007) note that the strongest effects are found when a combination of methods is utilized, such as combining modeling, contingent error correction, and repeated practice. In order to monitor the success of fluency-based interventions, curriculum-based measurement probes are reliable and valid tools that measure progress (e.g., Chard, Vaughn, & Tyler, 2002). Such measures have been used to identify effective interventions for various subtypes of low-performing readers (e.g., low fluency–high accuracy versus low fluency–low accuracy; Chafouleas, Martens, Dobson, Weinstein, & Gardner, 2004). Audrey L. Baumeister William Drew Gouvier

American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (DSM-IV-TR). Washington, DC: Author.

Brown, A. L., Palincsar, A. S., & Purcell, L. (1986). Poor readers: Teach, don’t label. In U. Neisser (Ed.), The school achievement of minority children: New perspectives (pp. 105–143). Hillsdale, NJ: Erlbaum. Chafouleas, S. M., Martens, B. K., Dobson, R. J., Weinstein, K. S., & Gardner, K. B. (2004). Fluent reading as the improvement of stimulus control: Additive effects of performance-based interventions to repeated reading on students’ reading and error rates. Journal of Behavioral Education, 13, 67–81. Chard, D. J., Vaughn, S., & Tyler, B. J. (2002). A synthesis of research on effective interventions for building reading fluency with elementary students with learning disabilities. Journal of Learning Disabilities, 35, 386–406. Cohen, L., & Dehaene, S. (2004). Specialization within the ventral stream: The case for the visual word form area. NeuroImage, 22, 466–476. Cunningham, A. E., & Stanovich, K. E. (1998). What reading does for the mind. American Educator, 22(Spring/Summer), 8–15. Daly, E. J., III, Lentz, F. E., & Boyer, J. (1996). The instructional hierarchy: A conceptual model for understanding the effective components of reading interventions. School Psychology Quarterly, 11, 369–386. Daly, E. J., Martens, B. K., Barnett, D., Witt, J. C., & Olson, S. C. (2007). Varying intervention delivery in response to intervention: Confronting and resolving challenges with measurement, instruction, and intensity. School Psychology Review, 36(4), 562–581. Donfrancesco, R., Mugnaini, D., & Dell’Uomo, A. (2005). Cognitive impulsivity in specific learning disabilities. European Child and Adolescent Psychiatry, 14, 270–275. Ehri, L. C. (1998). Grapheme-phoneme knowledge is essential for learning to read words in English. In J. Metsala & L. Ehri (Eds.), Word recognition in beginning reading (pp. 3–40). Hillsdale, NJ: Erlbaum. Goswami, U. (2008). Reading, dyslexia and the brain. Educational Research, 50, 135–148. Gough, P. B. (1996). How children learn to read and why they fail. Annals of Dyslexia, 46, 3–20. Gresham, F. M. (2004). Current status and future directions of school-based behavioral interventions. School Psychology Review, 33, 326–343. Hintze, J. M., Ryan, A. L., & Stoner, G. (2003). Concurrent validity and diagnostic accuracy of the dynamic indicators of basic early literacy skills and the comprehensive test of phonological processing. School Psychology Review, 32(4), 541–556. Martens, B. K., & Eckert, T. L. (2007). The instructional hierarchy as a model of stimulus control over student and teacher behavior: We’re close but are we close enough? Journal of Behavioral Education, 16, 82–90. Noell, G. H. (2003). Direct assessment of clients’ instructional needs: Improving academic, social, and emotional

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outcomes. In M. L. Kelley, D. Reitman, & G. H. Noell (Eds.), Practitioner’s guide to empirically based measures of school behavior (pp. 63–82). New York: Kluwer Academic/Plenum Publishers. Oka, E., & Paris, S. (1986). Patterns of motivation and reading skills in underachieving children. In S. Ceci (Ed.), Handbook of cognitive, social, and neuropsychological aspects of learning disabilities (Vol. 2). Hillsdale, NJ: Erlbaum. Pennington, B. F. (2009). How neuropsychology informs our understanding of developmental disorders.The Journal of Child Psychology and Psychiatry, 50, 72–78. Pennington, B. F., McGrath, L. M., & Smith, S. D. (2009). Genetics of dyslexia: Cognitive analysis, candidate genes, comorbidities, and etiologic interactions. In T. Goldberg & D. R. Weinberger (Eds.), Genetics of cognitive neuroscience (pp. 177–194). Boston: MIT Press. Simos, P. G., Fletcher, J. M., Bergman, E., Breier, J. I., Foorman, B. R., Castillo, E. M., et al. (2002). Dyslexia-specific brain activation profile becomes normal following successful remedial training. Neurology, 58, 1203–1213. Simos, P. G., Fletcher, J. M., Sarkari, S., Billingsley, R. L., Castillo, E. M., Pataraia, E., et al. (2005). Early development of neurophysiological processes involved in normal reading and reading disability: A magnetic source imaging study. Neuropsychology, 19(6), 787–798. Torgesen, J. K. (2002). The prevention of reading difficulties. Journal of School Psychology, 40(1), 7–26. Torgesen, J. K., Wagner, R. K., & Rashotte, C. A. (1999). Test of word reading efficiency. Austin, TX: PRO-ED. Turkeltaub, P. E., Gareau, L., Flowers, D. L., Zeffiro, T. A., & Eden, G. F. (2003). Development of neural mechanisms for reading. Nature Neuroscience, 6(6), 767–773. VanDerHeyden, A. M., & Witt, J. C. (2005). Quantifying context in assessment: Capturing the effect of base rates on teacher referral and a problem-solving model of identification. School Psychology Review, 34(2), 161–183. Whitehurst, G. J., & Lonigan, C. J. (1998). Child development and emergent literacy. Child Development, 69, 335–357.

REDUPLICATIVE PARAMNESIA

identical looking imposter. RP differs from Capgras syndrome in that though the person believes that a place or person has been duplicated, there is no sense of replacement and therefore the imposter belief is not present. First described by Pick in 1903, RP is not a rare syndrome, as was once thought, with prevalence estimates of up to 8% in neurological patients (Hakim, Verma, & Greiffenstein, 1988; Murai, Toichi, Sengoku, Miyoshi, & Morimune, 1997). It is most commonly associated with traumatic brain injury (TBI) and stroke, particularly when there is simultaneous damage to the right cerebral hemisphere and to both frontal lobes. It is usually a transient phenomenon occurring in the acute to subacute stages of acquired brain injury. Although typically seen in acute TBI and stroke, this syndrome has been described in a variety of other neurologic conditions including intracerebral hemorrhages, tumors, dementias, encephalopathies, and various psychiatric conditions (Forstl, Almeida, Owen, Burns, & Howard, 1991). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Pick initially used the term RP to describe reduplicative beliefs in a patient presumed to have diffusely cortical neurodegenerative disease (Pick, 1903). Weinstein and Kahn (1955) described cases with nonspecific focal brain lesions and described a reduplicative phenomenon as a form of denial of illness expressed in metaphorical language. More recent research reflects a consensus that acute right hemisphere and bilateral frontal pathology are necessary and sufficient for RP to occur (Alexander, Stuss, & Benson, 1979; Benson, Gardner, & Meadows, 1976; Hakim et al., 1988; Makiko, Murai, & Ohigashi, 2003; Moser, Cohen, Malloy, Stone, & Rogg, 1998; Murai et al., 1997; Ruff & Volpe, 1981). Although many theories have been advanced to explain how these lesions could produce this syndrome, the specific pathophysiology is unknown. From a clinical point of view, RP is generally a transient phenomenon and should not be confused with more persistent neurobehavioral problems. Recovery of RP is noted in conjunction with postinjury recovery and resolution of acute and subacute neuropsychological and other deficits (Kapur, Turner, & King, 1988; Ruff & Volpe, 1981).

DESCRIPTION

Reduplicative paramnesia (RP) is the delusional belief that a place or location has been duplicated, existing in two or more places simultaneously, or that it has been ‘‘relocated’’ to another site. It is one of the delusional misidentification syndromes along with Capgras syndrome where an individual believes that a person, most often a loved one, has been replaced by an

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

No single neuropsychological deficit, such as amnesia, can fully explain the development and resolution of RP. Benson et al. (1976) outline how the right hemispheric dysfunction alters spatial coding of the environment and severe frontal dysfunction prevents

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recognition of this alteration. In addition, anosognosic tendencies or monitoring deficits in self-produced errors are likely to be a prerequisite of the syndrome, and contingencies in life history might determine the content of delusion. Further research including neuropsychological analysis highlights the frontal and right hemispheric involvement of RP. Patterson and Mack (1985) found that RP represents a combination of perceptual and memory deficits as well as impaired ability to integrate information. Consistent with this finding, Kapur et al. (1988) identified three sets of cognitive impairments noted in a case of RP including memory disturbance, visuospatial deficits with a significant degree of left-sided inattention, and impaired reasoning ability. Hakim et al. (1988) found that patients with RP showed selective deficits in spatial reasoning with relative sparing of verbal reasoning. Moser et al. (1998) found learning, memory and frontal-executive functions were deteriorated with or without RP, but these impairments were more severe after the onset of RP. Some select studies have provided neuropsychological data before and after recovery from RP, suggesting that resolution of RP coincided with at least partial recovery of the underlying neuropsychological impairments (Hakim et al., 1988; Kapur et al., 1988). DIAGNOSIS

It is important to note that RP is a sign or symptom of underlying neurologic disturbance, but it is not specific to any single diagnostic group. Identification of RP is based on observation and patient and collateral report of the reduplicative phenomenon. Follow-up interview and observation are valuable to document the persistence and eventual resolution of this misidentification syndrome in conjunction with objective neurocognitive measures.

Benson, D. F., Gardner, H., & Meadows, J. C. (1976). Reduplicative paramnesia. Neurology, 26, 147–151. Forstl, H., Almeida, O. P., Owen, A. M., Burns, A., & Howard, R. (1991). Psychiatric, neurological, and medical aspects of misidentification syndromes: A review of 260 cases. Psychiatric Medicine, 21, 905–910. Hakim, H., Verma, N. P., & Greiffenstein, M. F. (1988). Pathogenesis of reduplicative paramnesia. Journal of Neurology, Neurosurgery, and Psychiatry, 51, 839–841. Kapur, N., Turner, A., & King, C. (1988). Reduplicative paramnesia: Possible anatomical and neuropsychological mechanisms. Journal of Neurology, Neurosurgery, and Psychiatry, 51, 579–581. Makiko, Y., Murai, T., & Ohigashi, Y. (2003). Postoperative reduplicative paramnesia in a patient with a right frontotemporal lesion. Psychogeriatrics, 3, 127–131. Moser, D. J., Cohen, R. A., Malloy, P. F., Stone, W. M., & Rogg, J. M. (1998). Reduplicative paramnesia: Longitudinal neurobehavioral and neuroimaging analysis. Journal of Geriatric Psychiatry and Neurology, 11, 174–180. Murai, T., Toichi, M., Sengoku, A., Miyoshi, K., & Morimune, S. (1997). Reduplicative paramnesia in patients with focal brain damage. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 10, 190–196. Patterson, M. B., & Mack, J. L. (1985). Neuropsychological analysis of a case of reduplicative paramnesia. Journal of Clinical and Experimental Neuropsychology, 7, 11–21. Pick, A. 1903. Clinical studies: III. On reduplicative paramnesia. Brain, 26, 260–267. Ruff, R. L., & Volpe, B. T. (1981). Environmental reduplication associated with right frontal and parietal lobe injury. Journal of Neurology, Neurosurgery, and Psychiatry, 44, 387–391. Weinstein, E. A., & Kahn, R. L. (1955). Denial of illness: Symbolic and physiological aspects. Springfield, IL: Charles C. Thomas.

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TREATMENT

RP is typically a transient syndrome found in the acute to subacute stages of an acquired brain injury. Resolution of the reduplicative phenomena typically occurs across the natural course of brain injury recovery. Small doses of neuroleptics might be beneficial when RP is associated with sleep–wake cycle disturbance (Makiko et al., 2003). Mark T. Barisa Alexander, M. P., Stuss, D. T., & Benson, D. F. (1979). Capgras syndrome: A reduplicative phenomenon. Neurology, 29, 334–339.

DESCRIPTION

As the name suggests, repetitive movement disorders (RMDs), also known as repetitive motion disorders, are impairments in motor functions caused by repetitive activities (National Research Council and Institute of Medicine [NRCIM], 2001). Other terms that have been used to describe this syndrome include repetitive or cumulative trauma disorders, repetitive strain injuries, overuse syndrome, work-related disorders, and regional musculoskeletal disorders (NRCIM, 2001). Symptoms of the disorder tend to

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be pain in the area, typically a joint or multiple joints, associated with overuse. Occupations that require repetitive actions place workers at higher risk for RMDs. Prevalence rates of RMDs vary according to the specific type of RMD syndrome, and there is no clear evidence that race or sex differences exist (Hogan & Gross, 2003). The latter differences that are reported in the literature are thought to be largely due to occupation or activity selection rather than endogenous sex differences. Differences in prevalence rates based on age does exist with carpal tunnel syndrome being more common in middle age and trigger finger being more common in the 50s and 60s (Tallia & Cardone, 2003). In 1992, RMDs were responsible for 60% of all occupational illness, with an 880% increase of reported RMDs over the previous decade to approximately 44 cases per 10,000 workers (NRCIM, 2001). RMDs result in approximately $27 million and $45 million per year in the United States (NRCIM, 2001). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The pathophysiology of RMDs focuses on repetition of movement and may be exacerbated by motion that is unnatural or overextended, poor posture, or muscle fatigue (Beers & Berkow, 2002). Other etiologies include trauma, friction, and systemic degenerative diseases. The development of RMDs is from microscopic tears in the tissue (Hogan & Gross, 2003). Specifically, microtears may occur in the muscle fibers, nerve fibers, tendons, and ligaments, or compression of that tissue, resulting in inflammation and a sensation of pain. The most frequently noted injuries from repetitive movements are tendinitis and bursitis. Tendinitis is characterized by pain secondary to an inflamed tendon, which may be exacerbated by motion (Hogan & Gross, 2003). Typical tendinitis conditions include tennis elbow, golfer’s elbow, and damage to the bicep or rotator cuff region. Bursitis is characterized by pain, tenderness, and decreased range of motion, and the typical areas of impairment include the knee, elbow, and hip (Hogan & Gross, 2003). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The clinical presentation of RMDs includes pain, paresthesias (abnormal sensations), numbness, dyspraxia or motor weakness, impaired range of motion, popping or clicking in the joints, and swelling or redness in the associated area (Tallia & Cardone, 2003). For some individuals, no presence of injury may be

detected; however, performing basic and essential tasks may be difficult. There is no evidence of cognitive impairments associated with RMDs. DIAGNOSIS

Diagnosis of RMDs typically occurs from clinical evaluation followed by imaging — which may provide evidence of derangement or compression of the tissue (Beers & Berkow, 2002). Electromyography may be utilized to evaluate nerve conduction, whereas lab tests may be utilized to rule out diabetes, anemia, or a thyroid dysfunction. Psychological evaluation may be warranted to rule out job dissatisfaction or other psychosomatic etiology. Numerous variants of RMDs include bursitis and tendonitis, as well as presentations such as carpal tunnel syndrome, epicondylitis, ganglion cyst, tenosynovitis, and trigger finger (Tallia & Cardone, 2003). Bursitis and tendonitis may be difficult to differentiate and often coexist (Hogan & Gross, 2003). TREATMENT

Treatment for RMDs usually includes reducing or stopping the motions that cause the symptoms. This may include resting the affected area and implementing appropriate ergonomics. Appropriate warm-up prior to intense physical exertion may reduce the pain and swelling experienced. Applying ice on the affected area and utilizing anti-inflammatory medications or analgesics may alleviate some pain experienced. Splints may also be utilized to reduce pressure on nerves and muscles. Physical therapy may be prescribed to alleviate symptoms, and corrective surgery may be considered in extreme and intractable cases. Treatment outcomes for those with RMDs tends to be good with typically complete recovery; however, without treatment the injury may be permanent resulting in complete loss of function (Beers & Berkow, 2002). Changes in the manner in which one performs the movement may also reduce the chance of reinjury. Javan Horwitz Natalie Horwitz Chad A. Noggle Beers, M., & Berkow, R. (2002). Neurovascular syndromes: Carpal tunnel syndrome. In The Merck manual of diagnosis and therapy. Whitehouse Station, NJ: Merck Research Laboratories.

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Hogan, K., & Gross, R. (2003). Overuse injuries in pediatric athletes. Orthopedic Clinics of North America, 34, 405–415. National Research Council and Institute of Medicine. (2001). Musculoskeletal disorders and the workplace: Low back and upper extremities. Washington, DC: National Academy Press. Tallia, A., & Cardone, D. (2003). Diagnostic and therapeutic injection of the wrist and hand region. American Family Physician, 67, 745–750.

RESTLESS LEGS SYNDROME DESCRIPTION

Restless legs syndrome (RLS) is a neurological disorder that primarily affects the sensorimotor functions and involves a powerful urge to move the legs in response to an uncomfortable and unpleasant sensation (Pearson et al., 2008; Silber et al., 2004; Smith & Tolson, 2008; Thomas & Watson, 2008), seemingly related to psychiatric disorders. These uncomfortable symptoms of RLS are usually more intense in the evening or at night, though individuals with the disorder often report fewer or less severe symptoms with increased movement of the legs (Silber et al., 2004; Smith & Tolson, 2008; Thomas & Watson, 2008). The prevalence of RLS in the general population has been reported to be between 5% and 10% and it is generally more prevalent in women than in men (Sajita & Ondo, 2008; Smith & Tolson, 2008; Thomas & Watson, 2008). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The precise etiology of RLS is still unclear, though there is evidence that central dopaminergic dysfunction is one possibility of the cause of RLS symptoms (Smith & Tolson, 2008; Thomas & Watson, 2008). The pattern of RLS symptoms coincides with the circadian pattern of dopamine levels as evidenced by the symptoms being the worst at night, when dopamine levels are at their lowest. Furthermore, certain agents that block dopaminergic pathways can exacerbate the symptoms of RLS (Smith & Tolson, 2008; Thomas & Watson, 2008). The results of brain imaging studies are often conflicting, but some have shown abnormal dopamine receptor binding or dopamine hyperactivity in individuals with RLS (Smith & Tolson, 2008). Iron has also been shown to be a factor in the etiology of RLS (Smith & Tolson, 2008; Thomas & Watson, 2008). RLS symptoms can be triggered by the conditions associated with iron deficiency, as

studies have suggested that patients with RLS have lower iron levels in their brains compared to their control counterparts (Sajita & Ondo, 2008; Smith & Tolson, 2008). Studies have also supported a genetic component of RLS (Sajita & Ondo, 2008; Silber et al., 2004; Smith & Tolson, 2008; Thomas & Watson, 2008). A positive family history of RLS has been associated with a younger onset of symptoms (Sajita & Ondo, 2008) as well as increased risk for developing the disorder (NINDS, 2009). The concordance rates of RLS among monozygotic twin pairs range from 54% to 83%, further enhancing the argument that genetics is a factor in the etiology (Sajita & Ondo, 2008; Thomas & Watson, 2008). Genome-wide scans have led to the discovery of the first three genes that cause RLS; specifically: BTBD9, MEIS1, and MAP2K5/LBXCOR1. All these genes have been linked to 70% of genetic RSL cases (Sajita & Ondo, 2008). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

There are two forms of RLS: primary and secondary. The primary form is idiopathic, and the age of onset varies. In the secondary form, the symptoms of RLS are caused by another condition, which may include renal failure, iron deficiency, neuropathy, and normal pregnancy (Pearson et al., 2008; Smith & Tolson, 2008; Thomas & Watson, 2008). The two forms are similar in presentation; however, treatment for each form can be quite different. For instance, resolving the underlying condition of the secondary form of RLS may lead to the resolution of RLS symptoms (Smith & Tolson, 2008). Therefore, it is important to rule out other conditions when diagnosing RLS. According to a revision by the International RLS Study Group (IRLSSG) in 2003, there are four essential diagnostic criteria for RLS, all of which focus on sensory symptoms. The first criterion is an urge to move the legs, which is usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. The second criterion is that the urge to move or the unpleasant sensations begin, or worsen, during periods of rest or inactivity. The third criterion is relief, either partial or total, from the urge to move or unpleasant sensations for as long as the activity continues. The fourth criterion is that symptoms are worse, or only exclusively experienced, in the evening or night hours (Sajita & Ondo, 2008; Thomas & Watson, 2008). There are additional criteria that are not necessary for diagnosing RLS, but may help with differential diagnosis. Supportive criteria for an RLS diagnosis include periodic limb movements (PLMs), positive family history of RLS, and positive therapeutic response to

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dopaminergic drugs (Sajita & Ondo, 2008; Smith & Tolson, 2008; Thomas & Watson, 2008).

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DIAGNOSIS

The diagnosis of RLS involves examining the patient’s history as well as assessing the patient for the aforementioned symptoms. There are several procedures that could be utilized to exclude other causes for the symptoms and to identify signs of secondary RLS. Some suggested procedures include neurological examination, routine laboratory tests, and electromyographic evaluation (Sajita & Ondo, 2008). There are several conditions with symptoms similar to those of RLS and differential diagnoses for RLS include akathisia, peripheral neuropathy, peripheral vascular disease, and nocturnal leg cramps (Sajita & Ondo, 2008; Smith & Tolson, 2008; Thomas & Watson, 2008). TREATMENT

There are both nonpharmacological and pharmacological treatments for the symptoms of RLS, but there is currently no cure for the disorder. Nonpharmacological treatments can be utilized as the primary treatment for RLS or in conjunction with medication. These treatments include avoiding caffeine, alcohol, and nicotine; engaging in mentally challenging activities; and taking iron replacement. Continually, regular exercise, countersensory measures, and discontinuation of antihistamines have also been shown to be effective nonpharmacological treatments (Sajita & Ondo, 2008; Thomas & Watson, 2008). Dopaminergic drugs tend to be the pharmacological treatment of choice; levodopa (L-dopa) being the first of this type to be used effectively to treat RLS (Sajita & Ondo, 2008; Silber et al., 2004). The only U.S. FDA approved treatments for RLS are ropinirole and pramipexole, which are both dopamine agonists (Smith & Tolson, 2008). Other drug therapies that may be helpful include low-potency opioids, benzodiazepines, and antiepileptic drugs (Sajita & Ondo, 2008; Silber et al., 2004). Silber et al. (2004) developed an algorithm for the management of RLS symptoms by dividing patients into three groups: intermittent, daily, and refractory. In intermittent RLS, the symptoms are bothersome enough when present to require treatment, but do not occur frequently enough to necessitate daily therapy. On the contrary, symptoms in daily RLS are frequent and troublesome enough to require daily therapy. Refractory RLS is defined as daily RLS that is currently being treated with a dopamine agonist. This agonist results in one or more of the following outcomes: inadequate initial response despite adequate

doses, response that has become inadequate with time despite increasing doses, intolerable adverse effects, and/or augmentation that is not controlled with additional earlier doses of the drug. Amy Zimmerman Raymond S. Dean Pearson, V. E., Gamaldo, C. E., Allen, R. P., Lesage, S., Hening, W. A., & Earley, C. J. (2008). Medication use in patients with restless legs syndrome compared with a control population. European Journal of Neurology, 15, 12–17. Satija, P., & Ondo, W. G. (2008). Restless legs syndrome pathophysiology, diagnosis, and treatment. CNS Drugs, 22(6), 497–518. Silber, M. H., Ehrenberg, B. L., Allen, R. P., Buchfuhrer, M. J., Earley, C. J., Hening, W. A., et al. (2004). An algorithm for the management of restless legs syndrome. Mayo Clinic Proceedings, 79(7), 916–922. Smith, J. E., & Tolson, J. M. (2008). Recognition, diagnosis, and treatment of restless legs syndrome. Journal of American Academy of Nurse Practitioners, 20, 396–401. Thomas, K., & Watson, C. B. (2008). Restless legs syndrome in women: A review. Journal of Women’s Health, 17(5), 859–868.

RETT’S SYNDROME DESCRIPTION

Rett’s syndrome (RS) is a neurodevelopmental disorder of infancy almost exclusively affecting females. RS is characterized by severe regression of cognitive, motor, language, and social abilities between the age of 4 and 18 months, following a seemingly normal period of development. Hallmark features include stereotypic hand movements (hand wringing), microencephaly, and autistic-like behaviors. Prevalence ranges from 1:10,000 to 1:22,000 with diverse representation among the world population. The syndrome is named after Andreas Rett who, in 1966, first described its clinical features. NEUROPATHOLOGY/PATHOPHYSIOLOGY

RS is a genetic disorder caused by mutation on the X-linked MECP2 gene, and subsequent MeCP2 protein deficiency (Amir et al., 1999; Hagberg, 2002). The majority of cases occur sporadically; inherited cases are rare. Genotype–phenotype studies have identified different clinical abnormalities associated with

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different MECP2 mutations (Percy, 2008a; Zhang & Minassian, 2008). Studies to determine the specific neuropathology/neurophysiology of RS have found decelerated head growth starting at 3–6 months leading to microencephaly, decreased size of the dendrites of pyramidal neurons in the frontal and temporal lobes, and abnormalities in the substantia nigra. Neuropathology also involves the precentral gyrus, frontal cortex, superior temporal area, and parietal cortex (Brodmann areas 4, 45, 22 and 40). MRI findings have revealed atrophy in selective regions of gray and white matter in the prefrontal, frontal, and anterior temporal regions (Ibrahim & Khan, 2008; Pizzamiglio et al., 2008). EEG findings are characterized by the appearance of focal, multifocal, and generalized epileptiform abnormalities and the occurrence of theta activity in the frontal-central regions. Frequent seizure activity is reported; however, video EEG monitoring is critical because many apparent seizures are not correlated with EEG activity (Glaze, 2002). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

There are four clinical stages of RS (Hagberg, 2002): (1) early onset stage, between the age of 6 and 18 months, which involves subtle hypotonia with decreased sitting or crawling, beginning loss of eye contact, disinterest in toys, subtle hand wringing, and decreased head growth; (2) rapid destruction stage, between the age of 1 and 4 years, involving loss of purposeful hand movement; emergence of the characteristic hand wringing, clasping, or clapping; repetitive hand movements to the mouth; loss of communication; autistic-like, repetitive and stereotyped behaviors; irritability; emotional outbursts; and disturbed sleep; gait apraxia; and breathing abnormalities; (3) plateau or pseudo stationary stage, between the age of 2 and 10 years, involving epileptic seizures, with improvements in awareness, attention, communication skills, and emotional state; and (4) late motor deterioration stage, involving loss of ambulation in previous walkers, spasticity, muscle weakness, rigidity and stiffness, dystonia, and scoliosis, with improvements in eye gaze and hand wringing. Overall cognitive and functional abilities are profoundly impaired. Most persons with RS communicate through eye gaze and hand gestures rather than language. Global cognitive skills are generally developed to an age level equivalent to 9 months. Daily living abilities generally correspond with age of 12–14 months. Psychological and behavioral health features of RS include anxiety and panic, lack of interest in play, and self-injury that is mostly in the form of

hand-biting and face-hitting (Pizzamiglio et al., 2008). Survival through 10 years of age is typical, with at least 80% survival to the age of 20 years and 50% survival for those over the age of 50 years (Percy, 2008b). Sudden death has been described in RS. Although the specific cause of death is often unclear, it may well involve autonomic dysfunction or a cardiac conduction system abnormality. DIAGNOSIS

Specific guidelines are used in the clinical diagnosis of RS (Ben Zeev Ghdoni, 2007; Hagberg, Aicardi, Dias, & Ramos, 1983; Hagberg et al., 1985; Hagberg & Witt-Engerstrom, 1986; Hagberg & Skjeldal, 1994). Essential criteria include normal head circumference at birth and apparently normal development, followed by deceleration of head growth, loss of purposeful hand skills with repetitive hand movements, severely impaired expressive language, gait apraxia, and torso apraxia/ataxia between the age of 1 and 4 years. Supportive evidence is present in some RS cases, but is not necessary for the diagnosis. Such evidence includes seizures, EEG changes, epileptiform discharges, scoliosis, teeth grinding, breathing difficulties, muscle rigidity, spasticity, abnormal sleep patterns, chewing and swallowing difficulties, growth retardation, and poor circulation of the lower extremities with cold feet or hands. The presence of any one of the following exclusion criteria rules out a diagnosis of classic RS: microcephaly at birth, loss of vision due to retinal disorder or optic atrophy, acquired brain damage after birth, evidence of growth retardation in utero, metabolic disorders or acquired neurological disorder from severe infection or head trauma, or any other degenerative disorder. Differential diagnosis with autism is important (Mount, Charman, Hastings, Reilly, & Cass, 2003). Genetic testing can confirm a clinical diagnosis in 70% to 80% of RS cases. TREATMENT

Treatment interventions have focused on the alleviation of core medical symptoms through medication management of breathing difficulties, sleep problems, seizure disorder, and motor difficulties. Occupational therapy, physiotherapy, and hydrotherapy are used to assist individuals with self-directed activities and mobility (Ben Zeev Ghidoni, 2008). Music therapy has been shown to interrupt hand movements and sooth individuals, but only while treatment is in progress. Therapeutic horseback riding has promoted balance and created positive emotional states (Pizzamiglio

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et al., 2008). Cognitive rehabilitation has focused on improving visual-motor and communication skills. Shane S. Bush Donna Rasin-Waters

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Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., & Zoghbi, H. Y. (1999). Rett syndrome caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics, 23, 185–188. Ben Zeev Ghidoni, B. (2007). Rett syndrome. Child and Adolescent Psychiatric Clinics of North America, 16, 723–743. Glaze, D. G. (2002). Neurophysiology of Rett syndrome. Journal of Child Neurology, 20, 740–746. Hagberg, B., & Witt-Engerstrom, I. (1986). Rett syndrome: A suggested staging system for describing impairment profile with increasing age towards adolescence. American Journal of Medical Genetics, 26, 47–59. Hagberg, B., & Sjeldal, O.H. (1994). Rett variants: A suggested model for inclusion criteria. Pediatric Neurology, 1, 5-11. Hagberg, B. (2002). Clinical manifestations and stages of Rett syndrome. Mental Retardation and Developmental Disabilities, 8, 61–65. Hagberg, B., Aicardi, J., Dias, K., & Ramos, O. (1983). A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: Report of 35 cases. Annals of Neurology, 14, 471–479. Ibrahim, S., & Khan, S. G. (2008). Rett syndrome: A classic presentation. Journal of Pediatric Neurology, 6, 191–194. Mount, R. H., Charman, T., Hastings, R. P., Reilly, S., & Cass, H. (2003). Features of autism in RS and severe mental retardation. Journal of Autism and Developmental Disorders, 33, 435–442. Percy, A. K. (2008a). Rett syndrome: Recent research progress. Journal of Child Neurology, 23, 543–549. Percy, A. K. (2008b). Rett syndrome: From recognition to diagnosis to intervention. Retrieved April 28, 2009, from www.medscape.com/viewarticle/576129 Pizzamiglio, M. R., Nasti, M., Piccardi, L., Zotti, A., Vitturini, C., Spitoni, G., et al. (2008). Sensory-motor rehabilitation in Rett syndrome: A case report. Focus on Autism and Other Developmental Disabilities, 23, 49–62. Zhang, Y., & Minassian, B. A. (2008). Will my Rett syndrome patient walk, talk, and use her hands? Annals of Neurology, 70, 1302–1303.

severe, noninflammatory encephalopathy with altered levels of consciousness and transient liver dysfunction. Although specific etiology is unknown, onset of the disorder typically occurs after a prodromal disease (e.g., upper respiratory infection, chickenpox, gastroenteritis) has begun to improve. During the 1970s, RS was second only to encephalitis as the most fatal virus-related illness of the developing nervous system. Salicylate use has been linked to the development of RS; consequently, decreased use of aspirin seems to have resulted in a dramatic decrease in cases during the 1980s (Evans, 1998). In the United Sates, most cases are seen in the late fall and winter with geographic clustering. Widespread outbreaks have been associated with influenza epidemics. Affected children are predominantly White; the disease is uncommon among Black children. There is no sex difference. Mortality has been estimated at approximately 30%; however, if the child survives the acute stage of the illness with no or low-grade coma, the long-term neurological consequences are limited. NEUROPATHOLOGY/PATHOPHYSIOLOGY

RS is almost exclusively a disorder of childhood. There is some evidence to suggest that RS is linked to the use of salicylates in children suffering from chickenpox. During the 1980s, research in the United Kingdom linked the occurrence of RS to aspirin exposure (Soumerai et al., 2002). Similar findings have also been found in French studies. Epidemiological research has linked the presentation most commonly with influenza A, influenza B, and varicella-zoster. Little is known or understood with regard to specific neuropathology of the syndrome. Nevertheless, the most salient evidence suggests a multiorgan etiology secondary to diffuse mitochondrial injury — itself of unknown origins (DeVivo, 1978; VanCoster et al., 1991). This has been proposed as histological damage and has been noted in mitochondria in the liver (e.g., hepatocytes) and the pancreas as well as cardiac and skeletal muscle fibers (Gascon, Ozand, & Cohen, 2007). Neurologically, similar damage has been noted in neurons and brain capillary endothelial cells. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

REYE’S SYNDROME DESCRIPTION

Reye’s syndrome (RS), first identified in 1963, is predominantly a childhood disease characterized by

During the prodrome phase of the disease, symptom presentation may correspond with the potential etiological disease (e.g., influenza A, B, or, varicellazoster). Upper respiratory infection is commonly seen as is vomiting. The latter has been proposed as a potential feature of brainstem involvement as the onset is sudden and often unremitting even in the face of

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pharmacological intervention that is often useful in halting such features when occurring secondary to systemic illness. In many instances, patients will recover and not progress beyond these features. However, in some instances symptoms worsen with the child soon developing prominent restlessness, disorientation, dysautonomia, tachycardia, sweating, and dilated pupils (Gascon et al., 2007). For those that progress beyond this presumed second stage, coma usually develops and seizures present in over 50% of patients in stage 3, followed by cerebrate posturing and respiratory dysfunction in stage 4, and ‘‘deeper’’ coma in stage 5 with no response to painful stimuli and absence of brainstem reflexes (Gascon et al., 2007). Upon recovery, the liver resumes functioning within normal limits; however, the secondary complications can cause long-term changes in cortical functioning. The majority of children who manifest mild levels of the disease and see remission prior to stage 3 appear to experience no long-term neurological sequelae (Hartlage et al., 1980). However, follow-up with survivors of coma grades III and IV have demonstrated the potential for psychomotor retardation, subtle perceptual difficulties, mental retardation, hyperactive disorder, and seizures (Preston et al., 1982). Emotional disturbance related to the onset of these permanent changes in the child’s functioning should be expected. DIAGNOSIS

RS is suspected in any child exhibiting sudden onset of coma and accompanying liver dysfunction. Clinical diagnosis is made when criteria outlined by the Centers for Disease Control are present. These include a prodromal illness, acute onset of vomiting 3–7 days after the onset of the prodromal illness, extreme changes in blood serum levels of glutamic-oxaloacetic transaminase (SGOT) and glutamic-pyruvic transaminase (SGPT) or serum ammonia concentrations, and microvesicular fatty deposits in the tissues, particularly the liver. Although laboratory findings are not diagnostic, they are essential for systemic care and consideration. Common findings include: (1) alanine aminotransferase and aspartate aminotransferase levels 20–30 times higher than normal once vomiting commences, (2) ammonia levels three times higher than normal at onset of coma, (3) increased lactic and organic acids due to respiratory and metabolic acidosis, (4) diffuse EEG slowing that is common in encephalopathic presentations, and (5) diffuse cerebral edema and ventricular compression on CT or MRI (Gascon et al., 2007). As noted, lethargy, combativeness, and/or coma are the most obvious physical signs. Depth and rate of

progression of coma appear to be related to prognosis. As the prodromal illness abates and vomiting commences, some patients remain at the ‘‘mild’’ stage of RS with lethargy but no loss of consciousness. Other patients experience a more severe stage of RS that involves a deep comatose state. Seizure activity may occur in patients experiencing deeper comas. Encephalopathy may persist from 1 to 4 days with gradual neurological improvement. Few, if any, long-term effects have been reported among survivors who exhibited mild stages of RS (i.e., no coma). Permanent neurological deficits have been linked with deeper comatose states. TREATMENT

Early recognition of the possibility of RS, before the development of serious neurological signs, is recommended. Indeed, avoiding the use of aspirin with children has dramatically cut the incidence of RS. Children who present with vomiting after a respiratory infection or chickenpox should be considered at high risk for RS. A physical, including measurement of blood serum levels of SGOT or SGPT, should be completed. If serum levels show SGOT or SGPT elevations greater than three times normal, hospitalization is indicated. Although no standard treatment regimen exists, hyperventilation and dehydrating agents (e.g., mannitol) have been used to reduce cerebral edema; intravenous administration of vitamin K and glucose are designed to correct liver dysfunction. If coma is present, a lumbar puncture is indicated to exclude the possibility of infection. A percutaneous liver biopsy will positively diagnose RS. For those children with no secondary complications from coma, no intervention other than treatment of the disease may be mandated. However, coma survivors and their families may need supportive services to adjust to their altered level of functioning. Counseling may address the anger and frustration felt with perceptual-motor and/or cognitive changes. Modifications of expectations both of the family and the educational system may need to be addressed. Depending upon the type of sequelae present, occupational therapy/physical therapy services and medication may also be required. Matthew Holcombe Raymond S. Dean Chad A. Noggle DeVivo, D. C. (1978). Reye’s syndrome: A metabolic response to an acute mitochondrial insult? Neurology, 28, 105–108.

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Evans, J. (1998). Reye’s syndrome. Health-related disorders in children and adolescents: A guidebook for understanding and educating (pp. 558–563). Washington, DC, US: American Psychological Association. Gascon, G. G., Ozand, P. T., & Cohen, B. H. (2007). Aminoacidopathies and organic acidopathies, mitochondrial enzyme defects, and other metabolic errors. In C. G. Goetz (Ed.), Textbook of neurology (3rd ed., pp. 641– 682). Philadelphia: Saunders Elsevier. Hartlage, L., Stovall, K., & Hartlage, P. (1980). Age related neuropsychological sequelae of Reye’s Syndrome. Clinical Neuropsychology, 2(2), 83–85. Preston, G., Sarnaik, A., & Nigro, M. (1982). Transient intellectual and psychosocial regression during recovery phase of stage V Reye’s syndrome.Journal of Developmental and Behavioral Pediatrics, 3(4), 206–208. Soumerai, S., Ross-Degnan, D., & Kahn, J. (2002). The effects of professional and media warnings about the association between aspirin use in children and Reye’s syndrome. In R. C. Hornik (Ed.) Public health communication: Evidence for behavior change (pp. 265–288). Mahwah, NJ US: Lawrence Erlbaum Associates Publishers. Van Coster, R. N., DeVivo, D. C., Blake, D., Lombes, A., Barrett, R., & DiMauro, S., et al. (1991). Adult Reye’s syndrome: A review with new evidence for a generalized defect in intramitochondrial enzyme processing. Neurology, 41, 1815–1821.

RHEUMATOID ARTHRITIS DESCRIPTION

Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that affects the connective tissues of the body (Akil & Amos, 1995; American College of Rheumatology [ACR], 2002; National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS], 2004). Often confused with osteoarthritis (OA), RA is a systemic disorder with symptoms including pain, swelling, stiffness, fatigue, muscle weakness, weight loss, anemia, occasional fevers, and loss of function in the joints (NIAMS, 2004). Symptoms wax and wane and may last only a few months without longterm damage. Some mild or moderate cases can have periods of severe symptoms, flares, and times when symptoms subside. In other cases, the symptoms remain active, last many years or a lifetime, and cause severe joint damage (NIAMS, 2004). RA is the most common inflammatory arthritis (Akil & Amos, 1995; Emery et al., 2002). It occurs

two to three times more frequently in women than in men, with an overall national prevalence of 2.1 million people, or approximately 1% of the adult population according to NIAMS. The disease usually begins in middle age and occurs more frequently in older populations, though children and young adults are also susceptible (NIAMS, 2004; Rindfleisch & Muller, 2005). Symptoms tend to decrease during pregnancy and flare up after childbirth (Akil & Amos, 1995; NIAMS, 2004). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Although the etiology of RA is not entirely understood, research often shows an interaction between environment and genetics (Akil & Amos, 1995; Rindfleisch & Muller, 2005). Researchers also believe an infection can be a likely cause, though the exact agent is not yet clear (NIAMS, 2004). Based on symptomatic changes during pregnancy, researchers are also hypothesizing that hormones may be a factor. Specifically, the tumor necrosis factor-alpha (TNF) and the immune system molecules interleukin 12 (IL-12) change along with hormone levels, possibly contributing to swelling and tissue damage (NIAMS, 2004). Joints of the hands and feet are usually the first areas to experience difficulties associated with RA. Symptoms generally occur in a symmetrical pattern; therefore, if one hand is affected, the other is also affected (NIAMS, 2004). Gradually, wrists, knees, and/or shoulders can become affected. Before prominent symptoms develop, the person may experience coolness of hands and feet as well as numbness and tingling, as these are signs of compression of the vasomotor nerve. Symptoms tend to appear over a period of weeks to months and usually begin in a single joint. The most frequently affected joints are those with the highest ratio of synovium to articular cartilage (Rindfleisch & Muller, 2005). The inflammation of the delicate anatomy of the joints is often the cause of redness, swelling, and pain in patients with RA. Joints are protected and surrounded by capsules and these capsules are lined with tissue called synovium. Synovium produces fluid that lubricates the joints and when the synovium becomes inflamed as a result of RA, the above mentioned symptoms occur (NIAMS, 2004). Prolonged inflammation can cause irreversible damage to the joint capsule and cartilage, and scar-like tissue called pannus may develop. Pannus can cause joints to become fixed in place (ankylosed) and may cause displacement and deformity of the joints. Continually, tissues near the joints, such as skin, bones, cartilage,

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ligaments, and muscles, can suffer from atrophy from the disuse (NIAMS, 2004). Osteoporosis can occur from generalized bone loss due to damaging consequences of RA (Akil & Amos, 1995; NIAMS, 2004). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Daily suffering is a likely product of RA, including constant pain. In some instances, RA can negatively affect daily routines and tasks of family life and decrease employment opportunities. Some people experience feelings of helplessness, anxiety, and depression related to the disease (NIAMS, 2004). Research indicates patients with RA in combination with a history of multiple episodes of depression experience more chronic pain and also tend to be more vulnerable to stress-related pain (Zautra et al., 2007). Consequently, both chronic pain and depression have been linked with difficulties in select domains of memory, attention, visuospatial ability, processing speed, and executive functioning on a day-to-day basis but not necessarily secondary to a neurological origin. DIAGNOSIS

In the early stages, RA is often difficult to diagnose, as the symptoms vary from case to case. Symptoms may be similar to other types of arthritis and joint conditions and thus other conditions need to be ruled out. Physician and rheumatologists use a variety of methods to diagnose RA and rule out other conditions. A patient’s medical history and description of the symptoms is imperative for the initial assessment. A physical examination includes examination of the joints, reflexes, and muscle strength. Furthermore, X-rays can be helpful as the disease progresses to determine the severity of joint deterioration (NIAMS, 2004). Blood tests are often used to help in diagnosing because many people with RA have autoantibodies in their blood called rheumatoid factors (NIAMS, 2004). These autoantibodies indicate that an autoimmune reaction is part of the disease process. An autoimmune reaction attacks the body’s own tissues, and an antibody is a protein that usually helps the body fight foreign substances (NIAMS, 2004). The rheumatoid factor is not detected in everyone diagnosed with RA, and it is especially difficult to detect in the early stages of the disease. In addition, some people who test positive for rheumatoid factor will never develop clinical symptoms of the disease (NIAMS, 2004).

Possible causes of positive test results for rheumatoid factor include other connective tissue diseases, viral infections, leprosy, liver disease, and tuberculosis (Akil & Amos, 1995). Physicians also utilize other laboratory tests when diagnosing, including a white blood count, a test for anemia, and an erythrocyte sedimentation rate test. An erythrocyte sedimentation rate measures inflammation of the body (NIAMS, 2004). An increased erythrocyte sedimentation rate and the presence of acute phase proteins are often found in patients with RA (Akil & Amos, 1995). RA must be differentiated from several disorders. These include scleroderma, lupus, fibromyalgia, infectious endocarditis, polyarticular gout, polymyalgia rheumatica, reactive arthritis, Still disease, thyroid disease, and psoriatic arthritis (Akil, & Amos, 1995; Rindfleisch & Muller, 2005). TREATMENT

Deterioration of the joints can occur within a few weeks of the onset of symptoms, thus early treatment is encouraged. Early treatment can decrease the rate of disease progression and improve the outcome and quality of life (ACR, 2002; Emery et al., 2002). Physicians and rheumatologists use a variety of treatments for RA, but the goals of treatment are to slow or stop joint deterioration, alleviate pain, and reduce inflammation, as there is no known cure for the disease (ACR, 2002; NIAMS, 2004). In treating symptoms of RA, medications can be used for pain relief and inflammation reduction. Taking disease modifying antirheumatic drugs (DMARDs) during the early stages can lessen joint damage (ACR, 2002; Emery et al., 2002). DMARDs are used to slow the course of the disease (NIAMS, 2004) and should be considered for all patients with RA (Rindfleisch & Muller, 2005). Furthermore, combinations of DMARDs can be more effective than single-drug prescriptions. Women of childbearing age should take precautions when taking DMARDs, as they can be harmful to fetuses (Rindfleisch & Muller, 2005). Other treatments considered include nonpharmacological interventions such as rest and exercise, stress reduction, and healthy diet (ACR, 2002; NIAMS, 2004). Splints and other orthopedic appliances are used to prevent or correct deformity of the joints, and physical therapy helps alleviate pain and swelling (ACR, 2002). Different types of surgeries are available to correct severe joint damage. Joint replacement, tendon reconstruction, and synovectomies are some common procedures. A synovectomy is the removal of inflamed synovial tissue, but is rarely performed

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since the tissue will eventually grow back by itself (ACR, 2002; NIAMS, 2004).

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Andrea Stephen Raymond S. Dean Akil, M., & Amos, R. S. (1995). Rheumatoid arthritis — I: Clinical features and diagnosis. British Medical Journal. (International edition), 310(6979), 587. American College of Rheumatology. (2002). Guidelines for the management of rheumatoid arthritis. Arthritis & Rheumatis, 46(2), 328–346. Emery, P., Breedveld, F. C., Dougados, M., Kalden, J. R., Schiff, M. H., & Smolen, J. S. (2002). Early referral recommendation for newly diagnosed rheumatoid

arthritis: Evidence based development of a clinical guide. Annals of the Rheumatic Diseases, 61, 290–297. National Institute of Arthritis and Musculoskeletal and Skin Diseases. (2004). Rheumatoid arthritis. Retrieved March 13, 2009, from http://purl.access.gpo.gov/ GPO/LPS80325 Rindfleisch, J. A., & Muller, D. (2005). Diagnosis and management of rheumatoid arthritis. American Family Physician, 72(6), 1037–1047. Zautra, A. L., Parrish, B. P., Van Puymbroeck, C. M., Tennen, H., Davis, M. C., Reich, J. W., et al. (2007). Depression history, stress, and pain in rheumatoid arthritis patients. Journal of Behavioral Medicine, 30(3), 187–197. Retrieved March 14, 2009, from ProQuest Nursing & Allied Health Source database. (Document ID: 1291750991).

S SANDHOFF’S DISEASE DESCRIPTION

Sandhoff’s disease is a rare and progressive genetic lysosomal storage dysfunction that leads to delayed myelination or demyelination of the central nervous system (CNS; Alkan et al., 2003; McKusick, 1998; Van der Kaamp & Valk, 1995). The disorder was first described and studied by Sandhoff, Andreae, and Jatzkewitz (1968); however, a series of subsequent studies allowed distinguishing the disorder’s specific types and their clinical symptomatology (GM2gangliosidoses variant 0; hexosaminidases A and B deficiency; hexosaminidases B deficiency; Sandhoff– Jatzkewitz–Pilz disease; total hexosaminidase deficiency; Sandhoff’s disease, infantile type; Sandhoff’s disease, juvenile type; Sandhoff’s disease adult type; McKusick, 1998). The most common form of Sandhoff’s disease manifests in infancy at approximately 3–6 months of age. The first symptoms include slow motoric and cognitive development and muscle weakness. Affected infants may lose voluntary motor skills (i.e., turning over, sitting, and crawling) and develop an exaggerated startle reaction. As the disease progresses, children with Sandhoff’s disease develop seizures, vision and hearing loss, intellectual disability, paralysis, and eventual death around age of 3. Other forms of Sandhoff’s disease, which tend to be less common, affect individuals in childhood, adolescence, or adulthood and are usually milder than Sandhoff’s infantile form (McKusick, 1998; National Institute of Health [NIH], 2009). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Sandhoff’s disease is an inherited disorder of sphingolipid metabolism characterized by an autosomal recessive pattern of inheritance. In Sandhoff’s disease, genetic mutations in the hexosaminidase beta-chain gene result in a hexosaminidase A (alpha beta) and B (beta beta) deficiency (Arfi et al., 2006; Caliskan, Ozmen, Beck, & Apak, 1993). The deficiency further

leads to the inactivity of hexosaminidase enzymes and the intracellular accumulation of GM2 ganglioside in lysosomes (Alkan et al., 2003; Yuksel, Yalcinkaya, Islak, Gunduz, & Seven, 1999). Eradication of the intracellular accumulation of lysosomal enzyme substrates, ganglioside GM2, and other glycolipids is not possible in Sandhoff’s disease (Kroll et al., 1995; Yuksel et al., 1999), and the genetic lysosomal storage impairment leads to delayed myelination or demyelination of the CNS (Alkan et al., 2003) causing a number of coordination, muscle control, and cognitive deficits. In addition to the widespread demyelination, the condition results in neuroaxonal loss, and anaerobic metabolism, affecting both white matter and grey matter (Alkan et al., 2003). Neuroimaging studies suggest that acute forms of Sandhoff’s disease result in homogeneous thalamic hyperdensity, mild cortical atrophy, a thin corpus callosum, and abnormal signal intensities in the caudate nucleus, globus pallidum, putamen, cerebellum, and brainstem (Yuksel et al., 1999). In some cases, signs of heart impairment, such as heart murmur and cardiomegaly, are present before the neurologic deterioration (Krevit et al., 1972). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Onset of Sandhoff’s disease usually occurs no earlier than 6 months of life, and the disease is not limited to any ethnic group. It is characterized by rapid progressive neurodegeneration; however, the symptoms differ depending upon the type of genetic mutation and time of onset. Sandhoff’s disease is generally classified into three main forms: infantile, juvenile, and adult, all referring to the onset of the condition. The infantile form of Sandhoff’s disease, the most common and acute form of the disease, is characterized by relatively early onset and appears in the first 6–18 months of life. Main clinical features include motor weakness and progressive motor retardation, exaggerated startle reactions to sound, early blindness, progressive mental deterioration, macrocephaly (an abnormally enlarged head), macular red cherry spots in the eyes, seizures, and myoclonus (shock-like contractions of a muscle).

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Other symptoms may include frequent respiratory infections, doll-like facial appearance, and an enlarged liver and spleen (Alkan et al., 2003; Yuksel et al., 1999). Although the life expectancy differs depending upon the severity of the condition, it typically leads to death by 3 years of age (Alkan et al., 2003). The juvenile form of Sandhoff’s disease is considered milder than the infantile form, with onset that occurs after the period of infancy and before adulthood. It is characterized by muscle weakness, hyperflexia of lower extremities, and impaired thermal sensitivity. In addition, impaired sexual functions, urinary incontinence, and postural dizziness are commonly reported (Neote, Brown, Mahuran, & Gravel, 1992). Juvenile Sandhoff’s may also be associated with mental retardation (Wakamatsu, Kobayashi, Miyatake, & Tsuji, 1992) and/or spinal muscular atrophy (Banerjee et al., 1991). Individuals affected with this form of the disease tend to survive to late adulthood (McKusick, 1998). The adult type has a less pronounced presentation as compared to other forms of Sandhoff’s disease. It is usually discovered later in life (i.e., in the early 30s), and the symptoms can include slowly progressive weakness of lower extremities and diffuse fasciculations. These symptoms may be further accompanied by moderate reduction in strength, widespread spontaneous fasciculations, and hyperactive deep tendon reflexes. Cognitive functioning tends to be unaffected (Gomez-Lira et al., 1995). Sandhoff’s disease is often confused and has similar presentation to Tay–Sachs’s disease. Unlike Tay–Sachs’s disease, which is characterized by the deficiency of hexosaminidases A, Sandhoff’s disease is known for the lack of hexosaminidases A and B; thus, the differentiation between the diseases is usually conducted through biochemical analysis and the activity measurement of the two hexosaminidase enzymes (McKusick, 1998). DIAGNOSIS

For a child to suffer from Sandhoff’s, both parents must be carriers and both must transmit the genetic mutation to the child. Thus, if both parents have the mutation, there is 25% chance their child will inherit the condition. Frequently, parents are given the opportunity to have a DNA screening if they are at high risk to determine their carrier status before they have children. The diagnosis of Sandhoff’s disease can be conducted both prenatally and after birth. Prenatal diagnosis of Sandhoff’s disease (infantile onset) is possible at about 16 weeks gestation through the detection and analysis of N-acetylglucosaminyl-

oligosaccharides in amniotic fluid and using high performance liquid chromatography (Warner, Turner, Toone, & Applegarth, 1985). Before the condition becomes apparent through physical examination, postnatal diagnosis can be conducted through the following procedures: a biopsy removing a sample of tissue from the liver, genetic testing, molecular analysis of cells and tissues (to determine the presence of a genetic metabolic disorder), enzyme essay, and occasionally a urinalysis to determine if the above-noted compounds are abnormally stored within the body. TREATMENT

There is no definitive or specific treatment for Sandhoff’s disease other than supportive therapy (Alkan et al., 2003), including proper nutrition and hydration. In order to prevent breathing problems, it is often recommended to keep the airway open. Anticonvulsants may help to control seizures. Generally, the development of treatment or cure of the Sandhoff’s disease, and other lysosomal storage diseases that affect the CNS, is extremely challenging. Due to the limitations imposed by the blood–brain barrier, the enzyme replacement therapy is not a feasible option (Arfi et al., 2006). In some ongoing clinical studies, a small number of affected children have received an experimental treatment using transplants of stem cells from umbilical cord blood. Other investigated treatment possibilities include gene therapy. Gene therapy, which is based on the ability of genetically modified calls to overexpress a particular enzyme, aims at restoring normal cellular metabolism (Arfi et al., 2005, 2006). Although the trials have not yet produced a treatment or cure, scientists continue to study these and other investigational approaches with a hope for cure or effective treatment (NIH, 2007). Anya Mazur-Mosiewicz Raymond S. Dean Alkan, A., Kutlu, R., Yakinci, C., Sigirci, A., Aslan, M., &, Sarac, K. (2003). Infantile Sandhoff’s disease: Multivoxel magnetic resonance spectroscopy findings. Journal of Child Neurology, 18, 425–428. Arfi, A., Bourgoin, C., Basso, L., Emiliani, C., Tancini, B., Chigomo, V., et al. (2005). Bicistronic lentiviral vector corrects -hexosaminidase deficiency in transduced and cross-corrected human Sandhoff fibroblasts. Neurobiology of Disease, 20, 583–593. Arfi, A., Zisling, R., Richard, E., Batista, L., Poenaru, L., Futerman, A. H., et al. (2006). Reversion of the

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biochemical defects in murine embryonic Sandhoff neurons using a bicistronic lentiviral vector encoding hexosaminidase alpha and beta. Journal of Neurochemistry, 6, 1572–1579. Caliskan, M., Ozmen, M., Beck, M., & Apak, S. (1993). Thalamic hyperdensity: Is it a diagnostic marker for Sandhoff disease. Brain and Development, 15, 387–388. Gomez-Lira, M., Sangalli, A., Mottes, M., Perusi, C., Pignatti, P. F., Rizzuto, N., et al. (1995). A common beta hexosaminidase gene mutation in adult Sandhoff disease patients. Human Genetics, 96, 417–422. Krivit, W., Desnick, R. J., Lee, J., Moller, J., Wright, F., Sweeley, C. C., et al. (1972). Generalized accumulation of neutral glycosphingolipids with GM2 ganglioside accumulation in the brain. Sandhoff’s disease (variant of Tay-Sachs disease). American Journal of Medicine, 52, 763–770. Kroll, R. A., Pagel, M. A., Roman-Goldstein, S., Barkovich, A. J., D’Agostino, A. N., & Neuwelt, E. A. (1995). White matter changes associated with feline GM2 gangliosidosis (Sandhoff disease): Correlation of MR findings with pathologic and ultrastructural abnormalities. American Journal of Neuroradiology, 16, 1219–1226. McKusick, V. A. (1998). Mandelian inheritance in man: A catalog of human genes and genetic disorders (12th ed.). Baltimore: The John Hopkins University Press. National Institutes of Health. (2009). Sandhoff disease. Retrieved February 21, 2009, from http://ghr.nlm.nih. gov/condition ¼ sandhoffdisease Neote, K., Brown C. A., Mahuran, D. J., & Gravel, R. A. (1991). Translation initiation in the HEXB gene encoding the beta-subunit of human beta-hexosaminidase. Journal of Biological Chemistry, 265, 20799–20806. Sandhoff, K., Andreae, U., & Jatzkewitz, H. (1968). Deficient hexozaminidase activity in an exceptional case of Tay-Sachs disease with additional storage of kidney globoside in visceral organs. Life Sciences, 7(6), 283–288. Van der Kaamp, M. S., & Valk, J. (1995). GM, gangliosidosis. In M. S. Van der Kaamp & G. M. Valk (Eds.), Magnetic resonance of myelin, myelination, and myelin disorders (Vol. 10, 2nd ed., pp. 81–89). Berlin, Germany: Springer Verlag. Wakamatsu, N., Kobayashi, H., Miyatake, T., & Tsuji, S. (1992). A novel exon mutation in the human beta-hexosaminidase beta subunit gene affects 3’ splice site selection. Journal of Biological Chemistry, 267, 2406–2413. Warner, T. G., Turner, W., Toone, J., & Applegarth, J. (1985). Prenatal diagnosis of infantile GM 2 gangliosidosis type II (Sandhoff disease) by detection of N-acetylglucosaminyloligosaccharides in amniotic fluid with high-performance liquid chromatography. Prenatal Diagnosis, 6, 393–400. Yuksel, A., Yalcinkaya, C., Islak, C., Gunduz, E., & Seven, M. (1999). Neuroimaging findings of four patients with Sandhoff disease. Pediatric Neurology, 21, 562–565.

SCHILDER’S DISEASE S DESCRIPTION

Schilder’s disease, also known as diffuse myelinoclastic sclerosis, is a rare demyelinating disease most commonly found in children. It is primarily characterized by dementia, poor attention, aphasia, tremors, balance instability, personality changes, incontinence, muscle weakness, headaches, vomiting, speech impairment, cortical blindness, signs of intracranial pressure, and psychiatric disturbances (Afifi, Follett, Greenlee, Scott, & Moore, 2001). Schilder’s disease is a progressive disease of the central nervous system, considered to be a variant of multiple sclerosis. Affecting males and females equally, the average age of onset is between 5 and 10 years of age. The onset of the disease is abrupt and commonly followed by a rapid deterioration of overall health. Death often occurs within months to years after onset (Kotil, Kalayci, Koseoglu, & Tugrul, 2002). Schilder’s disease was first termed in 1912 by Paul Schilder. Originally, however, the term was used to describe three separate diseases: adrenoleukodystrophy, subacute sclerosing panencephalitis, and myelinoclastic diffuse sclerosis (Poser, Goutieres, Carpentier, & Aicardi, 1986). Schilder’s disease was used to describe several demyelinating disorders of differing etiologies until eventual diagnostic criterion was created in 1985. The development of clinical diagnostic criteria limited the term to solely include instances consistent with subacute or chronic myelinoclastic diffuse sclerosis and the formation of at least one large plaque. Developed criteria made the term Schilder’s disease less ambiguous and emphasized clear criteria that distinguished myelinoclastic sclerosis from the original group of diseases that were incorporated under the same name. Diagnosis is difficult and one that is made by exclusion. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Neuroimaging techniques may reveal variable characteristics of Schilder’s disease. Specifically, imaging techniques may reveal large, focal lesions located in the parieto-occipital regions of the brain. Images that are indicative of the disease are those that present with an overall sparing of the brainstem, ring enhancement that is incomplete, both brain hemispheres that are generally involved equally and, lastly, images that are diffusion weighted, have a low signal, and a minimal mass effect (Canellas, Gols, Izquierdo, Subirana,

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& Gairin, 2007). The CT image will often reveal large bilateral or unilateral lesions of the white matter that are predominately within the centrum semiovale. However, there is not a specific neuroimaging pattern that is characteristic of Schilder’s disease (Afifi et al., 2001). The supratentorial lesions in the centrum semiovale that are large and spherical often mimic tumors, but they are able to be recognized and classified as a demyelinating disease due to the absence of mass effect and edema that is displayed through CT images (Garell et al., 1998). Overall, lesions of Schilder’s disease are distinctly outlined, large, and play a major role in the destruction of the myelin. Lesions typically involve an entire cerebral hemisphere and are often large enough to extend across the corpus callosum to the opposing hemisphere (Kotil et al., 2002). Lesions that are consistent with multiple sclerosis are often detected through examination of the spinal cord, brainstem, and optic nerves. The demyelination of white matter, microglial proliferation with fibrillar gliosis, a single focus that is large, and lymphocytic perivascular infiltrate are histological characteristics of multiple sclerosis that often present in Schilder’s disease (Kotil et al., 2002). White matter involvement generally becomes widespread and, as a result, various neurological deficits become apparent. The underlying neuropathology of Schilder’s disease is apparent through the neurological deficits that are associated with its presentation. In severe cases, progressive deterioration may present with dementia, bowel and bladder dysfunction, as well as papilledema. Increased cranial pressure is characteristic of the pseudotumoral type; the polysclerotic type will involve a progression that is consistent with multiple sclerosis. Lastly, a psychiatric form of the disease will present itself as mainly psychiatric symptoms, with major deficits in visual loss, including cortical blindness and hemianopia (Afifi et al., 2001). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Neuropsychological aspects of Schilder’s disease include the presence of aphasia, ataxia, hemiplegia, progressive dementia, memory disturbances, confusion, irritability, disorientation, and changes in personality. Increasing symptoms occur with the progression of the disease, and with the deterioration of the myelin. As the disease progresses effects of damage to the brainstem and cerebellum are apparent through the development of vertigo, dysarthria, dysphagia, and often paralysis of eye movement (Afifi et al., 2001). Diagnosis of the disease following the initial clinical presentation involves electoencephalogram (EEG), MRI, lumbar puncture, and

brain biopsy. It is a diagnosis made by exclusion; that is, all other possibilities must be ruled out before Schilder’s disease can be diagnosed. Neuropsychological assessment measures are not included in the diagnostic process. However, neuropsychological assessment of cognitive decline may reveal deficits similar to that of multiple sclerosis (NINDS, 2008). DIAGNOSIS

The common presentation of Schilder’s disease often appears similar to that of acute disseminated encephalomyelitis (ADEM), tumor, abscess, amyotrophic leukodystrophy (ALD), and multiple sclerosis. Appropriate diagnosis must include a histological assessment, biopsy, neuroimaging, laboratory tests, and history due to the commonality between diseases. Onset, duration of illness, co-occurring psychiatric disorders, history of previous treatment, family history, history of vaccinations, and viral infections are essential features that should be included in the appropriate assessment and diagnosis of Schilder’s disease (Garrell et al., 1998). Multiple sclerosis will present with abnormal immunoglobulin in the cerebral spinal fluid, which differentiates from Schilder’s disease in that there are no abnormalities of immunoglobulin in Schilder’s disease. Large areas of demyelination within the centrum semiovale are characteristic of Schilder’s disease that is different than the confluent and periventricular plaques that involve infratentorial and supratentorial structures of multiple sclerosis. Outside of the demyelinating lesions of Schilder’s disease, the brain will appear normal on an MRI, which is not characteristic of multiple sclerosis (Afifi et al., 2001). Schilder’s disease may also appear similar to a cerebral tumor or neoplasm on radiological images. The use of brain biopsy is then required to determine the correct diagnosis. Schilder’s disease must also be differentiated from ADEM. In comparison, ADEM usually is associated with a history of immunizations or viral infections and does not generally present with the generally large and symmetrical plaques in the centrum semiovale of both cerebral hemispheres, and does not typically include the lesions of the brainstem with which Schilder’s disease presents (Miyamoto et al., 2006). Of interest, the MRI of Schilder’s disease is consistent with that of ALD, with the distinction between the two relying on the fact that ALD lesions are primarily on the occipital lobes and appear more symmetrical. Furthermore, the presence of long chain fatty acids that are abnormal will indicate a diagnosis of ALD, in contrast to the normal chain of fatty acids that are diagnostically indicative of Schilder’s disease (Kotil et al., 2002).

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All other demyelinating disorders must be eliminated before exclusionary criteria can be met and a diagnosis of Schilder’s disease can be made. The diagnostic criterion that was established by Poser et al. (1986) was able to provide a clearer distinction between the demyelinating disorders.

TREATMENT

There is currently no cure for Schilder’s disease; therefore, treatment is focused on managing the symptoms that are associated with the rate of progression. The course of Schilder’s disease is unpredictable, and the prognosis depends on its course. Progression of the disease has several possibilities including, progressive, monophasic remitting and not remitting, and all types have the additional possibility of fatality. As the disease progresses, the severity and number of deficits increases (NINDS, 2008). Progression of Schilder’s disease is similar to that of multiple sclerosis, and therefore treatment methods are similar. Corticosteroids are the initial choice of treatment for Schilder’s disease and have proven to be the most effective. Alternative treatment methods include betainterferon and immunosuppressive therapy. Cases of Schilder’s disease that are of the progressive type tend to be less responsive to treatment of all types, and therefore neurological functioning continues to deteriorate regardless of treatment (Garrell et al., 1998). Further treatment focuses on symptomatic management, in which the primary concern is relief of symptoms in attempt to increase the level of daily functioning. Additional support is mainly in the form of occupational therapy, physiotherapy, and eventually nutritional support (NINDS, 2008). Pharmacological treatment is the initial choice and most effective throughout all levels of Schilder’s disease. Jamie Rice Charles Golden Afifi, A. K., Follett, K. A., Scott, W. E., & Moore, S. A. (2001). Optic Neuritis: A novel presentation of Schilder disease. Journal of Child Neurology, 16(9), 693–696. Canellas, A. R., Gols, A. R., Izquierdo, R., Subirana, M. T., & Gairin, X. M. (2007). Idiopathic inflammatorydemyelinating diseases of the central nervous system. Neuroradiology, 49, 393–409. Garell, P. C., Menezes, A. H., Baumbach, G., Moore, S. A., Nelson, G., Mathews, K., et al. (1998). Presentation, management and follow-up of Schilder disease. Pediatric Neurosurgery, 29, 86–91. Kotil, K., Kalayci, M., Koseoglue, T., & Tugrul, A. (2002). Myelinoclastic diffuse sclerosis (Schilder disease):

Report of a case and review of the literature. British Journal of Neurology, 16(5), 516–519. Miyamoto, N., Kagohashi, M., Nishioka, K., Fujishima, K., Kitada, T., Tomita, Y., et al. (2006). An autopsy case of Schilder’s variant of multiple sclerosis (Schilder disease). European Neurology, 55, 103–107. Poser, C. M., Goutieres, F., Carpentier, M., & Aicardi, J. (1986). Schilder’s myelinoclastic diffuse sclerosis. Pediatrics, 77(1), 107–112.

SCHIZENCEPHALY DESCRIPTION

Schizencephaly is a rare disease that leads to abnormal brain development (clefts) in one or both cerebral hemispheres. There are two types of schizencephaly, closed-lip (Type I) and open-lip (Type II). In both instance, schizencephaly is so rare that recent prevalence estimates are 1.54 per 100,000 people (Curry, Lammer, Nelson, & Shaw, 2005). Although the specific cause is unknown, it is currently classified as a neuronal migration problem and it is believed that this problem occurs during fetal development (1–7 months). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The defining features of schizencephaly are the cerebral clefts, either closed or open, lined with gray matter that extend from the pial surface of the cerebral cortex to the ependymal surface at the lateral ventricle. The clefts can occur in any region of the brain; however, they most commonly occur in the perisylvian regions (Close & Naul, 2009). Heterotopias (collection of gray matter in abnormal locations) and polymicrogyria (neurons that are abnormally distributed) line the clefts. Arachnoid cysts can also be associated with the disorder. Microcephaly has also been noted in some patients. Another interesting fact is that in 80% to 90% of such patients the septum pellucidum is not present, suggesting that schizencephaly may coexist with septo-optic-dysplasia (Close & Naul, 2009; Rajderkar, Phatak, & Kolwadkar, 2006). Two main theories surround the organic basis of schizencephaly: (1) neuronal migration fails at the point of the germinal matrix and (2) vascular trauma occurs postmigration. In comparison, neuronal migration dysfunction is the primary cause of this rare disorder. The neural migration causes clefts that are filled with CSF and the cleft is lined with gray matter (Close & Naul, 2009).

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The most prominent theory proposes that schizencephaly occurs because of an early focal destruction of the germinal matrix and surrounding brain tissue before the hemispheres are fully developed (Ross & Walsh, 2001). The origins of schizencephaly are not definitive. Some suspect that the lesions, or more accurately clefts, have multiple origins that can be metabolic, toxic, vascular, and infectious in origin (Curry et al, 2005; Rocella & Testa, 2003; Tietjen et al., 2007). Others focus on the LHX2 and EMX2 genes believing that this disease has a more genetic basis (Brunelli et al., 1996; Ho, 2001; Tietjen et al., 2007). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The defining feature in all cases of schizencephaly is the formation of clefts in the cerebral hemispheres; however, the presentation varies among patients. General features include developmental delay, mental retardation, motor deficits, and epilepsy (Barkovich, 2000; Denis et al., 2000). Patients with unilateral clefts and fused lips may have mild hemiparesis and seizures, but otherwise experience normal development. In closed-lip schizencephaly, a deep furrow exists that is lined with gray matter (Dubey, Gupta, Sharma, & Sharma, 2001; Wolpert & Barnes, 1992). Open cleft patients will most often have mild-to-moderate mental delay and hemiparesis. In the open-lip schizencephaly, the missing cerebral hemisphere creates a cavity that becomes filled with CSF. The severity of the manifestations is related to how much of the cortex is involved in the defect. DIAGNOSIS

Schizencephaly is most often diagnosed in childhood, although in a few instances it has been diagnosed in adulthood because of seizure onset. An interesting aspect of schizencephaly is the array of anomalies that can exist including ventriculomegaly, microcephaly, polymicogyria, gray matter heterotopias, dysgenesis of corpus callosum, absence of septum pellucidum, and optic nerve hypoplasia (Close & Naul, 2009; Rajderkar et al., 2006). The primary diagnostic features of closed-lip schizencephaly are defined by a few key features. Only a small area of the cerebral hemisphere is affected, there is no hydrocephalus, and there is a thin seam of gray matter (pial-ependymal cells) close together, explaining the name closed-lip schizencephaly. In closed-lip schizencephaly, the cleft walls that are lined with gray matter on each side block the CSF

space within the cleft. Closed clefts may be unilateral or bilateral (Close & Naul, 2009). According to Naidich (1988), there are two primary features in diagnosing open-lip schizencephaly: (1) presence of continuous ependymal gray matter and (2) lining of the cleft by a seam comprised of epidermal cells. From a differential diagnosis standpoint, several other medical conditions can be confused with schizencephaly. Specifically, it is important to rule out the following possible conditions: holoprosencephaly, porencephaly, hydranencephaly, and arachnoid cysts. Holoprosencephaly is characterized by facial anomalies and a thalamic midline mass within the monoventricular cavity. Hydranencephaly is characterized by a mostly absent cerebrum, with the meninges and cranial vault intact. Porencephaly is most similar in appearance to schizencephaly. It presents bilaterally in the vicinity of the Sylvian’s fissure. However, MRI or CT scans will show that there is no gray matter present along the clefts in porencephaly. Arachnoid cysts are not symmetrical in shape and do not communicate with the lateral ventricles (Hayashi, Tsutsumi, & Barkovich, 2002). TREATMENT

Unfortunately there is no cure for schizencephaly. The treatment focuses on the symptoms resulting from the abnormal brain development. A common treatment for all cases of schizencephaly is physical therapy to improve movement, ambulation, and symptoms of paralysis, spasticity, and/or hand movement difficulties. In cases where seizures occur, medication is the frontline treatment choice. If the seizures are not adequately managed with medication, surgery that would remove abnormal tissue surrounding the cleft is recommended (Guerrini & Carrozzo, 2001). In some cases of schizencephaly where hydrocephalus is present a ventricular shunt may be needed. The shunt helps relieve the accumulation of fluid and pressure. Teri J. McHale Henry V. Soper Barkovich, A. (2000). Congenital malformations of the brain and skull. In A. J. Barkovich(Ed.), Pediatric Neuroimaging (Vol. 3e, pp. 289–292). Brunelli, S., Faiella, A., Capra, V., Nigro, V., Simeone, A., Cama, A., et al. (1996). Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nature Genetics, 12, 94–96. Close, K., & Naul, L. (2009). Schizencephaly. eMedicine Specialties-Radiology. Retrieved from http://emedicine.

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medscape.com/article/413051-overview on April 22, 2009. Curry, C., Lammer, E., Nelson, V., & Shaw, G. (2005). Schizencephaly: Heterogeneous etiologies in a population of 4 million California births. American Journal of Medical Genetics, 137A, 181–189. Denis, D., Maugey-Laulom, B., Carles, D., Pedespan, J. M., Brun, M., & Chateil, J. F. (2001). Prenatal diagnosis of schizencephaly by fetal magnetic resonance imaging. Fetal Diagnosis and Therapy, 16(6), 354–359. Dubey, A., Gupta, R., Sharma, P., & Sharma, R. (2001). Schizencephaly type-1. Indian Pediatrics, 38, 949–951. Guerrini, R., & Carrozzo, R. (2001). Epilepsy and genetic malformations of the cerebral cortex. American Journal of Medical Genetics, 106, 160–173. Hayashi, N., Tsutsumi, Y., & Barkovich, A. (2002). Morphological features and associated anomalies of schizencephaly in the clinical population: detailed analysis of MR images. Neuroradiology, 44, 5. Ho, A. (2001). A genetic basis for schizencephaly: Lhx2 may play a role in schizencephaly, septo-optic dysplasia, and Joubert Syndrome. The Harvard Brain, 8, 1–18. Naidich, T. (1988). The neuro image quiz. Pediatric Neuroscience, 14, 54–56. Oh, K., Kennedy, A., Frias, A., & Byrne, J. (2005). Fetal Schizencephaly: Pre- and postnatal imaging with a review of the clinical manifestations. RadioGraphics, 25, 647–657. Rajderkar, D., Phatak, S., & Kolwadkar, P. (2006). Septooptic dysplasia with unilateral open lip Schizencephaly: A case report. Indian Journal of Radiological Imaging, 16(3), 321–323. Rocella, M., & Testa, D. (2003). Fetal alcohol syndrome in developmental age. Neuropsychiatric aspects. Minerva Pediatrics, 55, 63–69. Ross, M., & Walsh, C. (2001). Human brain malformations and their lessons from neuronal migration. Annual Review of Neuroscience, 24, 1041–1070. Tietjen, I., Bodell, A., Apse, K., Mendonza, A., Chang, B., Shaw, G., et al. (2007). Comprehensive EMX2 genotyping of a large schizencephaly case series. American Journal of Medical Genetics Part A, 143A, 1313–1316. Wolpert, S., & Barnes, P. (1992). MRI in pediatric neuroradiology. St. Louis, MO: Mosby Year Book.

SCLERODERMA DESCRIPTION

Scleroderma is a chronic group of rare autoimmune rheumatic diseases characterized by hardening and tightening (sclerosis) of the skin and connective tissues

(the fibers that provide framework and support to the body). The most visible symptom of the disorder is hardening of the skin. There are two forms of scleroderma, localized and systemic. Localized scleroderma, sometimes known as morphea, affects only the skin. This form is disabling but most often tends not to be fatal. It is characterized by hardening of the skin and sometimes a reduction in joint movement due to the hardening. Systemic scleroderma, or systemic sclerosis, is the generalized type of the disease. This form of the disease can be fatal as a result of damage to internal organs including the heart, lung, kidney, or intestinal tract. Systemic sclerosis is characterized by varying degrees of tissue scarring, hardening (fibrosis), and chronic inflammation within the internal organs. A large number of patients (85–95%) may experience Raynaud’s phenomenon, disorder that affects the blood vessels in the extremities, fingers, toes, ears, and nose. It is characterized by vasospastic spasms that cause the blood vessels to constrict and change color. It is estimated that about 250 people per million have some form of scleroderma. Scleroderma may run in families, but most often occurs without any known family history of the disease. Mortality can occur and is most often due to pulmonary hypertension and renal crisis. Survival is based on disease subtype and extent of organ involvement and averages about 12 years from diagnosis (Valentini & Black, 2002). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Sclerosis affects the organ systems; most obvious is the skin, but the disease can also affect the heart, lungs, kidneys, and GI tract. The symptoms are due to inflammation and occlusion due to an excessive production of collagen. The overproduction of collagen may be the result of a dysfunction in the autoimmune system, where the immune system would start to attack its own chromosomes. This chromosomal deterioration can cause genetic malfunction, and T cells would then accumulate that stimulate collagen depositing. Studies have determined that stimulation of the fibroblast cells is crucial to the disease process. Transforming growth factor (TGFb) begins to be overproduced in this disease process and the fibroblast then overexpresses the receptor. A secondary messenger system that begins transcription of proteins and enzymes responsible for collagen production is developed through an intracellular pathway that consists of SMAD2/SMAD3, SMAD4, and an inhibitor SMAD7. In systemic sclerosis, vascular dysfunction is one of the earliest symptoms. Vascular changes are usually

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seen in small arteries and arterioles. Severe changes in small blood vessels of the skin and internal organs are always present in systemic sclerosis. These changes may include formation of excess connective tissue (fibrosis) and T cell infiltration. The cause of systemic sclerosis is unclear; however, the following mechanisms are present in all areas: endothelial cell injury, fibroblast activation, and cellular derangement. Environmental factors may be a cause including silica and solvent exposure, and radiation or radiotherapy exposure. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Localized scleroderma presents with skin appearing tight, reddish, or scaly. Skin pigmentation alternates from hyperpigmentation to hypopigmentation. The blood vessels may be dilated and appear more visible, most obvious is the face. The skin of the hands may appear swollen or ‘‘puffy’’ at first. Skin may appear tight and shiny, and patients may present with loss of hair, decreased sweating, and an inability to fold or bend skin. There is a great variation amongst patients in terms of severity. Diffuse scleroderma can cause complications in numerous other organ systems throughout the body. Problems can occur in the musculoskeletal, pulmonary, gastrointestinal, and renal systems, along with other areas such as eyes and ears. Individuals have greater involvement of internal tissues and organs if they have a larger involvement of skin in the course of the disease. Over 80% of patients have vascular symptoms and reports of Raynaud’s phenomenon (Herrick, 2004). Deposits of calcium under the skin are also common in systemic sclerosis. Scleroderma may cause a decrease in saliva production and a greater prevalence of oropharyngeal and esophageal cancers. Musculoskeletal symptoms often begin with pain in the joints and morning stiffness. The first joint pains are typically nonspecific and can possibly lead to arthritis and cause discomfort in tendons and muscles. Palpable tendon friction rubs may be detected over moving joints. Pulmonary impairment is very common and the leading cause of mortality in the disease. Shortness of breath during physical activity and dry cough are the most common pulmonary symptoms found in scleroderma. Pulmonary hypertension or elevations in arterial pressure may also develop in some patients. Patients with rapidly developing diffuse scleroderma have a much higher risk of developing renal crisis. Renal involvement in scleroderma is considered a poor prognostic factor and is a frequent cause of death. Symptoms of a renal crisis include high blood pressure with organ

damage, high renin levels, kidney failure with accumulation of waste products in the blood, and destruction of red blood cells. Excess blood and proteins may also be found in the urine. Gastrointestinal symptoms include esophageal reflux, esophagitis, gastroesophageal reflux disease (GERD), bacterial overgrowth in the intestine, ischemic colitis, malabsorption, and a symptom called watermelon stomach (atypical blood vessels proliferate in a symmetrical pattern around the stomach). Finally, scleroderma may cause some neurological difficulties. In rare occasions, trigeminal neuralgia may occur. Trigeminal neuralgia is a neuropathic disorder that causes great pain in the facial features: eyes, nose, lips, jaw, scalp, and forehead. Other neurologic symptoms include possible carpal tunnel syndrome due to peripheral neuropathies. DIAGNOSIS

Criteria for classification of scleroderma have been determined by the American College of Rheumatology. Classification requires one major criterion or two minor criteria. The major criterion is proximal scleroderma that is characterized by thickening and tightening of the fingers. These changes may affect the face, neck, trunk, or entire extremity. Minor criteria include thickening, hardening and tightening of the skin, limited only to the fingers (sclerodactyly), scarring of the fingers, loss of substances from the finger pad, or pulmonary hardening at the base of the lungs (bibasilar pulmonary fibrosis) (Klippel, 2008). Diagnosis of the disease process may also be determined through the presence of autoantibodies, such as anti-centromere and anti-scl 70/anti-topoisomerase antibodies. Biopsies may also be conducted in order to determine diagnosis. Differential diagnoses include eosinophilia, eosinophilia-myalgia syndrome, primary biliary cirrhosis, pulmonary hypertension, reflex sympathetic dystrophy, and mycosis fungoides. Other disorders that need to be considered in differentiating scleroderma include: toxic oil syndrome, digital sclerosis of diabetes mellitus, vibration disease, radiation exposure, intestinal obstruction, infiltrative cardiomyopathy, and amyloidosis. Laboratory workups for diagnosis may include hamogram (to reveal anemia), urinalysis (proteinuria, hematuria), chest X-rays (pulmonary fibrosis), CT scans (alveolitis), and ECHO (pulmonary arterial pressure). TREATMENT

The US Food and Drug Administration has not approved any therapies for systemic sclerosis (Oliver &

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Winkelmann, 1989). Skin thickening can be treated with topical treatments that may improve pain and ulceration but do not alter the disease course. Nonsteroidal anti-inflammatory drugs, such as naproxen, can be used to ease painful symptoms associated with the disease. Prednisone is sometimes used but has been shown to provide limited benefit. Skin thickening can also be treated with D-penicillamine. Raynaud’s phenomenon can be treated with calcium channel blockers. Pruritus (itching) can be treated with moisturizers. Acute renal failure and high blood pressure with evidence of organ damage due to scleroderma are often treated with dialysis (Steen & Medsger, 2000). However, angiotensin-converting enzyme (ACE) inhibitors are beneficial and may benefit enough to discontinue renal replacement therapy. Pulmonary problems are often treated with a combination of cyclophosphamide and a small dose of steroids (Tashkin, Elashoff, & Clements, 2006). Pulmonary hypertension is treated with Bosentan and has proved significant in patients with systemic sclerosis related pulmonary hypertension (Steen, 2005). Surgery may be used in patients with severe Raynaud’s phenomenon. Amputation may be required in infected hand lesions. Hand surgery is used to correct flexion difficulties. Occasionally, removal or draining of calcium deposits is required. Erin L. Tireman Charles Golden Herrick, A. L. (2005). Pathogenesis of Raynaud’s phenomenon. Rheumatology, 44(5), 587–596. Jimenez, S. A., & Derk, C. T. (2004). Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Annals of Internal Medicine, 140(1), 37–50. Klippel, J. H. (2008). Primer on the rheumatic diseases (11th ed.). Atlanta, GA: Arthritis Foundation. Oliver, G. F., & Winkelmann, R. K. (1989). The current treatment of scleroderma. Drugs, 37(1), 87–96. Steen, V. D. (2005). The lung in systemic sclerosis. Journal of Clinical Rheumatology, 11(1), 40–46 Steen, V. D., & Medsger, T. A., Jr. (2000). Long term outcomes of scleroderma renal crisis. Annals of Internal Medicine, 133(8), 600–603. Tashkin, D. P., Elashoff, R., Clements, P. J., Goldin, J., Roth, M. D., Furst, D. E., et al. (2006). Cyclophosphamide versus placebo in scleroderma lung disease. New England Journal of Medicine, 354(25), 2655–2666. Valentini, G., & Black, C. (2002). Systemic sclerosis. Best practice and research in Clinical rheumatology, 16(5), 807–816.

SEMANTIC DEMENTIA S DESCRIPTION

Semantic dementia (SD) was first discovered in 1975. It is one of the main variants of frontotemporal dementia (FTD) (Rascovsky, Growdon, Pardo, Grossman, & Miller, 2009). SD involves degradation of conceptual knowledge and difficulties in understanding the meaning of objects and words, as well as naming (Coulthard et al., 2006). Other aspects of cognition, including visuospatial abilities, perceptual reasoning, executive functioning, and episodic memory may remain generally intact (Laisney et al., 2009). Understanding this disorder is important due to the increasing aging population, the often insidious onset, and diverse clinical presentation (Amici, GornoTempini, Ogar, Dronkers, & Miller, 2006). Differential diagnosis can be challenging for the different dementia syndromes but neuropsychological testing as well as radiological findings may be helpful tools. NEUROPATHOLOGY/PATHOPHYSIOLOGY

SD is a clinical syndrome and therefore there is not always a specific underlying pathology that can be identified (Garrard & Hodges, 2000). Pereira and colleagues (2009) note that although atrophy patterns for variants of FTD are observed, histologic FTD do not evidence clear differences. In general, SD is viewed as having non-Alzheimer’s type pathology. At the macroscopic level, abnormalities of the white and gray matter in the left temporal lobe have been observed, particularly the inferolateral portions and the pole (Garrard & Hodges, 2000). At a microscopic level, gliotic degeneration or nonspecific spongiotic changes have been discovered, as well as histological patterns common to Pick’s disease (Hodges, Garrard, & Patterson, 1998). Neuropathological findings have also revealed ubiquitin-positive, tau-negative neuronal inclusions (Hodges & Patterson, 2007). Radiological findings of SD have resulted in a number of observations regarding patterns of atrophy. Cortical atrophy has been found to remain relatively isolated to the inferior and anterior portions of the temporal lobe earlier in the disease process, but later affecting the temporal cortex more extensively (Reilly & Peelle, 2008). MRI findings have revealed left hemisphere atrophy, most prominent around the sylvian fissure of the temporal lobe (Hodges, Patterson, Oxbury, & Funnell, 1992; Hodges,

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Patterson, & Tyler, 1994). Cortical thickness analysis from volumetric MRI has found significant cortical thinning in the left temporal lobe, especially in the entorhinal cortex, temporal pole, and fusiform, parahippocampal and inferior temporal gyri (Rohrer et al., 2009). CT findings have illustrated diffuse ventricular enlargement and widening, most marked in the left anterior temporal region (Cummings & Duchen, 1981). PET studies have also shown atrophy in the temporopolar and perirhinal cortices (Hodges & Patterson, 2007). Pronounced hypoperfusion of the entire left hemisphere has been noted in SPECT (Poeck & Luzzatti, 1988).

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

SD is often referred to as ‘‘fluent aphasia’’ as spontaneous speech is often grammatically correct and fluent, despite a loss of semantic knowledge. Semantic paraphasias are quite common, however (Hodges et al., 1992). For example, a person may refer to a pencil as a pen. As the disease progresses, speech may become ‘‘empty’’ with limited use of nouns and reliance on vague fillers, such as ‘‘that,’’ ‘‘thing,’’ and ‘‘this’’ (Amici et al., 2006). Patients may use cliche´s, which may be strangely appropriate to the situation (e.g., ‘‘I don’t understand’’) (Hodges, Patterson, Graham, & Dawson, 1996). Associated behavioral symptoms in SD can be quite diverse, with the most frequently seen features including depression, repetitive motor behaviors, overeating, or changes in food preference (e.g., increased craving for sweets), emotional blunting, and changes in social interactions (Rosen et al., 2002). Neuropsychological findings have revealed decreased word retrieval on confrontation naming tasks, with little benefit from even multiple choice cues (Gorno-Tempini et al., 2004). Wilson and colleagues (2009) note impairment in reading low frequency words, with atypical spelling-to-sound translation. Patients may have difficulty with naming fingers, body parts, and shapes and they may be unable to discriminate left and right. Semantic fluency is often severely impaired, and depressed scores are found on phonemic fluency (Amici et al., 2006). Sentence repetition may be intact, as well as executing multi-step commands. Calculations may be normal, as well as digits backward. However, praxis may be impaired due to impaired object recognition (Amici et al., 2006). On bedside examination, patients may be oriented and be able to recall recent events although language deficits may greatly interfere with formal assessment (Garrard & Hodges, 2000).

In a longitudinal study by Libon and colleagues (2009), researchers found that group differences were notable between SD and other variants of frontotemporal lobar degeneration, and these were maintained over the duration of the illness, and suggest that the various disorders do not converge into one subtype over time. Hodges and colleagues (1999) found a distinct clinical profile when differentiating temporal and frontal variants of FTD from early Alzheimer’s disease. Those with SD evidenced isolated but profound anomia and surface dyslexia, but they are indistinguishable from the AD group when assessing story recall. DIAGNOSIS

Diagnosis is based on demonstration of the clinical features of SD that have been defined as: (1) selective impairment in semantic memory, resulting in severe anomia, impaired written and spoken single-word understanding, reduced general fund of knowledge about word-meaning, objects and persons, and diminished category fluency; (2) generally intact functions in other aspects of language comprehension and production; (3) intact working memory, visuospatial, and problem-solving skills; (4) generally intact episodic and autobiographical memory (Hodges et al., 1992). Other common variants of SD include progressive nonfluent aphasia (PNFA) that is characterized by agrammatism in speech production and/or comprehension, and labored speech, as well as logopenic progressive aphasia, which presents as word-finding difficulties, impaired sentence comprehension, and simple but accurate language output (Amici et al., 2006). The frontal variant of fronto-temporal dementia (fv-FTD) results in prominent changes in personality and social functioning, and common cognitive deficits involve executive dysfunction and working memory (Boxer & Miller, 2005; Coulthard et al., 2006). TREATMENT

To date, the Food and Drug Administration (FDA) has not established an approved treatment for SD. Boxer and colleagues (2009) investigated the use of Memantine in three subtypes of FTD, including SD. Unfortunately, SD groups declined on most of the cognitive and behavioral outcome measures. Cholinesterase inhibitors have been used in variants of FTD. There was no evidence of cognitive improvements, and in some cases, behavioral symptoms actually worsened

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(Amici et al., 2006). Amici and colleagues (2006) found out that serotonin-specific-reuptake inhibitors (SSRIs) can be helpful in addressing behavioral symptoms. Clearly there is a need for pharmacological advancement in the treatment of SD. Efficacious treatment is limited for those with focal brain damage due to stroke, let alone language-based neurodegenerative conditions (Henry, Beeson, & Rapcsak, 2008). In a review by Henry and colleagues (2008), it is noted that learning is possible in SD patients but greater reliance on autobiographic and perceptual information is important for vocabulary learning. They add that treatment may actually help to slow the rate of decline, particularly in the early stages of the process when aspects of semantic knowledge are accessible and episodic memory is generally intact. Amy R. Steiner Chad A. Noggle Amanda R. W. Steiner Amici, S., Gorno-Tempini, M., Ogar, J. M., Dronkers, N. F., & Miller, B. L. (2006). An overview on Primary Progressive Aphasia and its variants. Behavioural Neurology, 17, 77–87. Boxer, A. L., Lipton, A. M., Womack, K., Merrilees, J., Neuhaus, J., Pavlic, D., et al. (2009). An Open-label Study of Memantine Treatment in 3 subtypes of Frontotemporal Lobar Degeneration. Alzheimer Disease and Associated Disorders, July-Sep: 23 (3): 211–217. Boxer, A. L., & Miller, B. L. (2005). Clinical features of frontotemporal dementia. Alzheimer Disease Association Discord, 19(Suppl. 1), S3–S6. Coulthard, E., Firbank, M., English, P., Welch, J., Birchall, D., O’Brien, J., et al. (2006). Proton magnetic resonance spectroscopy in frontotemporal dementia. Journal of Neurology, 253, 861–868. Cummings, J. L., & Duchen, L. W. (1981). Kluver-Bucy syndrome in Pick’s disease: Clinical and pathological correlations. Neurology, 31, 1415–1422. Garrard, P., Hodges, J.R. (2000). Semantic dementia: clinical, radiological, and pathological perspectives. Journal of Neurology, 247: 409–422. Gorno-Tempini, M.L., Dronkers, N.F., Rankin, K.P., Ogar, J.M., Phengrasamy, L. et al. (2004). Cognition and anatomy in three variants of primary progressive aphasia. Annals of Neurology, 55 (3), 335–346 Henry, M. L., Beeson, P. M., & Rapcsak, S. Z. (2008). Treatment for anomia in semantic dementia. Seminars in Speech and Language, 29(1), 60–70. Hodges, J. R., Garrard, P., & Patterson, K. (1998). Semantic dementia and Pick complex. In A. Kertesz & D. Munoz (Eds.), Pick’s disease and Pick’s complex. New York: Wiley Liss.

Hodges, J. R., & Patterson, K. (2007). Semantic dementia: A unique clinicopathological syndrome. Lancet Neurology, 6(11), 1004–1014. Hodges, J. R., Patterson, K., Graham, N., & Dawson, K. (1996). Naming and knowing in dementia of Alzheimer’s type. Brain Language, 54, 302–325. Hodges, J. R, Patterson, K., Oxbury, S., & Funnell, E. (1992). Semantic dementia: Progressive fluent aphasia with temporal lobe atrophy. Brain, 115, 1783–1806. Hodges, J. R., Patterson, K., & Tyler, L. K. (1994). Loss of semantic memory: Implications for the modularity of mind. Cognitive Neuropsychology, 11, 505–542. Hodges, J. R., Patterson, K., Ward, R., Garrard, P., Bak, T., Perry, R., et al. (1999). The differentiation of semantic dementia and frontal lobe dementia (temporal and frontal variants of frontotemporal dementia) from early Alzheimer’s disease: A comparative neuropsychological study. Neuropsychology, 13(1), 31–40. Laisney, M., Matuszewski, V., Me´zenge, F., Belliard, S., de la Sayette, V., Eustache, F., et al. (2009). The underlying mechanisms of verbal fluency deficit in frontotemporal dementia and semantic dementia. Journal of Neurology, 256(7), 1083–1094. Libon, D. J., Xie, S. X., Wang, X., Massimo, L., Moore, P., Vesely, L., et al. (2009). Neuropsychological decline in frontotemporal lobar degeneration: A longitudinal analysis. Neuropsychology, 23(3), 337–346. Pereira, J. M., Williams, G. B., Acosta-Cabronero, J., Pengas, G., Spillantini, M. G., Xuereb, J. H., et al. (2009). Atrophy patterns in histologic versus clinical groupings of frontotemporal lobar degeneration. Neurology, 72(19), 1653–1660. Poeck, K., & Luzzatti, C. (1988). Slowly progressive aphasia in three patients: The problem of accompanying neuropsychological deficit. Brain, 111, 151–168. Rascovsky, K., Growdon, M. E., Pardo, I. R., Grossman, S., & Miller, B. L. (2009). The quicksand of forgetfulness’: Semantic dementia in one hundred years of solitude. Brain, Sep:132 (Pt 9): 2609–2616. Reilly, J., & Peelle, J. (2008). Effects of semantic impairment on language processing in semantic dementia. Seminars in Speech and Language, 29(1), 32–43. Rohrer, J.D., Warren, J.D., Modat, M., Ridgway, G.R., Douiri, A. (2009). Patterns of cortical thinning in the language variants of frontotemporal lobar degeneration. Neurology, May 5; 72 (18): 1562–1569. Rosen, H. J., Kramer, J. H., Gorno-Tempini, M. L., Schuff, N., Weiner, M., & Miller, B. L. (2002). Patterns of cerebral atrophy in primary progressive aphasia. American Journal of Geriatric Psychiatry, 89–97. Wilson, S. M., Brambati, S. M., Henry, R. G., Handwerker, D. A., Agosta, F., Miller, B. L., et al. (2009). The neural basis of surface dyslexia in semantic dementia. Brain, 132(1), 71–86.

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SHAKEN BABY SYNDROME S DESCRIPTION

Shaken baby syndrome (SBS), or inflicted traumatic brain injury (TBI), is caused by violent and forceful shaking of a child with or without contact of the child’s head against a hard surface. The whiplash type motion results in brain trauma including subdural hematoma, retinal hemorrhage, and diffuse axonal injury. The term ‘‘nonaccidental head injury’’ is used synonymously to emphasize that SBS does not refer to an accidental trauma. For example, when an infant sustains brain damage in a car accident, this would not be referred to as SBS, but rather a TBI. In short, SBS results from abusive shaking of an infant or child. NEUROPATHOLOGY/PATHOPHYSIOLOGY

The original triad for understanding the SBS was characterized by subdural hemorrhage, retinal hemorrhage, and encephalopathy all of which coincide with the shaking. Over time this triad has been questioned as having to occur in a consistent pattern (Squier, 2008). Recent studies have documented that parenchymal lesions are associated with SBS and further brain damage can include edema, bleeding, stroke, white matter contusional tears, and axonal injury (Bonnier et al., 2003). Even if brain damage can be objectified on neuroimaging, it is often challenging to determine if the brain was damaged due to an inadvertent drop versus someone intentionally shaking the baby. Geddes, Hacksaw, Vowles, Nickols, and Whitwell (2001) classified the following five categories for establishing SBS or nonaccidental brain injury: (1) brain injury where there was a confession by the perpetrator; (2) cases where SBS was established in criminal courts; (3) cases with unexplained brain injuries, but no conviction was made; (4) no permanent brain injury was objectified (i.e., neuroimaging), but caretaker(s) were convicted of inflicting physical injuries to the infant’s head or neck; and (5) major discrepancy remained unresolved between the caretaker’s explanation and a significant injury, such as a skull fracture. One of the greatest protections against common forms of brain trauma is the ability to keep the head stationary in response to an impact to the head or movements of the body. Consequently, because an infant has a proportionately large head in conjunction with weak neck muscles, there is less protection from

severe acceleration–deceleration forces to the brain. Particularly, severe rotational forces can have deleterious effects. The constellation of these factors is such that a baby’s brain cannot withstand severe shaking that would unlikely harm an older child or adult.

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

A full recovery applies to the patient having no longterm physical, cognitive, and emotional residuals. The detrimental sequelae associated with SBS include cerebral palsy, ongoing seizures, visual problems (secondary to retinal hemorrhages), speech and language problems, and behavioral problems (Karandikar, Coles, Jayawant, & Kemp, 2004). The sequelae associated with SBS is undoubtedly worse if the shaking takes place on more than one occasion. The signs and symptoms of SBS range on a continuum from a ‘‘low-dose’’ shaking/impact to a ‘‘high-dose’’ shaking/impact. The effects of severe craniocerebral injuries vary and can include decreased responsiveness, poor feeding, irritability, lethargy and hypotonia, seizures, vomiting, tachypnea, hypothermia, bradycardia, coma, fixed dilated pupils, and death (Karandikar et al., 2004). Associated injuries may also be seen outside of the brain itself. Specifically, prominent and multilayered retinal hemorrhages are present in the majority of cases. Acute skull fractures indicate that impact has accompanied the shaking (Talvik et al., 2007). Seizures and apnea were the most common symptoms noted by emergency health care personnel (Starling et al., 2004). The incidence of SBS varies across studies from 15–40.5 per 100,000 children (Talvik et al., 2007). The morbidity rates across studies ranges between 38–40% and 58–70%. Yet some studies even reported morbidity as high as 80–100%. This variable range is due to zcultural differences (studies were conducted in Scotland, North Carolina, and Estonia), magnitude of sample size, and the sensitivity of the outcome measures. The literature has pointed out that even if some of the infants or children ‘‘may look well immediately following the trauma, the child may be left with serious and permanent disabilities’’ (Talvik et al., 2007, p. 1164). Approximately one-third of the SBS survivors present with severe neurological disorders. Nearly a quarter of the victims die within a few hours to a few days of their brain injury. Fifty to ninety percent of the survivors are left with varying degrees of disabilities ranging from serious learning disabilities and behavioral disorders to paralyses, blindness, and permanent vegetative states (Talvik et al., 2007).

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DIAGNOSIS

The diagnosis of a brain trauma is based on loss of consciousness, posttraumatic amnesia, disorientation, and neurological signs (American Congress of Rehabilitation Medicine, 1993). Because infants are unable to respond to questions that are essential to retrospectively assess posttraumatic amnesia and disorientation, the diagnosis for milder brain traumas is far more challenging. Moreover, problems related to SBS are sometimes not detected until the child enters the educational system and behavioral problems and learning difficulties are observed by their teachers. But years later, the link between these learning and behavioral problems and SBS may never be convincingly established. Diagnosis cannot be confirmed unless the perpetrator confesses, reliable witnesses come forth, and/or there is conclusive objective evidence of brain damage consistent with SBS. A majority of the infants with SBS are under 2 years old (Talvik et al., 2007). Therefore, formal neuropsychological testing is extremely limited in this age group; however, long-term follow-up evaluations have documented that many survivors suffer from severe disabilities including a plethora of cognitive residuals. Predictors of poor outcome include shaking while the infant is under 6 months, apnea, impaired consciousness, and depending upon auxiliary respiratory support at presentation (Jennet & Bond, 1975). When testing a group of school-aged children who were shaken in their infancy, cognitive residuals included weaknesses in intelligence, working memory, attention, reasoning, mental planning and organization, and mental inhibition (Sitpanicic, Nolin, Fortin, & Gobeil, 2008). Careful investigation by medical professionals, child protective agencies, investigators, and prosecutors is important, since the legal consequences can be severe. Child protective services routinely refer cases suspected of SBS for court-ordered family medical and psychological evaluations. The medical evaluation includes a review of the medical findings in the case and a determination of the nature and cause of the injuries. Psychological evaluations of the adults assess current psychological functioning, parenting competencies, and risk factors for abuse such as substance abuse, personality factors, and the parent’s ability to provide predictable, consistent, and emotionally attuned caretaking. Parents are interviewed for medical history and, if forthcoming, a history of how the injuries occurred. Psychological evaluations are not used by the team to solely determine who injured the child. Fault and intentionality of the injury are determined by analyzing the injuries, access to the child, and witness and perpetrator statements.

These findings and recommendations regarding child placement and mental health interventions are conveyed to the parents, the courts, and child protective services for implementation. Collaborative decision making between physicians and psychologists enhance each discipline’s conclusions and minimize the likelihood of error. To this end, improved decision making protects children from abusive caretakers and, when appropriate, preserves families if a caretaker has not abused the child and is not at risk to abuse the child. When a parent is the perpetrator, the likely separation or limited contact with this parent can result in attachment issues.

TREATMENT

SBS should be viewed from a family system’s perspective. If an innocent parent is accused of SBS, it can be emotionally devastating to the entire family to be questioned about the possibility of intentional abuse. For parents who already blame themselves for an inadvertent fall, this questioning can exacerbate their self-blame. Although this is potentially detrimental to the already stressed family system, it is nonetheless an unavoidable component of intervening in abusive situations. Additionally, if a nonfamily caregiver is determined to be responsible for SBS, then the parents’ feelings of guilt, anger, and depression will likely affect the family system. If a partner or spouse has caused SBS, then this severely strains — if not permanently damages — the partnership. Overall, criminal investigations often take several months, if not years, before decisions are finalized, and during this time period, the family is constantly anchored to the tragedy of an innocent infant having been harmed. Having family issues that may have contributed to this trauma being played out in a court room strains the family system exponentially. If the couple separates, then the loss of a parent will alter the family dynamic, not only for the abused child but also for any siblings. Potential risk factors that trigger SBS should be dealt with by both education and therapeutic care. Risk factors can include, but are not limited to, unwanted pregnancy and/or poor coping mechanisms including uncontrolled anger reactions, substance abuse, and unrealistic expectations about a child’s behavior, particularly inappropriate reaction to or misinterpretation of crying as rejection or disobedience. For example, when an infant has colic and is difficult to soothe, and the sleepless nights are the rule rather than an exception, parents’ coping mechanisms are often maximally stressed. Thus, risk factors should be identified for expectant parents before and after

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pregnancy regarding preventive steps they can take. For example, the National Center on Shaken Baby Syndrome has developed the Period of PURPLE Crying program (Barr et al., 2009). This program identifies the triggers associated with crying in order to help caregivers understand and avoid negative responses to crying infants. The letters in PURPLE each stand for a property of crying in healthy infants that frustrates caregivers; that is, P for peak pattern, in which crying increases, peaks during the 2nd month and then declines; U for unexpected timing of prolonged crying bouts; R for resistance to soothing; P for pain-like look on the child’s face; L for long crying bouts; and E for late afternoon and evening clustering. The PURPLE materials reinforce that these cycles are normal and suggest ways for caregivers to soothe and cope with a baby’s inconsolable crying. First, parents are encouraged to use typical calming responses such as carrying, comforting, walking, and talking. Second, if the crying is too frustrating it is okay to put the baby down in a safe place, walk away, calm yourself, and then return to check on the baby. Third, never shake your baby. Parents need to be educated as to the possibility of severe postpartum imbalances that can result in severe depression and occasionally even psychotic reactions. Accordingly, they should have access to treatment in the event these symptoms occur. In sum, education and treatment are essential in order to reduce the frequency of SBS, which permanently harms innocent babies and devastates families. Continued research should be aimed at identifying the circumstances and triggers that caused caretakers to shake an infant. Ronald Ruff Saralyn Ruff Christina Weyer Jamora Ann M. Richardson American Congress of Rehabilitation Medicine, Mild Traumatic Brain Injury Committee, A. C. R. M., Head Injury Interdisciplinary Special Interest Group. (1993). Definition of mild traumatic brain injury. Journal of Head Trauma Rehabilitation, 8, 86–87. Barr, R. G., Rivara, F. P., Barr, M., Cummings, P., Taylor, J., Lengua, L. J., et al. (2009). Effectiveness of educational materials designated to change knowledge and behaviors regarding crying and shaken-baby-syndrome in mothers of newborns: A randomized controlled trial. Pediatrics, 123, 972–980. Bonnier, C., Nassogne, M. C., Saint-Martin, C., Mesples, C., Kadhim, H., & Se´bire, G. (2003). Neuroimaging of intraparenchymal lesions predicts outcome in shaken baby syndrome. Pediatrics, 112, 808–814.

Geddes, J. F., Hacksaw, A. K., Vowles, G. H., Nickols, C. D., & Whitwell, H. L. (2001). Neuropathology of inflicted head injury in children. Brain, 124, 1290–1298. Jennet, B., & Bond, M. (1975). Assessment of outcome after severe brain damage. Lancet, 1, 480–484. Karandikar, S., Coles, L., Jayawant, S., & Kemp, A. M. (2004). The neurodevelopmental outcome in infants who have sustained a subdural hemorrhage from non-accidental head injury. Child Abuse Review, 13, 178–187. Sitpanicic, A., Nolin, P., Fortin, G., & Gobeil, M. F. (2008). Comparative study of the cognitive sequelae of schoolaged victims of Shaken Baby Syndrome. Child Abuse and Neglect, 32, 415–428. Squier, W. (2008). Shaken Baby Syndrome: The quest for evidence. Developmental Medicine and Child Neurology, 50, 10–14. Starling, S., Patel, S., Burke, B., Sirotnak, A., Stronks, S., & Rosquist, P. (2004). Analysis of perpetrator admissions to inflicted traumatic brain injury in children. Archives of Pediatrics & Adolescent Medicine, 158, 454–458. Talvik, I., Ma¨nnamaa, M., Ju¨ri, P., Leito, K., Po˜der, H., Ha¨marik, M., et al. (2007). Outcome of infants with inflicted traumatic brain injury (shaken baby syndrome) in Estonia. Acta Paediatrica, 96, 1164–1168.

SHINGLES DESCRIPTION

Shingles, or herpes zoster, is a latent reaction to the varicella zoster virus (chickenpox) and is a member of the herpes virus family (Urman & Gottlieb, 2008). In order to develop shingles, the person must have first been infected with chickenpox (Urman & Gottlieb, 2008). People commonly contract chickenpox through inhalation; however, when the disease has returned in the form of shingles, it can no longer be transmitted to others (Urman & Gottlieb, 2008). Shingles is a relatively common disease, with 600,000 to 1 million cases being reported in the United States each year (Urman & Gottlieb, 2008) and a lifetime prevalence rate of 10–20% (Oaklander, 2001). Prevalence rates increase with age and in those with suppressed autoimmune function (Christo, Hobelmann, & Maine, 2007; Oaklander, 2001; Urman & Gottlieb, 2008). The most notable characteristic of shingles is the unique rash, which has a unilateral, dermatomal distribution and forms in the mid to lower thoracic region (Bajwa & Ho, 2001; Christo et al., 2007; Urman & Gottlieb, 2008). This rash may also be vesicular or bullous in nature (Bajwa & Ho, 2001). In some cases, there

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may be prodromal symptoms before the rash, such as fever, malaise, headache, and preherpetic neuralgia, or pain (Urman & Gottlieb, 2008). Pain can appear 7–100 days before other symptoms, although this is uncommon (Bajwa & Ho, 2001). Neuralgia can also occur while the rash is present or after it has disappeared, called postherpetic neuralgia (PHN) (Bajwa & Ho, 2001; Urman & Gottlieb, 2008). PHN can begin 30 days after skin lesions have disappeared and can last for over a year (Urman & Gottlieb, 2008). PHN is more common in the elderly, those suffering from immunosuppression diseases, trauma, X-irradiation, and malignancy (Bajwa & Ho, 2001; Kennedy, 2002; Urman & Gottlieb, 2008). Another risk factor is significantly lower levels of immunoglobulin G (Wrensch et al., 2005). Less common symptoms may include a bacterial super infection and ocular and neurological impairment (Urman & Gottlieb, 2008). In extreme cases, encephalitis can occur; however, this is much more likely in individuals with previously compromised immune systems (Kennedy, 2002). A common complication of shingles, PHN causes deficits in thermal, tactile, pinprick, and vibration sensations in the affected skin areas (Bajwa & Ho, 2001). Common symptoms of PHN are altered sensation, ongoing pain not produced by stimuli, and mechanical allodynic pain, pain to light skin touch but normal sensation to thermal stimulation (Christo et al., 2007; Kennedy, 2002; Oaklander, 2001). PHN may in part stem from the dorsal horn atrophy caused by the reactivation of the herpes zoster virus (Kennedy, 2002). It can cause cutaneous neuritis, can decrease sensitivity in nerve endings, and can decrease innervations (Oaklander et al., 1998). Individuals are more likely to develop PHN if their rash was more severe, or if they had increased neurosensitiviy disturbance, a prodrome to symptom presentation, demyelization with fibrosis, or dorsal horn atrophy (Christo et al., 2007). The number of sensory nerve terminals lost or affected by the herpes zoster virus is strongly correlated to the presence of PHN pain; the more terminals lost, the greater the likelihood the person will experience PHN pain (Oaklander et al., 1998). NEUROPATHOLOGY/PATHOPHYSIOLOGY

After the initial varicella zoster virus infection begins to subside, the virus lies dormant for years to decades in the dorsal root or trigeminal root ganglia in the cranial and spinal nerves (Bajwa & Ho, 2001; Kennedy, 2002). While it is dormant, the virus’s DNA is still integrated into the carrier’s DNA, but the viral proteins are not made (Urman & Gottlieb, 2008).

Because the virus contains double-stranded DNA, when it reactivates it is able to cause new and different symptoms from the chickenpox presentation (Christo et al., 2007; DeLengocky & Bui, 2007). During the acute stage, as the herpes zoster virus reactivates it travels along from the dorsal root ganglia to the central nervous system (CNS) then to the peripheral nerves (Bajwa & Ho, 2001). Eventually, the virus is transmitted to the sensory neurons and ultimately the skin (Urman & Gottlieb, 2008). Once the virus reaches the skin, it can travel more directly between skin cells or along the extracellular matrix (Urman & Gottlieb, 2008). This viral procession causes abnormalities in the CNS, such as an inflammation (Kennedy, 2002). Thoracic nerve areas 4 and 6 are commonly affected by the virus as well as the cranial sensory ganglia (Bajwa & Ho, 2001; DeLengocky & Bui, 2007). In the peripheral nervous system, the disease causes deafferentation, a persistent pain where sensory loss has occurred (Christo et al., 2007), or aberrant activity of peripheral neurons, which can cause sensitivity of these neurons and cell necrosis (Christo et al., 2007; Oaklander, 2001). Both the spinal and peripheral axons affected by the herpes zoster virus degenerate, replaced by collagen (Oaklander, 2001). This causes the intense burning and shooting pain associated with shingles (Christo et al., 2007). As the disease continues to spread, vesicles form, which eventually hemorrhage and crust over. The eruption of these vesicles is another source of pain for infected individuals (Christo et al., 2007).

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Shingles and PHN can be associated with anxiety, depression, impaired sleep, decrease in appetite, and diminished libido (Bajwa & Ho, 2001). Research has also shown that shingles can decrease a person’s quality of life (Katz, Cooper, Walther, Sweeney, & Dworkin, 2004). One study has found that 42% of those with shingles surveyed reported horrible and excruciating pain (Katz et al., 2004). It was found that this pain contributed to not only poorer physical functioning but also poorer social functioning (Katz et al., 2004). The more pain an individual reported, the higher the person’s emotional distress level was found to be (Katz et al., 2004). Overall, participants in higher amounts of pain reported decreased emotional well-being (Katz et al., 2004). Increased education on shingles and its symptoms was found to help

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decrease pain perception in affected individuals (Katz et al., 2004). Another neuropsychological symptom found in those with shingles is sensory response changes (Fleetwood-Walker et al., 1999). The sensory abnormalities, which develop as a result of the herpes zoster virus, cause increases in sensitivity to sensory stimuli in the affected extremities (Fleetwood-Walker et al., 1999). Most commonly, an increased sensitivity to thermal sensation has been found (Fleetwood-Walker et al., 1999). DIAGNOSIS

The most common method for diagnosis of shingles is clinical observation of the distinctive rash (Novatnack & Schweon, 2007). However, shingles is much harder to diagnose before the rash is present, and some individuals never develop a rash, named zoster sine herpete (Roxas, 2006). If shingles is suspected, a sample of fluid will be removed from a vesicle for testing (Novtnack & Schweon, 2007). Two common tests are the fluorescent antibody test or the polymerase chain reaction (PCR) test (Novtnack & Schweon, 2007). A viral culture can also be used but it is not as accurate because the varicella zoster virus is labile (Roxas, 2006). The PCR test has been found to be the most sensitive in detecting the herpes zoster virus’s DNA (Noratnack & Schweon, 2007; Roxas, 2006). This test can also aid in differential diagnosis. Pleurisy, cardiac complications, herniated nucleus pulposus, trigeminal neuralgia, and Bell’s palsy are all commonly considered during differential diagnosis (Roxas, 2006). Other differential diagnoses for shingles include herpes simplex or coxsackie virus (Bajwa & Ho, 2001). A Tzanck test can help discriminate between these diseases for accurate diagnosis (Bajwa & Ho, 2001). Common misdiagnoses for shingles include appendicitis, myocardial infarct, renal colic, and choletithiasis (Roxas, 2006). TREATMENT

Early intervention is essential in order to control and eliminate pain as quickly as possible (Bajwa & Ho, 2001). Due to the vast number of associated disorders, a combination of medications can provide the most thorough relief, such as antivirals, antidepressants, corticosteroids, opioids, and topical cre`mes such as lidocaine (Bajwa & Ho, 2001; Christo et al., 2007). For pain management, many of these medications are used along with nerve blockade, in which local anesthetics are injected in peripheral nerves to

produce relief (Bajwa & Ho, 2001). However, corticosteroids have not been shown to be effective relief for pain symptoms (Christo et al., 2007). Other treatments include capsaicin (the extract of hot chili peppers), a topical ointment that aids in the release of substance P and other neuropeptides, and ketamine, which aids in relieving pain by acting on calcium channels (Christo et al., 2007). For patients with compromised immune systems who experience pain, antiviral medications, such as acyclovir, valacyclovir HCl, and famciclovir have been found to be most effective in treating pain and healing lesions quickly (Bajwa & Ho, 2001). Because treatments for shingles can be costly and do not completely prevent PHN (Urman & Gottlieb, 2008), preventing the development of shingles and chickenpox has become essential (Christo et al., 2007). In 1995, a new vaccine Varivax (Merck) was developed and is now routinely administered to children (Christo et al., 2007; Urman & Gottlieb, 2008). In the future, the prevalence rates of both shingles and chickenpox are expected to decline (Christo et al. 2007). Research has also found that vaccinating elderly individuals at higher risk for development of shingles can help reduce the likelihood of developing the disease (Christo et al., 2007). The newer vaccine Zostavax (Merck) has been shown to decrease the incidence rate of shingles and of PHN in 50% of those who received the treatment (Christo et al., 2007). However, vaccines can also be costly and the duration of their effectiveness can vary (Urman & Gottlieb, 2008). Sarah E. West Charles Golden Bajwa, Z. H., & Ho, C. C. (2001). Herpetic neuralgia: Use of combination therapy for pain relief in acute and chronic herpes zoster. Geriatrics, 56, 18–24. Christo, P. J., Hobelmann, G., & Maine, D. N. (2007). Postherpetic neuralgia in older adults: Evidence-based approaches to clinical management. Drugs and Aging, 24, 1–19. DeLengocky, T., & Bui, C. M. (2008). Complete ophthalmoplegia with puillary involvement as an initial clinical presentation of herpes zoster ophthalmicus. The Journal of the American Osteopathic Association, 108, 615–621. Fleetwood-Walker, S. M., Quinn, J. P., Wallace, C., Blackburn-Munro, G., Kelly, B. G., Fiskerstrand, C. E., et al. (1999). Behavioural changes in the rat following infection with varicella-zoster virus. Journal of General Virology, 80, 2433–2436. Katz, J., Cooper, E. M., Walther, R. R., Sweeney, E. W., & Dworkin, R. H. (2004). Acute pain in herpes zoster and

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its impact on health-related quality of life. Clinical Infection Diseases, 39, 342–348. Kennedy, P. G. (2002). Varicella-zoster virus latency in human ganglia. Reviews in Medical Virology, 12, 327–334. Novatnack, E., & Schweon, S. (2007). Shingles: What you should know. Registered Nurses, 70, 27–31. Oaklander, A. L. (2001). The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles. Pain, 92, 139–145. Oaklander, A. L., Romans, K., Horasek, S., Stocks, A., Hauer, P., & Meyer, R. A. (1998). Unilateral postherpetic neuralgia is associated with bilateral sensory neuron damage. Annals of Neurology, 44, 789–795. Roxas, M. (2006). Herpes zoster and postherpetic neuralgia: Diagnosis and therapeutic considerations. Alternative Medicine Review, 11, 102–113. Urman, C. O., & Gottlieb, A. B. (2008). New viral vaccines for dermatologic disease. Journal of the American Academy of Dermatology, 58, 361–370. Wrensch, M., Weinberg, A., Wiencke, J., Miike, R., Sison, J., Wiemels, J., et al. (2005). History of chickenpox and shingles and prevalence of antibodies to varicella-zoster virus and three other herpes viruses among adults with glioma and controls. American Journal of Epidemiology, 161, 929–938.

SICKLE CELL DISEASE

gene are inherited. With SCT, the red cells contain about 60% of the normal hemoglobin and 40% of the hemoglobin S (Beulter, 2002). There appears to be a strong relationship between SCT and malaria. Specifically, the SCT may help protect against malaria as those who had the trait survived malaria more frequently than those who did not in areas where malaria was present and the trait originated (Beulter, 2002; Bloom, 1995; Bojanowski & Frey, 2002; Uthman, 1998). Continually, malaria and the prevalence of SCD tend to be distributed along the same geographic regions (Bloom, 1995). There is evidence to suggest that SCT migrated with people, as about 1 in 12 African Americans are carriers of the mutation (Bojanowski & Frey, 2002), or 7.8–9% of African Americans (Beulter, 2002; Uthman, 1998). In contrast to those with the disease, individuals with SCT do not have vaso-occlusive (painful) symptoms and tend to have a normal life expectancy (National Institute of Health [NIH], 2002). Extreme physiological stress, including intense exercise can increase problems associated with SCT (NIH, 2002), and in rare cases, traces of blood can appear in the urine (Bojanowski & Frey, 2002). Globally, it is estimated that 1 in 250,000 infants are born with SCD each year. The diseases mainly affect African, Mediterranean, Middle Eastern, and Asian Indian populations, but it occurs in people from other ethnic backgrounds and is increasing in Latino populations (Bojanowski & Frey, 2002).

DESCRIPTION

NEUROPATHOLOGY/PATHOPHYSIOLOGY

Sickle cell disease (SCD) is a group of inherited blood disorders caused by a genetic change in hemoglobin, the oxygen-carrying protein in red blood cells. These disorders are characterized by a loss of red blood cells and the destruction of the cell membrane causing a release of hemoglobin (Beulter, 2002; Bojanowski & Frey, 2002). The most common SCD is sickle cell anemia (Bojanowski & Frey, 2002; Uthman, 1998). Other forms of SCD include, S/beta thalassemia, hemoglobin SC disease, hemoglobin SD disease, and hemoglobin SO disease and are caused by the inheritance of the sickle cell gene and an altered beta-globin gene (Beulter, 2002; Bojanowski & Frey, 2002). The sickle cell gene is highly prevalent in the United States, but a very small percentage of the population has SCD because the individual must inherit the sickle gene from both parents to have the disease. Those who inherit a single sickle cell gene are said to have the sickle cell trait (SCT) (Uthman, 1998). SCT is a condition that occurs when one sickle hemoglobin (hemoglobin S) gene and one normal hemoglobin

SCD is caused when sickle cell hemoglobin replaces normal hemoglobin (Bloom, 1995). This replacement is initiated by a mutation in the beta-globlin, producing sickle hemoglobin (hemoglobin S) (Beulter, 2002; Bojanowski & Frey, 2002). Sickle hemoglobin polymerizes into rod-like structures and change the shape of normal red blood cells into the resemblance of an agricultural tool, called the sickle, thus the name SCD. Hemoglobin S tends to have a shorter life span, which can cause chronic anemia because of the reduced levels of hemoglobin and red blood cells. Hemoglobin S can also become trapped in blood vessels, limiting blood flow and decreasing oxygen. The lack of oxygen damages tissues and organs and can result in excruciating pain, which is often one of the chief complaints of individuals with SCD (Bloom, 1995; Bojanowski & Frey, 2002). When this impedes blood flow to the brain, ischemic stroke may occur. In fact, SCD is one of the more common risk factors of stroke in children, particularly African Americans as

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they are at greatest risk for SCD in general. Vascular obstruction associated with the sickling process contributes to both large and small infarctions when they occur. Although this proposes an ischemic presentation, cerebral venous thrombus and hemorrhage can occur. Individuals with SCD are at risk for frequent infections and tend to have a shorter life span (Bloom, 1995). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

One of the most reported symptoms of SCD is painful episodes, lasting a few days up to a few weeks. The pain can range from annoying to agonizing (Bloom, 1995) and the specific pain associated with SCD can develop as early as infancy (NIH, 2002). Painful episodes are the leading cause of emergency room visits and hospitalizations for individuals with SCD (Bojanowski & Frey, 2002; NIH, 2002). SCD pain can be categorized as acute, chronic, or mixed (NIH, 2002). The majority of the pain is caused when sickle cells block blood vessels, creating oxygen deprivation in some parts of the body. If blood flow is not restored, tissue can become inflamed and damaged. As sickle cells can cause blockage in any small blood vessel, pain and damage can occur in any part of the body. However, the chest, bones, and abdomen are where the painful episodes are most reported (Bloom, 1995). Individuals with SCD are especially vulnerable to infections. The spleen, which helps fight infections, can be severely damaged in patients with SCD due to oxygen loss (Bloom, 1995; Bojanowski & Frey, 2002), causing surgical removal of the spleen in extreme cases. Damage or removal of the spleen is especially dangerous for children based on its connection to the immune system. The younger the children when damage occurs, the more vulnerable they are to life-threatening infections. Furthermore, once an infection occurs, individuals with SCD are more difficult to treat, and the infection can be more severe than for healthy individuals (Bloom, 1995). As mentioned, sickle cell anemia is the most prevalent SCD (Bojanowski & Frey, 2002; Uthman, 1998). Once red blood cells become sickle shaped, they are destroyed. This then creates a deficiency in red blood cells and anemia develops (Bloom, 1995). Fatigue, shortness of breath, and a pale complexion are common symptoms of anemia (Bojanowski & Frey, 2002), though the first symptom of sickle cell anemia in an infant is often dactylitis. Dactylitis is caused by limited circulation to small bones in the fingers and toes and results in painful swelling. The consequences of sickle cell anemia are related to

limited oxygen reaching organs due to the jamming of sickled red cells known as an infarctive crisis. The loss of tissue resulting from plugged blood vessels is known as an infarction. This can create pain and organ function may suffer, including leg ulcers that can be the result of a loss of circulation. In fact, these infections are the most common cause of death related to sickle cell anemia (Uthman, 1998). Neurological complications are common in sickle cell anemia due to damage of the brain caused by decreased blood flow. The decreased blood flow can cause cerebral infarction and lead to a stroke for individuals with SCD. Acute hemiplegia is the most common residual, although all focal cerebral presentations can occur (Ropper & Brown, 2005). Common manifestations of stroke caused by SCD include hemiparesis, aphasia, visual difficulties, and seizures (Mankad & Dyken, 1992). DIAGNOSIS

Neonatal screening, when incorporated with diagnostic testing and appropriate care, has a key impact on the quality of life for individuals with SCD. In the United States, most states automatically provide genetic screenings for newborns, including SCD, and screenings can be requested in the other states. Most screening programs utilize isoelectric focusing to screen for disorders (NIH, 2002), whereas other programs use high-performance liquid chromatography (HPLC) (Bojanowski & Frey, 2002; NIH, 2002). HPLC separates the normal hemoglobin from the sickle hemoglobin and helps determine which types of hemoglobin are present in the blood. A complete blood count may also be useful because it describes many aspects of an individual’s blood. SCD will show a lower hemoglobin level and other red blood cell abnormalities. SCD can also be identified through the use of prenatal diagnosis, including chorionic villus sampling and amniocentesis (Bojanowski & Frey, 2002). Preimplantation genetic diagnosis is a technique that involves genetic testing of developing embryos before implantation occurs (Bloom, 1995; Bojanowski & Frey, 2002). TREATMENT

Several interventions are used to prevent and treat symptoms of SCDs. Antibiotics are used to prevent infections. Penicillin is utilized to prevent pneumococcal infections and is particularly important for children with SCD. Routine vaccinations are also recommended for individuals with SCD, though they may also require additional immunizations to help

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prevent infections (Bojanowski & Frey, 2002; NIH, 2002). As pain is one of the most common concerns with sickle cell anemia, pain management may be a critical aspect in treatment planning. Often, nonsteroidal anti-inflammatory drugs and opioids are used to manage pain (NIH, 2002). Blood transfusions are an option for individuals with frequent and severe painful episodes and severe anemia (Bojanowski & Frey, 2002; NIH, 2002). When used correctly, blood transfusions can prevent organ damage because transfusions may raise the oxygen in the blood and decrease the number of sickle cells (NIH, 2002). Furthermore, regular transfusions can reduce symptoms associated with SCD (Bojanowski & Frey, 2002). Cerebral circulatory disorder due to SCD occurring to red blood cell sludging related to the sickling process is most commonly treated with intravenous hydration and transfusion (Ropper & Brown, 2005). Andrea Stephen Raymond S. Dean

Beutler, E. (2002). Sickle cell disease. In L. Breslow (Ed.), Encyclopedia of public health (Vol. 4, pp. 1099–1100). New York: Macmillan Reference USA. Retreived March 15, 2009, from http://find.galegroup.com/gvrl/ infomark.do?&contentSet ¼ EBKS&type ¼ retrieve& tabID ¼ T001&prodId ¼ GVRL&docId ¼ CX3404000780& source ¼ gale&userGroupName ¼ munc80314&version ¼ 1.0 Bloom, M. (1995). Understanding sickle cell disease. Jackson, MS: University Press of Mississippi. Bojanowski, J., & Frey, R. J. (2002). Sickle cell disease. In S. L. Blachford (Ed.), Gale encyclopedia of genetic disorders (Vol. 2, pp. 1048–1056). Detroit, MI: Gale. Retrieved March 15, 2009, from http://find.galegroup.com/gvrl/ infomark.do?&contentSet ¼ EBKS&type ¼ retrieve& tabID ¼ T001&prodId ¼ GVRL&docId ¼ CX3405500351& source ¼ gale&userGroupName ¼ munc80314&version ¼ 1.0 Mankad, V. N., & Dyken, P. R. (1992). Neurological complications of sickle cell disease. In V. N. Mankad & R. B. Moore (Eds.), Sickle cell disease: Pathophysiology, diagnosis, and management (pp. 300–306). Westport, CT: Praeger. National Institutes of Health, National Heart, Lung and Blood Institute. (2002). The management of sickle cell disease. Retrieved March 21, 2009, from http://purl. access.gpo.gov/GPO/LPS22097 Ropper, A., & Brown, R. H. (2005). Adams and Victor’s principles of neurology (8th ed., pp. 660–746). New York: McGraw-Hill. [Cerebrovascular Disease] Uthman, E. (1998). Understanding anemia (pp. 95–98). Jackson, MS: University Press of Mississippi.

SJO¨GREN’S SYNDROME S DESCRIPTION

Sjo¨gren’s syndrome is a chronic autoimmune disorder that has a primary manifestation of dry mouth and dry eyes. The body’s immune cells attack and destroy exocrine glands that produce bodily fluids, resulting in poor tear and saliva production. The incidence is 1 in 70 Americans or about 40 million people. Sjo¨gren’s syndrome is the second most common autoimmune disorder of the class of rheumatic disorders that affect the musculoskeletal system (Wallace, 2005). Approximately 90% of patients with Sjo¨gren’s syndrome are women. The average age of onset is in the late 40s and perimenopausal women are the highest risk group (Wallace, Bromet, & Sjo¨gren’s Syndrome Foundation, 2005). Primary Sjo¨gren’s syndrome occurs in isolation and secondary occurs with another rheumatic or autoimmune disorder such as lupus or rheumatoid arthritis. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Sjo¨gren’s syndrome is an autoimmune disorder in which the body’s white blood cells attack the endocrine system, particularly the lachrymal glands of the eyes and the saliva glands of the mouth. The cell death of these moisture-producing glands limits the fluids the body can produce, creating dryness and inflammation. Due to the high concentration of cases in women, it is hypothesized that hormonal factors play a role in the development of Sjo¨gren’s syndrome, such as the decrease in androgen levels that occur during states of elevated estrogen levels like menopause (Sullivan, Dartt, & Meneray, 1998). This research has largely been based upon experimental studies with animals. Human leukocyte antigen genes have been hypothesized to be a heritable, genetic component of Sjo¨gren’s syndrome. The gene HLA-DR3 is frequently found in persons of European descent with primary Sjo¨gren’s syndrome (Dyson, 2005). The antinuclear antibodies SS-A (Ro) and SS-B (La) are found in 60–70% and 40% of patients, respectively (Dyson, 2005). There is no clear evidence that the disorder is heritable, but multiple family members can have conditions within the class of autoimmune rheumatic disorders. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

A number of authors describe the impairments in daily functioning that patients with Sjo¨gren’s syndrome face

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(Dyson, 2005; Hanger & Schneebaum, 2003; Wallace, 2005). Patients are unable to wear contact lenses and have to apply eye drops regularly. They may be sensitive to light and have blurred vision, with severe cases resulting in corneal ulcers. Patients complain of bad breath due to the lack of saliva to cleanse the teeth and prevent plaque buildup. Dietary habits change due to loss of taste, difficult and painful swallowing, and excessive need to drink fluids. Some patients have gastrointestinal symptoms such as gas, frequent urination, and diarrhea, which are embarrassing and limit their social contact. Female patients may complain of pain during sexual intercourse due to poor lubrication. Skin rashes may develop due to vascular conditions that affect blood flow and content. The development of arthritis may make it difficult for the patient to perform fine motor tasks without pain. Joint pain and frequent nighttime urination lead to unsatisfying sleep and fatigue that may be misinterpreted as depression when it is combined with reports of muscle pain and poor appetite. Patients may develop a raspy, hoarse voice due to inflammation of the larynx. It is estimated that 50% of patients report social isolation due to their symptoms (Wallace et al., 2005). Patients with Sjo¨gren’s syndrome, as with other chronic medical conditions, report higher incidence of emotional distress such as grieving the loss of identity and physical functioning, denial, anger, depression, suicidal ideations, and anxiety (Fremes & Carteron, 2003). DIAGNOSIS

In about 50% of cases, Sjo¨gren’s syndrome is secondary to or comorbid with rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and other rheumatic disorders (Wallace et al., 2005). Primary Sjo¨gren’s syndrome occurs independently of other autoimmune or neurological disorders. However, it is so highly associated with these conditions that patients diagnosed with primary Sjo¨gren’s syndrome are frequently evaluated for systematic lupus erythematosus, scleroderma, rheumatoid arthritis, polymyositis, dermatomyositis, thyroid disease, and autoimmune liver disease (Dyson, 2005). The presence of one of these disorders warrants further evaluation over the next several years. It is estimated that up to 40% of older adults report symptoms of dry eyes and mouth without confirmation of Sjo¨gren’s syndrome or any other disorder (Pompei, Murphy, & American Geriatric Society, 2006). The symptoms are subtle and difficult to identify with a mean onset of 6 years before diagnosis

(Wallace, 2005). The most common symptoms are severe dry eyes (keratoconjunctivitis sicca) and mouth (xerostomia). Other symptoms include dry nose or throat, swelling, difficulty swallowing and chewing food, and thrush (yeast infections of the mouth) (Yu & Scherer, 2007). In addition to the eyes (lachrymal glands) and mouth (salivary glands), the lungs, heart, gastrointestinal tract, pancreas, liver, kidney, and vagina may be affected (Pompei et al., 2006). Poor hydration of these organs and systems causes pain, fatigue, and poor performance of their respective functions (Yu & Scherer, 2007). Unexplained symptoms of bloating, indigestion, and constipation serve as symptoms and show gastrointestinal involvement (Fremes & Carteron, 2003). Irritable bladder syndrome, causing urgency, frequency, pain, and nighttime urination, is a symptom of kidney dysfunction, as are renal stones (Fremes & Carteron, 2003). Dehydrated blood vessels can lead to cutaneous vasculitis, swelling of the blood vessels that lead to skin rash; hyperviscosity, blood that is too thick; or blood conditions such as cryoglobulinemia (Wallace, 2005). Inflammation of the joints leads to arthritis, sometimes chronic, in up to 50% of patients (Fremes & Carteron, 2003). Inflammation of nerve cells can lead to carpal tunnel syndrome or neuropathy (Dyson, 2005). Wallace et al. (2005) reported that 62% of patients have serious dental complications such as excessive caries. Sjo¨gren’s syndrome may be diagnosed with a number of measures (Wallace, 2005). The Schirmer’s eye test measures the amount of cornea tearing. The eyes can also be assessed for keratoconjunctivitis sicca, inflammation of the cornea and conjunctiva due to dryness. The Rose Bengal staining test assesses the cornea for scarring, pitting, or other abnormalities such as ulcers. Tests of saliva production as well as clinical observation are utilized. A lip biopsy can also be performed to evaluate for chemical signs of inflammation. This procedure is rarely utilized because it is very painful. Full blood analyses should be conducted regularly to assess for rheumatic markers such as Ro antibodies, La antibodies, or HLA-DR3 markers (Wallace, 2005). Inflammation is evaluated through the erythrocyte sedimentation rate (ESR), which requires a small blood sample (Dyson, 2005). Some authors distinguish between Sjo¨gren’s syndrome and Sjo¨gren’s disease. Sjo¨gren’s disease indicates the involvement of exocrine glands throughout the body that are connected through the lymph system. Up to 5–10% of Sjo¨gren’s patients may develop this lymphoproliferative malignancy, leading to chronic and severe complications. The presence of Ro and La antinuclear antibodies put the patient at

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increased risk for developing lymphoma. This tendency to result in lymphoma is unique among autoimmune disorders. A rare subtype of Sjo¨gren’s syndrome is Mikulicz’s disease, which is readily diagnosed by enlarged parotid or salivary glands. These patients appear to have the mumps, have salivary glands that are tender to the touch, and excessive inflammation of the salivary glands (Wallace, 2005). TREATMENT

Wallace (2005) describes the treatment of Sjo¨gren’s syndrome as primarily symptomatic. He stated that traditional treatments include the use of artificial tears to moisten the eyes as needed. Mouth gels, hard candies, and sipping on water hydrate the mouth and throat and help to prevent dental decay by washing away bacteria and food particles. Humidifiers are used to treat the primary symptoms as well as the dry nose and throat that can result. Patients are encouraged to visit their optometrist and dentist regularly. Medications have shown some success at increasing salivation and soothing dry eyes. These are pilocarpine, cevimeline, and cyclosporine eye drops. Hydroxychloroquine may treat the immune process itself. Nonsteroidal anti-inflammatory medications may be utilized to treat musculoskeletal symptoms such as arthritis (Fremes & Carteron, 2003). It is important to evaluate and treat the emotional and cognitive symptoms associated with Sjo¨gren’s syndrome due to its chronic nature (Fremes & Carteron, 2003). Much research has confirmed the fact that treatment compliance is increased when the patient has a sense of control and optimism, which may be provided through education concerning symptoms, medical procedures, and treatment options. Psychotropic medications, therapy, and relaxation techniques should be recommended. Patients may feel isolated and need additional social support, increasing the need for family therapy or support groups. Jessie L. Morrow Charles Golden Dyson, S. (2005). Positive options for Sjogren’s syndrome: Self help and treatment. Alameda, CA: Hunter House. Fremes, R., & Carteron, N. (2003). A body out of balance: Understanding and treating Sjogren’s Syndrome. New York: Avery. Hanger, N. C., & Schneebaum, A. B. (2003). The first year — Lupus: An essential guide for the newly diagnosed. Emeryville, CA: Marlowe and Company.

Pompei, P., Murphy, J. B., & American Geriatric Society. (2006). Geriatrics review syllabus: A core curriculum in geriatric medicine. Hoboken, NJ: Blackwell Publishing. Sullivan, D. D., Dartt, D. A., & Meneray, M. A. (1998). Lacrimal gland, tear film, and dry eye syndromes 2: Basic science and clinical relevance. New York: Springer. Wallace, D. J. (2005). The lupus book: A guide for patients and their families (3rd ed.). New York: Oxford University Press. Wallace, D. J. (Ed.). Bromet, E. J., Sjogren’s Syndrome Foundation. (2005). The new Sjogren’s syndrome handbook. New York: Oxford University Press. Yu, W., & Scherer, W. (2007). What to eat for what ails you: How to treat illnesses by changing the food and vitamins in your diet. Beverly, MA: Fair Winds.

SLEEP APNEA DESCRIPTION

Sleep apnea is usually a chronic (ongoing) condition that disrupts sleep three or more nights each week. One often moves out of deep sleep and into light sleep when one’s breathing pauses or becomes shallow resulting in poor sleep quality and consequently fatigue during the day. In fact, sleep apnea is one of the leading causes of excessive daytime sleepiness. The Greek word ‘‘apnea’’ literally means ‘‘without breath.’’ There are three types of apnea: obstructive, central, and mixed; of the three, obstructive is the most common. Despite the difference in the root cause of each type, in all three, people with untreated sleep apnea pause in breathing or take shallow breaths, sometimes hundreds of times during the night, which can last for a few seconds to minutes often occurring 5–30 times or more an hour. Typically normal breathing resumes with a loud snort or choking sound as air tries to squeeze past the blockage (American Sleep Apnea Association, 2008). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The underlying physiology of sleep apnea varies based on the type of sleep apnea presented. Obstructive sleep apnea occurs when the muscles in the back of the throat relax. These muscles support the soft palate, the triangular piece of tissue hanging from the soft palate (uvula), the tonsils, and the tongue. When the muscles relax, the airway narrows or closes when taking a breath, and breathing momentarily stops. This may lower the level of oxygen in the blood. The brain senses this inability to breathe and

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briefly rouses the patient from sleep so that the patient can reopen the airway. This awakening is usually so brief that most patients don’t remember it. Obstructive sleep apnea is caused by repetitive upper airway obstruction during sleep as a result of narrowing of the respiratory passages. Patients with the disorder are most often overweight, with associated peripharyngeal infiltration of fat and/or increased size of the soft palate and tongue. Some patients have airway obstruction because of a diminutive or receding jaw that results in insufficient room for the tongue. These anatomic abnormalities decrease the cross-sectional area of the upper airway. Decreased airway muscle tone during sleep in combination with the pull of gravity in the supine position further decreases airway size, impeding airflow during respiration. Initially, partial obstruction may occur and lead to snoring. As tissues collapse further or the patient rolls over on his or her back, the airway may become completely obstructed. Whether the obstruction is incomplete (hypopnea) or total (apnea), the patient struggles to breathe and is aroused from sleep. Often, arousals are only partial and are unrecognized by the patient, even if they occur hundreds of times a night. The obstructive episodes are often associated with a reduction in oxyhemoglobin saturation. With each arousal event, the muscle tone of the tongue and airway tissues increases. This increase in tone alleviates the obstruction and terminates the apneic episode. Soon after the patient falls back to sleep, the tongue and soft tissues again relax, with consequent complete or partial obstruction and loud snoring (Patil, Schneider, Schwartz, & Smith, 2007). The combinations of the physiological characteristics causing obstructive sleep apnea may vary considerably among patients. Most obstructive apnea patients have an anatomically small upper airway with augmented pharyngeal dilator muscle activation maintaining airway patency awake, but not asleep. However, individual variability in several phenotypic characteristics may ultimately determine who develops apnea and how severe the apnea will be. These include: (1) upper airway anatomy, (2) the ability of upper airway dilator muscles to respond to rising intrapharyngeal negative pressure and increasing CO2 during sleep, (3) arousal threshold in response to respiratory stimulation, and (4) loop gain (ventilatory control instability). As a result, patients may respond to different therapeutic approaches based on the predominant abnormality leading to the sleep-disordered breathing. Occasionally, obstructive sleep apnea can be caused by less common medical problems, including hypothyroidism, acromegaly, and renal failure.

Neuromuscular disorders such as postpolio syndrome can result in inadequate neuromuscular control of the upper airway and lead to obstructive sleep apnea. Restrictive lung disease from scoliosis has also been associated with the disorder. Central sleep apnea, which is far less common, occurs when the brain fails to transmit signals to the breathing muscles. The patient may awaken with shortness of breath or have a difficult time getting or staying asleep. Like obstructive sleep apnea, snoring and daytime sleepiness can occur. Central sleep apnea, in its various forms, is generally the product of an unstable ventilatory control system (high loop gain) with increased controller gain (high hypercapnic responsiveness) generally being the cause. High plant gain can contribute under certain circumstances (hypercapnic patients). The most common cause of central sleep apnea is heart disease, and less commonly, stroke. People with central sleep apnea may be more likely to remember awakening than people with obstructive sleep apnea (White, 2005). Mixed (complex) apnea, as the name implies, is a combination of the two. With each apnea event, the brain briefly arouses people with sleep apnea in order for them to resume breathing, but consequently sleep is extremely fragmented and of poor quality. People with complex sleep apnea have upper airway obstruction just like those with obstructive sleep apnea, but they also have a problem with the rhythm of breathing and occasional lapses of breathing effort (Mayo Clinic, 1998). In general, sleep apnea may occur whether the patient is young or old, male or female. Even children can have sleep apnea. But certain factors put individuals at increased risk. In the case of obstructive sleep apnea, risk factors include: excess weight; neck circumference; high blood pressure (hypertension); a narrowed airway; being male; being older (sleep apnea occurs two to three times more often in adults older than 65); family history; use of alcohol, sedatives or tranquilizers; and smoking. In the case of central sleep apnea, risk factors include: being male, heart disorders, and stroke or brain tumor (these conditions can impair the brain’s ability to regulate breathing).The same risk factors for obstructive sleep apnea are also risk factors for complex sleep apnea. In addition, complex sleep apnea may be more common in people who have heart disorders (Mayo Clinic, 1998). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The most common complaints associated with sleep apnea involve loud snoring, disrupted sleep, and

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excessive daytime sleepiness. Patients with apnea suffer from fragmented sleep and may develop cardiovascular abnormalities because of the repetitive cycles of snoring, airway collapse, and arousal. The snoring and apneic episodes may be worse after the patient drinks alcohol or takes sleeping pills because these sedatives decrease pharyngeal muscle tone and can exacerbate obstructive sleep apnea. Although most patients are overweight and have a short, thick neck, some are of normal weight but have a small, receding jaw. Because many patients are not aware of their heavy snoring and nocturnal arousals, obstructive sleep apnea may remain undiagnosed; therefore, it is helpful to question the bedroom partner of a patient displaying symptoms such as chronic sleepiness and fatigue. People with sleep apnea may also complain of memory problems, morning headaches, mood swings or feelings of depression, a need to urinate frequently at night (nocturia), and impotence. Gastroesophageal reflux disease (GERD) may be more prevalent in people with sleep apnea. Children with untreated sleep apnea may be hyperactive and may be diagnosed with attention deficit hyperactivity disorder (ADHD). Daytime fatigue and sleepiness are the most significant complaints of the patient with obstructive sleep apnea with symptoms ranging along a continuum, for example, the patient falls asleep during sedentary activities, such as watching television or sitting in a movie theater. This can progress to falling asleep in embarrassing situations, such as during meals or when sitting in a car stopped at a traffic light. The patient often has to nap during the day, but typically wakes up unrefreshed. Patients with obstructive sleep apnea show neuropsychological impairments ranging from vigilance decrements, attentional lapses, and memory gaps to decreased motor coordination. In terms of neurobehavioral performance, studies have revealed objective daytime somnolence but little impairment in memory and motor domains (Kelly, Claypoole, & Coppel, 1990). Cerebral data have shown gray matter loss in the frontal and temporo-parieto-occipital cortices, the thalamus, hippocampal region, some basal ganglia and cerebellar regions, mainly in the right hemisphere. A decrease in brain metabolism is generally right-lateralized, but more restricted than gray matter density changes, and involves the precuneus, the middle and posterior cingulate gyrus, and the parieto–occipital cortex, as well as the prefrontal cortex. Even in cases of patients displaying only minor memory and motor impairments, there are still significant cerebral changes in terms of both gray matter density and metabolic levels, indicating that these patients

may benefit from cognitive reserve and compensatory mechanisms. Therefore, it is possible that cerebral changes in obstructive sleep apnea patients may precede the onset of notable neuropsychological consequences (Khalid, 2009). Neuropsychological evaluations can address the general deficits associated with sleep apnea such as the Beck Depression Inventory to assess depression, the Hopkins Verbal Learning Task to assess memory, and the Stroop Test to assess attention, mental speed, and mental control. Alternatively, a battery of tests such as the Halstead–Reitan or Luria–Nebraska Neuropsychological Battery, assessing a broad range of functional domains may be administered. These evaluations could be repeated after a treatment protocol has been instituted in order to assess pre- and postfunctioning. The neuropsychological evaluation may also be tailored according to the specific needs of the patient. For example, if the effects of a treatment were being assessed in terms of a patient’s driving ability, specific tests would be used to measure cognitive abilities accessed while driving a car. (1) Vigilance: subjects have to watch a beam on a screen moving up and down. They have to react on rarely occurring higher swings by pressing a button. (2) Alertness: simple reaction on a lamp flashing upwards. (3) Divided attention: patients have to press colored lamps when the corresponding color flashes on a board. In addition, they have to react to acoustic signs by pressing buttons and foot pedals when indicated by signals (Orth et al., 2005). DIAGNOSIS

A physician may make an evaluation based on the symptoms or may refer the patient to a sleep disorder center to undergo further evaluation that often involves overnight monitoring of breathing and other body functions during sleep. Tests to detect sleep apnea may include nocturnal polysomnograph, where the patient is hooked up to equipment that monitors heart, lung, and brain activity, breathing patterns, arm and leg movements, and blood oxygen levels asleep. Oximetry is another screening method that involves using a small machine that monitors and records the oxygen level in the blood while the patient is asleep. If the results are abnormal, the doctor may prescribe polysomnography to confirm the diagnosis. Oximetry doesn’t detect all cases of sleep apnea, so the doctor may still recommend a polysomnogram even if the oximetry results are normal. Portable cardiorespiratory testing has also demonstrated utility. Under certain circumstances, the

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doctor may provide the patient with simplified tests to be used at home to diagnose sleep apnea. These tests usually involve oximetry, measurement of airflow, and measurement of breathing patterns. A patient with obstructive sleep apnea may be referred by his or her doctor to an ear, nose, and throat doctor (otolaryngologist) to rule out any blockage in the nose or throat. An evaluation by a heart doctor (cardiologist) or a doctor who specializes in the nervous system (neurologist) may be necessary to look for causes of central sleep apnea.

TREATMENT

For milder cases of sleep apnea, the doctor may recommend lifestyle changes such as losing weight, quitting smoking, avoiding alcohol and medications such as tranquilizers and sleeping pills (Veasey et al., 2006). Other recommendations include sleeping on one’s side or abdomen rather than on one’s back. Nasal passages can be kept open at night by using a saline nasal spray, nasal decongestants, or antihistamines. These medications, however, are generally recommended only for short-term use. If these measures don’t improve signs and symptoms or if apnea is moderate to severe, a number of other treatments are available. Certain devices can help open up a blocked airway. In other cases, surgery may be necessary (Mayo Clinic, 1998). Most alternative medicines for sleep apnea have not been well studied. Acupuncture has shown some benefit but also needs more study and should therefore be used in conjunction with standard treatments rather than as a replacement. Gershom T Lazarus Antonio E. Puente American Sleep Apnea Association. (2008). Sleep apnea. Retrieved February 2009, from American Sleep Apnea Association Web site: http://www.sleepapnea.org/ Kelly, D. A., Claypoole, K. H., & Coppel, D. B. (1990). Sleep apnea syndrome: Symptomatology, associated features, and neurocognitive correlates. Neuropsychology Review, 1(4), 323–342. Mayo Clinic. (1998). Sleep apnea. Retrieved February 2009, from Mayo Clinic. Web site: http://www.mayoclinic. com/health/sleep-apnea/DS00148 Orth, M., Duchna, H. W., Leidag, M., Widdig, W., Rasche, K., Bauer, T. T., et al. (2005). Driving simulator and neuropsychological testing in OSAS before and under CPAP therapy. The European Respiratory Journal, 26 898–903.

Patil, S., Schneider, H., Schwartz, A., & Smith, P. (2007). Adult obstructive sleep apnea pathophysiology and diagnosis. Chest, 132(1), 325–337. Veasey, S. C., Guilleminault, C., Strohl, K. P., Sanders, M. H., Ballard, R. D., & Magalang, U. J. (2006). Medical therapy for obstructive sleep apnea: A review by the medical therapy for obstructive sleep apnea task force of the standards of practice committee of the American Academy of Sleep Medicine. Sleep: Journal of Sleep and Sleep Disorders Research, 29(8), 1036–1044. White, D. (2005). Pathogenesis of obstructive and central sleep apnea. American Journal of Respiratory and Critical Care Medicine, 172, 1363–1370. Yaouhi, K., Bertran, F., Clochon, P., Me´zenge, F., Denise, P., Foret, J. et al (2009). A combined neuropsychological and brain imaging study of obstructive sleep apnea. Journal of Sleep Research, 18(1), 36–48.

SOMATOFORM AND CONVERSION DISORDERS DESCRIPTION

Somatoform disorders are characterized by persistent bodily symptoms and concerns that cannot be fully accounted for by a diagnosable medical condition (Janca, Isaac, & Ventouras, 2006). The physical symptoms ‘‘suggest a general medical condition,’’ but ‘‘are not fully explained by a general medical condition, by the direct effects of a substance, or by another mental disorder’’ (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision [DSM-IV-TR]; American Psychiatric Association [APA], 2000, p. 485). The DSM-IV-TR lists the following somatoform disorders: somatization, undifferentiated somatoform, conversion, pain, hypochondriasis, body dysmorphic disorder, and somatoform disorder not otherwise specified (APA, 2000, p. 485). These will be described in detail. The DSM-IV-TR (APA, 2000) reports the following lifetime prevalence rates for the somatoform disorders: somatization disorder, 0.2–2% among women and less than 0.2% in men; conversion disorder, 0.01–0.5% in general population samples, up to 3% of outpatient referrals to mental health clinics, and 1–14% in general medical/surgical inpatients; hypochondriasis, 1–5% in the general population and 2–7% among primary care outpatients; and body dysmorphic disorder, 5–40% in clinical mental health settings in individuals with anxiety or depressive disorders; and 6–15% in cosmetic surgery and

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dermatology settings (APA, 2000, p. 509). The prevalence rates of somatoform disorders reported in the DSM-IVTR are significantly lower than those reported in other research studies. Somatoform disorders are often comorbid with anxiety (Karvonen et al., 2007; Leiknes, Finset, Moum, & Sandanger, 2007) and depression (Leiknes et al., 2007) at rates approaching 50%. High prevalence rates of somatoform disorders leads to increased usage of medical care. Patients with somatization had approximately twice the outpatient and inpatient medical care utilization and twice the annual medical care costs of patients without such difficulties (Barsky, Orav, & Bates, 2005). When Barsky et al. (2005) extrapolated their findings to the national level, they estimated that $256 billion a year in medical care costs are attributable to the incremental effect of somatization alone in the United States. Somatization is associated with female gender, lower level of education (Hiller, Rief, & Brahler, 2006; Karvonen et al., 2007), age greater than 45, lower household income, and a rural residence (Hiller et al., 2006). Research by Hiller et al. (2006) found that the most common complaints in patients with somatoform disorders were pain (e.g., back, head, joints, and extremities), food intolerance, sexual indifference, painful menstruation, and erectile/ ejaculatory dysfunction.

somatoform disorder exhibited the lowest scores of branched chain amino acids (BCAAs). The researchers hypothesized that because BCAA oxidation supplies energy to the muscle and nitrogen for the glucose alanine cycle, BCAAs may have an important function as a peripheral factor contributing to the development of unexplained physical symptoms. Neuroimaging studies suggest differences between individuals with somatoform disorders versus controls. Structural neuroimaging (morphometric MRI) in 10 individuals with conversion disorder revealed smaller mean volumes of the left and right basal ganglia and a smaller right thalamus than controls (LaFrance, 2009). Deficits in attention and inhibition have been observed in patients with sensory and motor conversion disorders (LaFrance, 2009). Using with SPECT and functional MRI, LaFrance (2009) identified that the anterior cingulate gyrus and the orbitofrontal cortex potentially mediate the hypothesized attention and inhibition findings observed in patients with sensory and motor conversion disorders. In addition, a PET study by Hakala et al. (2002) demonstrated that the patients diagnosed with somatization disorder or undifferentiated somatoform disorder had lower cerebral metabolism rates of glucose in bilateral caudate nuclei, left putamen, and right precentral gyrus compared with healthy volunteers.

NEUROPATHOLOGY/PATHOPHYSIOLOGY

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Research demonstrates increased levels of physiological arousal and subjective feelings of tension when compared with controls in patients with tendencies toward somatization (Rief, Shaw, & Fichter, 1998). Rief et al. (1998) found that persons demonstrating symptoms of somatization had higher morning salivary cortisol concentrations, higher pulse rates, lower levels of finger pulse volume, and subjective feeling of tension. They also found that during a mental stress task, these persons reported more subjective distress and had higher pulse rates, whereas controls exhibited habituation to the experimental situation. Campayo et al. (2007) found mean P300 latency was significantly higher in persons with somatization disorder compared with controls, demonstrating electrophysiological disturbances in the cognitive processing of information, particularly attention and memory. Rief et al. (2004) found that reduced amounts of certain amino acids are correlated with medically unexplained symptoms. In this study, persons with medically unexplained symptoms had significantly lower levels of plasma tryptophan (a principal precursor of serotonin), and individuals with diagnosable

Research on the neuropsychological performance of persons with somatoform disorders is inconclusive, possibly because of questionable test effort. One study comparing 10 women diagnosed with somatization disorder or undifferentiated somatoform disorder and 10 controls concluded that those with somatic symptoms performed significantly below controls in tests of semantic memory, verbal episodic memory, and visuospatial tasks and were slower to complete attentional tasks (Niemi, Portin, Aalto, Hakala, & Karlsson, 2002). However, Drane et al. (2006) found that many patients with psychogenic nonepileptic seizures (NES) did not put forth maximum effort during neuropsychological assessment based on the Word Memory Test and that when they did put forth valid effort, they demonstrated less objective evidence of neuropathology than did patients with bona fide epileptic seizures (ES). Research using Minnesota Multiphasic Personality Inventory-2 (MMPI-2) profiles of patients with somatoform disorders found that participants with pain disorder associated with psychological factors

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had elevated scores on MMPI-2 scales: Hs (Hysteria), D (Depression), and Hy (Hypochondriasis), with Hs and Hy higher than D (Monsen, 2001). Patients with conversion disorder have produced elevated scores on the MMPI-2 Hs Scale (Shiri, Tsenter, Livai, Schwartz, & Vatine, 2003). The Personality Assessment Inventory (PAI) has demonstrated utility in the diagnosis of NES. Wagner, Wymer, Topping, and Pritchard (2005) created a NES indicator by subtracting the Somatic Health Concerns Scale from the Somatic Conversion Scale (SOM-C), where a score greater than zero suggests NES based on the notion that NES participants present with greater conversion symptoms relative to overall health concerns. The NES indicator produced sensitivity of 84% and specificity of 73% for the diagnosis of NES versus ES (Wagner et al., 2005). However, research by Thompson, Hantke, Phatak, and Chaytor (2010) found the SOM-C scale alone to be just as useful at diagnosing NES. DIAGNOSIS

In the DSM-IV-TR (APA, 2000) common features of somatoform disorders include the presence of medically unexplainable physical symptoms that also cannot be explained by the direct effects of a substance or by another mental disorder (p. 485). As with other DSM-IV-TR diagnoses, ‘‘The symptoms must cause clinically significant distress or impairment in social, occupational, or other areas of functioning’’ (p. 485). The DSM-IV-TR (to which readers are directed for thorough diagnostic criteria) includes the following seven somatoform disorders (APA, 2000, p. 485): 1. Somatization disorder is a polysymptomatic disorder that begins with onset before age 30 extends over a period of years, and characterized by a combination of four or more pain symptoms: two or more gastrointestinal symptoms, one or more sexual symptom, and one or more pseudoneurological symptom. 2. Undifferentiated somatoform disorder is characterized by unexplained physical complaints, which last at least 6 months and are below the threshold for a diagnosis of somatization disorder. 3. Conversion disorder involves unexplained symptoms or deficits affecting voluntary motor or sensory function, suggesting a neurological condition or a general medical condition. Psychological factors are judged to be associated with the symptoms or deficits. 4. Pain disorder is characterized by pain as the focus of clinical attention. In addition, psychological factors

are judged to have an important role in pain’s onset, severity, exacerbation, or maintenance. 5. Hypochondriasis is the preoccupation with the fear or idea of having a serious disease based on the patient’s misperceptions of bodily symptoms or bodily functions. 6. Body dysmorphic disorder is the preoccupation with an imagined or exaggerated defect in physical appearance. 7. Somatoform disorder not otherwise specified is included for coding disorders with somatoform symptoms that do not meet the criteria for any specific somatoform disorders. The DSM-5 somatic symptoms disorders work group proposes replacing somatoform disorders with somatic symptom disorders and subsuming psychological factors affecting medical conditions and factitious disorders in this section because they involve presentation of physical symptoms and/or concern about medical illness (May 10, 2010, http:// www.dsm5.org/Pages/Default.aspx). The work group also proposes integrating somatization disorder, hypochondriasis, undifferentiated somatoform disorder, and pain disorder as complex somatic symptom disorder as they each share common features of somatic symptoms and cognitive distortions characterized by persistent (at least 6 months) multiple somatic symptoms (or one severe symptom) that are distressing to the patient, in addition to misattributions, excessive concern or preoccupation with symptoms and illness, and that the state of being symptomatic is chronic and persistent. The DSM-5 somatic symptoms disorders work group also proposes modifying the diagnostic criteria for conversion disorder, including removing the requirements that the clinician actively establish that the patient is not feigning and that there are associated psychological factors, and include the importance of obtaining positive evidence of the diagnosis from appropriate neurological assessment and testing (http://www.dsm5.org/Pages/Default.aspx). Lastly, body dysmorphic disorder is being given consideration as an anxiety and obsessive-compulsive spectrum disorder. It remains to be seen, however, which if any of these changes will be incorporated in the DSM-5. TREATMENT

Multiple strategies consisting of psychosocial and pharmacological treatments as well as educational interventions have been effective at managing somatoform disorders (Janca et al., 2006). In particular, cognitive behavioral therapy (CBT) has been effective

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across a spectrum of somatoform disorders including somatization disorder and its lower threshold variants, and also for the broader category of medically unexplained symptoms, reducing physical symptoms, psychological distress, and disability (Kroenke, 2007; LaFrance, 2009; Sumathipala, 2007). Group CBT for the treatment of body dysmorphic disorder and somatization disorder has also been found to be effective (LaFrance, 2009). In addition, Nanke and Rief (2003) found that using biofeedback in conjunction with individual CBT, physical therapy, and medical care in patients with somatization symptoms showed substantial reduction of catastrophizing of somatic sensations and a higher acceptance of psychosocial casual attributions. In addition to cognitive behavioral intervention, research has also demonstrated psychopharmacological interventions to be effective in the treatment of somatoform disorders. For example, Altamura et al. (2003) found that the use of levosulpiride, a selective antagonist of central dopamine receptors, led to reduced total number of somatoform disorder symptoms when compared with placebo. In addition, patients with somatoform disorders that include an obsessional component (e.g., hypochondriasis, body dysmorphic disorder) tend to respond well to selective serotonin reuptake inhibitors (Fallon, 2004). Luo et al. (2009) found that persistent somatoform pain disorder patients with comorbid depression demonstrated a superior analgesic response than the individuals without depression when taking fluoxetine, which they attributed to the antidepressant effect. Other randomized, controlled trials have also demonstrated efficacy of antidepressant compounds (e.g., St. John’s wort, opipramol [a tricyclic compound available in Germany]) in managing the symptoms of somatoform disorders (LaFrance, 2009). Melissa M. Swanson Mary E. Haines Timothy F. Wynkoop Altamura, A. C., DiRosa, A., Ermentini, A., Guaraldi, G. P., Invernizzi, G., Rudas, N., et al. (2003). Levosulpiride in somatoform disorders: A double-blind, placebocontrolled cross-over study. International Journal of Psychiatry in Clinical Practice, 7, 155–159. American Psychiatric Association. (2000). Diagnostic and statistical manual (4th ed., text revision). Washington, DC: Author. Barsky, A. J., Orav, E. J., & Bates, D. W. (2005). Somatization increases medical utilization and costs independent of psychiatric and medical comorbidity. Archives of General Psychiatry, 62, 903–910.

Campayo, J. G., Lopez, A. P., Lafita, C. A., Bara, I. M., Zaera, I. D., & Alvarez-Manzaneda, E. D. (2007). P300 endogen evoked potentials in somatization disorder: A controlled study. Actas Espanolas de Psiquiatria, 35, 52–58. Drane, D. L., Williamson, D. J., Stroup, E. S., Holmes, M. D., Jung, M., Koerner, E., et al. (2006). Cognitive impairment is not equal in patients with epileptic and psychogenic nonepileptic seizures. Epilepsia, 47, 1879–1886. Fallon, B. A. (2004). Pharmacotherapy of somatoform disorders. Journal of Psychosomatic Research, 56, 455–460. Hakala, M., Karlsson, H., Ruotsalainen, U., Koponen, S., Bergman, J., Stenman, H., et al. (2002). Severe somatization in women is associated with altered cerebral glucose metabolism. Psychological Medicine, 32, 1379–1385. Hiller, W., Rief, W., & Brahler, E. (2006). Somatization in the population: From mild bodily misperceptions to disabling symptoms. Social Psychiatry and Psychiatric Epidemiology, 41, 704–712. Janca, A., Isaac, M., & Ventouras, J. (2006). Towards better understanding and management of somatoform disorders. International Review of Psychiatry, 18, 5–12. Karvonen, J. T., Joukamaa, M., Herva, A., Jokelainen, J., Laksy, K., & Veijola, J. (2007). Somatization symptoms in young adult Finnish population: Associations with sex, educational level and mental health. Nordic Journal of Psychiatry, 61, 219–224. Kroenke, K. (2007). Efficacy of treatment for somatoform disorders: A review of randomized controlled trials. Psychosomatic Medicine, 69, 881–888. LaFrance, W. C. (2009). Somatoform disorders. Seminars in Neurology, 29, 234–246. Leiknes, K. A., Finset, A., Moum, T., & Sandanger, I. (2007). Current somatoform disorders in Norway: Prevalence, risk factors, and comorbidity with anxiety, depression, and musculoskeletal disorders. Social Psychiatry and Psychiatric Epidemiology, 42, 698–710. Luo, Y., Zhang, M., Wu, W., Li, C., Lu, Z., & Li, Q. (2009). A randomized double-blind clinical trial on analgesic efficacy of fluoxetine for persistent somatoform pain disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33, 1522–1525. Monsen, K. (2001). Psychological functioning and bodily conditions in patients with pain disorder associated with psychological factors. British Journal of Medical Psychology, 74, 183–195. Nanke, A., & Reif, W. (2003). Biofeedback-based interventions in somatoform disorders: A randomized control trial. Acta Neuropsychiatrica, 15, 249–256. Niemi, P. M., Portin, R., Aalto, S., Hakala, M., & Karlsson, H. (2002). Cognitive functioning in severe somatization — a pilot study. Acta Psychiatrica Scandinavica, 106, 461–463. Rief, W., Pilger, F., Ihle, D., Verkerk, R., Scharpe, S., & Maes, M. (2004). Psychobiological aspects of somatoform

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disorders: Contributions of monoaminergic transmitter systems. Neuropsychobiology, 49, 24–29. Rief, W., Shaw, R., & Fichter, M. M. (1998). Elevated levels of psychophysiological arousal and cortisol in patients with somatization syndrome. Psychosomatic Medicine, 60, 198–203. Shiri, S., Tsenter, J., Livai, R., Schwartz, I., & Vatine, J. J. (2003). Similarities between the psychological profiles of complex regional pain syndrome and conversion disorder patients. Journal of Clinical Psychology in Medical Settings, 10, 193–199. Sumathipala, A. (2007). What is the evidence for the efficacy of treatments for somatoform disorder? A critical review of previous intervention studies. Psychosomatic Medicine, 69, 889–900. Thompson, A. W., Hantke, N., Phatak, V., & Chaytor, N. (2010) The Personality Assessment Inventory as a tool for diagnosing psychogenic nonepileptic seizures. Epilepsia, 51, 161–164. Wagner, M. T., Wymer, J. H., Topping, K. B., & Pritchard, P. B. (2005). Use of the Personality Assessment Inventory as an efficacious and cost-effective diagnostic tool for nonepileptic seizures. Epilepsy & Behavior, 7, 301–304.

SOTOS’ SYNDROME DESCRIPTION

Sotos’ syndrome, also referred to as cerebral gigantism, is an overgrowth syndrome characterized by rapid growth during prenatal and postnatal phases, without an identified endocrine disorder. A person afflicted with the disorder will likely exhibit distinctive facial features, such as a protrusive forehead, greater than average distance between the eyes, and the eyes may have a downward slant. Advanced bone age, developmental delay and mental retardation are also common features of the disorder. Affected children may exhibit behavioral and learning difficulties. This is a nonprogressive neurological and genetic disorder (Brooks, Clayton, Brown, & Savage, 2005; Harris, 1998; National Organization for Rare Disorders [NORD], 2002). Sotos’ syndrome affects males and females equally, occurring in all ethnic groups throughout the world. The syndrome appears sporadically, although familial hereditary cases are not uncommon. In instances where familial inheritance is evident, an autosomal dominance has been suggested. There have been many cases where there is parent-to-child transmission over several generations (NORD, 2002; Rourke, 1995).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

Although Sotos’ syndrome is thought to be a hereditary disorder, the mode of transmission has been debated. The exact cause is unknown, and it is not clear whether all patients have the same root defect. Sixty to seventy-five percent of patients have shown a deletion or point mutation of a single gene, NSD1, located at chromosome 5q35. This indicates that haplo-insufficiency of NSD1 is possibly a major cause of Sotos’ syndrome. Furthermore, although a number of cases appear sporadic, it is likely that some cases go undiagnosed because of less pronounced dysmorphic facial features. Therefore, some cases that appear to be sporadic may, in fact, have a genetic link that has gone undetected (Brooks et al., 2005; NORD, 2002; Rourke, 1995). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Sotos’ syndrome is detected primarily by physical characteristics. There is rapid growth in the first 4 years of life, as well as prenatal overgrowth. The excessive growth is commonly evident at birth, even though growth hormone levels usually fall within a normal range. Growth rate is excessive in the first few years and then parallels the average height. Hypotonia, or low muscle tone, is usually present during infancy. Sitting, crawling, walking and other developmental milestones are often delayed. The hypotonia may improve as children get older. Bone age is usually advanced by the 4th year, and puberty will possibly occur early, yet within the normal age range. There is a distinctive craniofacial configuration possibly including a prominent forehead, a receding frontoparietal hairline, a dolichocephalic large head, increased distance between the eyes (hypertelorism), down-slanting of palpebral fissures, high narrow palate and a small, pointed chin. X-rays show a larger-than-average skull size, a high-orbital roof, and an increased interorbital distance. ECGs are commonly abnormal. Most patients will have a premature eruption of teeth. Around 50% of cases will also have a seizure disorder. As adults, those affected will reach a height 50% greater than that of the average adult height, yet the average excessive height will still fall within the upper range for normal height (Brooks et al., 2005; Gillberg, 2003; NORD, 2002). Behavioral problems and learning difficulties are prominent. Common behavioral problems may include aggressiveness, poor social relationships, destructiveness, compulsivity, and irritability. More

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than half display a low-frustration tolerance and sleep difficulties. There will likely be a delay in language and motor development, and 80–85% of patients will have a mental deficiency. Language is also deficient with a likelihood of echolalia, slurred speech, and poor articulation. There seems to be a large discrepancy between verbal and performance IQ, with performance IQ being lower than verbal IQ, probably as a result of perceptual problems. Two-thirds of those affected by Sotos’ syndrome will have an IQ ranging from 50 to 70, whereas the remaining one-third will have an IQ ranging from 70 to 90. Children will likely have behavioral problems, attention deficits, and cognitive dysfunction (Harris, 1998). DIAGNOSIS

There are no biochemical markers for Sotos’ syndrome. The diagnosis is made based on clinical grounds with the most characteristic manifestations being the excessive growth and the distinctive facial and cranial malformations. Without these physical characteristics, a diagnosis for Sotos’ syndrome will not be made. There are diagnostic tests used in differential diagnosis in order to exclude other possibilities including Fragile X syndrome, which can be ruled out or accepted by means of DNA analysis (NORD, 2002). There is often significant variation in the presentation of the disorder. In some cases, the signs may be so mild that a diagnosis is never made. According to Harris (1998), the classic diagnostic criteria for Sotos’ syndrome include rapid growth within the 1st year of life resulting in infants being over the 97th percentile for height. Accelerated growth rate continues for the next 4 years and then levels off to a normal rate of growth (NORD, 2002). Diagnosis is generally made in younger children based on the excessive growth, facial features, and developmental delay. According to Brooks et al. (2005), diagnosis will not likely be made if at least one of the following criteria are not met: height above the 97th percentile based on age, head circumference larger than the 97th percentile, and/or boneage greater than the 90th percentile. Any of the symptoms combined with developmental delay will likely lead to a diagnosis of Sotos’ syndrome (Brooks et al., 2005; Harris, 1998; NORD, 2002). TREATMENT

Important interventions include social skills training, behavior management, and management of mental retardation. Individual therapies including speech

therapy, occupational therapy, special education support, physical therapy, and behavioral therapy will help with the management of any mental retardation and behavioral problems. Although excessive height is not usually a concern for male children, some feel that it is a problem in female children and suggest high doses of estrogen to lessen linear growth. Psychological counseling is useful for those affected who exhibit behavioral problems and act immaturely for their age (Harris, 1998; NORD, 2002). Family therapy is essential to help parents understand and deal with the children’s difficulties. Kelly R. Pless Charles Golden Brooks, C. G. D., Clayton, P. E., Brown, R. S., & Savage, M. O. (2005). Brook’s clinical pediatric endocrinology. Oxford: Blackwell Publishing. Gillberg, C. (2003). Clinical child neuropsychiatry. New York: Cambridge University Press. Harris, J. C. (1998). Developmental neuropsychiatry: Assessment, diagnosis and treatment of developmental disorders (Vol. II). New York: Oxford University Press. National Organization for Rare Disorders. (2002). NORD Guide to rare disorders. Philadelphia: Lippincott Williams & Wilkins. Rourke, B. P. (1995). Syndrome of nonverbal learning disabilities: Neurodevelopmental manifestations. New York: Guilford Press.

SPINA BIFIDA DESCRIPTION

Spina bifida, which literally means ‘‘cleft spine’’ in Latin, is the most common birth defect related to the central nervous system (CNS). Spina bifida results from a malformation of the osseous (bony) spine (Izenberg, 2000; Wong, 1997), often developing during the first 28 weeks of pregnancy (Wong et al., 1999). Specifically, spina bifida involves the failure to close at the caudal end of the neural tube, which results in malformation of the spinal cord, vertebral column and individual vertebrae (Evans, 1987). Because spina bifida involves the CNS, it can manifest as a range of physical, psychological, and cognitive problems. The condition often affects the development of the brain, spinal cord, and/or their protective coverings (i.e., meninges) (Botto, Moore, Khoury, & Erickson, 1999).

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Although the causes of spina bifida are not fully known, it is commonly accepted that the disorder has a multifactorial etiology and may involve a combination of genetic, nutritional, and environmental causes. One of the primary environmental risks is insufficient intake of folic acid in the mother’s diet during pregnancy, which corresponds with about 70% of cases of all neural tube defects. The other 30% of cases are related to factors that may include maternal age, maternal fevers, intrauterine viral infections, hormonal effects, vitamin deficiencies, excess of vitamin A, maternal diabetes, maternal alcohol use, and other teratogens (Botto et al., 1999; Riccio & Pizzitola-Jarratt, 2005). Spina bifida is the most common neural tube defect in the United States and affects about 1,500– 2,000 of the more than 4 million babies born in the country each year. There is a significantly higher incidence of spina bifida in Caucasians than in African Americans (Riccio & Pizzitola-Jarratt, 2005; Shin, Besser, & Correa, 2008). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Although the primary defect in spinal bifida is related to a failure of the neural tube to close during embryonic development, there is evidence that the defect may also be related to splitting of the already closed neural tube. The splitting may be a result of an abnormal increase in cerebrospinal fluid (CSF) pressure during the first trimester of the pregnancy (Wong, 1997; Wong et al., 1999). The degree of neurological abnormality is positively correlated with the level of anatomic defects. As is the case with most neural tube disorders, spina bifida is related to a wide range of primary and secondary deficits. Infants born with spina bifida often suffer early complications, including problems related to walking and coordination, skeletal malformations, incontinence of urinary and bowel functions, limb numbness, hydrocephalus, and paralysis. (Chiartti et al., 2008; Riccio & Pizzitola-Jarratt, 2005; Shin et al., 2008). Secondary complications may include scoliosis, seizures, shunt complications, urinary tract infections, allergies, skin ulcerations, obesity, decreased growth, learning and cognitive problems, and emotional difficulties (Hoeman, 1997; Klingbeil, Baer, & Wilson, 2004; Simeonsson, McMillen, & Huntington, 2002). In addition, about 80% to 90% of children with spina bifida develop hydrocephalus (Riccio & Pizzitola-Jarratt, 2005; Wong, 1997). Depending upon whether the neural tissue is exposed to the external environment or covered by the skin, spina bifida has different presentations;

thus, it is categorized into two major groups: open and closed (Chiaretti et al., 2008). Spina bifida occulta, or the closed neural tube defect, refers to a defect that is not visible externally. This type of spina bifida is the ‘‘mildest’’ and most common form in which one or more vertebrae are malformed. Often the malformations within the vertebrae do not affect the spinal cord. It is estimated that about 10% to 30% of the general population have this form of spina bifida (Rauen, 1995). Spina bifida occulta rarely causes disability and may not be noticed unless there are associated neuromuscular manifestations, such as pain, muscle weakness, and bowel dysfunctions (Wong et al., 1999). Spina bifida cystica refers to the visible defects that are manifested by an external sac-like protrusion. On average, 1 out of 1,000 babies in the United States is born with this form of spinal bifida (Izenberg, 2000). Cystica, also referred to as spina bifida manifesta, has two forms: meningocele and myelomeningocele. In meningocele, the meninges protrude from the spinal opening, and the malformation may or may not be covered by a layer of skin. The protrusion is filled with the CSF and forms a balloon through a gap in the vertebrae. Meningocele may be harmless to the nervous system if the sac contains only CSF; however, if the sac traps nerves, the condition may cause difficulties controlling bladder and muscles. Meningocele usually requires surgery during infancy to place the meninges back inside and close the gap in the vertebrae (Izenberg, 2000). Some patients with meningocele may have few or no symptoms, whereas others may experience symptoms similar to closed neural tube defects (Wong, 1997). Myelomeningocele is the most severe type of spina bifida. As in meningocele, the meninges protrude through the gap in vertebrae forming a sac, but in myelomeningocele the spinal cord bulges as well. The sac can be covered by skin or the nerves with the spinal cord can be exposed. In myelomeningocele, the higher the gap occurs in the spinal column, the more severe the neuromuscular and cognitive disturbances. Usually, the affected individuals suffer paralysis below the abdominal vertebrae, have problems with the control of their bladder or bowel, and develop hydrocephalus (Izenberg, 2000). Myelomeningocele requires surgery within 24–48 hours of birth (Izenberg, 2000; Wong et al., 1999). In addition, individuals with myelomeningocele are at high risk of meningitis, an infection in the meninges. Children with myelomeningocele who also suffer from hydrocephalus may have cognitive difficulties and learning disabilities, including difficulties paying attention, problems with language and reading comprehension, and trouble learning math (Wong et al., 1999).

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NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Spina bifida is associated with significant clinical complications that often affect the quality of life and survival chances of the affected individuals (Shin et al., 2008). Complications in spina bifida range from minor physical problems to severe physical and mental disabilities. However, most people with spina bifida are of normal intelligence. The clinical manifestation of spina bifida vary depending upon the type and degree of spinal defect, the size and location of the malformation, whether or not skin covers it, whether or not spinal nerves protrude from it, and the type of involved spinal nerves. In general, all nerves located below the malformation are affected, and the higher the malformation occurs on the back, the greater the amount of neurologic damage and neuromuscular abnormality (Wong et al., 1999). Sensory disturbances, such as impaired pain perception, may accompany motor and muscular dysfunction. Moreover, defective nerve supply to the bladder involves sphincter and detrusor tone, which can cause dribbling of urine. Poor anal sphincter tone and poor anal skin reflex can result in a lack of bowel control and rectal prolapse. The abnormal nervation of the muscles in the lower extremities may produce joint deformities in utero. These usually involve flexion or extension contractures, talipes valgus or varus contractures, kyphosis, lumbosacral scoliosis, and dislocation of the hips (Wong et al., 1999). DIAGNOSIS Prenatal Diagnosis

There are several methods of testing for spina bifida prenatally. The most common screening methods are maternal serum alpha fetoprotein (MSAFP) screening, fetal ultrasound, and amniocentesis (Izenberg, 2000). nig.com is not in refs. The MSAFP test is usually performed between 16 and 18 weeks of pregnancy and assesses the level of a protein called alpha fetoprotein (AFP), which is produced by the fetus and placenta. Abnormally high levels of AFP in the mother’s bloodstream may indicate a possibility of developmental defect, including spina bifida. If high levels of AFP are detected, an ultrasound or amniocentesis is recommended for confirmation of diagnosis. Although amniocentesis cannot reveal the severity of spina bifida, finding high levels of AFP in the amniotic fluid may indicate the presence of the disorder. Postnatal Diagnosis

The symptoms of spina bifida vary from person to person; however, the postnatal diagnosis is based on

clinical manifestations and examination of the meningeal sac. Closed forms of spina bifida often have no outward signs of the disorder but may be recognized due to an abnormal tuft or clump of hair or a small dimple or birthmark on the skin at the site of the spinal malformation (Wong et al., 1999). The primary methods used in diagnosis are MRI, CT scans, and myelography (not in refs Wong et al., 1999). Mild cases of spina bifida not diagnosed during prenatal testing may be detected postnatally by X-ray during routine examination. TREATMENT

Currently, there is no cure for spina bifida because the nerve tissue cannot be replaced or repaired. Treatment for spina bifida may include surgery, medication, and physiotherapy and may involve a multidisciplinary approach involving specialties of neurology, neurosurgery, pediatrics, urology, orthopedics, rehabilitation, physical therapy, occupational therapy, and social services. The treatment usually focuses on the three most crucial areas: (1) difficulties associated with primary disorders, which include hydrocephalus, paralysis, orthopedic abnormalities, and genitourinary abnormalities; (2) possible secondary problems such as meningitis, hypoxia, and hemorrhage; and (3) other abnormalities, including cardiac or gastrointestinal malformations (Wong et al., 1999). Many individuals with spina bifida need assistive devices such as braces, crutches, or wheelchairs. Ongoing therapy and medical care are often necessary throughout the affected individual’s life. Surgery to close the newborn’s spinal opening is performed within 24–48 hours after birth to minimize the risk of infection and maximize the neurological outcome (Izenberg, 2000; Wong et al., 1999) The main preventive factor for spina bifida is folic acid supplementation. Studies have shown that by adding folic acid to their diets, women of childbearing age can reduce the risk of having a child with spina bifida and other neural tube defects (Wong, 1997; Wong et al., 1999). The current recommendation for women of childbearing age is to consume 400 mg of folic acid daily. Anya Mazur-Mosiewicz Raymond S. Dean Botto, L., Moore, C., Khoury, M., & Erickson, J. (1999). Neural-tube defects. New England Journal of Medicine, 341, 1509–1919. Chiaretti, A., Rendeli, C., Antonelli, A., Barone, G., Focarelli, B., Tobacco, F., et al. (2008). GDNF plasma levels in spina bifida: Correlation with severity of spinal damage and motor function. Journal of Neurotrauma, 25, 1477–1481.

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Evans, O. B. (1987). Manual of child neurology. Edinburgh, UK: Churchill Livingstone. Hoeman, S. (1997). Primary care of children with spina bifida. Nurse Practitioner, 22, 60–62. Hunter, A. (1993). Brian and spinal cord. In R. E. Stevenson, J. G. Hall, & R. M. Goodman (Eds.), Human malformation and related abnormalities (pp. 127–130). New York: Oxford University Press. Izenberg, N. (2000). Human diseases and conditions. New York: Charles Scribner’s Sons. Klingbeil, H., Baer, H., & Wilson, P. (2004). Aging with disability. Archives of Physical Medicine and Rehabilitation, 85, 68–73. Rauen, K. (1995). Guidelines for spina bifida health care services throughout life. Washington, DC: Spina Bifida Association of America. Riccio, C. A., & Pizzitola-Jarratt, K. (2005). Abnormalities of neurological development. In R. C. D’Amato, E. Fletcher-Janzen, & C. R. Reynolds (Eds.), Handbook of School Psychology. Hoboken, NJ: Wiley. Shin, M., Besser, L. M., & Correa, A. (2008). Prevalence of spina bifida among children and adolescents in metropolitan Atlanta. Birth Defects Research, 82, 748–754. Simeonsson, R. J., McMillen, J., & Huntington, G. S. (2002). Secondary conditions in children and youth with disabilities. Research in Mental Retardation and Developmental Disabilities, 8(3), 198–205. Wong, D. (1997). Pedatric nursing (5th ed.). Tulsa, OK: Mosby. Wong, D., Hockenberry-Eaton, M., Wilson, D., Winkelstein, M. L., Ahmann, E., & Divito-Thomas, D. (1999). Nursing car of infants and children (6th ed.). Tulsa, OK: Mosby.

SPINAL CORD INJURY DESCRIPTION

Spinal cord injury (SCI) involves damage to the spinal cord that results in a loss or interruption of normal sensation and/or motor function. Motor vehicle accidents are the most frequent cause of SCI. Other causes include falls, work-, sports-, and violence-related injuries. Males and young adults between the ages of 21 and 30 are at an increased risk of suffering from an SCI. Additional risk factors include alcohol and drug use (Sekhon & Fehlings, 2001). The etiology, level, and grade of injury, as well as the individual’s age at the time of the injury, are factors that influence prognosis. SCIs most commonly occur at the cervical level. Injuries affecting the first, second, or third cervical vertebrae are most frequently associated

with mortality. More severe neurogenic deficits and injury at a younger age (equal to or less than 15 years of age) are also associated with increased mortality (Shavelle, DeVivo, Paculdo, Vogel, & Strauss, 2007). Effective management of spinal cord injuries, including immobilization and the administration of methylprednisolone, improves survival rates and prognosis.

NEUROPATHOLOGY/PATHOPHYSIOLOGY

The primary mechanism of injury refers to the initial insult to the spinal cord. The initial impact may lead to a contused, compressed, lacerated, disrupted, and/or transected spinal cord. Cell injury and death result, as well as axonal demyelization. Neurons in the central nervous system are very limited in their ability to regenerate. The obstructing presence of oligodendrocytes and astrocytes are thought to play a role in restricting axonal regeneration. Secondary mechanisms refer to various processes or changes that follow an SCI. These changes or processes, which include vascular changes, electrolyte changes, biochemical changes, loss of energy metabolism, loss of neurotrophic factor support, free radical formation, and glutamate excitotoxity exacerbate the initial injury. Hemorrhage, edema, and ischemia may occur resulting in additional cell death through necrosis or apoptosis. Vascular changes result from the release of cytokines. SCI may initially result in hypertension and an increase in heart rate followed by an extended period of bradycardia and hypotension. Individuals with spinal cord injuries may also experience spinal shock, neurogenic shock, and/or thrombosis. Electrolyte changes that accompany spinal cord injuries include increased intracellular calcium and sodium levels and increased extracellular potassium levels (Agrawal & Fehlings, 1996; Yong & Koreh, 1986). After a SCI, macrophages remove cellular debris and a cavity is formed. Glial scar formation ensues creating an obstacle for neuroregeneration (Ao et al., 2007). X-rays, CT scans, MRI, and myelograms are radiographic studies used to identify spinal cord injuries (Brant-Zawadzki, Miller, & Federle, 1981; Kulkarni et al., 1987; Virapongse & Kier, 1982). Spinal cord injuries have been associated with intraspinal hemorrhage, cord edema, and contusion. On T2-weighted magnetic resonance images, intraspinal hemorrhage reveals reduced signal intensity, and cord edema and contusion reveal elevated signal intensity (Kulkarni et al., 1987). In instances where obvious cord abnormalities cannot be visualized, CT scans, MRIs,

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and myelograms may reveal skeletal and/or ligament injuries (Kulkarni et al., 1987). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Signs and symptoms of spinal cord injuries include edema of the cord, loss of movement, loss of sensation, pain, difficulty breathing, and loss of bowel or bladder control. Urinary infections, pressure ulcers, and pulmonary embolisms are common complications of spinal cord injuries (Harkonen, Lepisto, Paakkala, Patiala, & Rokkanen, 1979). The degree of motor and sensory impairment resulting from an SCI depends upon the severity and vertebral level of the injury. Individuals with incomplete spinal cord injuries have some intact sensory and/or motor function below the level of the injury, whereas individuals with complete spinal cord injuries have no sensory or motor function below the level of the injury. Complete injuries are associated with more severe impairments, as are injuries at higher levels of the vertebral column. Tetraplegia results from an injury to the cervical level of the spinal column, whereas paraplegia is the consequence of injury to the thoracic, lumbar, or sacral level of the spinal column. The level of sensory loss typically corresponds to the level of motor loss in individuals with complete spinal cord injuries. Respiratory support is often necessary for individuals with tetraplegia from C1-, C2-, or C3-level injuries, particularly if the injury is complete. Also, these individuals require great assistance in activities of daily living. Individuals injured at the C4 level can typically breathe independently; however, they, too, require aid in performing most daily activities. Mobility of the shoulders and upper arms are seen in individuals with injuries below the C5 level, and when aided by assistive devices, these individuals may be able to feed themselves and perform other activities of daily living. Injuries below the C6 level allow individuals use of their hands. Though finger movement is impaired, these individuals can drive with special equipment and may be able to live independently. The prospect of an independent life is even greater if the C7 level is uninjured. Injuries to the upper thoracic region (T1–T6) allow for normal movement of the upper extremities. Individuals with these injuries can use manual wheelchairs and live independently, though they may have difficulties with balance. Individuals with injuries below the T11 level may be able to walk with leg braces and other assistive devices (Trieschmann, 1988). The Functional Independence Measure and the Spinal Cord Independence Measure

(SCIM) are two instruments used to evaluate the functional capabilities and progress of individuals with spinal cord injuries. Research suggests the SCIM may be more effective in detecting some functional changes in individuals with tetraplegia, paraplegia, and incomplete spinal cord injuries (Catz, Itzkovich, Agranov, Ring, & Tamir, 2001). Besides physical deficits, there are also neuropsychological impairments related to spinal cord injuries. Spinal cord injuries have been associated with deficits in processing speed, motor speed, and verbal learning, as assessed by the Symbol Digit Modalities Test-Written, Grooved Pegboard, and Rey Auditory Learning Test, respectively (Hess, Marwitz, & Kreutzer, 2003). Even many years post-injury (M ¼ 17 years), research reveals that individuals with spinal cord injuries demonstrate impairments in processing speed; however, in that same study, no deficits in memory, visuospatial skills, attention, or executive functioning were demonstrated (Dowler et al., 1995). These abnormal neuropsychological findings can be attributed to the frequently occult comorbid occurrence of traumatic brain injury, which occurs in as many as 40% to 50% of persons presenting with SCI (Davidoff, Roth, Morris, Bleiberg, & Meyer, 1986; Richards, Brown, Hagglund, Bua, & Reeder, 1988). DIAGNOSIS

Initial indications that an individual may have suffered an SCI include dilated pupils, paralysis, signs of shock, edema, and head, neck, or back pain. X-rays, CT scans, MRIs, and/or myelograms are helpful in diagnosing spinal cord injuries, as they allow for the visualization of fractures and/or soft-tissue lesions. If an SCI is suspected, the individual should be immobilized and evaluated to see if their respiratory and circulatory systems are compromised. This evaluation often includes an assessment of the person’s vital signs, blood pressure, skin color, nail bed color, respiration, and responsiveness. A comprehensive neurological exam should also be conducted. The International Standards for Neurological Classification of Spinal Cord Injury, also called the American Spinal Injury Association (ASIA) Standards, can be used to assess the extent and level of sensory and motor impairments (Ditunno, Young, Donovan, & Creasey, 1994). The sensory examination involves a pinprick and light touch to key points corresponding to the 28 dermatomes. These points are tested bilaterally. Absent, impaired, or normal perception of the stimulus is scored as a 0, 1, or 2, respectively. Whether or not the individual is able to perceive sensation at the anal sphincter should also be noted. The motor

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examination involves the assessment of ten paired muscles, which are examined bilaterally. A 6-point scale, ranging from 0, total paralysis, to 6, normal movement with no limitation in range of motion, is used to rate the strength of the muscle pair. Whether or not the sphincter is able to contract should also be noted. The ASIA impairment scale has five grades, A, B, C, D, and E. Grade A denotes a complete injury. Grades B through D denote incomplete injuries of decreasing severity, and Grade E indicates normal functioning. Besides a neurological examination, an assessment of the autonomic nervous system is also recommended for individuals with spinal cord injuries, as autoregulation may be impaired (Alexander et al., 2009). Areflexia, hypotension, and/or bradycardia may be present as well as bowel, bladder, or sexual dysfunction. TREATMENT

Pharmacological and conservative treatments are available to individuals with spinal cord injuries. Methylprednisolone given in high doses within 8 hours of an acute SCI has been shown to be an effective pharmacological treatment associated with improved recovery (Bracken, 2001). To reduce the risk of further injury to the spinal cord, individuals with spinal injuries should be immobilized and receive appropriate treatment for orthopedic problems. Tetraplegia may be treated conservatively with skull traction and an orthopedic neck brace (Harkonen et al., 1979). Electronic wheelchairs, computers, leg braces, and other assistive devices as well as physical and occupational therapy may be helpful in improving the mobility and functional capacity of individuals with spinal cord injuries (Hulsebosch, 2002; Kakulas, 2004). New treatments focusing on regeneration of the spinal cord are presently being investigated. One strategy is the implantation of neuronal stem cells that could differentiate into healthy replacement neurons (Okano et al., 2003). Another approach to neuronal regeneration is the use of olfactory ensheathing cells, which are glial cells capable of promoting axonal growth (Ao et al., 2007). Other research is investigating factors that guide axonal growth during development in hopes that these factors may be able to promote regeneration later in life (Harel & Strittmatter, 2006). Neurotropic factors, including brainderived neurotropic factor, neurotrophin-3, and neurotropin-4, have been found to stimulate axonal growth (Bregman, McAtee, Dai, & Kuhn, 1997). Alyse Barker Mandi Musso William Drew Gouvier

Agrawal, S. K., & Fehlings, M. G. (1996). Mechanisms of secondary injury to spinal cord axons in vitro: Role of Naþ, Naþ-Kþ-ATPase, the Nþ-Hþ exchanger, and the Naþ-Ca2þ exchanger. Journal of Neuroscience, 16(2), 545–552. Alexander, M. S., Biering-Sorensen, F., Bodner, D., Brackett, N. L., Cardenas, D., Charlifue, S., et al. (2009). International standards to document remaining autonomic function after spinal cord injury. Spinal Cord, 47(1), 36–43. Ao, Q., Wang, A. J., Chen, G. Q., Wang, S. J., Zuo, H. C., & Zhang, X. F. (2007). Combined transplantation of neural stem cells and olfactory ensheathing cells for the repair of spinal cord injuries. Medical Hypotheses, 69(6), 1234–1237. Bracken, M. B. (2001). Methylprednisolone and acute spinal cord injury — an update of the randomized evidence. Spine, 26(24), 47–54. Brant-Zawadzki, M., Miller, E. M., & Federle, M. P. (1981). CT in the evaluation of spine trauma. American Journal of Roentgenology, 136(2), 369–375. Bregman, B. S., McAtee, M., Dai, H. N., & Kuhn, P. L. (1997). Neurotropic factors increase axonal growth after spinal cord injury and transplantation in the adult rat. Experimental Neurology, 148(2), 475–494. Catz, A., Itzkovich, M., Agranov, E., Ring, H., & Tamir, A. (2001). The spinal cord independence measure (SCIM): Sensitivity to functional changes in subgroups of spinal cord lesion patients. Spinal Cord, 39(2), 97–100. Davidoff, G., Roth, E., Morris, J., Bleiberg, J., & Meyer, P. R. (1986). Assessment of closed head injury in trauma-related spinal cord injury. Paraplegia, 24(2), 97–104. Ditunno, J. F., Young, W., Donovan, W. H., & Creasey, G. (1994). The international standards booklet for neurological and functional classification of spinal cord injury. Paraplegia, 32(2), 70–80. Dowler, R. N., O’Brien, S. A., Haaland, K. Y., Harrington, D. L., Feel, F., & Fiedler, K. (1995). Neuropsychological functioning following a spinal cord injury. Applied Neuropsychology, 2(3–4), 124–129. Harel, N. Y., & Strittmatter, S. M. (2006). Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nature Reviews Neuroscience, 7(8), 603–616. Harkonen, M., Lepisto, P., Paakkala, T., Patiala, H., & Rokkanen, P. (1979). Spinal-cord injuries associated with vertebral fractures and dislocations: Clinical and radiological results in 30 patients. Archives of Orthopaedic and Traumatic Surgery, 94(3), 185–190. Hess, D. W., Marwitz, J. H., & Kreutzer, J. S. (2003). Neuropsychological impairments after spinal cord injury: A comparative study with mild traumatic brain injury. Rehabilitation Psychology, 48(3), 151–156.

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Hulsebosch, C. E. (2002). Recent advances in pathophysiology and treatment of spinal cord injury. Advances in Physiology Education, 26(4), 238–255. Kakulas, B. A. (2004). Neuropathology: The foundation for new treatments in spinal cord injury. Spinal Cord, 42(10), 549–563. Kulkarni, M. V., McArdle, C. B., Kopanicky, D., Miner, M., Cotler, H. B., Lee, K. F., et al. (1987). Acute spinal cord injury: MR imaging at 1.5 T1. Radiology, 164(3), 837–843. Okano, H., Ogawa, Y., Nakamura, M., Kaneko, S., Iwanami, A., & Toyama, Y. (2003). Transplantation of neural stem cells into the spinal cord after injury. Seminars in Cell and Developmental Biology, 14(3), 191–198. Richards, J. S., Brown, L., Hagglund, K., Bua, B. G., & Reeder, K. (1988). Spinal cord injury and concomitant traumatic brain injury: Results of a longitudinal investigation. American Journal of Physical Medicine and Rehabilitation, 67(5), 211–216. Sekhon, L. H. S., & Fehlings, M. G. (2001). Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine, 26(245), S2–S12. Shavelle, R. M., DeVivo, M. J., Paculdo, D. R., Vogel, L. C., & Strauss, D. J. (2007). Long-term survival after childhood spinal cord injury. Journal of Spinal Cord Medicine, 30, S48–S54. Trieschmann, R. B. (1988) Spinal cord injuries: Psychological, social, vocational rehabilitation (2nd ed.). New York: Demos Publication. Virapongse, C., & Kier, E. L. (1982). Mitrizamide myelography in cervical-spine trauma — a modified technique using lateral fluoroscopy. Radiology, 144(3), 636–637. Yong, W., & Koreh, I. (1986). Potassium and calcium changes in injured spinal cords. Brain Research, 365(1), 42–53.

SPINAL MUSCULAR ATROPHIES DESCRIPTION

Spinal muscular atrophies (SMA) are a group of rare neuromuscular diseases that correspond with progressive degeneration of lower motor neurons of the medulla and spinal cord. The presentation arises from a defect in the survival motor neuron gene (SMN1), located on chr5q (Sumner, 2007), which causes a deficiency in essential proteins that feed the lower motor neurons (Lefebvre et al., 1995; Lefebvre et al., 1997; Lunn & Wang, 2008;). SMA presents with an annual incidence of 1 in 10,000 births (Wirth, 2000), and is a leading genetic cause of infant death. As the lower motor neurons degenerate in SMA, the affected individual’s muscles atrophy, leading to symmetrical,

proximal weakness. Global hypotonia, pulmonary insufficiency, and autonomic and bulbar dysfunction may also present (Graham, Athiraman, Laubach, & Sethna, 2009). Four different variants of SMA have been described. They are differentiated by the age of onset, the severity of symptoms, and the maximal motor function attained (Zerres & Davies, 1999). In SMA-1, symptoms develop in infancy and progress rapidly. Individuals are never able to sit or walk on their own. In severe cases, when the lungs become involved, infants may die due to respiratory distress. SMA-2 arises prior to 18 months of age and while infants may sit up on their own, they never are able to walk unaided. SMA-3 sufferers eventually can walk without assistance, but often exhibit muscular weakness. SMA-4 onset is not until adulthood and is associated with minimal symptoms (Lunn & Wang, 2008; Sumner, 2007). NEUROPATHOLOGY/PATHOPHYSIOLOGY

SMAs arise from degeneration of the anterior horn cells of the spinal cord and bulbar motor neurons. In rare instances, degeneration of the dorsal root ganglion cells and sensory columns and loss of neurons in the posteroventral nucleus of the thalamus may be seen. Neurogenic muscular atrophy develops characterized by groupings of small round fibers and type-I hypertrophied fibers on biopsy (Crawford & Pardo, 1996). The genetic basis for the SMAs have been mapped to 5q-11.2-13.3 leading to reduced levels of SMN protein because of mutations in the SMN1 gene . It is inherited in an autosomal recessive fashion. While SMN1 mutation is hallmark of the presentation, oweing to deficits in the SMN protein, the latter is not completely absent – one would not be able to live without any SMN protein (Schrank et al., 1997). Small amounts are produced by the SMN2 gene, which is nearly identical to SMN1. In fact, the number of SMN2 gene copies expressed by an individual in many respects determines the subtype of SMA, as greater numbers of SMN2 copies leads to higher amounts of SMN protein. which reduces symptom severity; lower numbers of SMN2 copies corresponds with lower SMN protein levels and greater severity of symptoms (Campbell et al., 1997). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Degeneration of spinal anterior horn neurons and occasionally brainstem nuclei correspond to a range

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of clinical characteristics, but the hallmark features include hypotonia, weakness, and cranial nerve palsies. Differentiation among the types is largely linked to age of onset and severity of symptoms, which both correspond with the amount of residual SMN2. For example, while type 1 manifests in infancy and leads to death, often before infants are 1 year old, type IV does not demonstrate symptom onset until the fourth decade of life and is not strongly linked to reduced life expectancy. Across all types, onset and progression is insidious, leading to somewhat generalized weakness, affecting proximal muscles prior to distal and caudal regions prior to rostral. Siddique, Sufit, and Siddique (2007) summarized the differences among groups, which are summarized in Table 1.

Diagnosis

The diagnosis of SMA is most appropriately done through a combination of EMG and muscle biopsy and histochemistry. As noted by Siddique et al. (2007), homozygous deletion of SMN is a sensitive test for confirming diagnosis across all types in comparison to one another and potential differentials. Fibrillation and normal-sized residual motor units present in denervated muscle fibers in type 1, whereas types 2 and 3 manifest large motor units with absence of spontaneous activity (Siddique, et al., 2007). Age of onset, nature of symptoms, and the amount of residual SMN2 can all aid in differentiating between the subtypes.

TREATMENT

The SMAs are incurable and currently treatment is limited. The primary goal, if it can be achieved, is to increase SMN levels, the depletion of which serves as the basis of the disorder. Different strategies have been proposed including the use of gene therapy vectors to provide a continuous source of exogenous SMN or activating the SMN2 promoter to modulate the endogenous SMN2 gene (Grzeschik, Ganta, Prior, Heavlin, & Wang, 2005; Hahnen et al., 2006; Riessland et al., 2006; Avila et al., 2007). However, while these have shown some efficacy in the laboratory, largely through animal models, there has been a lack of clearly positive evidence in translational research within the clinical setting (Oskoui & Kaufmann, 2008). Mildly positive findings have been reported in relationship to sodium butyrate, valproic acid, and potentially riluzole (Siddique et al., 2007). Given the lack of effective treatment to halt progression, interventions are often directed at symptom resolution. Physical and occupation therapy is often recommended to aid in maintaining ambulation and independence from a motoric standpoint. Braces may be required on the legs and used in combination with forearm crutches as the arms are affected less and may offer some means of compensation in ambulation. Eventually individuals may need to rely on wheelchairs. Oxygen and potentially even ventilation may be required as the disease progresses based on the extent of respiratory weakness. Feeding tubes are often needed in SMA type 1. Genetic counseling is recommended for parents who have a child with SMA or

Table 1 DIFFERENTIATION AMONG SPINAL MUSCULAR ATROPHIES Type

Age of Onset

Symptoms

Prognosis

SMA type 1

In utero–6 mos

Hypotonia Generalized weakness Poor sucking Poor swallowing Poor breathing Never able to sit up

95% die within first year

SMA type 2

3–15 mos

Proximal leg weakness Fasciculations Fine hand tremor Never able to walk No facial weakness

Often die prior to age 10 Some survive into adolescence and even adulthood Dependent upon respiratory symptoms

SMA type 3

15 mos–teens

Proximal leg weakness delayed obtainment of motor development milestones

Life expectancy shortened, but not specific Dependent upon respiratory symptoms

SMA type 4

20–40 years on average

Proximal weakness

Life expectancy not shortened

Adapted from Siddique et al. (2007).

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for SMA patients themselves who may be thinking of having children, most usually are types 3 or 4. Chad A. Noggle Michelle R. Pagoria Avila A. M., Burnett, B. G., Taye, A. A., Gabanella, F., Knight, M. A., Hartenstein, P., . . . Sumner CJ. (2007). Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. The Journal of Clinical Investigation, 117(3), 659–671. Campbell, L., Potter, A., Ignatius, J., Dubowitz, V., & Davies, K. (1997). Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype. American Journal of Human Genetics, 61(1), 40–50. Crawford, T. O., & Pardo, C. A. (1996). The neurobiology of childhood spinal muscular atrophy. Neurobiology of Disease, 3, 97–110. Graham, R., Athiraman, U., Laubach, A. E., & Sethna, N. F. (2009). Anesthesia and perioperative medical management of children with spinal muscular atrophy. Pediatric Anesthesia, 19, 1054–1063 Grzeschik, S. M., Ganta, M., Prior, T. W., Heavlin, W. D., & Wang, C. H. (2005). Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells. Annals of Neurology, 58(2), 194–202. Hahnen, E., Eyu¨poglu, I. Y., Brichta, L., Haastert, K., Tra¨nkle, C., Siebzehnru¨bl, F. A., . . . Blu¨mcke, I. (2006). In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy. Journal of Neurochemistry, 98(1), 193–202. Lefebvre, S., Burglen, L., Reboullet, S., Clermont, O., Burlet, P., . . . Zeviani., M. (1995). Identification and characterization of a spinal muscular atrophy-determining gene. Cell, 80, 155–165. Lefebvre, S., Burlet, P., Liu, Q., Bertrandy, S., Clermont, O., . . . Melki, J. (1997). Correlation between severity and SMN protein level in spinal muscular atrophy. Nature Genetics, 16, 265–269. Lefebvre, S., Burlet, P., Liu, Q., Bertrandy, S., Clermont, O., Munnich, A., . . . Melki, J. (1997). Correlation between severity and SMN protein level in spinal muscular atrophy. Nature Genetics, 16(3), 265–269. Lunn, M. R., & Wang, C. H. (2008). Spinal muscular atrophy. Lancet, 371, 2120–2133. Oskoui, M., & Kaufmann, P., (2008). Spinal muscular atrophy. Neurotherapeutics, 5(4), 499–506 Riessland, M., Brichta, L., Hahnen, E., & Wirth, B. (2006). The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells. Human Genetics, 120(1), 101–110.

Schrank, B., Gotz, R., Gunnersen, J. M., Ure, J. M., Toyka, K. V., . . . Sendtner, M. (1997). Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proceedings of the National Academy of Sciences of the United States of America, 94, 9920–9925. Siddique, N., Sufit, R., & Siddique, T. (2007). Degenerative motor, sensory, and autonomic disorders. In C. G. Goetz (Ed.), Textbook of clinical neurology (pp. 785–787). Philadelphia, PA: WB Saunders. Sumner, C. J. (2007). Molecular mechanisms of spinal muscular atrophy. Journal of Child Neurology, 22, 979–989. Wirth, B. (2000). An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Human Mutation, 15, 228–237. Zerres, K., & Davies, K. E. (1999). 59th ENMC International Workshop: Spinal Muscular Atrophies: Recent progress and revised diagnostic criteria 17–19 April 1998, Soestduinen, The Netherlands. Neuromuscular Disorders: NMD, 9, 272–278.

SPINOCEREBELLAR DEGENERATIVE DISORDERS DESCRIPTION

The spinocerebellar degenerative disorders are a group of diseases that, as their name suggests, involve neurodegeneration of the posterior regions of the brain including the cerebellum and spinal cord. However, degeneration of the brainstem and/or the basal ganglia may also occur similar to that seen in multiple system atrophy (MSA; Gilman & Quinn, 1996). In fact, most sporadic cases of spinocerebellar degeneration are now considered MSA. This grouping includes spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17, as well as dentatorubral-pallidoluysian atrophy (DRPLA), Friedrich’s ataxia, and MSA. While variability across presentations is seen in terms of the clinical features, limb and truncal ataxia, dysarthria, dysphagia, dystonia, pyramidal and extrapyramidal signs, and autonomic dysfunction are common. Cognitive deficits may also occur (Schmahmann & Sherman, 1998). NEUROPATHOLOGY/ PATHOPHYSIOLOGY

The spinocerebellar degenerative disorders are similar in that all presentations demonstrate relatively similar pathological features of deterioration of the cerebellum

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and/or other posterior brain regions. However, variability is seen across disease types in terms of their specific pathology, owing to their clinical differences. SCA1 demonstrates a constellation of pathological changes including loss of Purkinje and granule cells in the cerebellum; neuronal loss and gliosis of the dentate gyrus, inferior olives and pontine nuclei; and neuronal loss in the substantia nigra, putamen, pallid, and subthalamic nucleus (Scho¨ls, Amoiridis, Bu¨ttner, Przuntek, Epplen, & Riess, 2004). These changes have been associated with diffuse hypoperfusion involving the caudate and putamen of the basal ganglia as well as the cerebellum and brainstem (Gilman, Sima, Junck, Kluin, Koeppen, Lohman, & Little, 1996). These changes have also been noted in the cerebral cortex as well. SCA2 commonly presents with degeneration of the supratentorial and infratentorial regions (Brenneis, Bo¨sch, Schocke, Wenning, & Poewe, 2003). This includes the cerebellum (including Purkinje and granular cells and cerebellar peduncles), thalamus, pons, mesencephalon, nondominant orbitofrontal and tempromesial cortices, sensorimotor cortex bilaterally, inferior olives, and the cerebral cortex (Scho¨ls et al., 2004; Wu¨llner et al., 2005). SCA3 consists of degeneration involving the globus pallidus, substantia nigra, red nucleus, pontine nuclei, subthalamic nucleus, superior cerebellar peduncle, dentate nucleus, oculomotor nucleus, medial longitudinal fasciculus, anterior horn, spinocerebellar tracts, Clark’s nuclei, intermediolateral column, and lateral reticular nucleus (Ru¨b, de Vos, Schultz, Brunt, Paulson, & Braak, 2002). SCA6, unlike the first three types of spinocerebellar ataxia, is not associated with more widespread degeneration. Rather, this type is characterized by fairly focal degeneration of the cerebellum including loss of Purkinje and granular cells although deterioration of the dentate nucleus is also commonly seen (Takahashi, Ikeuchi, Honma, Hayashi, & Tsuji, 1998). Some studies have also reported reduced metabolism in the cerebral cortex (Soong, Liu, Wu, Lu, & Lee, 2001), while others have not (Honjo et al., 2004). SCA7, presents with a causative gene mutation of a translated CAG repeat expansion in gene coding for ataxin-7, which is expressed throughout the brain in the cytoplasm of neurons. This type present with primary atrophy of an olivopontocerebellar origin. SCA17 is associated with neuronal loss and atrophy of the caudate nucleus, putamen, thalamus, and both the frontal and temporal lobes, as well as loss of Purkinje cells in the cerebellum (Bruni et al., 2004; Rolfs et al., 2003). Reduced metabolism in the

basal ganglia and cerebellum are commonly noted (Minerop et al., 2005). Dentatorubral-pallidoluysian atrophy (DRPLA) presents in conjunction with leukodystrophic changes and calcifications in the regions of the basal ganglia in addition to cerebellar and brainstem atrophy. DNA analysis reveals multiple CAG repeats (Ikeuchi, Onodera, Oyake, Koide, Tanaka, & Tsuji, 1995). Degeneration of the dentatorubral pallidoluysian and fatigio-vestibular systems are hallmark features (Scho¨ls et al., 2004). Finally, Friedrich’s ataxia, is most commonly caused by loss of function mutations in the frataxin gene and corresponds with mutation on chromosome 9q13. Interestingly, cerebellar degeneration is not seen; rather, it affects the spinocerebellar tracts, posterior columns, and corticospinal tracts. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Across all forms of spinocerebellar degeneration, although variability is seen, neurocognitive residuals very much adhere to a profile indicative of prefrontal dysfunction that is consistent with what is recognized as cerebellar cognitive affective syndrome. Within this model and on functional imaging the cerebellum has demonstrated activation and thus a role in attention (Allen, Buxton, Wong, & Courchesne, 1997), general cognitive and verbal processing (Kim, Ugurbil, & Strick, 1994), semantic fluency and word generation (Klein, Milner, Zatorre, Meyer, & Evans, 1995), motor sequence learning (Jenkins, Brooks, Nixon, Frackowiak, & Passingham, 1994), and verbal and working memory (Desmond, Gabrieli, Wagner, Ginier, & Glover, 1997) among other areas. The cognitive influence of the cerebellum in these areas is not necessarily a one-toone link with the region and the function; rather, through indirect disruption of broader systems and loops including cerebrocerebellar circuitry, corticostriatal-thalamocortical circuitry and the frontal lobe. Schmahmann and Sherman (1998) have found deficits in executive functioning, language, and higher-order cognition in addition to personality changes as a result of cerebellar lesions. However, they further noted, that the nature of the deficits corresponded with the locality of the lesions, with posterior lesions corresponding with cognitive and behavioral/affective disturbances, and minor deficits in executive and visual-spatial functions corresponding with anterior lesions (Schmahmann & Sherman, 1998). Beyond this general profile of neurocognitive dysfunction, neuropsychological and other functional deficits vary based on the type of spinocerebellar degeneration.

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SCA1, as with most of the spinocerebellar degenerations, is associated with both cognitive and noncognitive residuals. General deficits in cognitive functioning and intellect have been reported in association with this type (Kish, el-Awar, Schut, Leach, Oscar-Berman, & Freedman, 1988), although it presents as one of the types with the lowest risk of dementia (Tang, Liu, Shen, Dai, Pan, Jing, Ouyang, & Xia, 2000). Consistent with what would be expected given the findings of Schmahmann and Sherman (1998), executive dysfunctions have been associated with SCA1 (Burk et al., 2001). In addition, these researchers noted verbal memory deficits (Burk et al., 2001). These cognitive deficits are noted in conjunction with additional neurological dysfunctions including ataxia, dysarthria, and bulbar deficits primarily. Spasticity, hyperreflexia, extensor plantar responses, and oculomotor signs may also be seen. SCA2 has been associated with deficits in immediate recall of non-contextual or non-categorized information such as list learning as well as delayed recall (Burk et al., 1999). Similar to that which is seen in frontal or subcortical patterns of memory dysfunction, improvement is seen when offered cueing and/or recognition. Simultaneously, executive function deficits were also observed. Dementia is seen in 20–40% of patients (Burk et al., 1999). In terms of features beyond cognition, ataxia is the other main neurological feature. The primary clinical manifestations of SCA3 include ataxia, hyperrefelxia, and spasticity. Dystonia, parkinsonism, ophthalmoplegia, and myotrophy are also commonly seen among other infrequent features. REM sleep disorder has been reported at higher rates in association with SCA3. From a cognitive standpoint, SCA3 has been associated with deficits in verbal and visual memory, verbal fluency, set-shifting, verbal and visual attention, and visuospatial and constructional abilities (Zawacki, Grace, Friedman, & Sudarsky, 2002; Kawai, Takeda, Abe, Washimi, Tanaka, & Sobue, 2004). SCA6, in comparison to all other types of spinocerebellar degeneration, is the least associated with cognitive dysfunction (Lee et al., 2003). Nevertheless, deficits have been noted, consistent with those features commonly noted in cerebellar dysfunction. Mild executive dysfunction has been reported in conjunction with the SCA6 type (Globas, Bo¨sch, Zu¨hlke, Daum, Dichgans, & Bu¨rk, 2003). In addition, retrieval based memory deficits, immediate memory deficits, and semantic and verbal fluency deficits have all been noted through research (Suenaga et al., 2008). Neurologically, ataxia, dysarthria, extrapyramidal

signs and horizontal nystagmus are all seen in relation to SCA6. SCA7 has an onset at approximately 25 years of age and initially presents with ataxia. However, as progression occurs, gradual loss of vision is seen. This is initially due macular degeneration that then eventually involves the retina and optic nerve. In comparison to other types, dementia is not commonly seen (Enevoldson et al., 1994). Tendon reflexes are commonly absent. Gaze palsy, dysphagia, and generalized muscle weakness often present. SCA17 is the least research type of spinocerebellar degeneration as it is the newest in terms of being recognized as a separate variation. Consequently, more specific findings regarding the neurocognitive profile associate with SCA17 could not be found. Dementia is commonly seen, and presents as early as 20 years of age (Scho¨ls et al., 2004). Executive dysfunction and deficits in higher-order cognition may be anticipated because of the cerebellar involvement (Schmahmann & Sherman, 1998), but it has not been specifically reported. What have been reported are affective and psychiatric disturbances in association with SCA17. Depression, irritability, aggression, personality changes, delusions, and hallucinations have been suggested in conjunction with the presentation (De Michele et al., 2003). Beyond ataxia, other neurological features have not been fully described. DRPLA is characterized by ataxia, choreoathetosis, myoclonus, and epilepsy (Scho¨ls et al., 2004). Cognitively, patients often present with a profile similar to that seen in conjunction with subcortical dementias in that patients demonstrate diminished executive functioning and retrieval-based memory deficits (Ikeuchi et al., 1995). Bradykinesia and bradyphrenia are often descriptive of the behavioral presentations of patients. DRPLA is strongly linked with psychiatric manifestations as well. Patients may develop visual or auditory hallucinations, but more commonly mood swings, irritability and immaturity, to the extent that individuals who almost act like children can be seen. Friedrich’s ataxia has been associated with a range of cognitive and other functional deficits. Impairments in attention, processing speed, visuoconstructive and visuospatial abilities, planning, and implicit learning have all been noted (Mantovan et al., 2006). Mantovan and colleagues (2006) also noted deficits in verbal fluency that was also noted by de Nobrega, Nieto, Barroso and Monton (2007) in semantic, phonemic, and action fluencies. Executive dysfunction commonly presents. Gait and limb ataxia, dysarthria, and lower extremity weakness are common. Medically, heightened risk of

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cardiomyopathy and diabetes have been reported (Fogel & Perlman, 2007).

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DIAGNOSIS

Clinically, differential diagnosis between the various types of spinocerebellar degeneration is difficult given the significant overlap. Thorough clinical interview and history taking as well as evaluation are essential. Some traits are more hallmark of certain SCAs and thus can aid in diagnosis. Laid out some points of differentiation. For example, pyramidal tract signs, dysphagia, and pale discs are indicative of SCA1. Slow saccades, axonal neuropathy, and severe pontine atrophy on MRI are more suggestive of SCA2. Pure cerebellar involvement is more suggestive of SCA6. Ataxia with progressive visual loss is more consistent with SCA7. Ataxia, chorea, and seizures are usually indicative of DRPLA. MRI is important in identifying atrophy related to the entire group of SCAs. However, in trying to differentiate the various types, focus must be placed on genetic assessment such as the locality of CAG repeats. Demonstration of CAG repeat expansion at the SCA1 locus is definitive of SCA1; when it is at the SCA2 locus it is indicative of SCA2; at locus SCA3, it suggests SCA3; SCA6 demonstrates the CAG repeat expansion at the CACNA1A gene; SCA7 demonstrates CAG repeat expansion at locus SCA7; SCA17 demonstrates CAG/CAA repeat expansion of the TBP/ SCA17 gene; and DRPLA demonstrates CAG repeat at the DRPLA locus. TREATMENT

There is no cure or specific treatment for any of the spinocerebellar degenerations. They are progressive in nature. Symptoms are addressed in accordance with standard practices. For example, parkinsonian symptoms are addressed medicinally similar to the manner in which they are treated in other presentations. When seizures arise, such as in the case of DRPLA, anticonvulsants are beneficial. Antipsychotic and antidepressant agents may be used to address psychotic and mood disturbances. Literature could not be found regarding the potential utility of psychostimulants in offsetting some of the frontalappearing cognitive residuals. Physical therapy is often required to aid in maintaining independence in ambulation. Individuals can often end up bound to a wheelchair. Speech therapy may also be utilized. Chad A. Noggle Michelle R. Pagoria

Allen, G., Buxton, R. B., Wong, E. C., & Courchesne, E. (1997). Attentional activation of the cerebellum independent of motor involvement. Science, 275, 1940–1943. Bu¨rk, K., Bo¨sch, S., & Globas, C., et al. (2001). Executive dysfunction in spinocerebellar ataxia type 1. Eur Neurol, 46, 43–48. Bu¨rk, K., Globas, C., Bo¨sch, S., et al. (1999). Cognitive deficits in spinocerebellar ataxia 2. Brain, 122, 769–777. Brenneis, C., Bo¨sch, S. M., Schocke, M., Wenning, G. K., & Poewe, W. (2003). Atrophy pattern in SCA2 determined by voxel-based morphometry. Neuroreport, 14, 1799–1802. Bruni, A. C., Takahashi-Fujigasaki, J., Maltecca, F., Foncin, J. F., Servadio, A., Casari, G., . . . Duyckaerts, C. (2004). Behavioral disorder, dementia, ataxia, and rigidity in a large family with TATA box-binding protein mutation. Arch Neurol, 61, 1314–1320. Desmond, J. E., Gabrieli, J. D., Wagner, A. D., Ginier, B. L., & Glover, G. H. (1997). Lobular patterns of cerebellar activation in verbal workingmemory and finger-tapping tasks as revealed by functional MRI. J Neurosci, 17, 9675–9685. De Michele, G., Maltecca, F., Carella, M., Volpe, G., Orio, M., De Falco, A., . . . Bruni, A. (2003). Dementia, ataxia, extrapyramidal features, and epilepsy: Phenotype spectrum in two Italian families with spinocerebellar ataxia type 17. Neurol Sci, 24, 166–167. de Nobrega, E., Nieto, A., Barroso, J., & Monton, F. (2007). Differential impairment in semantic, phonemic, and action fluency performance in Friedreich’s ataxia: Possible evidence of prefrontal dysfunction. J Int Neuropsychol Soc, 13, 944–952. Fogel, B. L., & Perlman, S. (2007). Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol, 6, 245–257. Gilman, S., Sima, A. A., Junck, L., Kluin, K. J., Koeppen, R. A., Lohman, M. E., & Little, R. (1996). Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol, 39, 241–255. Gilman, S., & Quinn, N. P. (1996). The relationship of multiple system atrophy to sporadic olivopontocerebellar atrophy and other forms of idiopathic late-onset cerebellar atrophy. Neurology, 46, 1197–1199. Globas, C., Bo¨sch, S., Zu¨hlke, Ch., Daum, I., Dichgans, J., & Bu¨rk, K. (2003). The cerebellum and cognition: Intellectual function in spinocerebellar ataxia type 6 (SCA6). J Neurol, 250, 1482–1487. Honjo, K., Ohshita, T., Kawakami, H., Naka, H., Imon, Y., Maruyama, H., . . . Matsumoto, M. (2004). Quantitative assessment of cerebral blood flow in genetically confirmed spinocerebellar ataxia type 6. Arch Neurol, 61, 933–937. Ikeuchi, T., Onodera, O., Oyake, M., Koide, R., Tanaka, H., & Tsuji, S. (1995). Dentatorubral-pallidoluysian atrophy (DRPLA): Close correlation of CAG repeat expansions

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with the wide spectrum of clinical presentations and prominent anticipation. Semin Cell Biol, 6, 37–44. Jenkins, I. H., Brooks, D. J., Nixon, P. D., Frackowiak, R. S., & Passingham, R. E. (1994). Motor sequence learning: A study with positron emission tomography. J Neurosci, 14, 3775–3790. Kawai, Y., Takeda, A., Abe, Y., Washimi, Y., Tanaka, F., & Sobue, G. (2004). Cognitive impairments in MachadoJoseph disease. Arch Neurol, 61, 1757–1760. Kim, S. G., Ugurbil, K., & Strick, P. L. (1994). Activation of a cerebellar output nucleus during cognitive processing. Science, 265, 949–951. Kish, S. J., el-Awar, M., Schut, L., Leach, L., Oscar-Berman, M., & Freedman, M. (1988). Cognitive deficits in olivopontocerebellar atrophy: Implications for the cholinergic hypothesis of Alzheimer’s dementia. Ann Neurol, 24, 200–206. Klein, D., Milner, B., Zatorre, R. J., Meyer, E., & Evans, A. C. (1995). The neural substrates underlying word generation: A bilingual functional imaging study. Proc Natl Acad Sci USA, 92, 2899–2903. Lee, W. Y., Jin, D. K., Oh, M. R., Lee, J. E., Song, S. M., Lee, E. A., . . . Lee, K. H. (2003). Frequency analysis and clinical characterization of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Korean patients. Arch Neurol, 60, 858–863. Mantovan, M. C., Martinuzzi, A., Squarzanti, F., Bolla, A., Silvestri, I., Liessi, G., . . . Angelini, C. (2006). Exploring mental status in Friedreich’s ataxia: A combined neuropsychological, behavioral and neuroimaging study. Eur J Neurol, 13, 827–835. Minnerop, M., Joe, A., Lutz, M., Bauer, P., Urbach, H., Helmstaedter, C., . . . Wu¨llner, U. (2005). Putamen dopamine transporter and glucose metabolism are reduced in SCA17. Ann Neurol, 58, 490–491. Rolfs, A., Koeppen, A. H., Bauer, I., Bauer, P., Buhlmann, S., Topka, H., . . . Riess, O. (2003). Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17). Ann Neurol, 54, 367–375. Ru¨b, U., de Vos, R. A., Schultz, C., Brunt, E. R., Paulson, H., & Braak, H. (2002). Spinocerebellar ataxia type 3 (Machado-Joseph disease): Severe destruction of the lateral reticular nucleus. Brain, 125, 2115–2124. Schmahmann, J. D., & Sherman, J. C. (1998). The cerebellar cognitive affective syndrome. Brain, 121, 561–579. Scho¨ls, L., Bauer, P., Schmidt, T., Schulte, T., & Riess, O. (2004). Autosomal dominant cerebellar ataxias: Clinical features, genetics, and pathogenesis. Lancet Neurol, 3, 291–304. Soong, B., Liu, R., Wu, L., Lu, Y., & Lee, H. (2001). Metabolic characterization of spinocerebellar ataxia type 6. Arch Neurol, 58, 300–304. Suenaga, M., Kawai, Y., Watanabe, H., Atsuta, N., Ito, M., Tanaka, F., . . . Sobue, G. (2008). Cognitive impairment

in spinocerebellar ataxia type 6. J Neurol Neurosurg Psychiatry, 79, 496–499. Takahashi, H., Ohama, E., Naito, H., Takeda, S., Nakashima, S., Makifuchi, T., & Ikuta, F. (1988). Hereditary dentatorubral-pallidoluysian atrophy: Clinical and pathologic variants in a family. Neurology, 38, 1065–1070. Tang, B., Liu, C., Shen, L., Dai, H., Pan, Q., Jing, L., Ouyang, S., & Xia, J. (2000). Frequency of SCA1, SCA2, SCA3/ MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. Arch Neurol, 57, 540–544. Wu¨llner, U., Reimold, M., Abele, M., Bu¨rk, K., Minnerop, M., Dohmen, B. M., . . . Klockgether, T. (2005). Dopamine transporter positron emission tomography in spinocerebellar ataxias type 1, 2, 3, and 6. Arch Neurol, 62, 1280–1285. Zawacki, T. M., Grace, J., Friedman, J. H., & Sudarsky, L. (2002). Executive and emotional dysfunction in Machado-Joseph disease. Mov Disord, 17, 1004–1010.

STIFF-PERSON SYNDROME DESCRIPTION

Formerly called stiff-man syndrome, stiff-person syndrome (SPS) was identified by Moersch and Woltman over 50 years ago (Tinsley, Barth, Black, & Williams, 1997). This rare condition is a progressive autoimmune disorder that is characterized by two sets of symptoms: (1) symmetrical muscle rigidity and stiffness of axial and distal muscles, and (2) episodic muscular spasms (Dalakas, 2008). Epidemiological data are limited; one clinic in Germany reviewed their records from a decade (1988–1998), and identified 52 SPS cases in 25,000 cases seen (Meinck, 2001). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The pathogenesis of this condition is uncertain, but it is hypothesized to be an autoimmune-mediated chronic encephalomyelitis. Glutamic acid decarboxylase (GAD) antibodies have been found in the majority of cases presenting with this syndrome, with a minority of cases also showing other antibodies (Ab), including amphiphysin Ab (Murinson & Guarnaccia, 2008). Antibodies are located in both the central and peripheral nervous systems; within the peripheral nervous system, there is a high concentration of Ab against pancreatic beta cells. The enzyme (i.e., GAD)

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plays a vital role in the conversion of glutamic acid to GABA, which is an inhibitory neurotransmitter found throughout the CNS (Darnell, Victor, Rubin, Clouston, & Plum, 1993). A link between SPS and type 1 diabetes, and SPS and other autoimmune disorders (e.g., thyroiditis and pernicious anemia) have also been reported. In addition, genetic evidence, for example, specific human leukocyte antigen (HLA) alleles, is noted in the literature supporting the co-occurrence of SPS and diabetes mellitus. Insulindependent diabetes is reported in upward of 35% of patients who are diagnosed with SPS. Both tetanus and SPS share pathophysiological features in that they have been associated with sympathetic hyperactivity secondary to a lack of synaptic inhibition of pregangliotic autonomic neurons (Benarroch, Freeman, & Kaufman, 2007). A primary association has been made between SPS and excessive firing of the motor unit, implicating disinhibition of the descending pathways to the Renshaw cells of the gamma motor system (Thompson, 1994).

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Onset has been noted to be insidious, most commonly during the fourth or fifth decades of life (Meinck, 2001). In addition, SPS has been noted to occur more frequently in women than in men. Initial symptoms include muscle stiffness in one or in both legs; unexplained falls, or difficulty initiating gait, especially when emotionally stressed. With symptom development, stiffness and rigidity occur initially in the axial extremities moving to distal extremities. Therefore, hyperlordosis and ankylosis are common. Spasms are also frequent, and they may occur spontaneously or in association with a range of activities, including exposure to stimuli including noise and touch, experience of emotional upset, and brisk movement. Spasms are generally bilateral, occur axially or in the proximal limbs, have ‘‘violent [and] jerky,’’ myoclonic characteristics, and are reduced in sleep. Other commonly associated features include eye movement disturbances, ataxia, exaggerated startle response, positive head retraction reflex, and the Babinski response to the plantar reflex. Fractures are also seen in this population. Paroxysmal autonomic dysfunction is seen in some patients. Variants of the condition exist, and they are termed stiff limb syndrome (SLS), progressive encaphalomyelitis with rigidity and myoclonus (PERM), and paraneoplastic SPS. According to Meincke (2001), these three syndromes represent variations of

SPS, although he states that there is some controversy within the field regarding this classification. For SLS, the stiffness exists in only one limb, whereas in PERM, the stiffness occurs axially and in the extremities, and sensory loss occurs. In SLS and PERM, there are spasms and autoimmunity against GAD. In paraneoplastic conditions, the anti-GAD antibodies are not always present and are more commonly present against amphiphysin. Limited information is available on neuropsychological presentations of this condition. One study of 10 patients, using standardized assessments of intelligence, memory, attention, and executive function, reported no substantive neuropsychological features (Ameli, Snow, Rakovcevic, & Dalakas, 2005). However, examinations of psychological status have noted the co-occurrence of phobias, in particular fears of open spaces and agoraphobia (Ameli et al., 2005; Tesch, Severus, & Holdorff, 1998). Some researchers (Ameli et al., 2005) have reported that concerns regarding the environment could be considered realistic, given the functional limitations (e.g., limited ability to engage in behaviors such as crossing streets) that co-occur with SPS. Other reports, primarily case and small-group studies, have identified depression, anxiety, and alcohol abuse co-occurring with SPS (Black, Barth, Williams, & Tinsley, 1998; Tinsley et al., 1997). For example, Gerschlager, Schrag, & Brown (2002) examined the psychological health of 24 persons diagnosed with SPS. In their study, self-reported quality of life, as measured by the Short Form-36 (SF-36) survey, was significantly reduced when compared with general population mean scores on this scale. In addition, scores on the SF-36 were correlated with the duration of the disease process and with scores on the Beck Depression Inventory. One case study also reported the presence of posttraumatic stress disorder in a patient who subsequently developed SPS (Dinnerstein, Collins, & Berman, 2007). Another retrospective report of nine patients found historical features in the majority of cases, including a major stressful life change happening within 6 months before permanent SPS symptoms began (in seven of nine cases), the presence of transient motor symptoms occurring years before the onset of SPS (five of nine), and childhood history of loss of home or loss/invalidation of one or both parents (seven of nine) (Henningsen, Clement, Kuchenhoff, Simon, & Meinck, 1996). Interestingly, eight cases were initially diagnosed with a psychiatric condition. Such a finding is consistent with other reports that 60% of patients with SPS have a comorbid psychiatric diagnosis (Kyriakos & Franco, 2002).

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DIAGNOSIS

Diagnosis is based on the clinical criteria of symptoms (i.e., rigidity and spasms). Standard neurological diagnostic procedures (e.g., CT, MRI) often produce limited differentiation of persons with this syndrome, with the exception of exclusion of other conditions. For example, few patients show abnormalities on MRI and evoked potential studies. The primary diagnostic procedure is assessment of serum autoantibodies to GAD-65 through immunocyctochemistry, Western blot or radioimmunoassay (Dalakas, 2008), as elevations have been reported in 60–80% of patients seen (Meinck, 2001). Another diagnostic feature is involvement of muscles without the presence of extrapyramidal or pyramidal tract signs but instead lowfrequency motor unit firing at rest in agonist and antagonist muscles. SPS must be differentially distinguished from other conditions with similar symptoms (e.g., multiple sclerosis, tetanus, neuromyotonia, spinal cord tumors) and movement disturbances of psychogenic origin. TREATMENT

The most commonly used treatment is benzodiazepines (e.g., diazepam). Diazepam and other GABA agonists, specifically barbiturates, have been shown to diminish neurological and psychiatric symptoms (Kyriakos & Franco, 2002). The use of substances that enhance GABA transmission (e.g., vigabatrin and baclofen) are also noted to reduce symptoms. Antispasmodic agents (e.g., tizanidine) and steroid medications, for example, methylprednisolone have been shown to decrease muscle stiffness and spasms. Via case reports, intravenous immunoglobulin has been associated with reports of reduced pain, and improved social functioning, general mental health, and vitality (Gerschlager et al., 2002). Jacqueline Remondet Wall Jennifer Mariner

Dalakas, M. C. (2008). Advances in the pathogenesis and treatment of patients with stiff person syndrome. Current neurology and neuroscience reports, 8(1), 48–55. Darnell, R. B., Victor, J., Rubin, M., Clouston, P., & Plum, F. (1993). A novel antineuronal antibody in stiff-man syndrome. Neurology, 43, 114–120. Dinnerstein, E., Collins, D., & Berman, S. A. (2007). A patient with post-traumatic stress disorder developing stiff person syndrome: Is there a correlation? Cognitive and Behavioral Neurology, 20(2), 136–137. Gerschlager, W., Schrag, A., & Brown, P. (2002). Quality of life is stiff-person syndrome. Movement Disorders, 17(5), 1064–1067. Henningsen, P., Clement, U., Ku¨chenhoff, J., Simon, F., & Meinck, H. M. (1996). Psychological factors in the diagnosis and pathogenesis of stiff-man syndrome. Neurology, 47(1), 38–42. Kyriakos, C. R., & Franco, K. N. (2002). Stiff-man syndrome: A case report and review of the literature. Psychosomatics, 43(3), 243–244. Meinck, H. M. (2001). Stiff man syndrome. CNS Drugs, 15(7), 515–526. Murinson, B. B., & Guarnaccia, J. B. (2008). Stiff-person syndrome with amphiphysin antibodies: Distinctive features of a rare disease. Neurology, 9(71), 1938–1939. Tesch, M., Severus, E., & Holdorff, B. (1998). Agoraphobia and ‘‘psychogenic’’ — attributed gait disorder as symptoms of ‘‘stiff-man’’ syndrome. Psychiatrische Praxis, 25(6), 310–311. Abstract obtained from Medline, PMID No. 9885845. Thompson, P. D. (1994). Stiff people. In C.D. Marsden & S. Fahn (Eds.), Movement disorders (3rd ed., pp. 373–405). Oxford: Butterworth. Tinsley, J. A., Barth, E. M., Black, J. L., & Williams, D. E. (1997). Psychiatric consultations in stiff-man syndrome. Journal of Clinical Psychiatry, 58(10), 444–449.

STRIATONIGRAL DEGENERATION DESCRIPTION

Ameli, R., Snow, J., Rakocevic, G., & Dalakas, M. C. (2005). A neuropsychological assessment of phobias in patients with stiff person syndrome. Neurology, 61(11), 1961–1963. Benarroch, E., Freeman, R., & Kaufman, H. (2007). Autonomic Nervous System. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 383–404). Philadelphia: Saunders Elsevier. Black, J. L., Barth, E. M., Williams, D. E., & Tinsley, J. A. (1998). Stiff-man syndrome: Results of interviews and psychologic testing. Psychosomatics, 39(1), 38–44.

Striatonigral degeneration is a progressive neurodegenerative disorder (Multiple System Atrophy, 2008). Striatonigral degeneration, Shy–Drager’s syndrome, and olivopontocerebellar atrophy comprise a class of disorders called multiple systems atrophy (MSA) (Adams & Jenkins, 2008; Cohen & Freedman, 2005). There is significant overlap between these disorders. Striatonigral degeneration is often referred to as MSA-p (parkinsonian type) as the initial predominant features are similar to those of Parkinson’s

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disease (PD), although autonomic failure and cerebellar dysfunction emerge over time (Adams & Jenkins, 2008; Appenzeller & Oribe, 1997; Multiple System Atrophy, 2008;). Because striatonigral degeneration presents as similar to PD, many researchers believe individuals with striatonigral degeneration are sometimes mistakenly diagnosed with PD due to the similarities. Common symptoms are those associated with parkinsonism, including poverty of movement (akinesia), slowed movements (bradykinesia), a flexed/stooped posture, and rigidity (Braffman, 1993; Lishman, 1998). A tremor may be present, but it is not a prominent sign as in PD (Shulman, Minagar, & Weiner, 2004). Cerebellar and autonomic difficulties develop over time and are common in the later stages. Cerebellar dysfunction includes a loss of muscle coordination (ataxia) and difficulties with movement and balance (Cohen & Freedman, 2005; Shulman et al., 2004). Gait ataxia and ocular difficulties develop where there are involuntary, jerky movements, making it difficult for the individual to have a steady gaze (Appenzeller & Oribe, 1997). Autonomic failure symptoms include urinary problems (frequency, urgency, and retention), breathing abnormalities while sleeping, erectile dysfunction, swallowing difficulties (dysphagia), and loss of sphincter control (Adams & Jenkins, 2008; Calabresi, Cupini, Mercuri, & Bernardi, 1993; Lishman, 1998). Orthostatic hypotension causing fainting is common, which can lead to complications from injuries sustained during falls (Adams & Jenkins, 2008; Lishman, 1998). Speech difficulties are also present, consisting of slowed, dysfluent speech with difficulties in articulation due to muscle incoordination. Speech impairment worsens with time as the disorder progresses. About one-third of cases present with inhalatory stridor, which is when a harsh sound is made upon inhalation (Adams & Jenkins, 2008). Onset of striatonigral degeneration is always in adulthood, usually between the ages of 50 and 60 (Adams & Jenkins, 2008; Berman, 2007). To date, there is no sex or racial preference (Shulman et al., 2004). The exact prevalence is unknown although estimates suggest 4 cases per 100,000 individuals (Adams & Jenkins, 2008; Appenzeller & Oribe, 1997). The mean survival rate is less than 10 years (Berman, 2007; Shulman et al., 2004). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Although the etiology is unknown, diffuse small neuronal loss and degeneration in the substantia nigra, caudate nucleus, putamen, and basal ganglia are commonly noted (Adams & Jenkins, 2008; Berman, 2007;

Braffman, 1993; Shulman et al., 2004). Gray matter shows a decrease in neurons and white matter shows a decrease in myelination (Adam & Jenkins, 2008). Autonomic failure is associated with neuronal loss in the spinal cord and brainstem (Blass, 2006; Lishman, 1998). Cerebellar dysfunction is associated with cerebellar and brainstem atrophy and olivopontocerebellar lesions. Cytoplasmic inclusions (glial cells with internal protein tangles) have been reported in the substantia nigra and other basal ganglia structures. Decreased dopamine levels resulting in bradykinesia are present. Research has also suggested abnormalities in the protein of alpha-synuclein (Adams & Jenkins, 2008). Autopsy reports have found neuron loss in the basal ganglia structures. Damaged areas have shown a proliferation of astrocytes with a corresponding increase in cell density. In striatonigral degeneration, no Lewy bodies (abnormal aggregates of protein inside nerve cells) are present and there is a lack of neurofibrillary tangles — a distinguishing characteristic from PD. Autopsy has confirmed degenerative changes in the putamen and caudate nucleus. The hallmark characteristic found upon autopsy is the presence of glial cytoplasmic inclusion bodies in affected structures involved in movement, balance, autonomic control, and cerebellar function (Berman, 2007; Shulman et al., 2004). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Clinically, individuals with striatonigral degeneration present with slow, stiff movements similar to those found in individuals with PD (Lishman, 1998). Their posture is stooped, and they tend to walk with a shuffling gait (Shulman et al., 2004). As such, frequent falls are common (Hannay, Howieson, Loring, Fischer, & Lezak, 2004). Limb movement is reduced (e.g., not using arm gestures when speaking, holding arms stiffly near body when walking) (Hannay et al., 2004) and, in general, individuals have difficulty initiating directed movement and performing tasks smoothly and slowly. Handwriting is messy and decreases in size (i.e., micrographia) (Shulman et al., 2004). Poor hygiene may be evident. Speech is halting. Anxiety, fatigue, and stimulants can exacerbate difficulties (Hannay et al., 2004). Neuropsychological testing has shown some cognitive deterioration over time that is generally dependent upon the level of cerebellar degeneration (Soliveri et al., 2000). As a result, global cognitive disturbance has not been reported (Adams & Jenkins, 2008). Measures requiring motor skills show impairment due to the

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effects of ataxia. Motor sequencing is particularly difficult (Soliveri et al., 2000). Difficulties with visual and visual-motor tasks have been reported (Berman, 2007; Cohen & Freedman, 2005) as have memory impairments, particularly verbal and figural working memory (Lange et al., 2003). Furthermore, there are executive problems similar to those seen in frontal lobe lesions (Cohen & Freedman, 2005; Shulman et al., 2004); attentional difficulties have been reported on the Stroop Color-Word Test (Meco, Gasparini, & Dorrichi, 1996). Oral reading is slow and verbal fluency is reduced (Meco et al., 1996; Soliveri et al., 2000). There has been inconsistency in reporting mood disturbances (Berman, 2007; Cohen & Freedman, 2005). DIAGNOSIS

Striatonigral degeneration is similar to PD and is commonly mistaken for it due to the similarity of symptoms (Appenzeller & Oribe, 1997). Several differences in symptoms make differential diagnosis possible, though conclusions are often not definitive. There is a poor response to the use of L-DOPA for treatment (Appenzeller & Oribe, 1997; Cohen & Freedman, 2005; Shulman et al., 2004). Striatonigral degeneration presents with inhalatory stridor, which rarely occurs in patients with PD. There is less of a resting tremor and more symptoms of autonomic system failure (Berman, 2007; Cohen & Freedman, 2005; Shulman et al., 2004). Lewy bodies are not present although they are characteristic of PD (Shulman et al., 2004). Although there is a lack of specific diagnostic tests for striatonigral degeneration currently, the utility of CT scans, MRIs, positron emission tomography (PET) scans, and electroencephalograms (EEGs) is being explored. Specifically, CT scans can show evidence of cerebellar or brain atrophy (Appenzeller & Oribe, 1997), and MRIs have shown evidence of cerebellar, striatum, and brainstem atrophy. Small neuron loss in the putamen and caudate nucleus has also been found, as has a diminished pars compacta in the substantia nigra (Braffman, 1993). Furthermore, decreased signal atrophy in the putamen has been noted (Shulman et al., 2004). From a functional imaging standpoint, PET scans have found evidence of down-regulation of postsynaptic D2 receptor binding and a lower than normal concentration of D1 and D2 receptors in the striatum (Appenzeller & Oribe, 1997). In addition, there is evidence of decreased glucose utilization in the frontal lobe, as well as decreased glucose utilization in the striatum (Cohen & Freedman, 2005). Finally, minor EEG abnormalities were found in the sleeping state, typically associated with autonomic sleep difficulties.

TREATMENT

There is no cure for striatonigral degeneration; treatments focus on alleviating symptoms. Medication can be used to assist with parkinsonian symptoms, including dopamine agonists such as pramipexole, ropinirole, and amantadine (Shulman et al., 2004). In comparison, L-DOPA has proven to be ineffective in alleviating symptoms; some cases have even reported a worsening of the condition after such treatment. Neuromuscular blocking agents can be used to improve transmission of impulses at the myoneural junction, thereby increasing muscular function. Occupational, physical, and speech therapy are recommended adjuncts to assist with walking/movement difficulty, dysfluent speech, and activities of daily living (Adams & Jenkins, 2008). Individuals often need assistance obtaining health services, and case management is advisable. Orthostatic hypotension is treated with a combination of pharmacotherapy and behavior management (Shulman et al., 2004). Sympathomimetic agents are used to increase standing blood pressure, and mineralocorticoids are used to enhance the reabsorption of sodium, thereby increasing blood pressure and reducing risk of lightheadedness and fainting. As falls are a common occurrence that can result in injury, safety precautions should be taken, including having access to emergency services, and caution when rising and walking. Individuals are advised to avoid common triggers of low blood pressure, such as dehydration and hot weather. Increased fluid and sodium intake is recommended. Other suggestions include sleeping with the head in an elevated position and wearing pressure stockings if necessary (Shulman et al., 2004). Christine Corsun-Ascher Charles Golden Adams, S. G., & Jenkins, M. E. (2008). Multiple system atrophy and Shy-Drager syndrome. In M. R. McNeil (Ed.), Clinical management of sensorimotor speech disorders (pp. 348–349). New York: Thieme. Aotsuka, A., & Paulson, G. W. (1993). Striatonigral degeneration. In M. B. Stern & W. C. Koller (Eds.), Parkinsonian syndromes (pp. 33–40). New York: Informa Health Care. Appenzeller, O., & Oribe, E. (1997). The autonomic nervous system. Philadelphia: Elsevier Health Sciences. Berman, S. A. (2007). eMedicine: Striatonigral degeneration. Retrieved December 5, 2008, from www.emedicine.com/neuro/topic354.htm Blass, J. P. (2006). Concise clinical pharmacology: CNS therapeutics. New York: McGraw-Hill Professional. Braffman, B. (1993). Neurodegenerative disorders. In J. Kucharczyk, M. E. Moseley, & A. James (Eds.),

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Magnetic resonance neuroimaging (p. 229). Boca Raton, FL: CRC Press. Calabresi, P., Cupini, L. M., Mercuri, N. B., & Bernardi, G. (1993). Age-related disorders of the autonomic nervous system. In F. Amenta (Ed.), Aging of the autonomic nervous system (pp. 304–305). Boca Raton, FL: CRC Press. Cohen, S., & Freedman, M. (2005). Cognitive and behavioral changes in the Parkinson’s-plus syndromes. In K. E. Anderson, W. J. Weiner, & A. Lang (Eds.), Behavioral neurology of movement disorders (pp. 172–174). Philadelphia: Lippincott Williams & Wilkins. Hannay, H. J., Howieson, D. B., Loring, D. W., Fischer, J. S., & Lezak, M. D. (2004). Neuropathology for neuropsychologists. In M. D. Lezak, D. B. Howieson, D. W. Loring (with H. J. Hannay, & J. S. Fischer) (Eds.), Neuropsychological assessment (4th ed., pp. 225–231). Oxford: Oxford University Press. Lange, K. W., Tucha, O., Alders, G. L., Preier, M., Csoti, I., Merz, B., et al. (2003). Differentiation of parkinsonian syndromes according to difference in executive functions. Journal of Neural Transmission, 110(9), 983–995. Lishman, W. A. (1998). Organic psychiatry: The psychological consequences of cerebral disorder. Hoboken, NJ: Blackwell Publishing. Meco, G., Gasparini, M., & Doricchi, F. (1996). Attentional functions in multiple system atrophy and Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 60(4), 393–398. Pahwa, R., & Koller, W. C. (1995). Defining Parkinson’s disease and parkinsonism. In J. H. Ellenberg, W. C. Koller, & J. W. Langston (Eds.), Etiology of Parkinson’s disease (pp. 17–18). New York: Informa Health Care. Shulman. L. M., Minagar, A., & Weiner, W. J. (2004). Multiplesystem atrophy. In R. L.Watts & W. C. Koller (Eds.), Movement disorders: Neurologic principles and practice (pp. 359–360). New York: McGraw-Hill Professional. Soliveri, P., Monza, D., Paridi, D., Carella, F., Genitrini, S., Testa, D., et al. (2000). Neuropsychological follow up in patients with Parkinson’s disease, striatonigral degeneration-type multisystem atrophy, and progressive supranuclear palsy. Journal of Neurology, Neurosurgery, and Psychiatry, 69(3), 290–291. Vinters, H. V. (1998). Diagnostic neuropathology. New York: Informa Health Care.

STURGE–WEBER SYNDROME DESCRIPTION

Sturge–Weber syndrome (SWS) is a progressive congenital disease that is commonly associated with the

port wine stain, an auburn colored birthmark, among other neurological and psychological deficits. SWS was first described by Sturge in 1879, as partial epilepsy caused by a lesion in the vasomotor brain center along with a characteristic neurocutaneous nevus. In 1922 and 1929, Weber described another case of SWS, although he named it ‘‘encephalotrigeminal angiomatosis.’’ Genetic causes of SWS are unknown, although rare monozygotic twin studies have led scientists to speculate that the syndrome originates from somatic gene mutation during early neonatal trimesters (Maiuri, Gangemi, Jaconetta, & Maiuri, 1989). SWS occurs in all sexes and races sporadically and equally. Treatments for SWS are symptomatically based and include aspirin, anticonvulsants, and dermal laser procedures.

NEUROPATHOLOGY/PATHOPHYSIOLOGY

The most common and apparent symptom associated with SWS is the trigeminal port wine stain, a birthmark most likely caused by agenesis of the cephalic venous plexus during the first neonatal trimester (Kossoff, Hatfield, Ball, & Comi 2004; McIntosh & Morse, 2006). Although the birthmark is seen in most cases of SWS, the majority (more than 50%) of infants born with the port wine stain birthmark do not have the associated neurological deficits found in SWS (Comi, 2003). The birthmark most frequently occurs unilaterally, although it does occur bilaterally, and develops on the face near the eyes. The port wine stain is caused by an overabundance of capillaries under the dermal layers. The birthmark has normal texture and can appear in a variety of colors, from light pink to deep red (Comi, 2003; McIntosh & Morse, 2006). The birthmark itself does not pose any neuropsychological or neurological symptoms. The most common neurolopathological feature of SWS is angioma, which is the excessive and abnormal growth of blood vessels on the surface of the brain. Research suggests that the angioma found in SWS results from abnormal maturation of the most primitive cephalic venous plexus during the first neonatal trimester (Comi, 2003, pp. 9, 19). Animal models of the angioma seen in SWS have been replicated in horses, although few have been scientifically researched (Comi, 2003). Further studies regarding abnormal brain structures of SWS have shown abnormal vascular structures in the leptomeninges, showing atrophic tissue and brain calcifications (Comi, 2003). Evidence also indicates that the meninges are significantly more thin and narrow in SWS patients (Di Trapani, Di Rocco, & Abbamondi, 1982).

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Brain calcifications frequently occur in SWS and are most commonly found in the cortical layers, which include the outermost layers of the brain. Brain calcifications consist of calcium and phosphorus deposits near parenchymal vessels and form within subcortical tissues in the cortex and vary greatly among patients (Comi, 2003). Although the structure of the brain calcifications is known, the origin and neuropsychological effect of brain calcifications in SWS are currently unknown and greatly disputed within scientific literature. According to Comi (2003), research suggests that SWS is caused by the complicated interplay between abnormal extracellular matrix, vascular innervations, and endothelium alongside the leptomeningeal angioma. Other physical abnormalities associated with SWS include glaucoma, increased vascularity of jaw tissue, and growth hormone deficits. Various oral manifestations are also frequently present in SWS patients. These include increased vascularity of the jaw tissue, swelling of soft oral tissue, enlargement of the jawbone, and arched palate. Secondary symptoms associated with increased vascularity include the premature loss of permanent teeth (Comi, 2003). Study results attribute abnormal brain structure to noradrenergic innervations in regard to the increased constriction in cortical vessels. It is hypothesized that such abnormalities would put SWS patients at a higher risk for chronic ischemia and seizures and in turn, brain injury (Comi, 2003). Studies have also shown that there is a high prevalence of growth hormone deficiency in SWS patients (61% in the SWS population and 0.03% in the general population) (Miller, Ball, Comi, & Germain-Lee, 2009). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

SWS is associated with several commonly occurring clinical symptoms including seizures, mental retardation (MR), migraines, glaucoma, and stroke-like episodes (Comi, 2003; Kossoff et al., 2004; McIntosh & Morse, 2006). Seizures are a frequent neurological symptom of SWS (occurring in approximately 70–80% of SWS patients), nearly 75% experiencing onset prior to 12 months of age, the mean age of onset being 9 months (Cody & Hynd, 1998; Kossoff, Buck, & Freeman, 2003; Morse & McIntosh, 2006). Seizures are not experienced by all SWS patients; while some SWS patients experience frequent and numerous seizures, others experience infrequent episodes. Seizures associated with SWS are generally focal in onset; however, they tend to generalize to other brain regions over time (McIntosh & Morse,

2006). Seizure type varies between patients. Seizure onset typically occurs within the first 2 years of the child’s life, with the majority occurring prior to age 1 (approximately 75%) (Cody & Hynd, 1998; Comi, 2003; McIntosh & Morse, 2006). Although SWS is not considered a fatal syndrome, seizures frequently give rise to the onset of morbid secondary symptoms, including motor delays, hemiatrophy and hemiplegia (30–50%) and brain lesions (Cody & Hynd, 1998; McIntosh & Morse, 2006). Hemiparesis and hemiplegia often occur as a result of acute seizure episodes and leave the SWS patient with either severe muscle weakness or paralysis of one or both sides of the body. Hemiatrophy and hemiplegia often cause permanent motor delays (Comi, 2003; McIntosh & Morse, 2006). Comi (2003) recently evidenced that SWS patients often experience weakness in the face or body that is contralateral to the port wine stain. In some cases, researchers have examined patients who have suffered acute ischemic brain injury resulting from acute seizure episodes (Comi, 2003). Studies show that the abnormal synaptic plasticity caused by seizures in the cortical tissue may lead to reoccurring epileptic episodes, supporting earlier research that seizures in SWS become more intense over time (Comi, 2003). In addition, approximately 60–80% of SWS patients have mild to severe MR, with only 8% of patients considered to have average cognitive functioning (Cody & Hynd, 1998; Comi, 2003; McIntosh & Morse, 2006). A strong correlation between age of seizure onset and cognitive functioning has been shown; although there is also scientific speculation that age of seizure onset is not as predictive of cognitive functioning as seizure intensity (Cody & Hynd, 1998; McIntosh & Morse, 2006). Seizures occurring during the child’s first year have been shown to significantly increase the risk for MR (Comi, 2003). This research is supported by the fact that MR is rarely seen in SWS patients who do not experience seizures (Aicardi, 1990). Headaches are another secondary symptom of seizures. Approximately 50% of SWS patients complain of headaches, the majority of which are diagnosed as migraines. Headaches commonly occur directly after the onset of a seizure. In some cases, headaches are symptomatic of the pressure experienced as a result of glaucoma (Cody & Hynd, 1998; Comi, 2003; McIntosh & Morse, 2006). According to Kossoff et al. (2004), the most common symptomology associated with headache in SWS includes unilateral pain, nausea, photophobia, phonophobia, and throbbing sensations. Kossoff et al. (2004) also found that the most common type of headache was the migraine. Neuropsychological symptoms associated with SWS include an increased risk for academic,

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intellectual, and behavioral problems. SWS patients are at a significantly high risk for pervasive developmental disorders (PDDs), particularly autism spectrum, MR, learning disabilities, and attention deficit hyperactivity disorder (ADHD) (close to 20% in SWS population and only 5–6% in the general population). PDDs develop at a significantly higher risk in SWS (Cody & Hynd, 1998). The most common PDD is autism, or autism spectrum disorders (Cody & Hynd, 1998). Depression has also been commonly seen in older children and adolescents. In general, early development appears more normal than later developmental stages in children diagnosed with SWS (Cody & Hynd, 1998). SWS patients often exhibit behavioral issues including increased disinhibition (Cody & Hynd, 1998). The majority of these children need to have specialized educational plans created for them. There is currently little research on specific neuropsychological deficits found in SWS.

DIAGNOSIS

SWS is categorized into three types. Type 1 is classified by the presence of the port wine stain along with leptomeningeal angioma, which consists of blood vessel tumors in the membranes covering the brain and spinal cord. In some Type 1 cases glaucoma is present. Type 2 consists of only the facial angioma, and glaucoma is sometimes present. Type 2 is categorized as having only the leptomeningeal angioma. Glaucoma is hardly ever present in Type 3 patients (Cody & Hynd, 1998; Comi, 2003; McIntosh & Morse, 2006). There are currently no known preventive methods for the development of SWS, and infants born with the port wine stain should be screened periodically throughout infancy and into early childhood for diagnostics, since certain neurological symptoms associated with SWS, including brain calcifications and lesions, may not be present or visible in early neuro-imaging scans (Comi, 2003). Diagnostic methods most frequently used in the diagnosis of SWS include positron emission tomography (PET), MRI, and single-photon emission computed tomography (SPECT) (Comi, 2003). TREATMENT

Laser treatment procedures are used to treat or decrease the visibility of the port wine stain. In certain circumstances, these procedures can be done on infants as early as 1 month old (McIntosh & Morse, 2006). The seizures found in SWS patients frequently intensify in severity and frequency as age increases, often becoming untreatable with anticonvulsants (Cody & Hynd, 1998). A study conducted by Wilfong, Buck, and Ball (2008)

shows that the most common form of anticonvulsant prescribed to SWS patients are sodium channel blockers, including levetiracetam, carbamazepine, and oxcarbazepine. In acute cases, vagus nerve stimulation or epilepsy surgery, known as hemispherectomy, can be used to treat seizures. A study by Wilfong et al. (2008) found that 81% of SWS patients who had undergone vagus nerve stimulation or hemispherectomy experience no postoperative seizures, with 53% of these patients no longer having to take anticonvulsants. Surgery is still highly controversial and considered to be a last resort for treating SWS, since studies show that approximately 47% of patients experience postoperative complications (Wilfong et al., 2008). Glaucoma is often treated with eye drops, corrective lenses, as well as surgery. Headaches are generally treated with aspirin. Ashley L. Ware Antonio E. Puente Aicardi, J. (1990). Epilespy in brain-injured children. Developmental Medicine and Child Neurology, 32, 191–202. Cody, H., & Hynd, G. W. (1998). Sturge-Weber syndrome. In L. Phelps (Ed.), Health-related disorders in children and adolescents: A guidebook for understanding and educating (pp. 624–628). Washington, DC: American Psychological Association. Comi, A. M. (2003). Pathophysiology of Sturge-Weber syndrome. Journal of Child Neurology, 18(8), 509–516. Di Trapani, G., Di Rocco, C., & Abbamondi, A. L. (1982). Light microscopy and ultrasound studies of SturgeWeber disease. Childs Brain, 9, 23–36. Kossoff, E. H., Buck, C., & Freeman, J. M. (2003). Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide. Study funded by the Sturge-Weber Foundation. Baltimore: Johns Hopkins. Kossoff, E. H., Hatfield, L. A., Ball, K. L., & Comi, A. M. (2004). Comorbidity of epilepsy and headache in patients with Sturge-Weber syndrome. Journal of Child Neurology, 20, 678–682. Maiuri, F., Gangemi, M., Jaconetta, G., & Maiuri, L. (1989). Sturge-Weber disease without facial nevus. Journal Neurosurgery Science, 33, 215–218. McIntosh, D. E., & Morse, M. M. (2006). Neurocutaneous syndromes. In L. Phelps (Ed.), Chronic health-related disorders in children: Collaborative medical and psychoeducational interventions (pp. 157–173). Washington, DC: American Psychological Association. Miller, R. S., Ball, K. L., Comi, A. M., & Germain-Lee, E. L. (2009). Growth hormone deficiency in children with Sturge-Weber syndrome. Study funded by the SturgeWeber Foundation. Unpublished manuscript. Wilfong, A., Buck, C., & Ball, K. (2008). Sturge-Weber syndrome: Trends in epilepsy therapy. Study funded by the SturgeWeber Foundation. Unpublished manuscript.

SUBCORTICAL VASCULAR DEMENTIA & 687

SUBCORTICAL VASCULAR DEMENTIA DESCRIPTION

Cerebral atherosclerosis has been known since the late 19th century. The vascular dementias represent the second most common form of dementia in the United States and Europe and are the leading cause of dementia in some sections of Asia. Vascular dementia also commonly co-occurs with Alzheimer’s disease. Subcortical vascular dementia is a particular subtype involving the small blood vessels of the brain that can mimic the primary neurodegenerative disorders by causing degradation of the white matter (MartinezLage & Hacinski, 1998). Consequently, it is marked by a more frontal-subcortical cognitive dysfunction profile owing to the predominance of white matter within this cerebral region. Furthermore, the presentation occurs most often in the setting of one or more vascular risk factors such as hypertension and/or diabetes mellitus (Caselli & Boeve, 2007). Current treatment focuses on controlling vascular risks and symptomatic treatment.

infarct dementia. Symptoms that suggest a subcortical vascular etiology include early gait involvement, urinary incontinence, and emotional/personality changes. Psychomotor slowing, a poor learning curve, impeded delayed recall with general improvement with cueing and/or recognition, and relative sparing of naming and other language skills have also been noted (Graham, Emery, & Hodges, 2004). Patients with vascular risk factors as part of their past medical history should also be suspected. Careful neurological examination may discern focal neurological deficits, though this is more common in multiinfarct dementia. As a result, neuropsychological assessment can be essential in evaluating neurocognitive status and the potential of a subcortical vascular dementia diagnosis. In this regard, the cognitive profile on testing tends toward more frontal-subcortical deficits and executive dysfunction. The degree of white matter disease seen on MRI correlates with the cognitive profile of patients, with more white matter disease accompanying more problems with working memory, especially compared with episodic memory (Libon et al., 2008), and executive and visuoconstructive tests as compared with memory and language tests (Price, Jefferson, Merino, Heilman, & Libon, 2005).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

The small arteries that feed the deep structures of the brain, the white matter tracts, and subcortical nuclei are vulnerable to lipohyalinosis and venous collagenosis due to vascular disease (Munoz, 2003). The most common causes are hypertension, hypercholesterolemia, diabetes mellitus, obstructive sleep apnea, and smoking. Microvascular disease has been associated with white matter changes on brain imaging (white matter hyperintensities on MRI, hypointensities on CT) and microhemorrhages as evinced by hemosiderin deposits. Small lacunar infarcts can also be seen in subcortical vascular dementia due to the same underlying pathophysiology. Rarely, in patients without common risk factors, other possible vascular etiologies must be explored. The prototype of this is cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Patients suffering from subcortical vascular dementia present with a similar onset and progression to that of primary neurodegenerative disorders, with a gradual onset and progressive decline as opposed to the sudden onset and stepwise decline seen in multi-

DIAGNOSIS

The diagnosis of subcortical vascular dementia is largely based on a combination of clinical judgment and neuroimaging. Before making a diagnosis of subcortical vascular dementia, the patient should have multiple cognitive deficits that are causing significant functional decline in his or her day-to-day life. This may be best accomplished through a comprehensive neuropsychological assessment that permits the evaluation of a variety of cognitive domains. Reversible causes should be ruled out, predominantly by laboratory studies including a complete metabolic panel, blood count, thyroid function, antinuclear antibody profile, sedimentation rate, B-12 level, and syphilis serology. In addition, the contribution of potential psychogenic factors, such as depression, must also be considered. Neuroimaging serves a capacity of both inclusion and exclusion. Regarding the latter, differentials including normal pressure hydrocephalus, tumors, and other potential causes may be ruled out via imaging. In regard to inclusionary criteria, neuroimaging can reveal whether there is enough subcortical vascular changes to support a diagnosis of subcortical vascular dementia. In comparison of the potential methods of imaging, the presence of white matter disease is more easily discerned on MRI

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imaging with FLAIR. In general, involvement of 25% or more of the white matter is believed to be enough to cause some cognitive disruption, whereas white matter changes of 50% or more is consistent with outright subcortical vascular dementia. Multiple lacunar infarcts in the white matter and subcortical structures can also be seen. TREATMENT

There are no proven treatments for subcortical vascular dementia. Conventional practice focuses on control of presumed vascular risk factors leading to the vascular damage. Diet and exercise can improve several common vascular risk factors, and smokers should be counseled on cessation. In models of secondary stroke prevention, statins have proved useful and are certainly of use in patients with hypercholesterolemia. Patients with obstructive sleep apnea should be placed on continuous positive airway pressure (CPAP). Antiplatelet agents can be used to reduce the risk of further vascular insult. Antihypertensives should be used for those with high blood pressure. Antiglycemics should be used for those with diabetes mellitus. Symptomatic treatment can be attempted. The most commonly used drugs are those currently used to treat Alzheimer’s disease, acetylcholinesterase inhibitors, and memantine (Erkinjuntti, Roma´n, & Gauthier, 2004). Another possible treatment is the vasodilator hydergine (Olin, Schneider, Novit, & Luczak, 2001). Glen Finney Caselli, R. J., & Boeve, B. F. (2007). The degenerative dementias. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 699–733). Philadelphia, PA: Saunders Elsevier. Erkinjuntti, T., Roma´n, G., & Gauthier, S. (2004). Treatment of vascular dementia — evidence from clinical trials with cholinesterase inhibitors. Journal of the Neurological Sciences, 226(1–2), 63–66. Graham, N. L., Emery, T., & Hodges, J. R. (2004). Distinctive cognitive profiles in Alzheimer’s disease and subcortical vascular disease. Journal of Neurology, Neurosurgery, and Psychiatry, 75, 61–71. Libon, D. J., Price, C. C., Giovannetti, T., Swenson, R., Bettcher, B. M., Heilman, K. M., et al. (2008). Linking MRI hyperintensities with patterns of neuropsychological impairment: Evidence for a threshold effect. Stroke, 39, 806–813. Martinez-lage, P., & Hacinski, V. (1998). Multi-infarct dementia. In H. J. M. Barnett, J. P. Mohr, B. M. Stein,

& F. M. Yatsu (Eds.), Stroke pathophysiology, diagnosis, and management (3rd ed., pp. 875–894). Philadelphia, PA: Churchill Livingstone. Munoz, D. G. (2003). Small vessel disease: Neuropathology. International Psychogeriatric, 15(Suppl. 1), 67–69. Olin, J., Schneider, L., Novit, A., & Luczak, S. (2001). Hydergine for dementia. Cochrane Database of Systematic Reviews, (2), CD000359. Price, C., Jefferson, A. L., Merino, J., Heilman, K., & Libon, D. J. (2005). Towards an operational definition of the ‘‘Research Criteria for Subcortical Vascular Dementia’’: Integrating neuroradiological and neuropsychological data. Neurology, 65, 376–382. Roman, G. C., Tatemichi, T. K., Erkinjuntti, T., Cummings, J. L., Masdeu, J. C., Garcia, J. H., et al. (1993). Vascular dementia: Diagnostic criteria for research studies — Report of the NINDS-AIREN International Workshop. Neurology, 43, 250–260.

SUNCT HEADACHE SYNDROME DESCRIPTION

SUNCT headache syndrome stand for short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. It is a relatively rare chronic headache syndrome (Sjaastad et al., 1989). First described in 1989 by Sjaastad and colleagues, the presentation constitutes a pattern of repeated (20 or more episodes), severe stabbing or throbbing pain in the temporal or orbital regions of the head in a unilateral formation that coincides with ipsilateral conjunctival injection and lacrimation. It is more commonly observed in males versus females, with symptom onset usually occurring in the fifth or sixth decade of life (Matharu, Cohen, Boes, & Goadsby, 2003). Of all the primary headache disorders, SUNCT headaches are most resistant to treatment (Goadsby & Lipton, 1997). Lidocaine, lamotrigine, gabapentin, topiramate, and oxcarbazepine have shown minimal yet positive results, as have others as discussed in the following (Cohen, 2007). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The neuropathological basis of SUNCT headaches has been localized to the inferior posterior hypothalamus (Cohen, Matharu, Kalisch, Friston, & Goadsby, 2004; Sprenger et al., 2005). More specifically, the headaches arise on the ipsilateral side of the hypothalamic activation. This has been demonstrated through

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functional MRI and blood oxygenation level dependent (BOLD) imaging. However, it is worth noting that this is etiology is not definitive of SUNCT, as similar activation has been noted in cluster headaches and paroxysmal hemicrania (Matharu, Cohen, Frackowiak, & Goadsby, 2006; Sprenger et al., 2004). Vascular-based structural lesions have also been documented in the area of the posterior fossa, either extra-axial or intra-axial, mostly vascular disturbances/malformations. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

As previously discussed, SUNCT headaches present as unilateral pain that coincides with conjunctival injection and tearing that are short lasting in duration. Ipsilateral cranial autonomic features accompany the presentation, most commonly lacrimation and conjunctival injection that are essential to diagnosis. The pain is most commonly localized to the temporal or orbital regions, although spread past midline as well as extension posteriorly to the occipital region have been noted (Manzoni et al., 1983). Patients often describe it as stabbing, throbbing, burning, or electrical pain lasting 10 to 60 seconds (Pareja & Sjaastad, 1997). Over the long term, individuals may experience periods of clustering where numerous headaches are experienced, while at other times they may remain asymptomatic. Phonophobia and photophobia commonly occur in conjunction with the headaches (Cohen, Matharu, & Goadsby, 2006). Ptosis may present. Neuropsychological deficits have not been directly related to the presentation. During symptomatic periods, individuals may present with deficits in attention, concentration, and retrieval-based memory. Visuospatial dysfunction may also be observed in conjunction with visual disturbances secondary to the headaches. During asymptomatic periods neuropsychological dysfunction has not been strongly associated with the presentation.

injection, lacrimation, nasal congestion, rhinorrhoea, ptosis, or eyelid edema (Matharu, Cohen, & Goadsby, 2004; May, Bahra, Bu¨chel, Turner, & Goadsby, 1999; Olesen, 2001). In some ways, the presentations lack of response to medicinal intervention may also be seen as diagnostic in nature (Monde´jar et al., 2006). Beyond the constellation of symptoms, as with other primary headache syndromes, diagnostic workup should include neuroimaging in the form of CT and/or MRI. This is recommended to rule-out and evaluate for the presence of intracranial lesions including aneurysms, other arteriovenous malformations, tumors/neoplasm, hydrocephalus, as well as other factors that may contribute to increased intracranial pressure. TREATMENT

Of all primary headache syndromes, SUNCT headache syndrome is recognized as the most highly refractory to treatment. Commonly used agents including sumatriptan, indomethacin, prednisone, aspirin, and carbamazepine (Goadsby & Lipton, 1997). Lamotrigine, gabapentin, topiramate, intravenous lidocaine and intravenous phenytoin have demonstrated the most encouraging results in treating SUNCT headaches (May et al., 2006). Combined treatment of some these agents with prednisone or prednisolone have also yielded positive results in more refractory cases (De Benedittis, 1996; Gardella, Viruega, Rojas, & Nagel, 2001; Graff-Radford, 2000; Morales-Ası´n et al., 2000; Pareja, Kruszewski, & Sjaastad, 1995). Several case reports have also suggested a potential efficacy of calcium antagonists including nifedipine, verapamil, diltiazem, and flunarizine (Gardella et al., 2001; Graff-Radford, 2000; Pareja et al., 1995; Raimondi & Gardella, 1998). Nonsteroidal, anti-inflammatory drugs such as ibuprofen, piroxicam, and naproxen have not shown benefit (Gardella et al., 2001; Pareja et al., 1995). Chad A. Noggle Michelle R. Pagoria

DIAGNOSIS

Diagnosis of SUNCT headache syndrome is symptom based as are the vast majority of primary headache presentations. Consequently, specific diagnostic criteria for SUNCT headache syndrome have been established (Goadsby & Lipton, 1997). As it stands, the diagnosis of SUNCT headache syndrome require 20 to 30 attacks of unilateral, moderately severe, orbital or temporal, stabbing or throbbing pain, lasting for 15–120 seconds and associated with at least one of the following cranial autonomic features: conjunctival

Cohen, A. S. (2007). Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. Cephalalgia, 27, 824–832. Cohen, A. S., Matharu, M. S., & Goadsby, P. J. (2005). Suggested guidelines for treating SUNCT and SUNA. Cephalalgia, 25, 1200. Cohen, A. S., Matharu, M. S., & Goadsby, P. J. (2006). Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA) — a prospective

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clinical study of SUNCT and SUNA. Brain, 129, 2746–2760. Cohen, A. S., Matharu, M. S., Kalisch, R., Friston, K., & Goadsby, P. J. (2004). Functional MRI in SUNCT shows differential hypothalamic activation with increasing pain. Cephalalgia, 24, 1098–1099. De Benedittis, G. (1996). SUNCT syndrome associated with cavernous angioma of the brainstem. Cephalalgia, 16, 503–506. Gardella, L., Viruega, A., Rojas, H., & Nagel, J. (2001). A case of a patient with SUNCT syndrome treated with the Janneta procedure. Cephalalgia, 21, 996–999. Goadsby, P. J., & Lipton, R. B. (1997). A review of paroxysmal hemicranias, SUNCT syndrome and other shortlasting headaches with autonomic feature, including new cases. Brain, 120, 193–209. Graff-Radford, S. B. (2000). SUNCT syndrome responsive to gabapentin (Neurontin). Cephalalgia, 20, 515–517. Manzoni, G. C., Terzano, M. G., Bono, G., Micieli, G., Martucci, N., & Nappi, G. (1983). Cluster headache: Clinical findings in 180 patients. Cephalalgia, 3, 21–30. Matharu, M. S., Cohen, A. S., Boes, C. J., & Goadsby, P. J. (2003). SUNCT syndrome: A review. Current Pain Headache Reports, 7, 308–318. Matharu, M. S., Cohen, A. S., Frackowiak, R. S., & Goadsby, P. J. (2006). Posterior hypothalamic activation in paroxysmal hemicrania. Annals of Neurology, 59, 535–545. Matharu, M. S., Cohen, A. S., & Goadsby, P. J. (2004). SUNCT syndrome responsive to intravenous lidocaine. Cephalalgia, 24, 985–992. May, A., Bahra, A., Bu¨chel, C., Turner, R., & Goadsby, P. J. (1999). Functional magnetic resonance imaging in spontaneous attacks of SUNCT: Short-lasting neuralgiform headache with conjunctival injection and tearing. Annals of Neurology, 46, 791–794. May, A., Leone, M., Afra, J., Linde, M., Sandor, P. S., Evers, S., & Goadsby, P. J. (2006). EFNS guidelines on the treatment of cluster headache and other trigeminalautonomic cephalalgias. EFNS Task Force. European Journal of Neurology, 13, 1066–1077. Monde´jar, B., Cano, E. F., Pe´rez, I., Navarro, S., Garrido, J. A., Vela´squez, J. M., & Alvarez, A. (2006). Secondary SUNCT syndrome to a variant of the vertebrobasilar vascular development. Cephalalgia, 26, 620–622. Morales-Ası´n, F., Espada, F., Lo´pez-Obarrio, L. A., Navas, I., Escalza, I., & In˜iguez, C. (2000). A SUNCT case with response to surgical treatment. Cephalalgia, 20, 67–68. Olesen, J. (2001). Revision of the international headache classification. An interim report. Cephalalgia, 21, 261. Pareja, J. A., Kruszewski, P., & Sjaastad, O. (1995). SUNCT syndrome: Trials of drugs and anesthetic blockades. Headache, 35, 138–142.

Pareja, J. A., & Sjaastad, O. (1997). SUNCT syndrome: A clinical review. Headache, 37, 195–202. Raimondi, E., & Gardella, L. (1998). SUNCT syndrome: Two cases in Argentina. Headache, 38, 369–371. Sjaastad, O., Saunte, C., Salvesen, R., Fredriksen, T. A., Seim, A., Røe, O. D., . . . Zhao JM. (1989). Shortlasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhea. Cephalalgia, 9, 147–156. Sprenger, T., Boecker, H., Tolle, T. R., Bussone, G., May, A., & Leone, M. (2004). Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology, 62, 516–517. Sprenger, T., Valet, M., Platzer, S., Pfaffenrath, V., Steude, U., & Tolle, T. R. (2005). SUNCT: Bilateral hypothalamic activation during headache attacks and resolving of symptoms after trigeminal decompression. Pain, 113, 422–426.

SYDENHAM’S CHOREA DESCRIPTION

Sydenham’s chorea (also known as hyponichyperkinetic syndrome, rheumatic chorea, chorea minor, and St. Johannis chorea) was first described by Thomas Sydenham’s in his book Schedula Monitoria de Noval Febris Ingressa published in 1686 (Jummani & Okun, 2001; Weiner & Normandin, 2007). Sydenham’s chorea is characterized by the spontaneous, jerking movements that occur and can be caused by medication, cerebral palsy, or most commonly, acute rheumatic fever (ARF) due to group A streptococcal (GAS) throat infection (Golden, Haut, & Moshe, 2006; Weiner & Normandin, 2007). Sydenham’s chorea is one of the most distinguishing features of ARF and prevalence rates of Sydenham’s chorea in those with ARF range from 10–30% (Golden et al., 2006; Pavone, Parano, Rizzo, & Trifiletti, 2006; Walker et al., 2007). This disorder occurs most commonly during childhood with the average age of onset ranging between 9 and 11 years of age (Jummani & Okun, 2001; Kiliç et al., 2007; Walker et al., 2007; Weiner & Normandin, 2007). Although cases of Sydenham’s chorea are rarer under the age of 5 and over the age of 18, symptoms of the disorder have been reported to manifest anytime between 2 and 21 years of age (Kiliç et al., 2007; Walker et al., 2007). Most cases of Sydenham’s chorea (up to two-thirds) are reported in females (Kiliç et al., 2007; Pavone et al., 2006; Walker et al., 2007).

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Disorders associated with Sydenham’s chorea are carditis and polyarthritis, which commonly occur during ARF as well; however, some research has shown that those who have ARF and chorea may be much less likely to develop carditis or arthritis (Kiliç et al., 2007; Walker et al., 2007). Other more rare associated disorders include mild mitral insufficiency and mitral regurgitation (Kiliç et al., 2007; Walker et al., 2007). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Although the exact pathogenesis of Sydenham’s chorea is unknown, it is suspected to be caused by an antibody response to an infection of the GAS carbohydrate and rheumatic fever (Kirvan, Swedo, Heuser, & Cunningham, 2003; Pavone et al., 2006). Researchers have asserted that this infection causes a cross-reactive immune response that attacks neurons in the brain, especially in the basal ganglia, which may explain the motor symptoms (Kirvan et al., 2003). The antibodies attack brain neurons because of the molecular similarity between streptococcal antigens and the neuronal antigens of the basal ganglia proteins (Kiliç et al., 2007; Pavone et al., 2006). Both clinical and MRI studies have shown that antibodies that attack the streptococcal infection are found in the basal ganglia and the cortex, and the number of antibodies present is associated with the severity and duration of symptoms (Jummani & Okun, 2001; Kirvan et al., 2003). These antibodies may cause further impairments in the central nervous system (CNS) through neuronal signal transduction and cell signaling (Kirvan et al., 2003). This impairment in signaling may be a result of the antibodies interfering with the gangliosides’ ability to bind with the neuronal receptors (Kirvan et al., 2003). The antibodies increase signal transduction causing the release of excitatory neurotransmitters, which may elicit dopamine release and play a role in the obsessive-compulsive symptoms, tics, and attention problems (Kirvan et al., 2003). Although the antibodies drastically interfere with the basal ganglia and the CNS, they do not cause permanent damage (Kirvan et al., 2003). The swelling caused by the infection appears to subside when properly treated, and no evidence of glial scarring or neuronal loss has been found (Pavone et al., 2006). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Early signs and symptoms include limping or unsteadiness in one leg in which the affected leg is dragged and shaking in the hand(s), which cannot be steadied (Jummani & Okun, 2001). Softer neurological

symptoms that occur early in the development of the disease can include ‘‘milkmaid’s grip,’’ the inability to hold a fist for a prolonged period (Weiner & Normandin, 2007), and ‘‘darting tongue’’ (Pavone et al., 2006). The hallmark symptom is the involuntary, spontaneous, and choreiform movements, which occur in the face and extremities (Golden et al., 2006; Jummani & Okun, 2001; Kiliç et al., 2007; Weiner & Normandin, 2007). Gait disturbances, hypotonia, muscle weakness, and incoordination are also characteristics of Sydenham’s chorea (Jummani & Okun, 2001; Kiliç et al., 2007). Psychological symptoms such as attention problems, emotionally lability, and obsessive-compulsive symptoms are commonly seen as deficits in reading, writing, and speaking (dysarthric speech difficulties) (Jummani & Okun, 2001; Kiliç et al., 2007; Kirvan et al., 2003; Pavone et al., 2006). In severe cases, ballistic movements, the inability to ambulate, and motor and vocal tics may be present (Pavone et al., 2006). Symptoms are considered to be mild through severe based on the activities that are affected by the disease, for example, the inability to ambulate would be indicative of severe symptoms (Kiliç et al., 2007). Chorea symptoms can be general, involving the whole body, or specific, affecting only part of the body (Kiliç et al., 2007). These symptoms usually subside after approximately 4 months but have been reported to last between 1 week to 2 years (Kiliç et al., 2007; Pavone et al., 2006). Psychological symptoms such as personality changes, obsessive-compulsive disorder (OCD), anxiety and mood swings as well as attention disorders have been noted in the literature (Kiliç et al., 2007; Walker et al., 2007; Weiner & Normandin, 2007). These symptoms are thought to occur because the antibodies, generated to attack the streptococcal infection, attack basal ganglia, increasing signal transduction causing the release of excitatory neurotransmitters, which may elicit dopamine release (Da Rocha, Correa, & Teixeria, 2008). One of the most common psychological disorders is OCD; behavioral symptoms of OCD may present 2–4 weeks before the symptoms of chorea (Da Rocha et al., 2008; Weiner & Normandin, 2007) and up to 70% of those with Sydenham’s chorea will develop the symptoms of OCD (Asbahr et al., 2005). Research has shown that OCD occurring with Sydenham’s chorea is very similar to childhood-onset OCD (Asbahr et al., 2005). The most common obsessions reported in those with Sydenham’s chorea are thoughts of aggression, contamination, hoarding, religion, symmetry, and somatization (Asbahr et al., 2005). Common compulsions that have been reported are cleaning, checking,

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repeating, counting, ordering, and hoarding (Asbahr et al., 2005). Motor and verbal tics have also been reported in those with Sydenham’s chorea (Asbahr et al., 2005). Common tic-like symptoms described are touching, blinking, rubbing, and staring (Asbahr et al., 2005). Symptoms of separation anxiety, although much less common, have been reported along with OCD symptoms, and the obsessions in these children are much more likely to be aggressive in nature than those without separation anxiety symptoms (Asbahr et al., 2005). DIAGNOSIS

Diagnoses of Sydenham’s chorea are made by clinical observations (Pavone et al., 2006). At this time, there are no confirmatory tests available; however, increases in levels of antistreptococcal titers have been shown to be present in 80% of those with the disease (Pavone et al., 2006). Because GAS respiratory infections are usually a precursor to the development of Sydenham’s chorea, close clinical examination is recommend post infection in order to diagnosis this disease as soon as possible (Pavone et al., 2006). Other factors associated with developing ARF and subsequent Sydenham’s chorea, especially in third world countries are poverty, malnutrition, and overcrowding (Walker et al., 2007). However, there have been more recent increases in ARF in the United States, which most likely cannot be attributed to the previously mentioned factors (Walker et al., 2007). In more highly developed countries with firstrate health care systems, interactions of different strains of streptococcus and/or genetic predispositions to ARF may be able to explain these increases (Walker et al., 2007). TREATMENT

Although the symptoms of Sydenham’s chorea usually spontaneously remit with treatment in 1–6 months, long-term treatment is often needed, especially for the accompanying ARF infection (Pavone et al., 2006; Walker et al., 2007). Pharmacological interventions are recommended in cases where symptoms are severe and interfere with daily functioning, or significant weight loss is experienced (Walker et al., 2007). One treatment for moderate to severe symptoms is the medication haloperidol for chorea and penicillin prophylaxis for the associate ARF (Kiliç et al., 2007). One study showed that remission of symptoms occurred within 1–12 months after treatment with haloperidol; however, treatment may

take longer, over a year, if other associated disorders, such as carditis, are present (Kiliç et al., 2007). Other studies have shown the recovery rate to be 50% for those treated with haloperidol (Golden et al., 2006). Other drugs, such as valproic acid and carbamazepine, and corticosteroids (prednisone), are increasingly being used (Kiliç et al., 2007; Walker et al., 2007). Corticosteroids have been shown to significantly decrease the course of chorea symptoms as well (Walker et al., 2007). Studies have shown that valproic acid and carbamazepine have shown improvement rates of 85% or higher, although relapses have been reported (Golden et al., 2006). Research has also provided evidence that the recovery rate for antiepileptic drugs is 83%, but they have found that valproate may lead to a much more rapid recovery, and, thus, is the recommended medication of choice for treatment of chorea (Golden et al., 2006). Carbamazepine, haloperidol, and sodium valproate may be effective in treating chorea symptoms because they operate on the dopaminergic or -aminobutryic acid (GABA) pathways (Walker et al., 2007). However, corticosteroids act on the antibodies or mechanisms of the immune system, which leads to the neuronal dysfunction present in chorea (Walker et al., 2007). Although Sydenham’s chorea symptoms usually remit without permanent damage with or without medication, damage to the heart valves due to ARF may persist in 63–94% of patients (Weiner & Normandin, 2007). Sarah E. West Charles Golden

Asbahr, F. R., Garvey, M. A., Snider, L. A., Zanetta, D. M., Elkis, H., & Swedo, S. E. (2005). Obsessive-compulsive symptom among patients with Sydenham chorea. Biological Psychiatry, 57, 1073–1076. Da Rocha, F. F., Correa, H., & Teixeira, A. L. (2008). Obsessive-compulsive disorder and immunology: A review. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 32, 1139–1146. Golden, A. S., Haut, S. R., & Moshe´, S. L. (2006). Nonepileptic uses of antiepileptic drugs in children and adolescents. Pediatric Neurology, 34, 421–432. Jummani, R. R., & Okun, M. S. (2001). Sydenham chorea. Archives of Neurology, 58, 311–313. Kiliç, A., Unu¨var, E., Burak, T, Go¨kçe, M, Omerog˘lu, R. E., Og˘uz, F., et al. (2007). Neurologic and cardiac findings in children with Sydenham chorea. Pediatric Neurology, 36, 159–164. Kirvan, C. A., Swedo, S. E., Heuser, J. S., & Cunningham, M. W. (2003). Mimicry and autoantibody-mediated

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neuronal cell signaling in Sydenham chorea. Nature Medicine, 9, 914–920. Pavone, P., Parano, E., Rizzo, R., & Trifiletti, R. R. (2006). Autoimmune neuropsychiatric disorders associated with streptococcal infection: Sydenham chorea, PANDAS, and PANDAS variants. Journal of Child Neurology, 21, 727–736. Walker, A. R., Tani, L. Y., Thompson, J. A., Firth, S. D., Veasy, L. G., & Bale, J. F. (2007). Rheumatic chorea: Relationship to systemic manifestations and response to corticosteroids. The Journal of Pediatrics, 151, 679–683. Weiner, S. G., & Normandin, P. A. (2007). Sydenham chorea: A case report and review of the literature. Pediatric Emergency Care, 23, 20–24.

SYNCOPE

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Those with syncope often experience specific physiological symptoms that result in a rapid loss of consciousness followed by a quick recovery. Clinical features of syncope, regardless of cause, are commonly related to posture, time of day, and precipitating factors such as emotions, injury, pain, and heat. Skin pallor and cardiovascular signs are also common (Brignole et al., 2004; Linzer et al., 1997a; Zaqqa & Massumi, 2000). In general, most syncopal events are precipitated by an overall feeling of weakness, lightheadedness, sweating, giddiness, blurry vision, tinnitus, or gastrointestinal symptoms. Regardless of the causes of syncope, all types end with cerebral hypoperfusion. During the syncopal event, most people are motionless after the loss of consciousness, but some may also exhibit myoclonic jerks. The pulse rate will be slow with shallow breathing and excessively low blood pressure.

DESCRIPTION

Syncope represents the medical term for fainting, and it is accompanied by a collection of physiological symptoms resulting from decreased or interrupted blood flow to the brain. It is characterized by a brief loss of consciousness and postural tone, most often occurring while standing.

NEUROPATHOLOGY/PATHOPHYSIOLOGY

A defining feature of all syncopal episodes is a rapid and sudden reduction or cessation of blood flow to the brain. In syncope, the blood hypoperfusion to the cerebral hemispheres and/or the brainstem reticular activating system results in a failure to maintain consciousness. Hypoperfusion can occur when there is cerebral vasoconstriction or global hypotension (Brignole et al., 2004; Kenny, 2002). In general, a series of neurohormonal events take place upon changes in body position, such as standing. The neurohormonal activity assists in maintaining cerebral perfusion in healthy individuals. In optimum situations when there is a decreased venous return, the resulting decreased filling of the left ventricle responds by increasing sympathetic tone and hypercontracting of the left ventricle. However, the hypercontracted left ventricle may, in some people, detect the left ventricular volume overload and inhibit sympathetic stimulation while still engaging the parasympathetic system, which can lead to hypotension, brachycardia, and syncope (Brignole et al., 2004; Kenny, 2002; Linzer et al., 1997b).

DIAGNOSIS

The diagnosis of syncope requires the assessment of the underlying causes; however, the most common diagnostic protocol involves a comprehensive history, physical examination, and ECG. This protocol helps identify 56–85% of cases (Kapoor, 2000; Linzer et al., 1997). Brignole et al. (2004) advised that three questions are mandatory in assessment: (1) Is the loss of consciousness related to syncope or not? (2) Does heart disease exist or not? and (3) Do the clinical features obtained in the history relate to the diagnosis? The assessment needs to identify the precursors to the syncopal event, the onset, the attack, and the end of the attack (Miller & Kruse, 2005) as well as any history of heart disease and/or other illnesses. In addition, it is important to differentiate syncope from other conditions that are nonsyncopal but also result in loss of consciousness. Nonsyncopal events that can lead to unconsciousness include disorders that have behavioral manifestations that are similar to syncope, such as seizures and attacks related to carotid origins (Brignole et al., 2004). Similar, nonsyncopal events that do not result in consciousness include falls and psychogenic pseudo-symptoms. The most common forms of syncope are reflex mediated, cardiac, orthostatic, and cerebrovascular (Limmer, Mistouich, & Krost, 2009; Miller & Kruse, 2005). According to Farwell and Sulke (2002) and Cadman (2001), 36–62% of syncopal episodes are reflex mediated, 10–30% are cardiac related, 2–24% are orthostatic related, and 1% are cerebrovascular related. The

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prognosis for most cases of syncope without cardiac disorder is positive. When a cardiac condition is identified, there is a 20–30% mortality rate within 1 year of the original event. There is also a 33% chance for sudden death within 5 years (Soteriades et al., 2002). Reflex-mediated syncope is often a result of autonomic reflex dysfunction caused by stress secondary to fear and/or pain. This results in an increase of vagal tone instead of increasing sympathetic tone. The three subtypes of reflex-mediated syncope are vasovagal, carotid sinus, and situational. Vasovagal syncope consists of three specific phases: prodrome symptoms, loss of consciousness, and the postsyncopal phase. In vasovagal syncope, an outside event most often precipitates the episode, such as prolonged standing, emotional stress, pain, physical straining, or trauma. Once the outside event triggers an episode, the first prodrome phase can consist of diaphoresis, gastric problems, fatigue, weakness, yawning, nausea, dizziness, and vertigo (Brignole et al., 2004). Loss of consciousness occurs in the next phase. The third phase, postsyncopal, can often last for hours, and rarely days. This phase can include protracted confusion, disorientation, nausea, dizziness, and an overall sense of not feeling well (Kenny, 2002). If the postsyncopal phase lasts more than a few days, it may indicate a more serious condition than vasovagal syncope and extensive evaluation should be given. Carotid sinus syncope is most often diagnosed if the patient has a history of syncopal events in connection with head movements, wearing tight collars, and even shaving, and mostly occurs in older patients (Miller & Kruse, 2005). Situational syncope is most often associated with micturition, defecation, coughing, or gastrointestinal problems. Cardiac syncope involves two basic subtypes: dysrhythmia-mediated and structural cardiopulmonary lesions. The common feature associated with both subtypes is the heart being unable to increase cardiac output to meet the associated demand. Neurologic syncope is the least common form of syncope and often occurs as a result of the reticular activating system of the brainstem becoming ischemic. It could also be a result of subarachnoid hemorrhage or subclavian steal. Psychiatric syncope occurs at a high rate in psychiatric patients. It is most often related to Axis I disorders, such as anxiety, panic, and major depressive disorders. Orthostatic syncope occurs when a person is in the upright position and their blood flow pools. In healthy individuals, sympathetic tone would be increased upon standing. In others, adequate sympathetic tone is not achieved, resulting in syncope. Possible causes can be related to neurological insult and drugs.

TREATMENT

Due to the fact that most people diagnosed with syncope (children and adults) do not have an underlying heart disease or abnormal heart rhythm (arrhythmia), extensive medical workup is not often needed. Most causes of syncope will be discovered with a thorough physical examination, as mentioned previously. The treatment for neurally mediated syncope is counterintuitive to our American diet. Consuming increased amounts of salt along with increased fluid intake assists in reducing the chance of dehydration and helps to maintain blood volume. People with syncope should become aware of the presyncope warning signs, such as sweaty palms, dizziness, and nausea. When the presyncope events are experienced, it is best to lie down with legs elevated (Atiga, Rowe, & Calkins, 1999; National Institute of Neurological Disorders and Stroke [NINDS], 2008). Overall it is best to reduce events that can exacerbate syncope, such as avoiding extreme heat, limiting alcohol intake, and not standing for long periods of time. Di Girolamo, Di Iorio, Leonzio, Sabatini, and Barsotti (1999) and Mahanonda et al. (1995) recommended tilt table training for those who have frequent syncope attacks. Zaqqa and Massumi (2000) indicated that medication treatment should be individualized. They state that considering the age of the patient, cooccurring disorders, and the side effects and safety of each medication is essential. Common first-line medications for adults are beta blockers and for children fludrocortisones (Scott et al., 1995). Teri J. McHale Stephen E. Prover Henry V. Soper Atiga, W., Rowe, P., & Calking, H. (1999). Management of vasovagal syncope. Journal of Cardiovascular Electophysiology, 10, 874–886. Bloomfield, D., Sheldon, R., Grubb, B., Calkins, H., & Sutton, R. (1999). Putting it together: A new treatment algorithm for vasovagal syncope and related disorders. American Journal of Cardiology, 84, 833–839. Brignole, M., Alboni, P., Benditt, D., Gergfeldt, L., Blanc, J., Bloch et al. (2004). Guidelines on management (diagnosis and treatment) of syncope — Update 2004. Europace, 6(6), 467. Retrieved from http://www.guideline.gov/ summary/summary.aspz?doc_id=6468 Cadman, C. S. (2001). Medical therapy of neurocardiogenic syncope. Cardiology Clinics, 19, 203–213. Di Girolamo, E., Di Iorio, C., Leonzio, L., Sabatini, P., & Barsotti, A. (1999). Usefulness of a tilt training program for the prevention of refractory neurocardiogenic syncope in adolescents: A controlled study. Circulation, 100, 1798–1801.

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Farwell, D., & Sulke, N. (2002). How do we diagnose syncope? Journal of Cardiovascular Electrophysiology, 13(Suppl. 1), S9–S13. Kapoor, W. (2000). Syncope. The New England Journal of Medicine, 343, 1856–1862. Kenny, R. (2002). Neurally mediated syncope. Clinics in Geriatric Medicine, 18, 191–210, vi. Limmer, D., Mistovich, J., & Krost, W. (2009). Beyond the basics: Syncope. EMS Magazine. Cygnus Business Media, 38(2), 52–55. Linzer, M., Yang, E., Estes, M., Wang, P., Vorperian, V., & Kapoor, W. (1997a). Clinical guideline: Diagnosing syncope: Part 1: Value of history, physical examination, and electrocardiography. Annals of Internal Medicine, 126(12), 989–996. Linzer, M., Yang, E., Estes, M., Wang, P., Vorperian, V., & Kapoor, W. (1997b). Clinical guideline: Diagnosing syncope: Part 2: Unexplained syncope. Annals of Internal Medicine, 127(1), 76–86. Mahanonda, N., Bhuripanyo, K., Kangkagate, C., Wansanit, K., Kulchot, B., & Nademanee, K. (1995). Randomized double-blind, placebo-controlled trial of oral atenolol in patients with unexplained syncope and positive upright tilt table test results. American Heart Journal, 130, 1250–1253. Miller, T., & Kruse, J. (2005). Evaluation of syncope. American Family Physician, 1–12. National Institute of Neurological Disorders and Stroke. (2008). NINDS Syncope Information page. Retrieved from the world wide web on March 16, 2009 www. ninds.nih.gov/disorders/syncope/cyncope.htm Scott, W. Pongiglione, G., Bromberg, B., Schaffer, M., Deal, B., Fish, F., et al. (1994). Randomized comparison of atenolol and fludrocortisone acetate in the treatment of pediatric neurally mediated syncope. American Journal of Cardiology, 76, 400. Soteriades, E., Evans, J., Larson, M., Chen, M., Chen, L., Benjamin, E., et al. (2002). Incidence and prognosis of syncope. New England Journal of Medicine, 347, 878–885. Zaqqa, M., & Massumi, A. (2000). Neurally mediated syncope. Texas Heart Institute Journal, 27(3), 268–272.

SYRINGOMYELIA DESCRIPTION

Syringomyelia results from a cyst, also called a syrinx, which develops and grows in the spinal cord leading to damage over time (Greitz, 2006). The disorder, which often occurs between the ages of 25 and 40, commonly develops gradually; however, onset may be rapid

following injury (i.e., straining or trauma). Symptoms include progressive — sometimes intermittent — weakness ranging to paralysis in the arms and legs, decline in sensation, bladder or bowel dysfunction, and severe pain (Madsen, Green, & Bowen, 1999). Syringomyelias may result from a number of conditions, but it is estimated that prevalence is 8.4 per 100,000, and more men than women manifest this disorder (Greitz, 2006). Prognosis following treatment shows modest improvements for most individuals; however, this is dependent upon the etiology, significance of neurologic impairment, and size and location of the syrinx (Attal, Parker, Tadie, Aghakani, & Bouhassira, 2004). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Although the exact pathophysiology of syringomyelia is unknown, multiple theories of pressure and flow gradients exist (Chang & Nakagawa, 2003). In essence, the spinal cord is surrounded by the cerebrospinal fluid (CSF), which serves to transport nutrients, remove waste, and protect the central nervous system. During the development of the nervous system, CSF fills the central canal. This canal ultimately closes, yet if CSF is obstructed in the spinal cord, the extra fluid will be diverted into the central canal and eventually develops into a syrinx (Madsen et al., 1999). Continued obstruction results in continued growth and ultimately spinal cord damage. Depending upon the area of impairment involved by the expansion of the syrinx, different regions and fiber tracts may be involved resulting in a variety of symptoms. Syrinx tends to impinge the spinothalamic fibers that moderate appreciation of pain and temperature, whereas medial lemniscus fibers, which moderate appreciation of touch, vibration, and position, remain intact until much later in the disease process (Koyanagi, Iwasaki, Hida, & Houkin, 2005). Damage to the anterior horns of the motor neurons in the spinal cord causes muscle atrophy, typically beginning in the hands and progressing proximally (Koyanagi et al., 2005). Horner syndrome may also be present secondary to damage to the intermediolateral cell column of sympathetic neurons (Koyanagi et al., 2005). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Depending upon the location and growth of the syrinx, nerve fibers may be affected that can result in a variety of symptoms. In general, pain, weakness, and stiffness may predominate in locations depending on

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the relative dermatomes involved (i.e., arms, legs, shoulders, and back). Motor functions tend to be compromised by the associated muscle atrophy and as a result, claw hand or spasticity in the lower extremities may be present (Madsen et al., 1999). In addition, reflexes in the arms may be diminished early in the disease process (Madsen et al., 1999). Sensory disturbance, usually lack of appreciation of temperature may occur, and, in particular, a ‘‘cape-like’’ pattern of loss of temperature and pain sensation along the back and arms may be present (Koyanagi et al., 2005). Typically, syringomyelia does not impact the dorsal column of the spinal cord (medial lemniscus), which moderates pressure, vibration, touch, and proprioception in the upper extremities, until much later in the disease process when astereognosis may be evident upon clinical evaluation (Koyanagi et al., 2005). Other manifestations of syringomyelia may include headaches, ulcers (particularly on the hands), edema, hyperhidrosis, neurogenic arthropathies, or scoliosis may be present (Madsen et al., 1999). Generally, there is no reported cognitive or academic impairments noted in syringomyelia; however, a variant occurring when the syrinx manifests near the brainstem results in a different condition called syringobulbia, which has reported cognitive impairments (Madsen et al., 1999).

communicating syringomyelia may experience hydrocephalus due to inflammation of the arachnoid membrane surrounding the brain (Oldfield et al., 1994). Noncommunicating syringomyelia occurs following either direct or indirect trauma to the spinal cord from a potential of multiple etiologies (i.e., meningitis, hemorrhage, tumor, arachnoiditis, or direct trauma), where the syrinx begins to grow and onset of symptoms may be immediate or even delayed several years following injury (Madsen et al., 1999). Differential diagnosis of syringomyelia include, but are not limited to, acute inflammatory demyelinating polyradiculoneuropathy, amyotrophic lateral sclerosis, ankylosing spondylitis, arteriovenous malformations, atlantoaxial instability associated with Down’s syndrome, brainstem gliomas, central pontine myelinolysis, cervical spondulosis, chronic inflammatory demyelinating polyradiculoneuropathy, diabetic neuropathy, ependymoma, hydrocephalus, limb-girdle muscular dystrophy, medulloblastoma, meningioma, multiple sclerosis, neural tube defects, spinal cord hemorrhage, spinal cord infarction, trauma, spinal epidural abscess, and spinal muscular atrophy (Greitz, 2006).

TREATMENT DIAGNOSIS

In the past, diagnosis of syringomyelia may have been difficult due to the fact that many early symptoms of this disorder are apparent in other more frequent disorders. With the advent of MRI, diagnosis of syringomyelia in the early stages of the disease process is much easier and is often the diagnostic tool of choice (Yeom et al., 2007). Other tests include electromyography (EMG) (which measures nerve conduction in the muscle and its weakness), lumbar puncture (to measure CSF pressure), or myelogram (which takes an X-ray within the context of an injection of contrast dye into the subarachnoid space). Two major variants of syringomyelia exist: communicating and noncommunicating syringomyelia (Oldfield et al., 1994). Communicating syringomyelia, named from the perception of connection between the brain and spinal cord, is characterized by the development of a syrinx in the cervical region of the spinal cord near the Chiari I malformation, which is part of the cerebellum that protrudes through the foramen magnum (Oldfield et al., 1994). Onset tends to be in early adulthood and may be caused by fluctuations of CSF or straining activities. Some individuals with

Treatment for syringomyelia, if symptomatic, tends to involve surgery, either singular or multiple, which may focus on enlarging the foramen magnum in the case of communicating syringomyelia, shunting and draining the syrinx fluid to alleviate symptoms, or even resecting a tumor in order to eliminate obstruction (Rhoton & Hamilton, 1999). In the past, surgeons would also shunt trauma-induced syringomyelias, yet this procedure often requires multiple surgeries. Currently, surgeons expand the space around the spinal cord by removing tethers, realigning the vertebrae, and adding ‘‘patches’’ that reinforce the dura surrounding the spine (Rhoton & Hamilton, 1999). Other forms of treatment, such as medications or radiation, are not therapeutic; however, medication may be prescribed to alleviate pain. Opioids are often combined with other medications utilized for treating neuropathic pain (Rhoton & Hamilton, 1999). In general, prognosis following surgery results in modest improvements for most individuals; however, treatment delays may have irreversible outcome on spinal cord damage (Attal et al., 2004). Javan Horwitz Natalie Horwitz Chad A. Noggle

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Attal, N., Parker, F., Tadie, M., Aghakani, N., & Bouhassira, D. (2004). Effects of surgery on the sensory deficits of syringomyelia and predictors of outcome: A long term prospective study. Journal of Neurology, Neurosurgery, and Psychiatry, 75(7), 1025–1030. Chang, H., & Nakagawa, H. (2003). Hypothesis on the pathophysiology of syringomyelia based on simulation of cerebrospinal fluid dynamics. Journal of Neurology, Neurosurgery, and Psychiatry, 74(3), 344–347. Greitz, D. (2006). Unraveling the riddle of syringomyelia. Neurosurgery Review, 29(4), 251–264. Koyanagi, I., Iwasaki, Y., Hida, K., & Houkin, K. (2005). Clinical features and pathomechanisms of syringomyelia associated with spinal arachnoiditis. Surgical Neurology, 63(4), 350–356. Madsen, P., III., Green, B., & Bowen, B. (1999). Syringomyelia. In H. Herkowitz, S. Garfin, & R. Balderston (Eds.), The spine (4th ed., pp. 1431–1459). Philadelphia, PA: W.B. Saunders Company. Oldfield, E., Muraszko, K., Shawker, T. H., & Patronas, N. (1994). Pathophysiology of syringomyelia associated with Chiari I malformation of the cerebellar tonsils: Implications for diagnosis and treatment. Journal of Neurosurgery, 80(1), 3–15. Rhoton, A., & Hamilton, A. (1999). Chiari malformation and syringomyelia. In E. Benzel (Ed.), Spine surgery: Techniques, complication avoidance, and management (pp. 793–812). Boston: Churchill-Livingstone. Yeom, J. S., Lee, C., Park, K. W., Lee, J. H., Lee, D. H., Wang, K. C., et al. (2007). Scoliosis associated with syringomyelia: Analysis of MRI and curve progression. European Spine Journal, 16(10), 1629–1635.

SYSTEMIC LUPUS ERYTHEMATOSUS DESCRIPTION

Systemic lupus erythematosus (SLE) is a chronic and potentially fatal multisystem autoimmune disease with a varied spectrum of neurological, neuropsychiatric, and cognitive presentations. Lesions within the central nervous system (CNS) may produce headache, seizures, psychosis, aseptic meningitis, cerebral vascular accidents (CVAs), transient ischemic attacks (TIAs), microvascular changes, white matter lesions, thrombosis, chorea, demyelinization syndromes, transverse myelitis, and cranial or peripheral neuropathies (Coı´n-Mejı´as et al., 2008; Leritz, Brandt, Minor, Reis-Jensen, & Petri, 2002; Loukkola et al., 2003; Schrott & Crnic, 1996). Affective disturbance (e.g., depression and anxiety) is also common (Schrott &

Crnic, 1996) as are skin rashes, joint ailments, and renal failure. The course of SLE is a fluctuating one, and although many may experience periods of remission, a number of individuals experience ongoing and disabling sequelae (Iverson, 1995). Individuals with SLE have a reduced life expectancy, in part, due to the increased risk of infection due to autoimmune suppression (Breitbach et al., 1998). Worldwide prevalence of SLE ranges between 15 and 50 per 100,000 with more cases cited in the United States than elsewhere and women eight times more likely to be diagnosed with SLE than men (Skeel, Johnstone, Yangco, Walker, & Komatireddy, 2000). Increased incidence has also been found in African Americans (up to three times more likely than White females) with increased mortality rates noted at a younger age in non-White females (Breitbach et al., 1998; Skeel et al., 2000). It remains uncertain whether these differences reflect genetic vulnerability or are a manifestation of other socioeconomic factors (Breitbach et al., 1998). Finally, SLE has an increased incidence in women of childbearing age, suggesting hormonal factors as a causative factor (Schrott & Crnic, 1996). SLE often presents with and without CNS involvement; neuropsychiatric SLE (NPSLE) is another term used to differentiate between these individuals with neuropsychological impairment included within the umbrella of CNS or neuropsychiatric involvement. Depending upon the criteria used, it is estimated that between 14–75% of SLE cases present with CNS involvement and those with CNS involvement are more likely to exhibit cognitive dysfunction (Coı´n-Mejı´as et al., 2008; Leritz et al., 2002).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

The precise etiology of SLE remains uncertain; however, the most accepted proposal is that of it being multifactorial including vascular causes, autoantibodies, and inflammatory mediators (Benedict, Shucard, Zivadinov, & Shucard, 2008). Antiphospholipid antibodies (aPLs), both lupus anticoagulant (LA) and anticardiolipin (aCL), have been identified as a contributor to vascular risk factors in SLE due to immune-mediated hypercoagulability (Leritz et al., 2002). This increases risk of thrombosis, which itself promotes focal symptoms such as CVA, TIA, and seizures. A noninflammatory vasculopathy involving small vessels may permit such antibodies to enter the CNS at which point they react with cell-surface or serum components (Mills, 1994). Cytokines have been proposed as an inflammatory mediator in the disease and have been established in the literature

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as being related to increased risk of cognitive deficits, both acute and over the long term. MRI abnormalities include diffuse hyperintensities within the deep white matter and cerebral atrophy with greater disease severity associated with positive aPLs (Benedict, Shucard, Zivadinov, & Shucard, 2008; Loukkola et al., 2003). Neural injury and death may be due to the production of antinuclear antibodies (ANA) and pro-inflammatory cytokines (Benedict et al., 2008; Schrott & Crnic, 1996). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Cognitive dysfunction in SLE patients has been well documented. Estimates suggest that 81% of individuals with CNS involvement or NPSLE, and 42% of those without CNS involvement demonstrate cognitive dysfunction (Loukkola et al., 2003; Skeel et al., 2000). Common cognitive complaints within the domains of attention, psychomotor speed, executive functioning, verbal fluency, and retrieval-based memory have been well documented (Holliday et al., 2003; Loukkola et al., 2003). Some researchers also note deficits in visuospatial skills and worse visual learning and memory relative to new learning and memory for verbal material (Benedict et al., 2008; Coı´n-Mejı´as et al., 2008; Mendez & Cummings, 2003). The presence of aPLs in SLE individuals has also been associated with a worse neuropsychological outcome (Leritz et al., 2002). Poorer neuropsychological performance in African American patients has also been attributed to psychosocial factors (Breitbach et al., 1998). Affective complaints are a common feature of SLE and may further adversely impact cognitive functioning (Breitbach et al., 1998). However, it appears that cognitive manifestations remain even when these factors are controlled for (Leritz et al., 2002) and do not fully explain deficits in processing speed, attention, and memory. The possible adverse affects of corticosteriod treatment (e.g., psychiatric manifestations and cognitive decline) should also be considered. Clinical manifestations are varied and represent a systemic disease process with a relapsing remitting course affecting multiple areas, as discussed earlier. Beyond cognitive domains, seizures represent another salient issue along neurological lines in patients with SLE, occurring in 25% of patients (Kaell, Shetty, Lee, & Lockshin, 1986). DIAGNOSIS

The diagnosis of SLE is made via the presence of ANA and double-stranded DNA titers, and elevated aPLs

in blood serum. Cerebrospinal fluid (CSF) may also show mild protein and lymphocyte elevations (Mendez & Cummings, 2003). MRI may show structural changes, including cerebral infarction, diffuse white matter changes, and cerebral atrophy. The clinical presentation of SLE is varied and neuropsychological assessment is a most sensitive tool in determining neurocognitive and functional status in these patients (Breitbach et al., 1998).

TREATMENT

Corticosteroids and anti-inflammatory agents are currently the treatments of choice for SLE. Psychiatric manifestations are common among persons with SLE, though it remains uncertain if these are related to primary CNS involvement, psychological factors associated with illness, or both (Iverson, 1995). As such, efforts to manage psychological factors and behaviors are warranted. Finally, the etiology of increased incidence in non-White females remains uncertain but may be attributed to socioeconomic status. Therefore, support, psychoeducation, and promotion of health promoting behaviors (e.g., maintaining proper diet, exercise, maintaining stress, medication adherence) are important in the treatment and maintenance of symptoms in persons with SLE (Iverson, 1995). Michelle R. Pagoria Chad A. Noggle

Benedict, R. H. B., Shucard, J. L., Zivadinov, R., & Shucard, D. W. (2008). Neuropsychology Review, 18, 149–166. Breitbach, S. A., Alexander, R. W., Daltroy, L. H., Liang, M. H., Boll, T. J., Karlson, E. W., et al. (1998). Determinants of cognitive performance in systemic lupus erythematosus. Journal of Clinical and Experimental Neuropsychology, 20, 157–166. Coı´n-Mejı´as, M. A., Peralta-Ramı´rez, M. I., Santiago-Ramajo, S., Morente-Soto, G., Ortego-Centeno, N., Callejas Rubio, J. L., et al. (2008). Alterations in episodic memory in patients with systemic lupus erythematosus. Archives of Clinical Neuropsychology, 23, 157–164. Holliday, S. L., Navarrete, M. G., Hermosillo-Romo, D., Valdez, C. R., Saklad, A. R., Escalante, A., et al. (2003). Validating a computerized neuropsychological test battery for mixed ethnic lupus patients. Lupus, 12, 697–703. Iverson, G. L. (1995). The need for psychological services for persons with systemic lupus erythematosus. Rehabilitation Psychology, 40, 39–49.

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Kaell, A.T., Shetty, M., Lee, B. C., & Lockshin, M. D. (1986). The diversity of neurological events in systemic lupus erythematosus. Prospective clinical and computed tomographic classification of 82 events in 71 patients. Archives of Neurology, 43, 273–276. Leritz, E., Brandt, J., Minor, M., Reis-Jensen, F., & Petri, M. (2002). Neuropsychological functioning and its relationship to antiphospholipid antibodies in patients with systemic lupus erythematosus. Journal of Clinical and Experimental Neuropsychology, 24, 527–533. Loukkola, J., Laine, M., Ainiala, H., Peltola, J., Meta¨noja, R., Auvinen, A., et al. (2003). Cognitive impairment in systemic lupus erythematosus and neuropsychiatric systemic lupus erythematosus: A population-based

neuropsychological study. Journal of Clinical and Experimental Neuropsychology, 25, 145–151. Mendez, M. F., & Cummings, J. L. (2003). Dementia: A clinical approach (3rd ed.). Philadelphia: ButterworthHeinemann. Mills, J. A. (1994). Systemic lupus erythematosus. New England Journal of Medicine, 330, 1871–1879. Schrott, L. M., & Crnic, L. S. (1996). Increased anxiety behaviors in autoimmune mice. Behavioral Neuroscience, 110, 492–502. Skeel, R. L., Johnstone, B., Yangco, D. T., Walker, S. E., & Komatireddy, G. R. (2000). Neuropsychological deficit profiles in systemic lupus erythematosus. Applied Neuropsychology, 7, 96–101.

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Takayasu’s disease, also known as Takaysu’s arteritis, is a rare and chronic inflammatory vascular disorder that primarily affects the aorta and its main branches as well as the pulmonary arteries and results in absent limb pulses and retinopathy (Bassa, Desai, & Moodley, 1995). Takayasu’s disease predominantly affects Asian females with an overall male-to-female ratio of 1 to 8.5. In the majority of cases, the age of onset is between 10 and 20 years of age; however, there is still a sizeable variety in presenting age (Batchelor & Dean, 1996; Tann, Tulloh, & Hamilton, 2008). The incidence of Takayasu’s arteritis is estimated to be 2.6 cases per 1 million persons each year (Hall et al., 1985). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Takayasu’s arteritis emerges in response to aortic burden, in addition to involvement of the aorta’s main branches, resulting in systemic vascular and potential immune response. Degradation of these structures has been associated with invasion of the media and adventitia of the vessels by giant cells (Bartt & Topel, 2007). Infectious processes, particularly tuberculosis, have been linked to the pathophysiology of the disease. Takayasu’s arteritis can be divided into two stages: acute and chronic. Inflammation of the adventitial vessels of the arterial walls occurs in the acute stage. This initial phase is usually followed by a prolonged chronic phase, in which the elastic tissue is replaced by fibrosis. In addition, thickening exists in all three layers (Tann et al., 2008). At that point, there is typically a progressive and gradual deterioration of function due to vascular occlusion (Batchelor & Dean, 1996). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

There are many signs and symptoms of Takayasu’s arteritis, including a diminished pulse, hypertension, vascular bruits, and angina. Patients may present with

neurological symptoms, such as transient ischemic attacks, hypertensive encephalopathy, seizures, dizziness, vertigo, and/or headaches (Batchelor & Dean, 1996; Kerr et al., 1994; Tann et al., 2008). Furthermore, patients may complain of fatigue, pain in the extremities, or unexplained weight loss. DIAGNOSIS

Diagnosis of Takayasu’s arteritis can be quite difficult, as the symptoms and signs are nonspecific, and the course of the disease varies from patient to patient (Kerr et al., 1994). In many cases, blood pressure is elevated and abnormal blood movement can be heard with a stethoscope (The Johns Hopkins Vasculitis Center, 2009). Furthermore, blood tests may reveal anemic conditions that are also common in Takayasu’s arteritis. Conventional catheterization angiography is a popular procedure for the initial diagnosis for Takayasu’s arteritis, though it may be unreliable in the early phase of the disease because it may not detect significant abnormalities. In addition, research on the use of MRI with 3-D contrastenhanced angiography has shown the method to be exceptionally helpful in the early diagnosis and follow-up of Takayasu’s arteritis. These diagnostic procedures reveal morphological changes, as well as subtle pathological changes in the arterial wall (Halefoglu & Yakut, 2005). TREATMENT

Treatment for Takayasu’s arteritis is often focused on inducing remission and/or managing complications of the disease. Medical treatment typically involves high-dose corticosteroids with immunosuppressants. Glucocorticoid therapy alone is usually the first line of treatment for Takayasu’s arteritis patients. If this is unsuccessful, other agents can be added, including cyclophosphamide, azathioprine, and methotrexate. Hypertension is exacerbated by glucocorticoid therapy, making treating patients with this condition as well as Takayasu’s arteritis difficult. Some patients require surgical and endovascular procedures, which relieve ischemic complications (Batchelor & Dean, 1996; Tann et al., 2008). If left untreated,

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Takayasu’s arteritis can result in death from cerebral hemorrhage, renal failure, heart failure, myocardial infarction, cerebral thrombosis, or aneurysm rupture (Fields et al., 2006). Amy Zimmerman Raymond S. Dean Bartt, R. E., & Tropel, J. L. (2007). Autoimmune and inflammatory disorders. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 1155–1184). Philadelphia, PA: Saunders Elsevier. Bassa, A., Desai, D. K., & Moodley, J. (1995). Takayasu’s disease and pregnancy. South African Medical Journal, 85, 107–112. Batchelor, E. S., Jr., & Dean, R. S. (1996). Pediatric neuropsychology: Interfacing assessment and treatment for rehabilitation. Needham Heights, MA: Allyn & Bacon. Fields, C. E., Bower, T. C., Cooper, L. T., Hoskins, T., Noel, A. A., Panneton, J. M., et al. (2006). Takayasu’s arteritis: Operative results and influence of disease activity. Journal of Vascular Surgery, 43(1), 64–71. Halefoglu, A. M., & Yakut, S. (2005). Role of magnetic resonance imaging in the early diagnosis of Takayasu arteritis. Australasian Radiology, 49, 377–381. Hall, S., Barr, W., Lie, J. T., Stanson, A. W., Kazmier, F. J., & Hunder, G. G. (1985). Takayasu arteritis: A study of 32 North American patients. Medicine, 64, 89–99. Kerr, G. S., Hallahan, C. W., Giordano, J., Leavitt, R. Y., Fauci, A. S., Rottem, M., & Hoffman, G. S. (1994). Takayasu arteritis. Annals of Internal Medicine, 120(11), 919–929. Tann, O. R., Tulloh, R. M. R., & Hamilton, M. C. K. (2008). Takayasu’s disease: A review. Cardiology in the Young, 18, 250–259. The Johns Hopkins Vasculitis Center. (2009). Takayasu’s arteritis. Retrieved May 5, 2009, from http://vasculitis. med.jhu.edu/typesof/takayasu.html#symptoms

TARDIVE DYSKINESIA DESCRIPTION

Beginning in the 1950s, neuroleptic medication revolutionized the treatment of schizophrenia; however, it quickly became apparent that one major risk of treatment with neuroleptic medication was the development of tardive dyskinesia (TD). In early descriptions of the disorder, TD was characterized by (1) involuntary, abnormal movements of the body; (2) occurrence either late in the treatment regimen or after the discontinuation of medication,

persistence of motor abnormalities for months or years; and (3) poor response to treatment (Crane, 1969). Although some advances have been made in understanding the pathophysiology of TD, researchers still debate underlying mechanisms, and there is no consistently effective treatment for the disorder. The development of atypical antipsychotics and their widespread use as an alternative to phenothiazine-based antipsychotics has greatly reduced the incidence of TD. Prevalence of TD among patients receiving chronic pharmacotherapy with antipsychotics is approximately 20% after the first 3 years of exposure, with a 5% increase in new cases per year of treatment with neuroleptic medication. Individuals at higher risk for developing TD include the elderly, females, persons with affective disorders, alcohol abuse, sensitivity to acute extrapyramidal symptoms, and mutations of D2 and D3 receptor genes. A longitudinal study examined patients with and without TD over 10 years and found a relatively benign long-term course for most, with some patients entering remission and others maintaining a relatively stable course (Gordos et al., 1994). For others, however, TD symptoms proved intractable and severely disabling. NEUROPATHOLOGY/PATHOPHYSIOLOGY

TD is associated with degeneration of neurons in the mesencephalon, primarily the basal ganglia and subthalamic nucleus. To date, researchers have yet to reach a consensus on the mechanism(s) underlying TD. Two theories dominate TD literature, the dopamine hypersensitivity hypothesis and a free radical hypothesis. The most prominent theory is the dopamine hypersensitivity theory that proposes that long-term use of antipsychotic medication results in an upregulation of postsynaptic dopamine receptors in the basal ganglia. One study, using positron emission tomography (PET) scans to assess D2 receptor binding in eight schizophrenics who had never been exposed to antipsychotic medication and nine schizophrenics who had taken antipsychotics for a mean of 16 years, found a 34% increase in D2-binding potential in patients subjected to long-term exposure of antipsychotic medication (Silvestri et al., 2000). In this study, the patient with the highest D2-binding potential developed TD. One researcher found enlarged caudate nuclei in the early stages of treatment of young schizophrenics and proposed that it is possible that the enlargement may be the result of interaction between treatment with neuroleptics and neuronal plasticity of the DA system Chakos and

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colleagues (1994) proposed that enlargement of the caudate nuclei may be the result of interaction between treatment with neuroleptics and neuronal plasticity. Inconsistencies in the DA supersensitivity hypothesis include the fact that the number of DA receptors increases over a course of days, but symptoms of TD do not typically develop for months or years. Second, in many instances receptor concentrations do return to normal densities, but the symptoms of TD persist. The free radical hypothesis of TD suggests that neuronal degeneration may result from oxidative damage caused by free radical formation. The free radical hypothesis holds that by blocking dopamine receptors, antipsychotics cause an increase in dopamine production resulting in increased free radical production by monoamine oxidase inhibition in areas of the brain that receive large quantities of oxygen, such as the basal ganglia (Lohr, Kuczenski, & Niculescu, 2003). Lohr et al. (2003) further suggests that certain antipsychotics may cause increases in reactive oxygen via mitochondria. Other mechanisms proposed for increased risk of TD include decreases in or damage to neurons that release GABA, especially in the striatum, and increased release of glutamate and aspartate as a result of D2 receptor blockage that normally inhibits the release of glutamate. One study examined cerebrospinal fluid from individuals with and without TD and found increased levels of N-acetylaspartate, aspartate, and N-acetylglutamate. Some research has found relationships between loss of striatal cholinergic neurons and TD (Margolese, Chouinard, Kolivakis, Beauclair, & Miller, 2005). Also, recent evidence suggests that reduced levels of brain-derived neurotrophic growth factor (BDNF) are found in schizophrenic patients with TD and that levels of BDNF are inversely correlated with dyskinetic movements (Tan, Zhou, & Zhang, 2005). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

TD is marked by severe motor impairment primarily affecting the tongue, lips, jaw, face, trunk, extremities, and the respiratory system; the onset of symptoms has been documented in patients after a short time of treatment with neuroleptic medication (months), after discontinuing neuroleptic medication, or after reinstatement of neuroleptic medication after a period of time without administration. Spontaneous dyskinesias are rare but have been reported in patients who have never received neuroleptic medication. Involuntary movements are most frequently seen in

the oral region of patients with TD and may escalate in severity to effect speech. Stereotypical features of the oral-facial region include protrusion of the tongue, grimacing, rolling, pursing, sucking motions of the lips, or contractions of the jaw. Other anatomical regions may present with jerky or choreiform movements, atheosis, and uncoordinated movements of the respiratory muscles. Swallowing may become difficult as well as maintaining balance. Many patients present with a peculiar, shuffling gait. Involuntary movements made by patients with TD may be socially unacceptable and may cause awkwardness in social situations, not only to the patients, but to relatives and friends of the patient as well. Patients vary in the degree to which they are disturbed by the abnormal and involuntary motions, though most patients are at least somewhat bothered. DIAGNOSIS

The Abnormal Involuntary Movement Scale (AIMS) was published in 1976 and is the most commonly used assessment instrument in the diagnosis of TD. Clinicians rate overall severity of movements as well as the severity of movements in seven anatomical positions (tongue, lips, jaw, face, upper extremities, lower extremities, and trunk) on 5-point rating scales (0 ¼ none, 1 ¼ minimal, 2 ¼ mild, 3 ¼ moderate and 4 ¼ severe). Lane, Glazer, Hansen, Berman, and Kramer (1985) proposed several conventions in order enhance interrater reliability including rating severity based on three dimensions (amplitude, severity, and frequency) as well as criteria for distinguishing abnormal movements in various anatomical parts. A score of 2 ‘‘mild’’ or 1 ‘‘moderate’’ on the AIMS is indicative of TD. Another widely used TD assessment is the Dyskinesia Identification System, Condensed User Scale (DISCUS: Kalachnik & Sprague, 2006), which has been shown to be of particular value in assessing for TD among persons with intellectual deficiency. The DISCUS examination has more stringent rules for standardized administration and interpretation than the AIMS or other available scales, and, thus, is psychometrically preferable to other assessment scales for TD. Schooler and Kane (1982) suggest using prerequisites in order to make diagnoses on a progressive scale. They first state that patients must meet three criteria: a history of 3 months of neuroleptic medication, at least moderate abnormal, involuntary motor functions, and the absence of other conditions that may account for the abnormal movements. These criteria in culmination with information pertaining to the persistence of abnormal movements, the dose history

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of the patient, and the time in which patients have been on medication and exhibited movements may allow diagnoses to be assigned. The progressive diagnoses that they suggest include probable TD, masked probable TD, transient TD, withdrawal TD, persistent TD, and masked persistent TD. TREATMENT

Some research suggests that medications that reduce free radical formation may be effective in preventing TD. Tacopherol is an antioxidant that counteracts free radicals and shows promise in the treatment and, possibly, the prevention of TD. Researchers have examined possible effects of using vitamin E, a free radical scavenger, as a treatment of TD. Results of such studies have been mixed, and no consistent consensus has been reached on the efficacy of vitamin E treatment for TD. Given the relatively low risks associated with its use, many clinical authors suggest treatment with vitamin E is a safe ‘‘add-on’’ for patients with TD, since it might be of value and is unlikely to be of any detriment to the client. Paradoxically, medication-induced TD is often treated using low doses of the same medications that purportedly caused the disorder in the first place. Although no drugs have proven to effectively eliminate symptoms of TD, the incidence of TD has been reduced since the development of newer, atypical, antipsychotic medications that have a reduced propensity toward the development of TD. Olanzapine is a newer antipsychotic that has shown promise for the treatment of schizophrenia with reduced incidence in TD as well as less change in brain volume (Lieberman et al., 2005), less damage to striatal neurons (Margolese et al., 2005), and fewer extrapyramidal symptoms (Geddes, Freemantle, Harrison, & Bebbington, 2000). Olanzapine may protect the brain against free radical formation (Tollefson, Beasley, Tamura, Tran, & Potvin, 1997). Mandi Musso Alyse Barker William Drew Gouvier Chakos, M. H., Lieberman, J. A., Bilder, R. M., Borenstein, M., Lerner, G., Bogerts, B., et al. (1994). Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. American Journal of Psychiatry, 151(10), 1430–1436. Crane, G. E., Ruiz, P., Kernohan, W. J., Wilson, W., & Royalty, N. (1969). Effects of drug withdrawal on tardive dyskinesia. Activitas Nervosa Superior, 11(1), 30–35.

Elkashef, A. M., Buchanan, R. W., Gellad, F., Munson, R. C., & Breier, A. (1994). Basal ganglia pathology in schizophrenia and tardive dyskinesia: An MRI quantitative study. American Journal of Psychiatry, 151(5), 752–755. Geddes, J., Freemantle, N., Harrison, P., & Bebbington, P. (2000). Atypical antipsychotics in the treatment of schizophrenia: Systematic overview and metaregression analysis. British Medical Journal, 321, 1371–1376. Gordos, G., Casey, D. E., Cole, J. O., Perenyi, A., Kocsis, E., Arato, M., et al. (1994). Ten-year outcome of tardive dyskinesia. American Journal of Psychiatry, 151(6), 836–841. Kalachnik, J. E., & Sprague, R. L. (2006). The Dyskinesia Identification System Condensed User Scale: Reliability, validity, and a total cut-off score for mentally ill and mentally retarded populations. Journal of Clinical Psychology, 49, 177–189. Lane, R. D., Glazer, W. M., Hansen, T. E., Berman, W. H., & Kramer, S. I. (1985). Assessment of tardive-dyskinesia using the Abnormal Involuntary Movement Scale. Journal of Nervous and Mental Disease, 173(6), 353–357. Lieberman, J. A., Tollefson, G. D., Charles, C., Zipursky, R., Sharma, T., Kahn, R. S., et al. (2005). Antipsychotic drug effects on brain morphology in first-episode psychosis. Archives of General Psychiatry, 62, 361–370. Lohr, J. B., Kuczenski, R., & Niculescu, A. B. (2003). Oxidative mechanisms and tardive dyskinesia. CNS Drugs, 17(1), 47–62. Margolese, H. C., Chouinard, G., Kolivakis, T., Beauclair, L., & Miller, R. (2005). Tardive dyskinesia in the era of typical and atypical antipsychotics: Part 1: Pathophysiology and mechanisms of induction. Canadian Journal of Psychiatry, 50(9), 541–547. Schooler, N. R., & Kane, J. M. (1982). Research diagnoses for tardive dyskinesia (letter). Archives of General Psychiatry, 39, 486–487. Silvestri, S., Seeman, M. V., Negrete, J. C., Houle, S., Shammi, C. M., Reminton, G. J., et al. (2000). Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: A clinical PET study. Psychopharmacology, 152, 174–180. Tan, Y. L., Zhou, D. F., & Zhang, X. Y. (2005). Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia: Association with dyskinetic movements. Schizophrenia Research, 74(2–3), 263–270. Tollefson, G. D., Beasley, C. M., Tamura, R. N., Tran, P. V., & Potvin, J. H. (1997). Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol. American Journal of Psychiatry, 154, 1248–1254.

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TARLOV CYSTS DESCRIPTION

Tarlov cysts, also known as sacral perineural cysts, are a rare cause of localized or radiating back pain and leg pain, caused by the development of cerebrospinal fluid–filled cysts in the sacral area of the spine. They often cause dull, nebulous sciatic pain, which makes both assessing and diagnosing Tarlov cysts difficult (Landers & Seex, 2002). Frequently, they are asymptomatic, meaning that their existence causes no pain, and therefore may need no intervention. The prevalence of Tarlov cysts represents about 4.5% out of all cases of back pain (Prashad, Jain, & Dhammi, 2007). Of all cases of Tarlov cysts, only about 20% of cases are symptomatic and may require treatment (Prashad et al., 2007). It should be noted that the relevant literature uses the terms Tarlov cysts, sacral cysts, and perineural cysts interchangeably; thus, these terms should be treated as synonymous. Specifically, Tarlov cysts are spinal root lesions, most often seen in the sacral area of the spine at about S-2 or S-3 (Voyadzis, Bhargava, Fraser, & Henderson, 2001). Both injury and congenital etiologies can cause spinal root lesions that fill up with cerebrospinal fluid. In contrast with a diverticula, which is an open fluidfilled lesion, Tarlov cysts are closed, meaning that they fill gradually (Voyadzis et al., 2001). For this reason, the use of radiopaque dye during myelography studies to locate the cyst has been largely unsuccessful. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Isadore Tarlov, who initially discovered the presence of Tarlov cysts while studying autopsy cases, identified several unique characteristics of Tarlov cysts. First, he found that Tarlov cysts always form between the endoneurium and perineurium, which are both layers of connective tissue enclosing nerve fibers. He also noted that there can be cases of multiple Tarlov cysts that impinge spinal nerves (Voyadzis et al., 2001). Cases of multiple Tarlov cysts can encapsulate a spinal nerve and affect neighboring nerves, which often causes radiculating back, leg, and buttocks pain. The pathogenesis of Tarlov cysts remains greatly debated. Originally, Tarlov speculated that the perineural cysts were due to inflammation within the nerve root sheath (Acosta, Hinojosa, Schmidt, & Weinstein, 2003). Another possible etiology that Tarlov suggested was hemorrhaging of the subarachnoid space, which can lead to cyst formation.

More recent research has yielded two major hypotheses. First, much research suggests that subarachnoid hemorrhaging and cyst formation can be caused by localized injury or trauma to the lumbar area (Acosta et al., 2003). Another common presumption is that Tarlov cysts are congenital, caused by either a natural propensity to form spinal cysts, or a type of congenital connective tissue disorder (Acosta et al., 2003). Although disparity remains among researchers, the idea of multiple etiologies is commonly espoused. Although sacral cysts are the most common, Tarlov cysts have been found in multiple places along the spinal column (Voyadzis et al., 2001). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Tarlov cysts can cause a wide range of possible symptoms and pathologies. Most patients with either one or multiple Tarlov cysts report experiencing some sort of radiculopathy or neuropathy, which is to generally say that most patients experience some nerve dysfunction. Specific symptomatology includes either a dull or more intense pain in the back, legs, sacrum, buttocks, or genital area. In addition, Tarlov cysts can cause motor weakness and bladder incontinence (Acosta et al., 2003). Frequently, patients report sensory disturbances such as hypesthesia or paresthesia. Hypesthesia is a reduction in tactile sensitivity, whereas paresthesia is described as a persistent itching or burning condition. Both of these symptoms can be induced by nerve damage caused by the expansion of Tarlov cysts in the sacral area of the anterior spinal column. Given the multiple locations in which Tarlov cysts can be found, symptomatology is extremely variable in this medical condition. Depending on cyst location, dyspareunia may be a reported symptom, which is the experience of pain during sexual intercourse, usually due to a physical condition. The prevalence of dyspareunia and Tarlov cysts are more common in women than men; generally, 80% of all cases of perineural cysts are women (Acosta et al., 2003). Due to the consistent saturation of cerebrospinal fluid in the sacrum, erosion and sacral fractures can occur, causing a greater amount of lumbar pain (Acosta et al., 2003). Patients often describe Tarlov cysts as causing a nebulous pain that is exacerbated by standing, sitting, or even coughing. These actions can impose pressure on the subarachnoid space, which stores cerebrospinal fluid. This compression on the subarachnoid space forces cerebrospinal fluid down to the S-2 or S-3 area, where the Tarlov cysts are harbored. As the cerebrospinal fluid begins to fill the spinal root lesion

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(Tarlov cyst), swelling occurs, which can impact surrounding nerves (Acosta et al., 2003). Current research suggests that Tarlov cysts rarely present with neurological symptoms, though it does happen. Common neurological complaints include general or localized motor weakness, hypesthesia, and paresthesia. Due to their sensory symptomatology, Tarlov cysts do not overtly mediate cognitive functioning; however, they may impact neuropsychological testing in indirect ways, such as distractibility due to excessive pain or dysfunctional sensory feedback. Sitting, especially for long durations, can be painful and difficult for patients with Tarlov cysts, making cooperation through a long battery of testing unlikely. DIAGNOSIS

Diagnosis of Tarlov cysts tends to be incidental in nature, due to their asymptomatic nature. Tarlov cysts are most often identified through the use of CT or MRI scans, which both successfully locate perineural cysts (Voyadzis et al., 2001). Radiopaque dye is also used but tends to be less successful. Because Tarlov cysts are closed lesions, radiopaque dye may take weeks to flow into the cysts, enabling the identification of Tarlov cysts. More recently, water-based dye is being used, which facilitates diagnosis fairly quickly (Acosta et al., 2003). Recently, a classification system was introduced to give further description to sacral cysts and to assist their accurate diagnosis. Type I sacral cysts are known as extradural cysts, which do not contain spinal nerve roots. Type II cysts are extradural cysts with spinal nerve roots, and Type III cysts are intradural (Nabors, Pait, & Byrd, 1988). The differential diagnoses for Tarlov cysts tend to be more common than symptomatic perineural cysts. One relatively frequent differential diagnosis is that of meningocele. It is a rare form of spina bifida, involving meningeal cysts. These cysts appear quite similar to Tarlov cysts and can present with similar symptoms (Smith & Davis, 1980). Arachnoid cysts, which are cerebrospinal fluid-filled cysts, grow on the arachnoid layer of the spinal cord and should be considered as a differential diagnosis when assessing the presence of spinal cysts. Lastly, neurofibroma is a nerve sheath tumor caused by dysfunctional Schwann cells. The symptomatology of neurofibroma tends to be more severe than Tarlov cysts, causing significant cognitive deficits. Because Tarlov cysts are usually asymptomatic, they are quite often discovered accidentally through the use of CT or MRI. Previous research argues that though the cysts cause no overt symptoms, they should be consistently monitored for cyst expansion or increased subarachnoid pressure (Landers et al.,

2002). Monitoring asymptomatic perineural cysts are important, due to their potential to expand impinging surrounding bone, tissue, and nerve roots.

TREATMENT

Treatment for Tarlov cysts remains disputed, though several empirically studied options do exist. One nonsurgical intervention that is used quite often is draining the accumulated cerebrospinal fluid from the cyst or cysts. This is done through the use of a lumboperitoneal shunt that has been found to be successful as a shortterm therapy (Acosta et al., 2003). In order for this treatment to remain efficacious, continuous draining must take place to avoid the inevitable accumulation of cerebrospinal fluid from subarachnoid pressure. Another possible treatment is through the use of corticosteroids or other anti-inflammatory medication. Typically, this would be the first step of treatment taken, though it may not suffice in more malignant cases. Isadore Tarlov promulgated complete excision of the cyst, the affected nerve root, and the attached ganglion. After Tarlov’s discovery of Tarlov cysts, he began to surgically excise the cysts, and found that this method was longitudinally more successful than shunting (Acosta et al., 2003). Presently, cyst excision is practiced, though the surgical risk is disputed. Because Tarlov cysts are fairly benign, many argue that excision is too drastic an intervention. Cyst excision should be an intervention reserved for individuals who experience a great amount of pain due to either multiple or enlarged cysts and have experienced no alleviation from either anti-inflammatory medication or cerebrospinal fluid shunting. Ryan Boddy Charles Golden Acosta, F. L., Hinojosa, A., Schmidt, M. H., & Weinstein, P. R. (2003). Diagnosis and management of sacral Tarlov cysts: Case report and review of the literature. Journal of Neurosurgery, 15(2), 1–7. Landers, J., & Seex, K. (2002). Sacral perineural cysts: Imaging and treatment options. British Journal of Neurosurgery, 16(2), 182–185. Nabors, M. W., Pait, T. G., & Byrd, E. D. (1988). Updated assessment and current classification of spinal meningeal cyst. Journal of Neurosurgery, 68, 366–377. Prashad, B., Jain, A. K., & Dhammi, I. K., (2007). Tarlov cyst: Case report and review of the literature. Indian Journal of Orthopedics, 41(4), 401–403. Smith, H. P., & Davis, C. (1980). Anterior sacral meningocele: Two case reports and discussion of surgical approach. Neurosurgery, 7(1), 61–67.

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Voyadzis, J. M., Bhargava, P., & Henderson, F. (2001). Tarlov cysts: A study of 10 cases with review of the literature. Journal of Neurosurgery, 95(1), 25–32.

TAY–SACHS’ DISEASE DESCRIPTION

Tay–Sachs’ disease is a genetic neurodegenerative disorder of lipid storage, corresponding with deficient activity of hexosaminidase A (Hex-A) (Kolodny, 1997). This activity serves to catalyze gangliosides, thus this decreased activity results in a buildup of ganglioside GM2 in tissues throughout the body as well as nerve cells in the brain. Although cases have been reported across the globe, Tay–Sachs’ disease presents most commonly in Ashkenazi Jews with a carrier prevalence of 3.3% (Petresen, Rotter, & Cantor, 1983). The classic description of Tay–Sachs’ disease has focused on the early-onset variant in which infants develop normally for the first few months of life, but as ganglioside GM2 builds up in the brain, mentation, and physical functioning regress. Eventually infants present with blindness, deafness, dysphagia, and decerebrate posturing prior to death. In the rarer, late-onset variant where symptoms manifest when the individual is in their 20s, and sometimes early 30s, progressive neurological deterioration in conjunction with disturbed gait and psychiatric features are observed (Hurowitz, Silver, Brin, Williams, & Johnson, 1993; Rosebush et al., 1995). Emerging evidence also suggests that carriers of Tay–Sachs’ disease, who have long been believed to be asymptomatic, actually demonstrate increased prevalence of mild psychiatric and neurological features (Federico et al., 1988). To date, there is no cure or effective treatment for the presentation (Desnick & Kaback, 2001). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Once considered no different from gangliosidosis, Tay-Sachs’ disease is now considered an infantile form of this grouping with distinct enzyme deficiencies and genetic mutations (Lake, 1997). Inherited as an autosomal recessive trait, it is relatively common in Ashkenazi Jews. GM2-ganglioside levels may be more than 100 times their regular state. Hexosaminidase activity is deficient leading to residual N-acetylgalactosamine on GM2-gangliosidose (Okada & O’Brien, 1969).

Anatomically, infants develop megalencephaly by 2 years of age if they survive that long. Prior to this, the brain may appear microcephalic at birth or even normal in size and swells as the disease progresses. The volumetric growth is due to neuronal swelling and hyperplasia of astrocytes due to the excessive levels of GM2-ganglioside. Meganeurite formation in the cerebral cortex also occurs related to these increased levels (Siegel & Walkley, 1994). Demyelination occurs disrupting the differentiation between gray and white matter. On MRI with subsequent phosphorus spectroscopy, high signal intensity and severe metabolic changes in the subcortical white matter membrane-bound phosphates and in the basal ganglia have been reported (Mugikura et al., 1996; Schengrund, 1990). Cerebellar atrophy has been reported by some as the most common finding, primarily involving the cerebellar vermis (Streifler, Gornish, Hadar, & Gadoth, 1993). Mutations, which permit residual activity of Hex-A, result in juvenile and adult onset of Tay–Sachs’ disease, whereas no activity results in the infantile form (Yacubian et al., 2000). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Clinically, infants demonstrate normal development for the first few months of life. A heightened startle response may be noted during this asymptomatic period. As the disease progresses, a plateau of psychomotor development is reached followed by retardation. Hypotonia and spasticity eventually develop. Seizures also develop within the first 2 years of life. In the later stages, infants become blind, oftentimes deaf, and exhibit decerebrate posturing prior to death. In comparison, the late-onset subtype is marked by signs of motor neuron and cerebellar involvement as well as dysarthria and psychiatric features (Gravel, Clark, Kaback, Mahuran, & Sandhoff, 1995; Hurowitz et al., 1993; Rosebush et al., 1995). Emerging findings suggest that even carriers of Tay–Sachs’ disease present with neurological and psychiatric residuals. Cognitive impairment, cerebellar ataxia, and psychiatric manifestations have all been said to present at higher rates in Tay–Sachs’ disease carriers as opposed to noncarriers (Zelnika, Khazanovb, Sheinkmanc, Karpatid, & Pelegd, 2000). DIAGNOSIS

Diagnosis is initially suggested based on clinical presentation, demographic, and medical history including family history given more than 80% are of Jewish

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decent. Amniotic fluid and chorionic villi may be removed early in pregnancy for analysis, in which Tay–Sachs’ disease may be determined (Maertens & Dyken, 2007). DNA testing in combination with enzyme analysis can be definitive (Eiris, Chabas, Coll, & Castr- Gato, 1999). In regard to differential diagnosis, cerebroretinal syndromes, leukodystrophies, and other gangliosidoses variants should be considered, but the combination of the aforementioned DNA testing and enzyme analysis can prove definitive. TREATMENT

There is no cure or standard treatment for Tay–Sachs’ disease. The approach is supportive and symptom based. Anti-epileptic drugs may be used to control seizure activity. Feeding tubes may be needed if dysphagia develops. Gene transfer and cell engraftment of neural stem cells have been tested in animal models as a means of express Hex-A (Guidotti et al., 1999), but it is not being tested in humans yet. Haloperidol, phenothiazines, and other D2 receptor blockers as well as tricyclic antidepressants might promote storage of gangliosides in the neurons (Rosebush, 1995; Renshaw, Stern, Welch, Schouten, & Kolodny, 1992) and thus should be avoided in late-onset Tay–Sachs’ disease if considered to treat psychiatric features. For example, Navon and Baram (1987) demonstrated that imipramine caused cellular depletion of Hex-A. Chad A. Noggle Desnick, R. J., & Kaback, M. M. (2001). Future perspectives for Tay-Sachs disease. Advances in Genetics, 44, 349–356. Eliris, J., Chabas, A., Coll, M. J., & Castr- Gato, M. (1999). Late infantile and juvenile form of GM2-gangliosidosis variant B1. Revista de Neurologia, 29, 435–438. Federico, A., Palmeri, S., Mangano, L., Mondelli, M., Rossi, A., & Guazzi, G. C. (1988). Clinical and neurophysiological changes in carriers from a family with type O chronic GM2 gangliosidosis with ALS phenotype. In R. Savayre, L. Douste-Blazy, & S. Gatt (Eds.), Lipid storage disorders. Biological and medical aspects (pp. 253–258). New York: Plenum Press. Gravel, R. A., Clark, J. T. R., Kaback, M. M., Mahuran, D. J., & Sandhoff, K. (1995). The GM2 gangliosidoses. In C. R. Scriver, A. L. Beaudet, W. S. Sly, & D. Valle (Eds.), The metabolic and molecular basis of inherited disease (pp. 2839–2879). New York: McGraw-Hill. Guidotti, J. E., Mignon, A., Haase, G., Caillaud, C., McDonell, N., Kahn, A., et al. (1999). Adenoviral gene therapy of the Tay-Sachs disease in hexosaminidase A-deficient knock-out mice. Human Molecular Genetics, 8, 831–838.

Hurowitz, G. I., Silver, J. M., Brin, M. F., Williams, D. T., & Johnson, W. G. (1993). Neuropsychiatric aspects of adult onset Tay-Sachs disease: Two case reports with several new findings. The Journal of Neuropsychiatry and Clinical Neurosciences, 5, 30–36. Kolodny, E. H. (1997). The GM2 gangliosidoses. In R. N. Rosenberg, S. B. Pruisner, S. Di Mauro, R. L. Barchi, L. M. Kunkel (Eds.), The molecular and genetic basis of neurological disease (pp. 531–540). Boston: ButterworthHeinemann. Lake, B. (2007). Lysosomal and peroxisomal disorders. In Goetz, C. (Ed.), Textbook of clinical neurology (pp. 657– 753). Philadelphia, PA: Saunders Elsevier. Lichtenberg, P., Navon, R., Wertman, E., & Lerer, B. (1988). Postpartum psychosis in adult GM2 gangliosidosis. A case report. The British Journal of Psychiatry, 153, 387–389. Maertens, P., & Dyken, R. (2007). Storage diseases: Neuronal ceroid-lipofuscinoses, lipidoses, glycogenoses, and leukodystrophies. In Goetz, C. (Ed.), Textbook of clinical neurology (pp. 613–639). Philadelphia, PA: Saunders Elsevier. Mugikura, S., Takahashi, S., Higano, S., Kurihara, N., Kon, K., & Sakamoto, K. (1996). MR findings in Tay-Sachs disease. Journal of Computer Assisted Tomography, 20, 551–555. Navon, R., & Baram, D. (1987). Depletion of cellular betahexosaminidase by imipramine is prevented by dexamethasone: Implication for treating the psychotic hexosaminidase A deficient patients. Biochemical and Biophysical Research Communications, 148, 1098–1103. Okada, S., & O’Brien, J. S. (1969). Tay-Sachs’s disease: generalized absence of a beta-D-N-acetylhexosaminidase component. Science, 165, 698–700. Petresen, G. M., Rotter, J. I., & Cantor, R. M. (1983). The TaySachs gene in North American Jewish population: Geographic variations and origin. American Journal of Human Genetics, 35, 1258–1269. Renshaw, P. F., Stern, T. A., Welch, C., Schouten, R., & Kolodny, E. H. (1992). Electroconvulsive therapy treatment of depression in a patient with adult GM2 gangliosidosis. Annals of Neurology, 31, 342–344. Rosebush, P. I., MacQueen, G. M., Clarke, J. T., Callahan, J. W., Strasbery, P. M., & Mazurek, M. F. (1995). Late onset Tay-Sachs disease presenting as catatonic schizophrenia: Diagnostic and treatment issues. Journal of Clinical Psychiatry, 56, 347–353. Schengrund, C. L. (1990). The role(s) of gangliosides in neural differentiation and repair: A perspective. Brain Research Bulletin, 24, 131–141. Siegel, D. A., & Walkley, S. U. (1994). Growth of ectopic dendrites on cortical pyramidal neurons in neuronal storage diseases correlates with abnormal

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accumulation of Gm2 ganglioside. Journal of Nuerochemistry, 62, 1852–1862. Streifler, J. Y., Gornish, M., Hadar, H., & Gadoth, N. (1993). Brain imaging in late-onset GM2 gangliosidosis. Neurology, 43, 2055–2058. Yacubian, E., Rosemberg, S., Garrido Neto, T., Suely, K. N., Vale´rio, R., & Jorge, C. (2000). Phosphorus magnetic resonance spectroscopy in late-onset Tay-Sachs disease. Journal of Child Neurology, 16(5). Zelnika, N., Khazanovb, V., Sheinkmanc, A., Karpatid, A. M., & Pelegd, L. (2000). Clinical manifestations of psychiatric patients who are carriers of Tay-Sachs disease possible role of psychotropic drugs. Neuropsychobiology, 41, 127–131.

caudal end, preventing movement toward the head of the individual. Stretching can occur due to differences in growth rates or flexion and extension of the area. Neurochemical changes — impairments in oxidative metabolism — are central to this syndrome and relate to depressed electrophysiological activity, leading to changes in ratios of the enzyme, cytochrome oxidase (Fuse, Patrickson, & Yamada, 1989). The effects of these changes result in hypoxemia and brain and spinal cord ischemia (Yamada, Zinke, & Sanders, 1981).

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

TETHERED SPINAL CORD SYNDROME DESCRIPTION

Tethered spinal cord syndrome is characterized by extraneous tissue attachments that limit and abnormally stretch the spinal cord, resulting in anomalous lower limb sensorimotor functions, incontinence, and musculoskeletal deformities (Iskandar & Oakes, 2001). The disorder is related to spina bifida myelomeningocele, yet other etiologies exist including dermal sinus tract, diastematomyelia, lipoma, tumor, thickened or tight filum terminale, history of spine trauma, and history of spine surgery (Iskandar & Oakes, 2001). A tethered spinal cord results from abnormal development of the neural tube, where the lower portion of the spinal cord remains attached to the skin near the posterior lumbar vertebrae and fails to ascend as in normal development (Barson, 1970). Thus, the spinal cord remains connected to the thecal sac, where the spinal nerves’ roots exist. As growth occurs, the spinal cord is tethered at that location, leading to stretching and resulting in damage to the spinal cord and blood supply disruption. Prevalence for tethered spinal cord is approximately 5–25 per 100,000; and prognosis varies based on severity and etiology of the tethering, yet most individuals will live a generally full and fairly normal life (Iskandar & Oakes, 2001). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The pathophysiology of tethered spinal cord syndrome is characterized by the mechanical stretching of an inelastic spinal cord that is anchored on the

Clinical presentation of tethered spinal cord syndrome includes abnormalities on the lower back (i.e., hairy patches, tumors, lesions, or dimples), spinal (i.e., scoliosis) and foot deformities, weakness in the lower limbs, and incontinence (French, 1983). While symptoms are typically evident in childhood, sensorimotor problems and incontinence may not develop until adulthood (French, 1983). Etiology may be varied as described previously, and symptoms may include lower limb movement or sensory impairments, pain in the lower extremities or back, muscle weakness, and may include incontinence of bowel and bladder. With regard to sensorimotor impairments, motor dysfunction in the individual with tethered spinal cord syndrome may manifest as lower extremity muscle atrophy, hyperreflexia, and pathologic plantar response (also known as the Babinski response) which is indicative of compromise to the central nervous system (Schneider, 1996). Sensory dysfunctions typically manifest as abnormal pain, temperature, and proprioception often in a patchy distribution (Schneider, 1996). Neuropathic bladder, which tends to worsen with age (70% for adults versus 20–30% for children), results in urinary urgency and frequency, incomplete voiding, and incontinence (French, 1983). With dysfunctional bladder, there is frequently associated recurrent and chronic infection that may lead to renal failure. Females with tethered spinal cord may suffer from ineffective labor and postpartum rectal prolapse secondary to an atonic pelvic floor (Schneider, 1996). With the exception of previously noted impairments, cognitive and academic functions are typically in the normal ranges for tethered spinal cord syndrome.

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DIAGNOSIS

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Tethered spinal cord is often diagnosed through an MRI, which will conclusively reveal a tethered spinal cord on the distal end. This tethering will result in abnormal stretching of the spinal cord, which can lead to previously discussed symptoms. Other diagnostic measures include a myelogram, which is an X-ray following contrast injection of the spinal canal’s thecal sac, or ultrasound for the purposes of demonstrating pressure on the nerves of the spinal cord (McCullough, Levy, DiChiro, & Johnson, 1991). Diagnosis is generally considered accurate following imaging; thus, differential diagnosis is often not problematic. A positive diagnosis of tethered cord syndrome warrants ruling out Chiari malformation and Ehlers– Danlos syndrome due to the correlation of these diagnoses (Schneider, 1996). TREATMENT

Surgical treatment is considered paramount with tethered spinal cord syndrome due to the often irreversible nature of the neurologic symptoms (Johnson & Levy, 1995). The goal of surgery in children is to prevent further deterioration, while the goal of surgery in adults is to restore function and alleviate symptoms. In general, sensorimotor improvements are noted following surgical detethering (Johnson & Levy, 1995). Additional treatment tends to be supportive and to alleviate symptoms. NSAIDs, opiates, synthetic opiates, Cox-2 inhibitors, atypical tricyclic antidepressants, and anticonvulsive medications are often prescribed but there is little evidence that these provide consistent and persisting relief (Huttmann, Krauss, Collmann, Sorensen, & Roosen, 2001). Transcutaneous Electrical Nerve Stimulation units may provide some benefit, but this has not been fully validated (Huttmann et al., 2001). Javan Horwitz Natalie Horwitz Chad A. Noggle Barson, A. (1970). The vertebral level of termination of the spinal cord during normal and abnormal development. Journal of Anatomy, 106, 489–497. French, B. (1983). The embryology of spinal dysraphism. Clinical Neurosurgery, 30, 295–340. Fuse, T., Patrickson, J., & Yamada, S. (1989). Axonal transport of horseradish peroxidase in the experimental tethered spinal cord. Pediatric Neuroscience, 15, 296–301.

Huttmann, S., Krauss, J., Collmann, H., Sorensen, N., & Roosen, K. (2001). Surgical management of tethered spinal cord in adults: Report of 54 cases. Journal of Neurosurgery, 95, 173–178. Iskandar, B., & Oakes, W. (2001). Anomalies of the spine and spinal cord. In D. McLone (Ed.), Pediatric neurosurgery: The surgery of the developing nervous system (4th ed., pp. 307–324). Philadelphia, PA: W.B. Saunders. Johnson, D., & Levy, L. (1995). Predicting outcome in the tethered cord syndrome: A study of cord motion. Pediatric Neurosurgery, 22, 115–119. McCullough, D., Levy, L., DiChiro, G., & Johnson, D. (1991). Toward the prediction of neurological injury from tethered cord: Investigation of cord motion with magnetic resonance. Pediatric Neurosurgery, 16, 3–7. Schneider, S. (1996). Tethered cord syndrome: The neurological examination. In S. Yamada (Ed.), Tethered cord syndrome (pp. 49–54). Park Ridge, IL: AANS. Yamada, S., Zinke, D., & Sanders, D. (1981). Pathophysiology of ‘‘tethered cord syndrome.’’ Journal of Neurosurgery, 54, 494–503.

THORACIC OUTLET SYNDROME DESCRIPTION

Thoracic outlet syndrome (TOS) occurs when nerves and/or vessels are compressed in the core of the neck resulting in problems with nerve and vascular functions, both locally and distally (Ruckley, 1983). TOS has a number of possible origins including pressure due to a cervical rib, a defect in the clavicle or first rib, an aneurysm, a tumor, problems with the anterior scalene muscle, a contraction of the costoclavicular space, and/or other space-inhabiting lesions (Woods, 1978). Consequently, compression occurs at different areas including the thoracic outlet, the cubital tunnel, the carpal tunnel, and Guyon’s canal. In some cases, several points of compression may occur between the cervical spine and hand with less pressure producing symptoms in each area. In fact, multiple crush syndrome exists when a patient has concomitant TOS, carpal tunnel syndrome, and ulnar nerve compression at the elbow (Urchel & Kourlis, 2007). Women, particularly those who are slim and/or have dropping shoulders, are more likely to have TOS than men (Ruckley, 1983). According to Woods (1978), 71% of the cases he reviewed were women, while 29% were men. In addition, the range of the patients’ ages was 10–84, with 37 being the mean (Woods, 1978).

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NEUROPATHOLOGY/PATHOPHYSIOLOGY

As suggested, TOS originates from compression of nerves or blood vessels, or both, because of a disruption of the passageway through the area between the base of the neck and the armpit known as the thoracic outlet. The anatomical location of the thoracic outlet is surrounded by muscle (e.g., anterior scalene muscle), bone (e.g., clavicle or ribs), and other tissue. Any defect or alteration of these tissues that infringes upon the thoracic outlet, thereby compressing the nerves (i.e., brachial plexus) and/or vessels (subclavian artery and veins) that pass through the tunnel leads to TOS. Given that this can occur at different sites from different tissues, functional outcomes can vary, therefore TOS may be best classified as an umbrella diagnosis representing an entire group of disorders. Eighty to 90% of TOS cases are comprised of neurological defects, which occur more in women, whereas vascular compression occur more in men. However, vascular symptoms present more serious health issues, as irreversible hand injury and damage to the entire arm may occur. Neurological symptoms are usually less critical, as an aching pain in the neck, arm, and/or shoulder is most often reported (Ruckley, 1983). The compression against the first rib causes several vascular and nerve problems including edema, venous distension, Paget–Schroetter’s syndrome, loss of a pulse, aneurysm, paresthesias, motor weakness, Raynaud’s phenomenon, ischemia, and temperature changes (Urchel & Kourlis, 2007). In a study by Urchel and Kourlis (2007), no patients died due to TOS. One of the main complications occurred when the remains of a rib were left in the first surgery, which caused TOS to recur. In very few patients, a large amount of bleeding, nerve injuries, and Horner’s syndrome occurred. In their study on 5,102 patients with TOS, Urchel and Kourlis (2007) found that the outcome was good in 85%, fair in 12%, and poor in only 3%. In addition, 95% of the patients reported progress shortly after surgery (Urchel & Kourlis, 2007). Repetitive motions, especially of the hands and shoulders, often cause TOS. Clavicular trauma from pregnancy, polio, and bad posture can also cause TOS. Furthermore, breast surgery, such as radical mastectomies and implants, can contribute to TOS. Two other causes include hypertrophy and extreme opening of the median sternotomy retractor (Urchel & Kourlis, 2007). The most common cause of TOS is a neck injury resulting from an auto accident, which accounted for 61% of the 459 cases Woods (1978) reviewed. More specifically, rear-end collisions,

resulting in a whiplash injury accounted for 44% of the cases. Industrial accidents were responsible for 23% of the TOS cases, and miscellaneous trauma accounted for 8% (Woods, 1978). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Woods (1978) reviewed 459 patients with TOS, documenting the various symptoms that appeared related to the disorder. There were several symptoms that occurred in the majority of TOS patients, such as arm pain, neck pain/stiffness, numbness and tingling of the hand, weakness of grip, and anterior scalene pressure (Woods, 1978). These represent the hallmark symptoms that correspond with the anatomical abnormalities of TOS impacting the subclavian artery and/or veins and the brachial plexus. In comparison, the clinical presentation in vascular TOS is usually acute, and depends upon whether the compression is arterial or venous (Sessions, Ranavaya, & Brooks, 2002). Beyond those sensory and motor symptoms noted above, Woods (1978) reported several neuropsychological effects the disorder had on his patients. Fortyeight percent reported postural vertigo, 44% reported blurred vision, 54% reported retro-orbital pain, and 31% reported problems with concentration, focusing, and memory. Moreover, 85% reported occipital headaches, 18% stated their gait had become unsteady, while 11% reported syncopal attacks. All of these were due to vertebral artery compression (Woods, 1978). Sessions et al. (2002) present the number of cases with TOS who have headaches that initiate in the occipital lobe, and then spread over the rest of the cranium, becoming global tension headaches. Although it is uncommon, the cephalalgia is hemicranial and can cause unilateral facial pain on the side of the TOS; these can become more painful than the upper extremity symptoms (Sessions et al., 2002). Fields, Lemak, and Ben-Menachem (1986) identified several neurological effects due to TOS in a majorleague baseball pitcher. His depth perception as well as his ability to transfer two-dimensional displays into three-dimensional displays was impaired. A neuroophthalmologic evaluation divulged no left visual field deficit, but during testing, the most frequent error the baseball pitcher made was the rotation of objects in space, which affected his ability to catch the balls returned on his left side by the catcher. When presented with a stimulus from both sides, he was unaware of the object in his left visual field. The neuro-ophthalmologic assessment also showed the presence of an incongruous upper left homonymous quadrantanopia, as well as acquired myopia secondary

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to ciliary spasm. Moreover, he also experienced weakness on the left side of his face (Fields et al., 1986). The frustration involved with trying to obtain successful treatment may cause patients to lose motivation, and often there are deficits in their home, work, and social lives. More specifically, many patients reported difficulties styling their hair, driving, opening jars/bottles, and completing household chores such as vacuuming (Sessions et al., 2002). DIAGNOSIS

Accurate diagnosis of TOS must include a history of the patient and physical examination (Urchel & Kourlis, 2007). Woods (1978) discusses the necessity of a psychological evaluation, because each TOS case requires legal attention that is often complicated by the fact that patients commonly suffered from financial losses due to disability (Woods, 1978). Many tests are used to diagnose TOS including EMG, nerve conduction velocity (NCV), and cervical spine and chest radiographic studies, such as MRI (Urchel & Kourlis, 2007). Radiographs of the cervical spine should be employed in all TOS patients (Ruckley, 1983). Urchel and Kourlis (2007) found that when the NCV moved down to less than 85 m/s of the median or ulnar nerves across the thoracic outlet, the patient had TOS. Such methods are essential when attempting to differentiate TOS from those presentations that may demonstrate some degree of clinical overlap including but not limited to brachial neuritis, carpal tunnel syndrome, cervical radiculopathy, peripheral neuropathy, reflex sympathetic dystrophy, and rotator cuff instability. Connective tissue diseases or infections may also be considered.

relived the pain for some of these patients (Woods, 1978). Surgery might be necessary if patients have an NCV of less than 60 m/s (Urchel & Kourlis, 2007). Due to the possibility for severe complications, surgery should be carried out by a well-qualified and experienced surgeon (Ruckley, 1983). According to Urchel and Kourlis (2007), surgery first entails anterior scalenectomy, neurolysis of C7, C8, and T1 nerve roots and brachial plexus, first rib resection, and resection of the costoclavicular ligament. Patients with pseudo recurrences and real recurrences required a second procedure (Urchel & Kourlis, 2007). Rachel Rock Antonio E. Puente Fields, W. S., Lemak, N. A., & Ben-Menachem, B. (1986). Thoracic outlet syndrome: Review and reference to stroke in a major league pitcher. American Journal of Roentgenology, 146(4), 809–814. Ruckley, C. V. (1983). Thoracic outlet syndrome. British Medical Journal, 287(6390), 447–448. Sessions, R. T., Ranavaya, M. I., & Brooks, C. N. (2002). The office diagnosis of thoracic outlet syndrome: A closer look. Disability Medicine, 2(4), 116–130. Urchel, H. C., & Kourlis, H. (2007). Thoracic outlet syndrome: A 50-year experience at Baylor University Medical Center. Baylor University Medical Center Proceedings, 20(2), 125–135. Woods, W. W. (1978). Thoracic outlet syndrome. The Western Journal of Medicine, 128(1), 9–12.

THYROTOXIC MYOPATHY

TREATMENT

Many TOS patients, especially those with an NCV surpassing 60 m/s, benefit from physical therapy; however, those with motor and vascular nerve difficulties cannot undergo physical therapy. Physical therapy serves to improve posture, strengthen the shoulder, loosen the muscles in the neck, and allow for space between the first rib and the clavicle. Patients may also need to modify their sleep and work habits, and lose weight (uchel). Woods (1978) treated his patients with TOS with medications, such as muscle relaxants, anti-inflammatory drugs, and ibuprofen. Almost one-fourth of his patients received physiotherapy, which proved beneficial in about 50% of the cases. In some of his patients, Woods also used transcutaneous electrostimulation, which temporarily

DESCRIPTION

Thyrotoxic myopathy, also referred to as hyperthyroid myopathy, is a neuromuscular disorder that develops when the thyroid produces an overabundance of thyroxine. The disorder occurs in the majority of patients who have hyperthyroidism, which is caused by either Graves’ disease or a multinodular goiter. The incidence of myopathy among thyrotoxic patients can be as high as 82%. Common symptoms include muscle pain, fatigue, and exercise intolerance. In addition, there is a progressive weakness and wasting away of muscles, primarily those in the thighs and shoulders. The disease may progress to a point that suggests a motor system disease, especially if there is tremor and twitching during muscle

THYROTOXIC MYOPATHY & 713

contraction. Muscle weakness is predominantly proximal, which may be associated with respiratory problems and difficulty swallowing. Whereas thyrotoxicosis, the high metabolism syndrome resulting from elevations in thyroid hormone levels, is more prevalent in women, thyrotoxic myopathy is equally distributed between the sexes, which actually implies that men with high thyroid levels are more susceptible to the myopathy (Becker, 2001; Fleisher, 2005; Victor, Ropper, & Adams, 2002; Vinken, 1992). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Electromyograhy (EMG) displays abnormalities in proximal muscles. These anomalies are detected even when the patient is not experiencing relative weakness. Serum creatine kinase (CK) is usually normal, which indicates the scarcity of muscle fiber damage seen in the biopsy of the muscle. The main finding from the EMG is a nonselective muscle fiber atrophy. Motor nerve conduction studies are typical, but sensory amplitudes and conduction velocities may be reduced. Thyroxine impacts how striated muscle fibers contract, but has no impact on nerve fiber conduction or neuromuscular transmission. Therefore, in hyperthyroidism, the length of a muscle contraction is reduced, resulting in a lessening of muscle power and increased muscle fatigue (Becker, 2001; Victor, 2002). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

A person afflicted with thyrotoxic myopathy typically complains of weakness when rising from a low chair, climbing stairs, performing activities that require the arms to be raised above the head, or any activity that would require the movement of pelvic or shoulder muscles. Furthermore, the patient will experience pain and muscle stiffness in the extremities. Consequently, muscular atrophy is likely to be found upon clinical examination, particularly of the pectoral and pelvic girdle muscles (Vinken, 1992, 1998). Thyrotoxic myopathy is sometimes distinguished into two categories: chronic and acute thyrotoxic myopathy. In chronic thyrotoxic myopathy, the clinical presentation is a slow, progressive weakness, and atrophy with weight loss. The degree of weakness is variable and can be severe. With chronic thyrotoxic myopathy, the weakness is mostly experienced in the pelvic and shoulder girdle muscles. Acute thyrotoxic myopathy has been described as more rarely seen. The patient here will present with profound muscle weakness that progresses rapidly within a

few days. The patient may also suffer from respiratory insufficiency. Reflexes may be lessened or absent; however, sphincter functioning remains (Vinken, 1992, 1998).

DIAGNOSIS

Patients who are experiencing thyrotoxic myopathy will have an excess of thyroxine, and therefore have hyperthyroidism. A diagnosis of hyperthyroidism is performed by testing plasma thyroid stimulating hormone (TSH). Lower than normal levels of TSH are indicative of the disorder. The severity of hyperthyroidism is determined by measuring the levels of plasma-free thyroxine. In order to confirm thyrotoxic myopathy, a muscle biopsy can show atrophy of Types I and II fiber groups. While the EMG is usually normal, it may show short and polyphasic motor unit potentials in proximal muscles and creatine excretion will be elevated (Victor et al., 2002).

TREATMENT

Improvement of thyrotoxic myopathy requires treatment of the thyrotoxicosis or hyperthyroidism. Treatment of hyperthyroidism includes radioactive iodine, antithyroid drugs, or a thyroidectomy. Radioiodine is appropriate for patients who have reached normal thyroid hormone levels, who are over 40, who are unsuitable for surgery, or for those who have recurrent hyperthyroidism. The two antithyroid drugs most commonly used are propylthiouracil and methimazole. They work to prevent coupling of iodotyrosines in the thyroid gland. Antithyroid drugs are used as an ultimate treatment, or to prepare a patient for a thyroidectomy or treatment with radioiodine. The goal is to maintain a euthyroid state. Lastly, a thyroidectomy is preferred for patients who have a relatively large goiter, and for pregnant women and children (Doherty & Way, 2005; Fleisher, 2005; Victor et al., 2002). Successful treatment of thyrotoxicosis usually results in improvement of the muscle weakness within a few months. Strength improves before muscle wasting begins to reverse. EMG changes and muscle weakness resolve gradually once a normal thyroid environment is reached. Full recovery may take several months. Propranolol may help alleviate muscle weakness (Vinken, 1998). Kelly R. Pless Charles Golden

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Becker, K. L. (2001). Principles and practice of endocrinology and metabolism. Philadelphia: Lippincott Williams & Wilkins. Doherty, G. M., & Way, L. M. (2005). Current surgical diagnosis & treatment. New York: McGraw-Hill Professional. Fleisher, L. A. (2005). Anesthesia and uncommon disease. Philadelphia: Elsevier Health Sciences. Victor, M., Ropper, A. H., & Adams, R. D. (2002). Adam and Victor’s manual of neurology. New York: McGraw-Hill Professional. Vinken, P. J. (1992). Handbook of clinical neurology. Philadelphia: Elsevier Health Sciences. Vinken, P. J. (1998). Systemic diseases: Handbook of clinical neurology series. Philadelphia: Elsevier Health Sciences.

TODD’S PARALYSIS DESCRIPTION

Robert Bentley Todd described postictal paralysis in his Lumleian Lectures that were given to the Royal College of Physicians in 1849. He termed it epileptic hemiplegia, which later became known as Todd paralysis (Koehler, Bruyn, & Pearce, 2000). Todd’s paralysis is a muscle weakness or paralysis that occurs in the postictal period following a seizure, often of the partial type. More rarely, it may follow a secondarily generalized seizure. In comparison, it is not known to follow absence seizures. The paralysis may be localized to the limbs affected by the seizure (Luders & Comair, 2000). As such, the weakness or paralysis may affect any muscle group but is rarely bilateral. Symptoms may last for minutes to days and duration is often in proportion to the length of the seizure (Adams & Victor, 276). Gallmetzer et al. (2004) reported that 13.4% of their sample of 328 seizure patients had postictal paralysis of mean duration 173.5 seconds and range 11 seconds to 22 minutes. Symptoms tend to last longer following focal status epilepticus but resolve over time (Luders & Comair, 2000). Todd’s paralysis resolves on its own without treatment. NEUROPATHOLOGY/PATHOPHYSIOLOGY

The cause of Todd’s paralysis is unknown, although several theories have been posited. John Hughlings Jackson conceptualized it as an electrical exhaustion that follows the rapid and repetitive neuronal discharges of the seizure, which he credited as Todd

and Robertson’s hypothesis (Koehler et al., 2000). This may occur due to depletion of glucose in the neurons at the focal sight of the seizure (Popp, 233). It may also be a function of the excitotoxicity that occurs during the ictal or seizure period, or due to an excess or deprivation of oxygen or neurotransmitters (Luders & Comair, 2000). Another theory states that neuronal inhibition of the motor centers continues to occur postictally after completion of the seizure (Gallmetzer et al., 2004). This theory was originally postulated by Gowers in 1881. This may occur due to inactivation of N-methyl-D-aspartic acid (NMDA) receptors that would restrict the opening of ion channels, thus prohibiting neural communication to complete a movement. The last hypothesis states that Todd’s paralysis may be a cardiovascular phenomenon in which seizure activity causes vasomotor and metabolic changes such as arterial venous shunting, which restricts blood flow to a focal region of the brain for a short duration of time, or cerebral hyperperfusion, which increases blood flow (Yarnell, 1975). Kimura, Sejima, Ozasa, and Yamaguchi (1998) presented two cases of focal seizures in children that resulted in Todd’s paralysis. The authors utilized technetium-99m-HMPAO SPECT imaging to evaluate the patients’ cerebral blood flow patterns following the seizure. Both cases showed contralateral cerebral hyperperfusion, or increased blood flow, within 36 hours of cessation of seizure activity, which continued after the paralysis had resolved and about 24 hours after cessation of seizure activity. MRI and EEG were normal and were thus seen as evidence against cerebral infarct. Furthermore, the authors concluded that increased cerebral blood flow did not seem to cause the Todd’s paralysis since the paralysis resolved more rapidly. Bergen, Rayman, and Heydemann (1992) reported two case studies of bilateral Todd’s paralysis following focal seizure. Both patients had bilateral muscle weakness or paralysis of the arms and legs which lasted several minutes. The patients had flaccid muscle tone with unimpaired sensation of touch and pinprick. EEG and clinical observation showed that their seizures began in the supplementary motor cortex of the frontal lobe. They stated that this localization was further supported by the interconnection with the primary motor cortex, which would explain the more severe cases of transient paralysis. Todd’s paralysis occurs more often in patients with a tumor than in those with any other neurological condition that causes their seizures (Merritt, 1963). The condition is also associated with vascular lesions and arteriovenous malformations.

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NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Because the effects of Todd’s paralysis rarely last more than 24 hours, neuropsychological testing would have to be performed during that brief period to find deficits of performance. Such impairments would be expected to include poor performance on motor tasks involving the affected side. Other neurological symptoms occur when the parietal, occipital, or frontal lobes are affected. Aphasia and other disturbances of speech, poor eye position, and disturbed vision may be disrupted and sensory changes and hallucinations have been reported. Decreased level of consciousness may follow the seizure and resolve rapidly (Mahadevan & Garmel, 2005).

frequency activity on the contralateral side. The EEG may also be normal (Schwartzman, 2006). Von Kummer, Back, and Ay (2006) reported that they found no significant abnormalities on conventional MRI, MRA, DW1, or P1. TREATMENT

Due to the short duration of symptoms, no treatment is warranted or conducted. The condition resolves on its own without intervention. The treatment and prognosis of the patient will depend upon his or her seizure activity. The presence of Todd’s paralysis may increase the risk for recurrent seizures so patients should be carefully monitored (Mahadevan & Garmel, 2005). Jessie L. Morrow Charles Golden

DIAGNOSIS

Todd’s paralysis most commonly follows unilateral motor seizure activity and less commonly follows generalized seizure. It is found most often in children and infants, although it can occur in adults. Symptoms last from minutes to hours, rarely for more than 24 hours (Niedermeyer & Lopes da Silva, 2004). Diagnosis is exclusionary and based upon history of seizure. When history is unknown, imaging techniques should be used to assess for head injury or stroke and drug levels should be analyzed to rule out withdrawal (Mahadevan & Garmel, 2005). Because Todd’s paralysis lateralizes the location of the seizure to the cerebral hemisphere contralateral to the muscle paralysis, it is useful for identification of the seizure focus. This measure is reliable even when the seizure activity spreads from the locus of onset throughout the cortex (Luders & Comair, 2000, p. 90). Due to the short duration of symptoms, imaging may not be completed during every episode. This is supported by the fact that weakness or paralysis that occurs following a seizure does not guarantee that there is cortical bleeding or damage. However, when seizure and Todd’s paralysis follows head trauma, patients should be evaluated for acute subdural hematoma because the trauma increases the risk of infarct (Anschel, 2006). Imaging techniques have found various results from normal functioning to cerebral slowing. An EEG of the patient during an episode of Todd’s paralysis may show marked slowing in the cerebral hemisphere contralateral to the side of motor weakness (Niedermeyer & Lopes da Silva, 2004). Gustavson, McIntyre, and Roberts (2003) presented a case study in which the patient’s EEG during postictal paralysis showed higher amplitude and lower

Anschel, D. (2006). Neurology (6th ed.). New York: McGrawHill Professional. Bergen, D. C., Rayman, L., & Heydemann, P. (1992). Bilateral Todd’s Paralysis after focal seizures. Epilepsia, 33(6), 1101–1105. Gallmetzer, P., Leutmezer, F., Serles, W., Assem-Hilger, E., Spatt, J., & Baumgartner, C. (2004). Postictal paresis in focal epilepsies — incidence, duration, and causes: A video-EEG monitoring study. Neurology, 62(12), 2160– 2164. Gustavson, A. R., McIntyre, B. B., & Roberts, H. W. (2003). Electrographic correlates of seizures with Todd’s Paralysis. A case report. Clinical Neurophysiology, 114(2), 393. Koehler, P. J., Bruyn, G. W., & Pearce, J. (2000). Neurological eponyms. New York: Oxford University Press. Luders, H., & Comair, Y. G. (2000). Epilepsy surgery. Baltimore, MD: Lippincott Williams & Wilkins. Mahadevan, S. V., & Garmel, G. M. (2005). An introduction to clinical emergency medicine. New York: Cambridge University Press. Kimura, M., Sejima, H., Ozasa, H., Yamaguchi, S. (1998). Technetium-99m-HMPAO SPECT in patients with hemiconvulsions followed by Todd’s paralysis. Pediatric Radiology, 28(2), 92–94. Merritt, H. (1963). Textbook of neurology. London: Kimpton. Niedermeyer, E., & Lopes da Silva, F. H. (2004). Electroencephalography: Basic principles, clinical applications, and related fields. Baltimore, MD: Lippincott Williams & Wilkins. Schwartzman, R. J. (2006). Differential diagnosis in neurology. Fairfax, VA: IOS Press. Von Kummer, R., Back, T., & Ay, H. (2006). Magnetic resonance imaging in ischemic stroke. New York: BirkhauserSpringer. Yarnell, P. R. (1975). Todd’s Paralysis: A cardiovascular phenomenon? Stroke, 6, 301–303.

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TOURETTE’S SYNDROME AND OTHER TIC DISORDERS DESCRIPTION

Tourette’s syndrome disorder is named after Gilles de la Tourette, a late 19th century French neurologist. Although the term ‘‘Tourette’s disorder’’ is used in the Diagnostic and Statistical Manual (fourth ed., text revision) (DSM-IV-TR; American Psychiatric Association [APA], 2000) and in the literature, it is more commonly referred to as Tourette’s syndrome (TS). TS is a neurodevelopmental disorder characterized by the presence of multiple motor and vocal/phonic tics. Motor tics are rapid and repetitive movements that occur suddenly. They may be innocuous movements of any part of the body or, less frequently, obscene gestures referred to as copropraxia (Cavanna, Servo, Monaco, & Robertson, 2009). Vocal or phonic tics are rapid, meaningless sounds or noises. They can include sniffing, grunting, barking, and squeaking, or may be more complex and include syllables, words, or phrases (Leckman, Bloch, King, & Scahill, 2006). Although many researchers use the term ‘‘vocal,’’ the term ‘‘phonic’’ tic is more often preferred, as the noises may not incorporate the individual’s vocal cords (Jankovic & Mejia, 2006). The phonic tics may also be obscene in nature, referred to as coprolalia (Cavanna et al., 2009). The tics occur multiple times per day and individuals often report that the tics are preceded by an intense urge to move and/or make noise and are then followed by a sense of relief (Leckman et al., 2006). The mean age of TS onset is approximately 6 years of age, although the copropraxic and coprolalic nature of the tics tends to emerge later, at about 14 years of age (Jankovic, 1997). Boys are more predisposed to tic disorders, at a rate of about 3.5:1.0 (Dure & DeWolfe, 2006). Other tic disorders include those that do not meet full diagnostic criteria for TS and include chronic multiple motor tic, or phonic, chronic single, transient, and nonspecific tic disorder (Tourette Syndrome Classification Study Group [TSCSG], 1993).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

In Gilles de la Tourette’s primary description of the disorder, he reported its familial nature (Abelson et al., 2005). Evidence from twin studies has indicated a genetic component (Price, Kidd, Cohen, Pauls, & Leckman, 1985), but the search for a clear genetic

marker for the disorder has not been fruitful (O’Rourke, Scharf, Yu, & Pauls, 2009). The role of the basal ganglia in TS was posited from observations that tic disorders may develop in individuals with lesions in this region (e.g., Pulst, Walshe, & Romer, 1983), and neuroimaging studies support this hypothesis (Peterson et al., 2003). Animal studies suggest that basal ganglia dysfunction leads to the disinhibition of excitatory neurons in the ventral thalamus, in turn leading to disinhibition of cortical motor areas (Gilbert, 2006). SPECT studies of TS generally indicate reduced blood flow in the basal ganglia and basal ganglia asymmetry (e.g., greater left-sided dysfunction; Butler, Stern, & Silbersweig, 2006). In persons with tic disorders, PET, fMRI, and SPECT studies provide convergent data that the basal ganglia, frontal cortex, midbrain, and paralimbic regions exhibit abnormal activity, whereas the motor cortex and supplemental motor area exhibit increased activity (Hampson, Tokoglu, King, Constable, & Leckman, 2009). Clinical observations that dopamine antagonists decrease tics and dopamine agonists (e.g., Ritalin) elicit or increase tics suggest that persons with an abundance of D1 receptors may be at higher risk for the development of tic disorders (Gerfn et al., 1990). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Beyond the presence of tics, there do not appear to be neuropsychological deficits specific to TS (Zinner & Coffey, 2009). In fact, one respected authority reports that persons with TS without comorbid psychopathology demonstrate higher psychometric intelligence than predicted (Denckla, 2006). Although individuals with TS may present with a reduction in fine motor dexterity (Bornstein, 1991), the primary effects of the tics on fine motor skills must be considered. TS is often comorbid with other psychiatric disorders. Consequently, the neuropsychological deficit pattern tends to be consistent with comorbid disorders (Osmon & Smerz, 2005). TS is most often comorbid (about 60% of the time) with attention deficit hyperactivity disorder (ADHD; Denckla, 2006) and slightly less frequently (about 50% of the time) with obsessive-compulsive disorder (OCD; Hounie et al., 2006). In one large primary care clinic study (N ¼ 3,500), only 8% of individuals with TS had no comorbid psychiatric diagnosis (Freeman et al., 2000). In addition to ADHD and OCD, TS is also often comorbid with depression, learning disorders, and conduct disorder (Zinner & Coffey, 2009).

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DIAGNOSIS

The diagnosis of TS is based on observation (Cavanna et al., 2009), as suggested by the multidisciplinary TSCSG (1993). The criteria developed by the TSCSG (1993) included (1) multiple motor and one or more vocal/phonic tics present at some time during the course of the syndrome (though not necessarily concurrently); (2) tics occur multiple times per day for greater than 1 year; (3) onset occurs prior to age 21; (4) anatomic location, number, type, and severity of tics may change over time; (5) medical conditions do not account for the tics; and (6) the tics must be witnessed. The DSM-IV-TR (APA, 2000) modifies the TSCSG (1993) criteria by adding ‘‘[the tics] cause marked distress of significant impairment in social, occupation, or other important areas of functioning,’’ age of onset prior to age 18, and the tics may not be absent for any longer than three consecutive months (p. 116). The tic disorder workgroup for the forthcoming DSM-5 proposes removal of the criterion that tics may not be absent for longer than 3 months based on research evidence that a person with TS may experience periods of quiescence from tic movements, but that the tics ultimately recommence (APA, in press). Persons may present with motor or vocal/phonic tics that do not meet criteria for TS (cf. TSCSG, 1993). For example, multiple motor tic or phonic tic disorder incorporates all the criteria for TS except the tics are either motor or vocal (not both). Single tic disorder incorporates all the criteria for TS except the tics are restricted to a single motor or vocal/phonic tic. Individuals with transient tic disorder may exhibit either single or multiple motor and/or vocal tics, but the tics are not present for longer than 12 consecutive months and must have begun more than 1 year ago. Persons diagnosed with nonspecific tic disorder exhibit tics but do not meet full criteria for TS or any of the other tic disorders. Each of the criteria lists for TS and other tic disorders contain the criterion that the tics are not due to a general medical condition. Medical conditions that mimic features of TS include akathisia, chorea, dystonia, hyperekplexia, myoclonus, restless leg syndrome, rituals, and stereotypies (Jankovic & Mejia, 2006) TREATMENT

Double-blind studies have demonstrated the effectiveness of pergolide (a dopamine agonist), clonidine (an alpha-2 adrenergic agonist), mecamylamine (a nonselective and noncompetitive antagonist of the nicotinic acetylcholine receptors), and tetrabenazine (a vesicular monoamine transporter inhibitor) in the control of

tics, and clonidine has demonstrated effectiveness in combination with methylphenidate in the treatment of ADHD in children with tics without significantly increasing tics in a large multicenter, randomized, double-blind study (TSCSG, 2002). Compared with more recently developed medications (e.g., levetiracetam, an antiseizure medication), individuals prescribed clonidine exhibit a small but significant reduction in tic frequency (Hedderick, Morris, & Singer, 2009). Cannabis has also shown promise, although studies have not been randomized (Dure & DeWolfe, 2006). Treatment of choice for ADHD is neurostimulant medication. Anecdotal information had suggested the use of methylphenidate in individuals with comorbid ADHD and TS may exacerbate the tics (Feinberg & Carroll, 1979). However, the results of one long-term longitudinal study suggested that relatively few persons experience increase in tics while taking methylphenidate (Gadow & Sverd, 2006), and the TSCSG (2002) study indicated an incidence of tics with methylphenidate use at 20%, and with placebo at 22% (the prevalence of tics with clonidine was 26%). When TS is comorbid with OCD, selective serotonin reuptake inhibitors (SSRIs) are the first-line approach (in particular, fluoxetine, fluvoxamine, sertraline, and paroxetine; Coffey et al., 2000). If SSRIs are not successful in controlling symptoms, the second-line approach is clomipramine (a non-SSRI similar to tricyclic antidepressants; Coffey et al., 2000). Behavioral interventions for TS include relaxation training, biofeedback, massed negative practice, selfmonitoring, and contingency management (Wilhelm et al., 2003; Woods, Himle, & Conelea, 2006). Available online is a 2-hour National Tourette’s Syndrome Association (NTSA)-streamed video geared to professionals that provides instruction in the comprehensive behavioral intervention for tics approach for treating TS (NTSA, 2010, tsa-usa.org). In 2007, deep brain stimulation (DBS) was allowed as a humanitarian device exemption by the Food and Drug Administration for use with patients for whom pharmacologic interventions are not successful in treatment of their OCD. However, DBS use in TS is still under investigation with its use studied only in adults (Marks, Honeycutt, Acosta, & Reed, 2009). Mary E. Haines Melissa M. Swanson Timothy F. Wynkoop Abelson, J. F., Kwan, K. Y., O’Roak, B. J., Baek, D. Y., Stillman, A. A., Morgan, T. M., et al. (2005). Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science, 310, 317–320.

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American Psychiatric Association. (in press). American psychiatric association: DSM-5 development. Retrieved on March 30, 2010, from http://www.dsm5.org American Psychiatric Association. (2000). Diagnostic and statistical manual (4th ed., text revision). Washington, DC: Author. Bornstein, R. A. (1991). Neuropsychological performance in adults with Tourette’s syndrome. Psychiatry Research, 37, 229–236. Butler, T., Stern, E., & Silbersweig, D. (2006). Functional neuroimaging of Tourette syndrome: Advances and future directions. In J. T. Walkup, J. W. Mink, & P. J. Hollenbeck (Eds.), Advances in neurology volume 99: Tourette syndrome (pp. 115–129). Philadelphia: Lippincott Williams & Wilkins. Cavanna, A., Servo, S., Monaco, F., & Robertson, M. (2009). The behavioral spectrum of Gilles de la Tourette syndrome. Journal of Neuropsychiatry & Clinical Neurosciences, 21, 13–23. Coffey, B. J., Biederman, J., Smoller, J. W., Geller, D. A., Sarin, P., Schwartz, S., et al. (2000). Anxiety disorders and tic severity in juveniles with Tourette’s disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 39, 562–568. Denckla, M. B. (2006). Attention deficit hyperactivity disorder: The childhood co-morbidity that most influences the disability burden in Tourette syndrome. In J. T. Walkup, J. W. Mink, & P. J. Hollenbeck (Eds.), Advances in neurology volume 99: Tourette syndrome (pp. 17–21). Philadelphia: Lippincott Williams & Wilkins. Dure, L. S., & DeWolfe, J. (2006). Treatment of tics. In J. T. Walkup, J. W. Mink, & P. J. Hollenbeck (Eds.), Advances in neurology volume 99: Tourette syndrome (pp. 190–196). Philadelphia: Lippincott Williams & Wilkins. Feinberg, M., & Carroll, B. J. (1979). Effects of dopamine agonists and antagonists in Tourette’s disease. Archives of General Psychiatry, 36, 979–985. Freeman, R. D., Fast, D. K., Burd, L., Kerbeshian, J., Robertson, M. M., & Sandor, P. (2000). An international perspective on Tourette’s syndrome: Selected findings from 3,500 individuals in 22 countries. Developmental Medicine and Child Neurology, 42, 436–447. Gadow, K. D., & Sverd, J. (2006). Attention deficit hyperactivity disorder, chronic tic disorder, and methylphenidate. In J. T. Walkup, J. W. Mink, & P. J. Hollenbeck (Eds.), Advances in neurology volume 99: Tourette syndrome (pp. 197–207). Philadelphia: Lippincott Williams & Wilkins. Gerfn, C. R., Engber, T. M., Mahan, L. C., Susel, Z., Chase, T. N., Monsma, F. J., Jr., et al. (1990). D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science, 250, 1429–1432.

Gilbert, D. L. (2006). Motor cortex inhibitory function in Tourette syndrome, attention deficit disorder, and obsessive compulsive disorder: Studies using transcranial magnetic stimulation. In J. T. Walkup, J. W. Mink, & P. J. Hollenbeck (Eds.), Advances in neurology volume 99: Tourette syndrome (pp. 107–114). Philadelphia: Lippincott Williams & Wilkins. Hampson, M., Tokoglu, F., King, R. A., Constable, R. T., & Leckman, J. F. (2009). Brain areas coactivating with motor cortex during chronic motor tics and intentional movements. Biological Psychiatry, 65, 594–599. Hedderick, E. F., Morris, C. M., & Singer, H. S. (2009). Double-blind, crossover study of clonidine and levetiracetam in Tourette syndrome. Pediatric Neurology, 40, 420–425. Hounie, A. G., Rosario-Campos, M. D., Diniz, J. B., Shavit, R. G., Ferrao, Y. A., Lopes, A. C., et al. (2006). Obsessivecompulsive disorder in Tourette syndrome. In J. T. Walkup, J. W. Mink, & P. J. Hollenbeck (Eds.), Advances in neurology volume 99: Tourette syndrome (pp. 22–38). Philadelphia: Lippincott Williams & Wilkins. Jankovic, J. (1997). Phenomenology and classification of tics. In J. Jankovic (Ed.), Neurologic clinics (pp. 267–275). Philadelphia: W. H. Saunders Company. Jankovic, J., & Mejia, N. I. (2006). Tics associated with other disorders. In J. T. Walkup, J. W. Mink, & P. J. Hollenbeck (Eds.), Advances in neurology volume 99: Tourette syndrome (pp. 61–68). Philadelphia: Lippincott Williams & Wilkins. Leckman, J. F., Bloch, M. H., King, R. A., & Scahill, L. (2006). Phenomenology of tics and naturally history of tic disorders. In J. T. Walkup, J. W. Mink, & P. J. Hollenbeck (Eds.), Advances in neurology volume 99: Tourette syndrome (pp. 1–16), Philadelphia: Lippincott Williams & Wilkins. Marks, W. A., Honeycutt, J., Acosta, F., & Reed, M. (2009). Deep brain stimulation for pediatric movement disorders. Seminars in Pediatric Neurology, 16, 90–98. National Tourette Syndrome Association. (2010). Comprehensive behavior intervention for tics (CBIT). Retrieved on April 16, 2010, from tsa-usa.org/Medical/medsci.html O’Rourke, J. A., Scharf, J. M., Yu, D., & Pauls, D L. (2009). The genetics of Tourette syndrome: A review. Journal of Psychosomatic Research, 67, 533–545. Osmon, D. C., & Smerz, J. M. (2005). Neuropsychological evaluation in the diagnosis and treatment of Tourette’s syndrome. Behavior Modification, 29, 746–783. Peterson, B. S., Thomas, P., Kane, M. J., Schahill, L., Zhang, H., Bronen, R., et al. (2003). Basal ganglia volumes in patients with Gilles de la Tourette syndrome. Archives of General Psychiatry, 60, 415–424. Price, R. A., Kidd, K. K., Cohen D. J., Pauls, D. L., & Leckman, J. F. (1985). A twin study of Tourette syndrome. Archives of General Psychiatry, 42, 815–820.

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Pulst, S. M. Walshe, T. M., & Romer, J. A. (1983). Carbon monoxide poisoning with features of Gilles de la Tourette’s syndrome. Archives of Neurology, 40, 443–444. Tourette Syndrome Classification Study Group. (1993). Definitions and classification of tic disorders. Archives of Neurology, 50, 1013–1016. Tourette Syndrome Classification Study Group. (2002). Treatment of ADHD in children with tics: A randomized controlled trial. Neurology, 58, 527–536. Woods, D. W., Himle, M. B., & C. A. Conelea (2006). Behavior therapy: Other interventions for tic disorders. In J. T. Walkup, J. W. Mink, & P. J. Hollenbeck (Eds.), Advances in neurology volume 99: Tourette syndrome (pp. 234–239), Philadelphia: Lippincott Williams & Wilkins. Wilhelm, S., Deckersbach, T., Coffey, B. J., Bohne, A., Peterson, A. L., & Baer, L. (2003). Habit reversal versus supportive psychotherapy for Tourette’s disorder: A randomized controlled trial. American Journal of Psychiatry, 160, 1175–1177. Zinner, S., & Coffey, B. (2009). Developmental and behavioral disorders grown up: Tourette’s disorder. Journal of Developmental and Behavioral Pediatrics, 30, 560–573.

TRANSIENT GLOBAL AMNESIA DESCRIPTION

Transient global amnesia (TGA) is a disorder of unknown etiology typically occurring in adults between the ages of 34 and 92. Characteristic symptoms are sudden onset of both retrograde and anterograde amnesia lasting approximately 24–36 hours usually. Patients with this disorder tend to be confused and ask repetitive questions. TGA tends to occur only once in a patient’s lifetime, although a review of the more recent literature indicates that as many as 16% of patients may have recurrences. Males have a slightly higher occurrence of TGA than do females, with a male-to-female ratio of 4:3. The incidence rate is uncertain. Precursors to the condition include coitus, cold baths, migraines, pain, and strong emotional episodes. The disorder tends to last from 4 to 8 hours but may last as long as 24 hours. TGA usually resolves itself gradually without medical intervention. NEUROPATHOLOGY/PATHOPHYSIOLOGY

TGA’s exact pathology is not yet conclusively understood. Many of the findings with recent literature have

employed the use of a variety of neuroimaging technology including PET and diffusion-weighted MRI (DWI), which have indicated numerous brain regions that are affected in TGA (Strupp et al., 1998). PET and DWI research have suggested that areas of the brain specific to memory appear disrupted during the occurrence of a TGA. Theoretical proposals have suggested a potential role of medial temporal lobe seizure activity or a vascular etiology such as bilateral medial temporal lobe ischemia related to posterior cerebral artery (PCA) distribution (Love & Biller, 2007). Consistent with the latter vascular proposal, research using DWI techniques has pointed out the presence of tiny lesions in the hippocampus as well as diffuse lesions throughout other areas of the brain (Winbeck et al., 2005). Still the most commonly associated antecedent remains emotional distress (Miller, Petersen, Metter, Millikan, & Yanagihara, 1987). Owing to this, to date, the most accepted theory of TGA is that of a psychogenic basis, given the extent of neurological disruption presumed to be required to create such a complete cognitive, in particular amnestic, disruption. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Although TGA patients are said to recover from their memory loss, neuropsychological results indicate that there may be a protracted deficit in verbal memory loss and impairment in verbal IQ scores (Pantoni et al., 2005). These results may occur even when patients return to their jobs and families with no subsequent complaints of neuropsychological difficulties. As suggested, the classic presentation of TGA is of a total amnesia (retrograde and anterograde), including loss of autobiographical memories (Quinette et al., 2006). Onset is sudden with complete resolution usually occurring within 24–36 hours. During the episode there are no sensory or motor deficits, visual disturbances, or brainstem abnormalities (Love & Biller, 2007). Upon resolution of symptoms, patients generally return to baseline and there is no recollection of the TGA period. DIAGNOSIS

Generally TGA is diagnosed by the presence of the symptomology already outlined; however, other disorders must be ruled out. Differential diagnosis involves ruling out the following disorders: transient ischemic attacks (TIAs), epilepsy, psychogenic disturbance, encephalitis, trauma, tumors, migraine, alcohol

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abuse, and hypoglycemia. Theories suggest that the disorder may have vascular causes or may be connected to migraines. TGA has also been said to be connected to allergic encephalopathy as a result of antitetanus serum; angiography; pituitary tumor; polycythemia; myxomatous degeneration of the mitral valve; and intoxication with digitalis, clioquinol, or diazepam. However, the most common link cited is of a psychogenic basis related to significant emotional stress (Miller et al., 1987). In differentially diagnosing TGA, it is important to recall that TGA patients do not have recognizable seizures and rarely display EEG abnormalities. Neuroimaging is generally unremarkable beyond features that may be seen in a fair portion of patients within this age range (e.g., small vessel ischemic changes). They are able to perform complex motor skills, and no neurologic signs or symptoms beyond memory loss and repetitive questioning are present. They tend to be oriented only to person.

TREATMENT

The symptoms of TGA resolve roughly within one day and therefore are not treated aggressively in an active sense. Rather, preventive measures (e.g., imaging and EEG) may be sought to determine if symptoms of TGA may be precursors or symptoms of further damage or the presence of other disorders. It is suggested that the patient and family be reassured and that invasive procedures be avoided. Those individuals with a history of migraines or at risk for cerebrovascular disorders should be closely monitored. Some physicians have found that prophylaxis with antiplatelet therapy is helpful when migraines are co-occurring with TGA. At onset of TGA symptoms in a patient, it is important to reassure the patient and the patient’s family. In addition, psychoeducational intervention by hospital personnel would be helpful in explaining what is known about the disorder and what the patient and family can expect after the disorder is resolved. In some cases, subsequent compensatory interventions may be advisable to assist the patient in adjusting to more chronic verbal memory or verbal IQ deficits. Typically, however, neither the patient nor the patient’s family or coworkers report any subsequent deficit that impairs career functioning or interpersonal interactions. Thus, in general, patients would rarely require the services of a psychologist as a result of TGA. Matthew Holcombe Raymond S. Dean

Love, B. B., & Biller, J. (2007). Neurovascular system. In C. G. Goetz (Ed.), Textbook of clinical neurology (3rd ed.). Philadelphia, PA: W. B. Saunders Elsevier. Miller, J. W., Petersen, R. C., Metter, E. J., Millikan, C. H., & Yanagihara, T. (1987). Transient global amnesia: Clinical characteristics and prognosis. Neurology, 37(5), 733–737. Pantoni, L., Bertini, E., Lamassa, M., Pracucci, G., & Inzitari, D. (2005). Clinical features, risk factors, and prognosis in transient global amnesia: A follow-up study. European Journal of Neurology, 12(5), 350–356. Quinette, P., Guillery-Girard, B., Dayan, J., de la Sayette, V., Marquis, S., Viader, F., et al. (2006). What does transient global amnesia really mean? Review of the literature and thorough study of 142 cases. Brain, 129, 1640–1658. Strupp, M., Bruning, R., Wu, R. H., Deimling, M., Reiser, M., & Brandt, T. (1998). Diffusion-weighted MRI in transient global amnesia: Elevated signal intensity in the left mesial temporal lobe in 7 of 10 patients. Annuals of Neurology, 43(2), 164–170. Winbeck, K., Etgen, T., von Einsiedel, H. G., Ro¨ttinger, M., & Sander, D. (2005). DWI in transient global amnesia and TIA: Proposal for an ischaemic origin of TGA. Journal of Neurology Neurosurgery and Psychiatry, 76(3), 438–441.

TRANSIENT ISCHEMIC ATTACKS DESCRIPTION

Historically, transient ischemic attacks (TIAs) were defined as ‘‘a sudden onset of focal cerebral neurological dysfunction (e.g., hemiplegia) attributable to blood vessel disease which resolves in less than 24 hours’’ (Loring, 1999). Recently, the definition has been revised to ‘‘a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction’’ (Albers et al., 2002; Easton et al., 2009). Unilateral weakness, clumsiness, and/or heaviness are the most common initial symptoms of TIA. Other frequent presenting symptoms include unilateral sensory symptoms (numbness or tingling), dysphasic or dysarthric speech, and vision changes (partial vision loss, field cut, blurring or diminished vision). Multiple symptoms typically present simultaneously, gradually wear off over a few minutes, and are often accompanied by mild headache. Particularly in the elderly, misdiagnosis is believed to be common because patients may present with symptoms that are believed to be independently common in the elderly population including dizziness or vertigo, balance issues, falls, disorders of consciousness, or unawareness of deficits (Rancurel, 2005). On

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average, symptoms of a TIA last 10 minutes or less. Those that last longer than 1 hour are often evidenced as infarcts on today’s more sensitive imaging technology, and therefore are not technically meeting the criteria for the definition and are better subsumed under the criteria for mild stroke. TIAs and minor strokes comprise over half of all cerebrovascular events and are believed to imminently precede 20–30% of major disabling strokes (Pendlebury, Giles, & Rothwell, 2009; Rothwell & Warlow, 2005). Conversely, studies have shown that following a TIA, conversion to stroke appears to be at a rate of 10–15% at 3 months, with half occurring within 48 hours (Easton et al., 2009), much higher than previously thought. Because of the high conversion rate to full stroke, TIAs are considered a neurologic emergency that require immediate clinical and laboratory investigation targeted toward stabilizing the event and preventing acute infarction. However, there is considerable variation in how patients with suspected TIA are managed in the acute phase. Some health care facilities provide immediate emergency inpatient care, whereas others recommend an outpatient clinical assessment. Recent guidelines recommend that hospitalization be considered for patients who experienced their first TIA within the past 48 hours (Johnston, Nguyen-Huynh, & Schwarz, 2006). Some of the advantages of in-hospital observation include improved ability to expedite workup and treatment and to facilitate the use of tissue plasminogen activator (tPA) in the event an acute stroke occurs (Nguyen-Huynh & Johnston, 2005). According to the guidelines, urgent (within 24–48 hours) assessment and evaluation are recommended for those not admitted to acute care. Epidemiologically, varying criteria, lack of recognition, and lack of reporting make it difficult to estimate the incidence of TIA, but current estimates in the United States range from 200,000 to 500,000 per year with a population prevalence of approximately 5 million (Johnston, 2002). The prevalence of TIA in men is 2.7% for ages 65–69 and 3.6% for ages 75–79, compared with 1.6% for women aged 65–69 years and 4.1% for women aged 75–79 years (Price, Psaty, O’Leary, Burke, & Gardin, 1993). Notably, silent vascular infarct is also quite prevalent, with a 43% incidence rate above the age of 75 (Howard et al., 1998). Rates of TIA have been found to be higher in African Americans than in Caucasians (Kleindorfer et al., 2005) and appear to be higher during the week, perhaps because patients are less likely to seek medical attention on the weekend (Giles, Flossman, & Rothwell, 2006).

NEUROPATHOLOGY/PATHOPHYSIOLOGY

Although their mechanism is not fully understood, TIAs are often thought of as temporary strokes that usually reverse themselves. They are associated with hypertension and can involve any part of the vascular system. Neuropathologic studies to date have shown that these transient attacks are usually linked to an atherosclerotic thrombosis. Clinically, it is important to separate attacks that last only a few minutes (up to 1 hour) and result in no permanent damage from those of longer duration, which are more likely embolic in nature. Neuroimaging studies, such as diffusion- and perfusion-weighted MRI in particular, have had a positive influence on our understanding of the pathophysiology of TIA in recent years. MRI allows for confirmation of focal ischemia rather than another possible cause of a patient’s deficit, improves accuracy of diagnosis of the vascular origin and cause of TIA, and examines the extent of previous cerebrovascular injury (Easton et al., 2009). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Differential diagnosis of TIA includes a broad range of other possible etiologies that can produce transient neurological episodes including migraine, focal seizures, hypoglycemia, multiple sclerosis, benign paroxysmal positional vertigo, and psychological etiologies including panic attacks, dissociative disorders, and somatization. Even so, if the patient presents with stroke risk factors and transient deficits occur in a typical vascular pattern, TIA should be high on the list of probable diagnoses, and a formal diagnostic workup should be completed (Blumenfeld, 2002). Although by definition TIAs do not result in permanent cognitive impairment by themselves, research has found that individuals with TIAs frequently do exhibit cognitive impairment upon further testing, suggesting that TIAs often reflect larger issues with vascular-related cognitive impairments. In a study of patients over the age of 60 years with hypertension, 12.3% showed cognitive impairment as measured by the Mini Mental State Examination and less than one-third of the patients had adequate blood pressure control (Vinyoles, De la Figuera, & GonzalezSegura, 2008). Other studies have found that about 50% of individuals with both carotid artery occlusion and TIAs have mild cognitive impairment, even though structural brain damage was not evident

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(Bakker et al., 2003). Additionally, in a study of 2,105 patients who meet criteria for stroke, a large percentage (87%) were shown to exhibit cognitive syndromes compared with 36% of 309 TIA patients (Hoffmann, Schmitt, & Bromley, 2009). Transient episodes of cognitive impairment, including aphasia and amnestic syndromes, often lead one to evaluation for TIAs, although epilepsy can be another precipitator. In patients who report symptoms often associated with TIAs, a history of transient weakness has been shown to be associated with memory impairments, although episodic numbness, loss of vision, inability to speak, and severe dizziness were not shown to be correlated with memory loss (Takahashi et al., 2009). Even patients who exhibit stroke risk factors in the absence of any identifiable vascular event appear to be at greater risk for exhibiting cognitive impairment later in life, particularly those with average or lower levels of cognitive functioning earlier in life (Elkins et al., 2004). Because many of these factors are modifiable, it again reinforces the need for primary prevention. Although fatigue is more commonly reported post mild stroke, it is fairly frequent following TIA (56% vs. 29%) (Winward, Sackley, Metha, & Rothwell, 2009). DIAGNOSIS

A number of tools have been devised for use in the acute identification of TIA or stroke including FAST (Face, Arm, Speech, Time test; Nor et al., 2004), LAPSS (Los-Angeles Pre-hospital Stroke Scale; Kidwell, Starkman, Eckstein, Weems, & Saver, 2000), CPSS (Cincinnati Pre-hospital Stroke Scale; Kothari, Pancioli, Liu, Brott, & Broderick, 1999), and ROSIER (Recognition of Stroke in the Emergency Room; Nor et al., 2005). Generally, these tools were designed to aid in the rapid differential diagnosis of stroke from other conditions in order to increase a patient’s eligibility for thrombolysis within the first 3 hours following onset of a cerebrovascular event. A history and physical examination is used to diagnose, prognosticate, and identify the potential cause of a TIA. Routine blood tests including complete blood count, serum electrolytes, creatinine, and fasting blood glucose and lipid levels are also recommended as part of the diagnostic workup (Johnston et al., 2006). Carotid imaging including carotid ultrasound, CT angiography, or MR angiography should be completed as soon as possible (within 24–48 hours) in patients with TIA who would be considered candidates for endarterectomy/stenting if a carotid stenosis were identified. ECG is recommended in all patients

to diagnose atrial fibrillation and rule out other arrhythmias or acute myocardial ischemia (Elkins et al., 2002). Brain imaging is frequently utilized during diagnostic evaluation in order to exclude stroke imitators such as tumors or subdural hematomas, to localize the site of the ischemia, and to differentiate between hemorrhagic and ischemic infarcts. Although CT and conventional MRI are the most commonly used methods of neuroimaging, recent studies have shown particular sensitivity for suspected TIA utilizing diffusion-weighted imaging (DWI) (Redgrave, Coutts, Schulz, Briley, & Rothwell, 2007; Redgrave, Schulz, Briley, Meagher, & Rothwell, 2007; Schulz, Briley, Meagher, Molyneux, & Rothwell, 2003, 2004). In addition to brain imaging, other techniques to image the vascular system may be utilized including catheter angiography, duplex sonography, perfusion studies with MR or CT, and transcranial Doppler sonography. With the recent development of high-resolution DWI technology, many infarcts that would have been previously diagnosed as TIAs have been found to be associated with ischemic lesions that are not visible on conventional MR studies (Warach & Kidwell, 2004). Patients with new DWI abnormalities are 2–5 times more likely to have a stroke in the days following a TIA (Purroy et al., 2004). In individuals who present with TIA, silent brain infarcts and leucoaraiosis are frequent findings (Norrving, 2008), suggesting that the TIA is actually part of an overall profile of cerebrovascular events. Notably, evidence of a previous stroke is found in 20% of acute stroke patients utilizing CT scan, suggesting that the previous events were often clinically silent (Brainin, McShane, Steiner, Dachenhausen, & Seiser, 1995). TREATMENT

The primary treatment for TIA is antiplatelet therapy. Other useful interventions include the administration of blood pressure–lowering medications, statins, or anticoagulation for atrial fibrillation. In addition, a TIA may be the first indicator that an endarterectomy is warranted and is the treatment of choice, if symptomatic carotid stenosis is identified. Studies suggest that through the use of these interventions, the risk of recurrent stroke could be reduced by 80–90% (Hackam & Spence, 2007). Because the goal of TIA management is prevention of a future stroke, efforts to control modifiable risk factors, such as diet, cholesterol, smoking, and physical activity level are critical. With regard to secondary prevention, research efforts have focused on validating scales that utilize

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specific clinical factors in predicting risk of a subsequent stroke. The ABCD scale (age [A], blood pressure [B], clinical features [C], and duration of symptoms [D]) and ABCD(2) scale (all the previous with diabetes diagnosis [D]) were developed in an effort to predict risk of a subsequent stroke and as a method for triaging these patients (Asimos et al., 2009; Rothwell et al., 2005). Recent research has demonstrated the added value of MRI with the ABCD(2) tool in predicting recurrent stroke in those with a high score, showing a 90-day recurrent stroke risk of 32.1% versus 0.0% in those with a low score (Coutts et al., 2008). Inpatient multidisciplinary stroke rehabilitation has been shown to significantly benefit outcomes following stroke (Langhorne & Duncan, 2001), but TIA seldom warrants inpatient rehabilitation services. Although rehabilitation efforts are generally reserved for those with more moderate to severe strokes, patients who present with TIA but experience impairments from cerebrovascular disease that have previously gone undetected may also benefit, particularly from experts trained in the diagnosis and rehabilitation of mild deficits. A recent study investigating the benefits of an individualized stroke care program for those with TIA or mild stroke found that providing follow-up occupational and neuropsychological screening 4–6 weeks after discharge, with therapy when appropriate, improved satisfaction at 6 months post event. Patients who were more satisfied were better able to perform activities of daily living (ADLs) and experienced a higher quality of life with less depressive symptoms reported (Arts, Kwa, & Dahmen, 2008). Currently, a randomized controlled trial (CRAFTS trial) is underway that is investigating the application of the cardiac rehabilitation model following TIA (Lennon & Blake, 2009). The model focuses on lifestyle interventions and supervised aerobic activity to reduce modifiable risk factors and improve healthpromoting behaviors. Outcomes will include measures of blood pressure, lipid profile, smoking and diabetic status, exercise, healthy eating, cardiovascular fitness, and health-related quality of life. It is hypothesized that similar to the benefits shown for recurrent cardiac event, this model will result in decreased risk for subsequent cerebrovascular event due to the similarity in modifiable risk factors. Another concern following TIA is whether driving restriction is appropriate and necessary. Historically, countries that attempt to restrict driving privileges following TIA or minor stroke have had poor compliance (McCarron, Loftus, & McCarron, 2008). In spite of this, the recent research supporting

a high conversion rate to full stroke after TIA provides further support for the enforcement of driving restrictions following TIA. Lori S. Terryberry-Spohr Amy J. Goldman Albers, G. W., Caplan, L. R., Easton J. D., Fayad, P. B., Mohr, J. P., Saver, J. L., et al. (2002). Transient ischemic attack — proposal for a new definition. The New England Journal of Medicine, 347, 1713–1716. Arts, M. L., Kwa, V. I., & Dahmen, R. (2008). High satisfaction with an individualized stroke care program after hospitalization of patients with a TIA or minor stroke: A pilot study. Cerebrovascular Diseases, 25(6), 566–571. Asimos, A. W., Johnson, A. M., Rosamond, W. D., Price, M. F., Rose, K. M., Catellier, D, et al. (2010). A multicenter evaluation of the ABCD(2) score’s accuracy for predicting early ischemic stroke in admitted patients with transient ischemic attack. Annals of Emergency Medicine, 55(2), 201–210. Bakker, F. C., Klijn, C. J., Jennekens-Schinkel, A., van der Tweel, I., Tulleken, C. A., & Kappelle, L. J. (2003). Cognitive impairment in patients with carotid artery occlusion and ipsilateral transient ischemic attacks. Journal of Neurology, 250(11), 1340–1347. Blumenfeld, H. (2002). Neuroanatomy through clinical cases. Sunderland, MA: Sinauer Associates. Brainin, M., McShane, L. M., Steiner, M., Dachenhausen, A., & Seiser, A. (1995). Silent brain infarcts and transient ischemic attacks. A three-year study of first-ever ischemic stroke patients: The Klosterneuburg Stroke Data Bank. Stroke, 26(8), 1348–1352. Coutts, S. B., Eliasziw, M., Hill, M. D., Scott, J. N., Subramaniam, S., Buchan, A. M., et al. (2008). An improved scoring system for identifying patients at high early risk of stroke and functional impairment after an acute transient ischemic attack or minor stroke. International Journal of Stroke, 3(1), 3–10. Easton, J. D., Saver, J. L., Albers, G. W., Alberts, M. J., Chaturvedi, S., Feldmann, E., et al. (2009). Definition and evaluation of transient ischemic attack: A scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke, 40(6), 2276– 2293. Elkins, J. S., O’Meara, E. S., Longstreth, W. T., Jr., Carlson, M. C., Manolio, T. A., & Johnston, S. C. (2004). Stroke

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risk factors and loss of high cognitive function. Neurology, 63(5), 793–799. Elkins, J. S., Sidney, S., Gress, D. R., Go, A. S., Bernstein, A. L., & Johnston, S. C. (2002). Electrocardiographic findings predict short-term cardiac morbidity after transient ischemic attack. Archives of Neurology, 59(9), 1437–1441. Giles, M. F., Flossman, E., & Rothwell, P. M. (2006). Patient behavior immediately after transient ischemic attack according to clinical characteristics, perception of the event, and predicted risk of stroke. Stroke, 37(5), 1254–1260. Hackam, D. G., & Spence, J. D. (2007). Combining multiple approaches for the secondary prevention of vascular events after stroke: A quantitative modeling study. Stroke, 38(6), 1881–1885. Hoffmann, M., Schmitt, F., & Bromley, E. (2009). Vascular cognitive syndromes: Relation to stroke etiology and topography. Acta Neurologica Scandinavica, 120(3), 161–169. Howard, G., Wagenknecht, L. E., Cai, J., Cooper, L., Kraut, M. A., & Toole, J. F. (1998). Cigarette smoking and other risk factors for silent cerebral infarction in the general population. Stroke, 29(5), 913–917. Johnston, S. C. (2002). Clinical practice. Transient ischemic attack. The New England Journal of Medicine, 347(21), 1687–1692. Johnston, S. C., Nguyen-Huynh, M. N., & Schwarz, M. E., Fuller, K., Williams, C. E., Josephson, S. A., et al. (2006). National Stroke Association guidelines for the management of transient ischemic attacks. Annals of Neurology, 60, 301–313. Kidwell, C. S., Starkman, S., Eckstein, M., Weems, K., & Saver, J. L. (2000). Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke, 31(1), 71–76. Kleindorfer, D., Panagos, P., Pancioli, A., Khoury, J., Kissela, B., Woo, D., et al. (2005). Incidence and short-term prognosis of transient ischemic attack in a population-based study. Stroke, 36(4), 720–723. Kothari, R. U., Pancioli, A., Liu, T., Brott, T., & Broderick, J. (1999). Cincinnati Prehospital Stroke Scale: Reproducibility and validity. Annals of Emergency Medicine, 33(4), 373–378. Langhorne, P., & Duncan, P. (2001). Does the organization of postacute stroke care really matter? Stroke, 32(1), 268–274. Lennon, O., & Blake, C. (2009). Cardiac rehabilitation adapted to transient ischaemic attack and stroke (CRAFTS): A randomized controlled trial. BMC Neurology, 9, 9. Loring, D. W. (Ed.). (1999). INS dictionary of neuropsychology. New York: Oxford University Press. McCarron, M. O., Loftus, A. M., & McCarron, P. (2008). Driving after a transient ischaemic attack or minor stroke. Emergency Medicine Journal, 25(6), 358–359.

Nguyen-Huynh, M. N., & Johnston, S. C. (2005). Is hospitalization after TIA cost-effective on the basis of treatment with tPA? Neurology, 65(11), 1799–1801. Nor, A. M., Davis, J., Sen, B., Shipsey, D., Louw, S. J., Dyker, A. G., et al. (2005). The Recognition of Stroke in the Emergency Room (ROSIER) scale: Development and validation of a stroke recognition instrument. Lancet Neurology, 4(11), 727–734. Nor, A. M., McAllister, C., Louw, S. J., Dyker, A. G., Davis, M., Jenkinson, D., et al. (2004). Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients. Stroke, 35(6), 1355–1359. Norrving, B. (2008). Leucoaraiosis and silent subcortical infarcts. Revue Neurologique (Paris), 164(10), 801–804. Pendlebury, S. T., Giles, M. F., & Rothwell, P. M. (2009). Transient ischemic attack and stroke. New York: Cambridge University Press. Price, T. R., Psaty, B., O’Leary, D., Burke, G., & Gardin, J. (1993). Assessment of cerebrovascular disease in the Cardiovascular Health Study. Annals of Epidemiology, 3(5), 504–507. Purroy, F., Montaner, J., Rovira, A., Delgado, P., Quintana, M., & Alvarez-Sabin, J. (2004). Higher risk of further vascular events among transient ischemic attack patients with diffusion-weighted imaging acute ischemic lesions. Stroke, 35(10), 2313–2319. Rancurel, G. (2005). [Transient ischemic attacks in the elderly: New definition and diagnostic difficulties]. Psychol Neuropsychiatr Vieil, 3(1), 17–26. Redgrave, J. N., Coutts, S. B., Schulz, U. G., Briley, D., & Rothwell, P. M. (2007). Systematic review of associations between the presence of acute ischemic lesions on diffusion-weighted imaging and clinical predictors of early stroke risk after transient ischemic attack. Stroke, 38(5), 1482–1488. Redgrave, J. N., Schulz, U. G., Briley, D., Meagher, T., & Rothwell, P. M. (2007). Presence of acute ischaemic lesions on diffusion-weighted imaging is associated with clinical predictors of early risk of stroke after transient ischaemic attack. Cerebrovascular Diseases, 24(1), 86–90. Rothwell, P. M., & Warlow, C. P. (2005). Timing of TIAs preceding stroke: Time window for prevention is very short. Neurology, 64(5), 817–820. Rothwell, P. M., Giles, M. F., Flossmann, E., Lovelock, C. E., Redgrave, J. N., Warlow, C. P., et al. (2005). A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack. Lancet, 366(9479), 29–36. Schulz, U. G., Briley, D., Meagher, T., Molyneux, A., & Rothwell, P. M. (2003). Abnormalities on diffusion weighted magnetic resonance imaging performed several weeks after a minor stroke or transient ischaemic attack. Journal of Neurology, Neurosurgery, and Psychiatry, 74(6), 734–738.

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Schulz, U. G., Briley, D., Meagher, T., Molyneux, A., & Rothwell, P. M. (2004). Diffusion-weighted MRI in 300 patients presenting late with subacute transient ischemic attack or minor stroke. Stroke, 35(11), 2459–2465. Takahashi, P. Y., Dyrbye, L. N., Thomas, K. G., Cedeno, O. Q., North, F., Stroebel, R. J., et al. (2009). The association of transient ischemic attack symptoms with memory impairment among elderly participants of the Third US National Health and Nutrition Examination Survey. Journal of Geriatric Psychiatry and Neurology, 22(1), 46–51. Vinyoles, E., De la Figuera, M., & Gonzalez-Segura, D. (2008). Cognitive function and blood pressure control in hypertensive patients over 60 years of age: COGNIPRES study. Current Medical Research and Opinion, 24(12), 3331–3339. Warach, S., & Kidwell, C. S. (2004). The redefinition of TIA: The uses and limitations of DWI in acute ischemic cerebrovascular syndromes. Neurology, 62(3), 359–360. Winward, C., Sackley, C., Metha, Z., & Rothwell, P. M. (2009). A population-based study of the prevalence of fatigue after transient ischemic attack and minor stroke. Stroke, 40(3), 757–761.

TRANSVERSE MYELITIS DESCRIPTION

Transverse myelitis (TM) is a rare, neuroimmunological disorder related to focal spinal cord inflammation and neural injury. The end result of the process is varying degrees of motor, sensory and autonomic dysfunction (Bruna, Martinez-Yelamos, MartinezYelamos, Rubio, & Arbizu, 2006; Montalban, 2006). The acute presentation is divided based on the nature of the symptoms. Acute complete transverse myelitis (ACTM) is characterized by symmetrical and moderate to severe loss of function; acute partial transverse myelitis (APTM) presents in an asymmetrical manner with mild loss of spinal cord function (Ford, Tampieri, & Francis, 1992; Scott, Kassab, & Singh, 2005). Relapsing TM on the other hand, as the name suggests, demonstrates periods of active symptomology with periods of remission, or near remission in-between. When individuals with relapsing myelitis experience acute symptomatic periods, they often present as ACTM. Epidemiology suggests an annual incidence of five people per million (Levin et al., 2009). The process may have its roots in a number of underlying pathological forces including multi focal central nervous

system disease, direct injury to the spinal cord, a part of a systemic or autoimmune disease, or as an isolated, idiopathic entity (de Seze et al., 2001).

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Acute transverse myelitis arises secondary to parainfectious inflammation of the spinal cord (Jeffery, Mandler, & Davis, 1993: Misra, Kalita, & Kumar, 1996). When it presents in a recurrent fashion, it has been more commonly noted as a symptom in relation to Lyme disease, herpes simplex virus infection, systemic lupus erythematosus, Sjo¨rgen’s syndrome, primary antiphospholipid syndrome, sarcoidosis, various forms of vasculitis, or an array of idiopathic inflammatory demyelinating disorders (IIDD). In these instances, CSF analysis may reveal mild pleocytosis, modest numbers of lymphocytes, elevated protein levels or oligoclonal bands (OCB) (Cordonnier et al., 2003; Montalban, 2006). However, idiopathic forms have also been noted and are believed to be related to an autoimmune process (Kim, 2003; Tippett, Fishman, & Panitch, 1991). MRI often shows focal demyelination in the spinal cord involving all elements of the spinal cord on that transverse plane as opposed to unilateral involvement. When it only part of a cross section is affected, it is termed partial transverse myelitis. Further enhancement may be seen with gadolinium infusion. Similar demyelinating lesions may be observed in the cerebral hemispheres. This is usually seen when an intraparenchymal or perivascular cellular influx in the spinal cord actually results in the breakdown of the blood–brain barrier causing the variable demyelination and neuronal injury (Kerr & Ayetey, 2002). Some cases of TM eventually expand into multiple sclerosis (MS) but is fairly rare, occurring in only 2% of cases within 5 years of symptom onset (Scott, Bhagavatula, Snyder, & Chieffe, 1998; Scott et al., 2005). In comparison, progression to Devic’s disease (a.k.a. neuromyelitis optica) is more likely, occurring in more than 10% of cases of relapsing myelitis (Kim, 2003). It is noted that this is in regard to ACTM, whereas partial transverse myelitis has shown a greater frequency of progression to MS (Ford et al., 1992). Negative MRI at the onset of symptoms suggests a low risk for progression to MS (Morrissey et al., 1993). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Clinically, TM is characterized by the emergence of paraparesis or paraplegia, ascending parasthesias,

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loss of deep sensibility in the feet, spincter dysfunction, and bilateral Babinski (Ropper & Brown, 2005). The sensorimotor features may be symmetrical or asymmetrical and develop over the course of hours or days and often resolve over several days as well. Sensation is lost below the level of the lesion and radicular pain presents at a level even with the lesion. The motor symptoms eventually take on an upper-motor neuron paralysis appearance with hyper-reflexia and bilateral extensor plantar responses (Hammerstaad, 2007). Finally, autonomic dysfunction may also be observed including temperature dysregulation and vasomotor instability. Neurocognition is not commonly associated with TM except when lesions are noted in cerebral cortex. DIAGNOSIS

Neuroimaging with MRI of the spine and brain is essential to diagnosis with concentration being placed on the identification of aforementioned signs of demyelination. While these lesions are hallmark of TM, it is not suggestive of definitive diagnosis (Polman et al., 2005; Wingerchuk, Lennon, Pittock, Lucchinetti, & Weinshenker, 2006). Such scans also allow for ruleout of cerebrovascular events as the basis of the clinical features. Additional workup should include CSF analysis making notation of pleocytosis, protein levels, and/or OCB. Workup should also consider those presentations that TM may present in relation to including Lyme disease, herpes simplex virus infection, systemic lupus erythematosus, Sjo¨rgen’s syndrome, primary antiphospholipid syndrome, sarcoidosis, various forms of vasculitis, or an array of IIDD. TREATMENT

Treatment for TM is not highly defined as there have been few clinical trials undertaken as most patients’ symptoms remit spontaneously after several days past the peak of clinical features. High doses of corticosteroids are commonly employed and can prove beneficial. These are most often used in idiopathic cases. For individuals who fail to respond to steroids, plasmapharesis can be effective (Weinshenker et al., 1999). When progression to MS is believed to be probable (i.e., asymmetric involvement of the spine in conjunction with cerebral lesions), interferon beta-1a treatment has been found to delay the onset of MS (Jacobs et al., 2000). In those instances where progression to Devic’s disease seems likely because of identification of neuromyelitis optica antibodies, prophylactic immunosuppression can be useful. Azathioprine, interferonbeta, and rituximab have all shown some efficacy

(Cree et al., 2007; Papeix, Deseze, Pierrot-Deseilligny, Tourbah, & Lebrun, 2005). Chad A. Noggle Michelle R. Pagoria Agmon-Levin, N., Kivity, S., Szyper-Kravitz, M., & Shoenfeld, Y. (2009). Transverse myelitis and vaccines: A multi-analysis. Lupus, 18(13), 1198–1204. Bruna, J., Martinez-Yelamos, S., Martinez-Yelamos, A., Rubio, F., & Arbizu, T. (2006). Idiopathic acute transverse myelitis: A clinical study and prognostic markers in 45 cases. Multiple Sclerosis, 12, 169–173. Cordonnier, C., de Seze, J., Breteau, G., Ferriby, D., Michelin, E., Stojkovic, T., et al. (2003). Prospective study of patients presenting with acute partial transverse myelopathy. Journal of Neurology, 250, 1447–1452. Cree, B. A. C., Lamb, S., Morgan, K., Chen, A., Waubant, E., & Genain, C. (2005). An open label study of the effects of rituximab in neuromyelitis optica. Neurology, 64, 1270–1272. de Seze, J., Stojkovic, T., Breteau, G., Lucas, C., MichonPasturel, U., Gauvrit, J. Y. et al. (2001). Acute myelopathies: Clinical, laboratory and outcome profiles in 79 cases. Brain, 124, 1509–1521. Ford, B., Tampieri, D., & Francis, G. (1992). Long-term follow-up of acute partial transverse Myelopathy. Neurology, 42, 250–252. Hammerstaad, J. (2007). Strength and reflexes. In C. G. Goetz (Ed.), Textbook of clinical neurology (pp. 242–287). Philadelphia, PA: Saunders Elsevier. Jacobs, L. D., Beck, R. W., Simon, J. H., Kinkel, R. P., Brownscheidle, C. M., Murray, T. J., et al. (2000). Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. New England Journal of Medicine, 343, 898–904. Jeffery, D. R., Mandler, R. N., & Davis, L. E. (1993). Transverse myelitis: Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events. Archives of Neurology, 50, 532–535. Kerr, D. A., & Ayetey, H. (2002). Immunopathogenesis of acute transverse myelitis. Current Opinion Neurology, 15, 339–347. Kim, K. K. (2003). Idiopathic recurrent transverse myelitis. Archives of Neurology, 60, 1290–1294. Misra, U. K., Kalita, J., & Kumar, S. (1996). A clinical, MRI and neurophysiological study of acute transverse myelitis. Journal of the Neurological Sciences, 138, 150–156. Montalban, X. (2006). The importance of long-term data in multiple sclerosis. Journal of Neurology, 253, vi9–vi15. Morrissey, S. P., Miller, D. H., Kendall, B. E., Kingsley, D. P., Kelly, M. A., Francis, D. A., et al. (1993). The significance of brain magnetic resonance imaging abnormalities at

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presentation with clinically isolated syndromes suggestive of multiple sclerosis. Brain, 116, 135–146. Papeix, C., Deseze, J., Pierrot-Deseilligny, C., Tourbah, A., & Lebrun, C. (2005). French therapeutic experience of Devic’s disease: A retrospective study of 33 cases. Neurology, 64(Suppl. 1), A328. Polman, C. H., Reingold, S. C., Edan, G., Filippi, M., Hartung, H. P., Kappos, L., et al. (2005). Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria. Annals of Neurology, 58, 840–846. Ropper, A. H., & Brown, R. H. (2005). Adams and Victor’s principles of neurology (8th ed., pp. 529–545). New York: McGraw-Hill. Scott, T. F., Bhagavatula, K., Snyder, P. J., & Chieffe, C. (1998). Transverse myelitis comparison with spinal cord presentations of multiple sclerosis. Neurology, 50, 429–433. Scott, T. F., Kassab, S. L., & Singh, S. (2005). Acute partial transverse myelitis with normal cerebral magnetic resonance imaging: Transition rate to clinically definite multiple sclerosis. Multiple Sclerosis, 11, 373–377. Tippet, D. S., Fishman, P. S., & Panitch, H. S. (1991). Relapsing transverse myelitis. Neurology, 41, 703–706. Weinshenker, B. G., O’Brien, P. C., Petterson, T. M., Noseworthy, J. H., Lucchinetti, C. F., Dodick, D. W., et al. (1999). A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Annals of Neurology, 46, 878–886. Wingerchuk, D. M., Lennon, V. A., Pittock, S. J., Lucchinetti, C. F., & Weinshenker, B. G. (2006). Revised diagnostic criteria for neuromyelitis optica. Neurology, 66, 1485–1489.

TRAUMATIC BRAIN INJURY DESCRIPTION

Traumatic brain injury (TBI) refers to the ‘‘physiological disruption of brain functioning caused by an external force resulting in an acceleration/deceleration or a direct blow to the head’’ (Carroll, Cassidy, Holm, Kraus, & Coronado, 2004, p. 113). TBIs occur across a continuum of severity, ranging from a mild blow to the head, which results in brief disorientation but full recovery, to multiple crushing blows that lead to death. Of all TBIs, approximately 80% are mild in severity with the remaining being moderate to severe (10% each, respectively). Statistics from the Centers for Disease Control and Prevention (CDC, 2006) indicate that each year in the United States well over 1.5 million individuals sustain a TBI. The CDC (2006) estimated that over 2% of the U.S. population has some types of TBI-associated disability. Motor vehicle accidents are

the most common cause for TBI in younger individuals, whereas in the elderly falls are most frequent. TBI is the leading cause of death in people under the age of 40 and males tend to sustain more severe brain injuries. TBI-related costs in the United States are estimated at approximately $60 billion dollars annually (Finkelstein, Corso, & Miller, 2006). NEUROPATHOLOGY/PATHOPHYSIOLOGY

TBIs are broadly classified into two categories: open brain injuries and closed brain injuries. An open brain injury is where the intracranial cavity is breached by a foreign object, for example, a gunshot to the head. A closed brain injury occurs when there is a damage to the brain, but the skull remains intact. This would include acceleration/deceleration injuries, such as those commonly sustained in motor vehicle accidents. For both the open and the closed TBIs, a further distinction captures when and how the brain is damaged as follows: (a) primary damage and (b) secondary damage. Primary brain damage occurs directly from the forces resulting in, for example, focal lesions, mechanical compression, or diffuse tearing and shearing of brain tissues. Secondary damage refers to the brain damage that occurs in the hours or days after the impact, and includes damage caused by neurosurgical intervention, brain swelling, ischemia, brain infection, posttraumatic seizures, vasospasm, obstructive hydrocephalus, and hypoxia (Granacher, 2003). Secondary damage also includes metabolic and neurotransmitter changes associated with neuronal damage. In fact, research has captured TBI-related neurochemical and neurometabolic cascades that onset in the hours and days after the initial injury that leads to increased cell swelling and subsequent cell death (Bullock et al., 1998). As the individual’s cerebral edema fluctuates, so does the level of consciousness, orientation, and agitation. Indeed, the length of loss of consciousness and disorientation provides important indicators for capturing TBI severity. In all, no unitary profile of TBI is seen. Rather, the resulting TBI symptom profile and recovery pattern are often variable and dependent upon the multifactorial interaction of pathology, severity, and environmental factors (Dykeman, 2003; Masson et al., 1996). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Neuropsychological examinations are the accepted method for quantitatively determining the level of cognitive and emotional functioning after TBI. In the inpatient setting, neuropsychological consultation can

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assist the health care team to understand the interaction among the patient’s physical, cognitive, and emotional symptoms. Neuropsychologists may also be called upon to comment on issues of capacity, readiness for discharge, and placement needs. As these severely brain-injured patients stabilize and recover from their injuries, they are usually better able to tolerate more comprehensive neuropsychological testing. Gauging whether the patient is putting forth adequate effort should be addressed and becomes crucial especially when the case involves legal issues. A comprehensive neuropsychological assessment typically assesses domains such as attention and concentration, memory and learning, language, visuospatial skills, executive functioning, and emotional functioning. Mild TBI patients are infrequently hospitalized. However, neuropsychological testing can be requested in the early stages of recovery to assess the more subtle deficiencies that are present. Most mild TBI patients have a favorable recovery, but a minority continues to present with residual difficulties months or even years post accident. The DSM-IV (American Psychiatric Association [APA], 2000) specifies that if the TBI residuals persist beyond 3 months, then the diagnosis of a postconcussional disorder is warranted. A postconcussional disorder is typically composed of physical, emotional, and cognitive symptoms that occur subsequent to a TBI. According to DSM-IV (2000), the documented cognitive deficit should include deficits ‘‘in either attention (concentration, shifting focus of attention, performing simultaneous cognitive tasks) or memory (learning or recalling information)’’ (APA, p. 704). Other cognitive symptoms such as slowed motor movement, problems with executive functioning, and word finding difficulties may be prominent as well. Physical symptoms may include disordered sleep, headache, dizziness, and sensitivity to noise, medications, and light. Emotional symptoms include irritability, anxiety, depressive, affective lability, or other personality changes. Note that the diagnosis of the postconcussional disorder is most often used for milder forms of TBIs, whereas for very severe cases DSM-IV offers the diagnosis of dementia due to head trauma, with or without behavioral disturbances. DIAGNOSIS

Introduced by a team of neurosurgeons in Scotland, the Glasgow Coma Scale (GCS) measures eyeopening, motor response, and verbal response and rates the severity of a TBI according to the patient’s ability in each of these domains (Teasdale & Jeanette, 1974). The GCS, which ranges from 3 to 15, classifies

TBI severity as mild (13–15), moderate (9–12), and severe (3–8). In general, the higher the GCS score, the better the prognosis. The GCS rating can be determined at the scene of the accident, and when indicated is repeated throughout the hospitalization, to determine the length of the coma or disorientation. It is important to note that the GCS score can be confounded by intoxication, pain, and medications. Although the GCS is the gold standard for triaging the more severe TBI patients, it often lacks the needed sensitivity for capturing mild TBIs (Marshall, 1989; Ruff, 2005; Stambrook, Moore, Lubusko, Peters, & Blumenschein, 1993). For example, if a patient receives a perfect score of 15 at admission to the emergency department, clinicians cannot rule out the likelihood of a mild TBI. Since the loss of consciousness associated with the mild TBI is usually brief, by the time health care providers arrive at the scene (if at all), the GCS will not retrospectively capture the patient’s altered state. The most reliable diagnostic indicator for assessing a mild TBI is the patient’s inability to store continues memories, and this inability to track ongoing events is called ‘‘posttraumatic amnesia.’’ In response to concerns that many mild TBIs were going undiagnosed, the American Congress of Rehabilitation Medicine in 1993 established a set of diagnostic criteria for mild TBI. Table 1 summarizes these guidelines for mild TBI, which also provide cutoffs for diagnosing more severe TBIs. Recently, these guidelines have received further support by the World Health Organization Table 1 DIAGNOSTIC CRITERIA FOR MILD TBI BY THE AMERICAN CONGRESS OF REHABILITATION MEDICINE SPECIAL INTEREST GROUP ON MILD TRAUMATIC BRAIN INJURY* A traumatically induced physiological disruption of brain function, as manifested by at least one of the following: & any loss of consciousness; & any loss of memory for events immediately before or after the accident; & any alteration in mental state at the time of the accident (e.g., feeling dazed, disoriented, or confused); and & focal neurological deficit(s) that may or may not be transient; But where the severity of the injury does not exceed the following: & loss of consciousness of approximately 30 minutes or less; & after 30 minutes, an initial Glasgow Coma Scale (GCS) score of 13–15; and & posttraumatic amnesia not greater than 24 hours. *Developed by the Mild Traumatic Brain Injury Committee of the Head Injury Interdisciplinary Special Interest Group (1993).

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Neurotrauma Task Force on mild TBI (Carroll et al., 2004), and thus these guidelines are becoming the accepted standard for diagnosing mild TBI. Note that these diagnostic criteria do not depend upon neuroimaging. Indeed, many individuals with mild TBIs are never referred for neuroimaging. Thus, neuroimaging should not be used as the sole perimeter for determining the presence or absence of a mild TBI (Bazarian et al., 2005; Bigler, 2001; Iverson, Lovell, Smith, & Frazen, 2000; Ruff, Iverson, Barth, Bush, & Broshek, 2009). TREATMENT

Poorer outcomes in individuals with TBIs have been associated with gender, age, repeated TBIs, premorbid psychopathology, structural intracranial injuries, increased stressors, and substance use (Edna & Cappelen, 1987; Hibbard et al., 2000; Iverson, 2006; Ponsford et al., 2000; Rapoport & Feinstein, 2000). An integrated understanding of the individual that is not limited to a specific discipline, but rather attempts to captures a patient-based perspective can help the clinicians to assess how synergistic symptom interactions can lead to poor outcomes (Ruff, 2005). To capture these interactions, it is essential for clinicians to also determine the individual’s premorbid and comorbid functioning across the emotional, cognitive, and physical domains, as well as address the effects of the TBI on vocational, social, and recreational functioning in the individual’s daily lives. Given there is no unitary profile of TBI, treatment and intervention are symptom based. Physical deficits may be addressed within the context of physical and/ or occupational therapy. In severe cases, where language is impacted, speech therapy may be used. Thorough neuropsychological assessment may prove priceless in identifying cognitive deficits upon which rehabilitation plans may be built. In conjunction with this, residuals that may interfere with an individual’s return to school or work can be identified and addressed along, cognitive, behavioral, and physical lines. Emotional/psychiatric residuals may be addressed with psychotherapy and/or psychopharmacological intervention. Christina Weyer Jamora Ronald Ruff American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed. TR). Washington, DC: Author. Bazarian, J., McClung, J., Shah, M., Cheng, Y. T., Flesher, W., & Kraus, J. (2005). Mild traumatic brain injury in the United States, 1998–2000. Brain Injury, 19, 85–91.

Bigler, E. (2001). Quantitative magnetic resonance imaging in traumatic brain injury. Journal of Head Trauma Rehabilitation, 16, 117–134. Bullock, R., Zauner, A., Woodward, J., Myseros, J., Choi, S., Ward, J., et al. (1989). Factors affecting excitatory amino acid release following severe human head injury. Journal of Neurosurgery, 89, 507–518. Carroll, L., Cassidy, J., Holm, L., Kraus, J., & Coronado, V. G. (2004). Methodological issues and research recommendations for mild traumatic brain injury: The WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. Journal of Rehabilitation Medicine, 43, 113–125. Centers for Disease Control and Prevention. (2006). Traumatic brain injury in the United States: Emergency department visits, hospitalizations and deaths. Retrieved July 31, 2007, from http://www.cdc.gov/ncipc/tbi/TBI_in_ US_04/TBI_ED.htm Dykeman, B. F. (2003). School-based intervention for treating social adjustment difficulties in children with traumatic brain injury. Journal of Instructional Psychology, 30(3), 225–230. Edna, T., & Cappelen, J. (1987). Late post-concussional symptoms in traumatic head injury. An analysis of frequency and risk factors. Acta Neurochirurgica, 86, 12–17. Finkelstein, E., Corso, P., & Miller, T. (2006). The incidence and economic burden of injuries in the United States. New York: Oxford University Press. Granacher, R. (Ed.). (2003). The epidemiology and pathophysiology of traumatic brain injury. In Traumatic brain injury: Methods for clinical assessment and forensic neuropsychiatric assessment (pp.1–24). Boca Raton, FL: CRC Press. Hibbard, M., Bogdany, J., Uysal, S., Kepler, K., Silver, J., Gordon, W., et al. (2000). Axis II psychopathology in individuals with traumatic brain injury. Brain Injury, 14, 45–61. Iverson, G. (2006). Complicated vs uncomplicated mild traumatic brain injury: Acute neuropsychological outcome. Brain Injury, 20, 1335–1344. Iverson, G., Lovell, M., Smith, S., & Frazen, M. (2000). Prevalence of abnormal CT scans following mild traumatic brain injury. Brain Injury, 14, 1057–1061. Marshall, L. (1989). A neurosurgeon’s view of the epidemiology of minor and moderate head injury. In J. Hoff, T. Anderson, & T. Cole (Eds.), Mild to moderate head injury (pp. 29–34). Boston: Blackwell Scientific. Masson, F., Salmi, L. R., Maurette, P., Dartigues, J. F., Vecsey, B., Garros, B., & Erny, P. (1996). Characteristics of head trauma in children: Epidemiology and a 5-year followup. Archives de Pediatric, 3, 651–660. Ponsford, J., Willmont, C., Rothwell, A., Cameron, P., Kelly, A., Nelms, R., et al. (2000). Factors influencing outcome following mild traumatic brain injury in adults. Journal of the International Neuropsychological Society, 6, 568–579.

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Rapoport, M., & Feinstein, A. (2000). Outcome following traumatic brain injury in the elderly: A critical review. Brain Injury, 14, 749–761. Ruff, R. (2005). Two decades of advances in understanding of mild traumatic brain injury. The Journal of Head Trauma Rehabilitation, 20, 5–18. Ruff, R., Iverson, G., Barth, J., Bush, S., & Broshek, D. (2009). Recommendations for diagnosing a mild traumatic brain injury. A National Academy of Neuropsychology position paper. Archives of Clinical Neuropsychology, 24, 3–10. Stambrook, M., Moore, A., Lubusko, A., , Peters, L., & Blumenschein, S. (1993). Alternatives to the Glasgow Coma Scale as a quality of life predictor following traumatic brain injury. Archives of Clinical Neuropsychology, 8, 95–103. Teasdale, G., & Jennett, B. (1974). Assessment of coma and impaired consciousness: A practical scale. Lancet, 2, 81–84.

TRIGEMINAL NEURALGIA DESCRIPTION

Trigeminal neuralgia (TN), also known as ‘‘tic douloureux,’’ is an uncommon disorder that typically presents as paroxysmal, brief, recurrent, unilateral facial pain (Sadosky, McDermott, Brandenburg, & Strauss, 2008). To date, two variants of the disorder have been identified: typical and atypical. Typical TN is thought to be caused by the compression of the fifth cranial nerve (trigeminal nerve), although the causes of atypical TN are unknown. Prevalence estimates vary, largely due to the difficulty in diagnosis (Sadosky et al., 2008). However, the most recent epidemiological data suggest an incident rate ranging from 4.7 to 8.0 per 100,000 persons in the United States. TN is more likely to affect women than men (3.4:2.2). TN generally develops after the age of 50 and reaches a peak in the seventh decade of life, affecting about 1 in 1,000 persons aged 75 years and older. The disorder rarely occurs in children, although a small number of cases have been identified in children as young as 3 years of age (Bennetto, Patel, & Fuller, 2008). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Vascular compression of the trigeminal nerve root is the most common cause of TN (Edlich, Winters, Britt, & Long, 2006). Other causes include a primary

demyelinating disorder or arteriovenous malformation, as well as cysts and tumors near the pons or medulla. An aberration of an artery or vein generally underlies vascular compression, which may in turn lead to irritative foci from the subsequent local demyelination. These foci may produce ectopic impulses resulting in the pain associated with TN. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Pain is the essential feature of TN and is generally unilateral, although it may be bilateral (10% to 12%). Further, TN tends to wax and wane, with episodes lasting from a few seconds to several minutes (Sadosky et al., 2008). Attacks may occur several times a day, while remitting up to years before an episode reappears. Generally, the intensity and frequency of attacks increase over time (Carlson, 2007). Neuropsychological studies were not located in the literature; however, some information regarding psychological factors associated with TN was found. Researchers have noted an increased rate of depression and anxiety in persons with chronic facial pain, as well as the presence of personality disorders (Kight, Gatchel, & Wesley, 1999; Korszun, Hinderstein, & Wong, 1996). Further, Curren et al. (1995) reported that 67% of chronic facial pain patients endorsed a history of sexual and/or physical abuse. In another study of 141 patients, 25% met criteria for posttraumatic stress disorder (Sherman et al., 2005). DIAGNOSIS

TN pain is often initially misdiagnosed as a dental problem or mental health problem. Thus, it is not uncommon for individuals with TN to have seen several different professionals before TN is considered. The current diagnostic standards, according to the International Headache Society, include paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, which affect one or more divisions of the trigeminal nerve. Additionally, at minimum, the pain has one of the following characteristics: The pain is intense, sharp, superficial, or stabbing; it is precipitated from trigger areas or by trigger factors; attacks in the individual patient are stereotyped; no clinically evident neurologic deficit is present; and the pain is not attributed to another disorder (ICHD, 2004). More recently, Zebenholzer, Wo¨ber, Vigl, Wessely, and Wo¨ber-Bingo¨l (2006) have suggested that better diagnosis may result from altering the current diagnostic standard to a more liberal taxonomy to allow for individual variance.

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Neuroimaging may be useful in accurate diagnosis, although the evidence is mixed. More recent research suggests that the routine use of imaging identifies structural causes of TN in 15% of the cases; thus, it is considered only potentially useful as a diagnostic tool (Gronseth et al., 2008).

TREATMENT

Treatment approaches include pharmacological, surgical, motor stimulation, and/or biobehavioral. For those persons without identified structural lesions, the initial treatment usually consists of carbamazepine, with nearly 70% of TN patients achieving significant relief from pain (Gronseth et al., 2008; He, Wu, & Zhou, 2006). The use of carbamazapine may have side effects that are intolerable to the patient (e.g., drowsiness, nausea and vomiting, and dizziness). Over time, patients may become resistant to carbamazepine as a monotherapy and need the addition of other agents (e.g., gabapentin) to optimize pain control. Other anticonvulsant agents that have demonstrated efficacy in the management of TN include oxcarbazepine, gabapentin, lamotrigine, topiramate, and phenytoin. Additional pharmacological treatments include baclofen, benzodiazepines (e.g., clonazepam), opioids (e.g., methadone and morphine), and Botox injections. Surgical interventions may provide relief for those whose pain is refractory to medication. Microvascular decompression is the most promising surgical option and involves the separation or removal of the offending vessel. Studies suggest that 64% of individuals achieved complete relief from pain 10 years postprocedure and remained pain free 20 years. Gamma knife radiosurgery has been effective for short-term relief from pain, although data are not as promising as that of vascular decompression (Linskey, Ratanatharathorn, & Pen˜agaricano, 2008; Tronnier, Rasche, Hamer, Kienle, & Kunze, 2001). Biobehavioral treatment focuses on relaxation skills (progressive muscle, breathing) but also psychological factors that may be contributing to chronic pain, such as depression or PTSD (Carlson, 2007). These treatments have been shown to be effective for this patient group. Jennifer Mariner Jacqueline Remondet Wall Bennetto, L., Patel, N. K., & Fuller, G. (2008). Trigeminal neuralgia and its management. British Medical Journal, 334(7586), 201–205.

Carlson, C. R. (2007). Psychological factors associated with orofacial pains. Dental Clinics of North America, 51, 145–160. Curren, S. L., Sherman, J. J., Cunningham, L. C., Okeson, J. P., Reid, K. I., & Carlson, C. R. (1995). Physical and sexual abuse among orofacial pain patients: Linkages with pain and psychological distress. Journal of Orofacial Pain, 10, 141–150. Edlich, R. F., Winters, K. L., Britt, L. D., & Long, W. B. (2006). Trigeminal neuralgia. Journal of Long-Term Effects of Medical Implants, 16(2), 185–192. Gronseth, G., Cruccu, G., Alksne, J., Argoff, C., Brainin, M., Burchiel, K., et al. (2008). Practice parameter: The diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology, 71(15), 1183–1190. He, L., Wu, B., & Zhou, M. (2006). Non-antiepileptic drugs for trigeminal neuralgia. Cochrane Database of Systematic Reviews, 3, 1–29. International Headache Society. (2004). International Classification of Headache Disorders, 2nd edt. ICHD-II. Cephalalgia 2004; 24 (Suppl 1). Kight, M., Gatchel, R. J., & Wesley, L. (1999). Temporomandibular disorders: Evidence for significant overlap with psychopathology. Health Psychology, 18, 177–182. Korszun, A., Hinderstein, B., & Wong, M. (1996). Comorbidity of depression with chronic facial pain and temporomandibular disorders. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 82(5), 496–500. Linskey, M. E., Ratanatharathorn, V., & Pen˜agaricano, J. (2008). A prospective cohort study of microvascular decompression and gamma knife surgery in patients with trigeminal neuralgia. Journal of Neurosurgery, 109(Suppl.), 160–172. Sadosky, A., McDermott, A. M., Brandenburg, N. A., & Strauss, M. (2008). A review of the epidemiology of painful diabetic peripheral neuropathy, postherpetic neuralgia, and less commonly studied neuropathic pain conditions. Pain Practice, 8(1), 45–56. Sherman, J. J., Carlson, C. R., Wilson, J. F., Okeson, J. P., & McCubbin, J. A. (2005). Post-traumatic stress disorder among patients with orofacial pain. Journal of Orofacial Pain, 19, 309–317. Tronnier, V. M., Rasche, D., Hamer, J., Kienle, A. L., & Kunze, S. (2001). Treatment of idiopathic trigeminal neuralgia: Comparison of long-term outcome after radio frequency rhizotomy and microvascular decompression. Neurosurgery, 48(6), 1261–1268. Zebenholzer, K., Wo¨ber, C., Vigl, M., Wessely, P., & Wo¨berBingo¨l, Ç. (2006). Facial pain and the second edition of the international classification of headache disorders. Headache, 46, 259–263.

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TROPICAL SPASTIC PARAPARESIS T DESCRIPTION

Tropical spastic paraparesis (TSP) is a chronic and progressive inflammatory disease primarily affecting the spinal cord (Osame et al., 1986). TSP was first described in the late 19th century (Strachan, 1897). Human T-cell lymphotropic virus type-I- (HTLV-I)associated myelopathy (HAM) was later described in 1986 (Gessain et al., 1986; Osame et al., 1986; and it was shortly recognized that TSP and HAM are part of the same syndrome. HTLV-I is considered the likely cause of TSP/HAM (Carod-Artal, 2009). It is estimated that 20 million people are infected with HTLV-I throughout the world, and 0.3% to 4% will develop TSP/HAM (Carod-Artal, 2009). TSP is rarely diagnosed in the United States, but it occurs most often in southern Japan and the Caribbean basin (Osame et al., 1987), as well as West and Central Africa and some Latin American regions (Edlich, Arnette, & Williams, 2000). Those who contract the disease typically live in these endemic areas, have had sexual contact with infected individuals in the endemic areas, are intravenous drug users (IDU), or have had sexual contact with IDUs (Dixon et al., 1990; Kramer et al., 1995). Organ transplantation, blood transfusion, and breast-feeding have also been linked to transmission (Toro et al., 2002). NEUROPATHOLOGY/PATHOPHYSISOLOGY

The pathophysiology of TSP/HAM also remains unclear. It has been suggested that the syndrome may be an autoimmune response from an HTLV reaction against CNS antigens (Levin et al., 2002). Some have further suggested that TSP/HAM may be similar to multiple sclerosis (MS), due to increased IgG and oligoclonal IgG in the cerebrospinal fluid (CSF), the preponderance of cases occurring in women, and the similar type of response pattern to MS-related treatments (Osame et al., 1987). Others have suggested that TSP/HAM is due to direct pathogenic action of the tax viral protein (Nagai & Jacobson, 2001; Orland, 2003). The pathology of TSP/HAM includes the spinal column, particularly at the thoracic level, with atrophy occurring around the lateral columns (Iwasaki, 1990). These lesions have been linked to perivascular and parenchymal lymphocytic infiltration (Umehara & Osame, 2003). Brain lesions have been identified in some cases of TSP/HAM, but there is very little that is understood

about the nature of the lesions, and how they may be related to spinal cord lesions (Moe et al., 2000). Yukitake et al. (2008) reviewed spinal cord MRIs of 38 patients with TSP/HAM. They found that patients who evidenced T2-hyperintensities evidenced severe paraparesis that rapidly progressed, which resulted in severe motor impairment. Kuroda et al. (1995) found that 30 of the 36 patients assessed demonstrated multiple white matter lesions on T2-weighted cranial MRI, with two fulfilling the criteria for MS. PuccioniSohler et al. (2007) found that the 17 patients assessed evidenced time-progressive and extensive multifocal white matter hyperintensities on T2-weighted images in the supra- and infratentorial areas of the brain. In addition, two patients had similar presentations in the spinal cord and gadolinium-enhancing brain lesions suggesting active disease (Puccioni-Sohler et al., 2007). Morgan et al. (2007) noted that white matter lesions are commonly observed on brain’s MRI in HTLV-I carriers, but they do not help to discriminate those with TSP/HAM. Overall, there appears to be definite patterns of lesions on brain and spinal MRI; however, understanding the clinical correlates of these findings are where the study is needed. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Patients can present with a variety of symptoms in TSP/HAM but those that may occur include widespread pyramidal signs, urinary urgency or incontinence, constipation, noncompressive paraparesis in the lower limbs, and subtle sensory changes (Arau´jo, Afonso, Schor, & Andrada-Serpa, 1993). Other changes may include disabling pain, which may occur in the lumbar region and radiate down the legs (Franzoi et al., 2005). In some cases, researchers assert that cognitive functioning is generally preserved in TSP/ HAM (Orland, 2003). However, this is quite debatable in the literature, given that many cases of TSP/HAM appear to mimic MS. Thus, in addition to the noted abnormal neuroimaging results that have been in relation, the HTLV-I or TSP/HAM patients could lead one to presume that cognitive deficits also may be present. Nevertheless, these symptoms may be less likely to gain attention when detecting the disease process. Silva, Mattos, Alfano, and Araujo (2003) found that HTLV-1 carrier groups and those with TSP/ HAM exhibited a lower performance on neuropsychological testing when compared with controls. There were no observable differences between asymptomatic infected carriers and those with TSP/HAM. Observable changes included psychomotor slowing, deficits in alternate attention (mental flexibility),

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poor verbal and visual memory, including recognition, decreased verbal fluency, and diminished visuomotor/construction skills. They pointed out that comorbid mood disorder was commonly observed in TSP/HAM, which could weaken this effect. They concluded that TSP/HAM as well as asymptomatic infection can be associated with mild cognitive deficits (Silva et al., 2002). In a study of 43 patients, 31 of whom were women and diagnosed with TSP, it was found that at least 50% of the patients with TSP exhibited cognitive and affective impairment. Deficits were noted on the subtests of the WAIS, including digit span, digit symbol, object assembly, and picture arrangement. Deficits were also noted on the Benton Visual Retention Test. Overall, they found a positive relationship between cognitive and motor symptoms (Cartier & Gomez, 1999). Overall, the research supports a subcortical type of disruption that can occur in cases of TSP/HAM. These findings are consistent with the type of profile that is commonly seen in MS as well as HIV infection. DIAGNOSIS

In endemic areas of HTLV-I infection, differential diagnosis can be challenging for TSP/HAM and myelopathies of other etiologies as well as primary progressive MS (Puccioni-Sohler et al., 2007). Clear diagnostic criteria for TSP/HAM have yet to be established, which can also be especially complicating for mild cases of TSP/HAM (Orland, 2003). However, the World Health Organization has described certain characteristics of the condition. These may include diffuse hyperreflexia, clonus, leg weakness, loss of vibratory sense, and bladder dysfunction. In order to formally diagnose, confirmation of the presence of HTLV I or II virus of the antibodies must be detected in the CSF or peripheral blood (Orland et al., 2003). In the CSF, a diagnosis can be made using ELISA/ western blot or by also using polymerase chain reaction in the CSF and the antibody index (AI) (Arau´jo, Leite, Lima, & Silva, 2009). TREATMENT

Carod-Artal (2009) noted that many forms of treatment have been utilized in small open trials for TSP/HAM, but the efficacy has been limited to date. These treatments include plasma-exchange, intravenous immunoglobulins, corticosteroids, lamivudine, green-tea, danazol, pentoxifylline, lactobacillusfermented milk, zidovudine, monoclonal antibodies (daclizumab), valproic acid, and interferon. Earlier

published studies note that similar to MS, corticosteroids and interferon — alpha or beta — have been successful in relieving some symptoms of TSP/HAM (Osame et al., 1987; Weiner & Hafler, 1988). In a systematic review of the effectiveness and safety of different interventions for treating HTLV-I and TSP/HAM, Uthman & Uthman (2007) found that high-dose human lymphobastoid interferon resulted in high efficacy with an acceptable degree of side effects. They concluded in their review that there was no significant benefit of using zidovudine plus lamivudine. They also noted that the data are limited because of small study sizes, short study durations, and some compromises noted in the designs (Uthman & Uthman, 2007). Amy R. Steiner Chad A. Noggle Amanda Steiner Arau´jo, A. C., Afonso, C. R., Schor, D., & Andrada-Serpa, M. J. (1993). Spastic paraparesis of obscure origin. A case-control study of HTLV-I positive and negative patients from Rio de Janerio, Brazil. Journal of Neurological Science, 116(16), 165–169. Arau´jo, A. Q., Leite, A. C., Lima, M. A., & Silva, M. T. (2009). HTLV-1 and neurological conditions: When to suspect and when to order a diagnostic test for HTLV-1 infection? Arquivos De Neuro-Psiquiatria [serial on the Internet; cited 2009 Aug 27], 67(1), 132–138. Retrieved from http://www.scielo.br/scielo.php?script ¼ sci_arttext& pid ¼ S0004-282X2009000100036&lng ¼ en. doi: 10.1590/ S0004-282X2009000100036. Carod-Artal, F. J. (2009). Immunopathogenesis and treatment of myelopathy associated to the HTLV-I virus. Revista De Neurologia, 48(3), 147–155. Cartier, L., & Gomaz, A. (1999). Subcortical dementia in HTLV-I tropical spastic paraparesis. Study of 43 cases. Revista me´dica de Chile, 127(4), 444–450. Dixon, P. S., Bodner, A. J., Okihiro, M., Milbourne, A., Diwan, A., & Nakamura, J. M. (1990). Human Tlymphotropic virus type I (HTLV-I), and tropical spastric paraparesis or HTLV-I associated myelopathy in Hawaii. Western Journal of Medicine, 152, 261–267. Edlich, R., Arnette, J., & Williams, F. (2000). Global epidemic of human T-cell lymphotropic virus type-I (HTLV-I). Journal of Emergency Medicine, 18, 109–119. Franzoi, A.C., Araujo, A.Q.C. (2005). Disability profile of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis using the Functional Independence Measure (FIM). Spinal Cord, 43, 236–240. Gessain, A., Francis, H., Sonan, T., Sonan, T., Giordano, C. et al. (1986). HTLV-1 and Tropical Spastic Paraparesis in Africa. The Lancet, 2 (8508), 698–698.

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Iwasaki, Y. (1990). Pathology of chronic myelopathy associated with HTLV-I infections (HAM/TSP). Journal of Neurological Science, 96, 103–123. Kramer, A., Maloney, E. M., Mogan O. S., Rodger-Johnson, P., Manns, A., Murphy, E. L., et al. (1995). Risk factors and cofactors for human T-cell lymphotropic virus type I (HTLV-I) associated meylopathy/tropical spastic paraparesis (HAM/TSP) in Jamaica. American of Journal Epidemiology, 142, 1212–1220. Kuroda, Y., Matsui, M., Yukitake, M., Kurohara, K., Takashima, H. et. al. (1995). Assessment of MRI criteria for MS in Japanese MS and HAM/TSP. Neurology, 45, 30–33. Levin, M. C., Lee, S. M., Kalume, F., Morcos, Y., Dohan, F. C., et al. (2002). Autoimmunity due to molecular mimicry as a cause of neurological disease. Natural Medicine, 8, 509–513. Moe, M. A., Matsuoka, E., Moritoyo, T., Umehara, F., Suehara, M., Hokezu, Y., et al. (2000). Histopathological analysis of four autopsy cases of HTLV-I associated myelopathy/tropical spastic paraparesis: inflammatory changes occur simultaneously in the entire central nervous system. Acta Neuropathologica, 100, 245–252. Morgan, D. J., Caskey, M. F., Abbehusen, C., Oliveira-Filho, J., Araujo, C., et al. (2007). Brain Magnetic resonance imaging white matter lesions are frequent in HTLV-1 carriers and do not discriminate from HAM/TSP. AIDS Research and Human Retroviruses, 23(12), 1499–1504. Nagai, M., & Jacobson, S. (2001). Immunopathogenesis of human T cell lymphotropic virus type I-associated myelopathy. Current Opinions in Neurology, 14, 381–386. Orland, J. R., Engstrom, J., Fridey, J., Sacher, R. A., Smith, J. W., et al. (2003). Prevalence and clinical features of HTLV neurologic disease in the HTLV outcomes study. Neurology, 61,1588–1594. Osame, M., Usuku, K., Izumo, S., Ijichi, N., Amitani, H., Igata, A., et al. (1986). HTLV-I associated myelopathy, a new clinical entity Lancet, May 3; 1(8488):1031–1032. Osame, M., Matsumoto, M., Usuku, K., Izumo, S., Ijichi, N., Amitani, H., et al. (1987). Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemia like cells. Annals of Neurology, 21, 117–122. Puccioni-Sohler, M., Yamano, Y., Rios, M., Carvalho, S. M. F., Vasconcelos, C. C. F., Papais-Alvarenga, R., et al. (2007). Differentiation of HAM/TSP from patients with multiple sclerosis infected with HTLV-I. Neurology, 68, 206–213. Silva, M., Mattos, P., Alfano, A., & Arau´jo, A. (2003). Neuropsychological assessment in HTLV-1 infection: A comparative study among TSP.HAM, asymptomatic carriers, and healthy controls. Journal of Neurosurgery Psychiatry, 74, 1085–1089. Strachan, H. (1897). On a form of multiple neuritis prevalent in the West Indies. Practitioner (London), 59, 477–484.

Umehara, F., & Osame, M. (2003). Histological analysis of HAM/TSP pathogenesis. In: K. Sugamura, T. Uchicyama, M. Masso, & M. Kannagi, (Eds.), Two decades of adult T-cell leukemia and HTLV-I research. Tokyo: Japan Scientific Societies Press. Uthman, O. A., & Uthman, R. T. (2007). Interventions for the treatment of Human T-lymphotropic virus type-1associated myelopathy: A systematic review of randomized controlled trials. Neurology Asia, 12, 81–87. Weiner, H. L., & Hafler, D. A. (1988). Immunotherapy of multiple sclerosis. Annals of Neurology, 23, 211–222. WHO (1989). Virus disease: Human T lymphotropic virus type I, HTLV-I. The Weekly Epidemiological Record, 64, 382–383. Toro, C., Rodes, B., Aguilera, A., Caballero, E., Benito, R., Tuset, C., et al. (2002). Clinical Impact of HTLV-1 Infection in Spain: Implications for Public Health and Mandatory Screening. Journal of Acquired Immune Deficiency Syndromes, 30(3), 366–368. Yukitake, M., Takase, Y., Nanri, Y., Kosugi, M., Eriguchi, M., Yakushiji, Y., et al. (2008). Incidence and clinical significances of human T-cell lymphotropic virus type I-associated myelopathy with T2 hyperintensity on spinal magnetic resonance images. Internal Medicine, 47(21), 1881–1886. [Epub 2008 Nov 4].

TROYER’S SYNDROME DESCRIPTION

Troyer’s syndrome is an autosomal recessive disorder that involves both developmental and degenerative processes. First identified in 1967, it is classified as a rare disease, which means that it impacts less than 200,000 individuals in the United States. The disease was first identified in the Amish, but recently has been identified in other populations. It is a complicated form of hereditary spastic paraplegia (HSP), a term used to describe a group of clinically heterogeneous neurodegenerative disorders in which the main feature is progressive lower limb spasticity. Being a complicated form of HSP, it differs from the pure form in that additional neurological signs such as mental retardation (MR), deafness, optic neuropathy, or extrapyramidal symptoms are present (Proukakis et al., 2004). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The complete pathogenic basis of Troyer’s syndrome is unclear. However, the putative pathogenesis of

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Troyer’s syndrome is a mutation in the SPG20 gene, which is responsible for encoding the protein spartin. Specifically, the 1110delA mutation in exon 4 appears to be the causal mutation in the SPG20 gene (Patel et al., 2002). This gene is widespread throughout both adult and fetal tissue and mutation in SPG20 invariably causing a complete loss protein spartin through either increased protein degradation or impaired translation (Bakowska, Wang, Xin, Sumner, & Blackstone, 2008), resulting in the manifestation of the Troyer’s syndrome. Radiological studies have noted that Troyer’s syndrome may actually be a combination of brain abnormality and motor neuron disease (Auer-Grumbach et al., 1999). According to Proukakis et al. (2004), axonal degeneration of the corticospinal tracts, fasciculus gracilis, and the spinocerebellar tracts are common underlying pathology in Troyer’s syndrome. Together, these make up the longest motor and sensory axons in the nervous system, and damage begins at the most distal portion near the neuromuscular junction, and works its way back to the cell soma. Blood tests have been found normal in patients with Troyer’s syndrome (Proukakis et al., 2004), however, electrophysiological studies by Auer-Grumbach et al. (1999) found motor nerve conduction to be below normal and compound motor action potentials to be markedly reduced, although sensory potentials and conduction were both in the normal range. Likely due to the degeneration in the aforementioned motor neurons, patients with Troyer’s syndrome may display chronic denervation and loss of motor units in the lower extremities. Also likely due to the degeneration and chronic denervation, muscle fiber atrophy is possible. MRI scans have repeatedly demonstrated deep white matter abnormalities in patients with Troyer’s syndrome (Auer-Grumbach et al., 1999; Proukakis et al., 2004). Although there is no uniform pattern of signal change in Troyer’s syndrome, there are some consistencies in the location of these hyperintensities as the temporoparietal periventricular white matter and posterior limbs of the internal capsule appear to be most highly implicated. There is also evidence of severe corpus callosum thinning throughout its entire length and a poorly defined cingulate gyrus, most notably in the frontal and posterior horns. Callosal changes appear to owe to a hypoplastic callosum rather than atrophy, due to the otherwise normal cerebral volume. This appears to implicate a fundamental cerebral developmental abnormality possibly due to impaired axonal growth or deficient myelination (Auer-Grumbach et al., 1999).

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The first presenting feature of Troyer’s syndrome is a mild delay in reaching early milestones, specifically walking and talking, when compared to unaffected individuals (Proukakis et al., 2004). On average, patients with Troyer’s syndrome will begin to walk at around 16 months of age, and talk at approximately 17 months. Throughout the later years, there is a slow deterioration of both, though a consistent timeline for this deterioration does not exist. The gait deterioration generally consists of a combination of spastic and ataxic features, a wide base, inward turned feet, and frequent reflexive plantar extension. Many of these patients are confined to a wheel chair by the 5th decade. Because there is no distinct pattern of cerebral white matter disease, the specific cognitive deficits in Troyer’s syndrome are inconsistent. However, in addition to a reduced IQ (Cross & McKusick, 1967), usually in the borderline range, generalized learning difficulties exist throughout the lifespan. There does not appear to be evidence of progressive cognitive decline. Cerebellar signs, which usually include dysdiadochokinesia (inability to make rapid hand movements), terminal dymetria (lack of coordination involving over- or under-shooting the intended position), choreoathetoid movements (continuous involuntary rapid, highly complex jerky movements), and dystonic limb posturinga, do, however, become more pronounced with age. Sensory exams are unremarkable with Troyer’s syndrome patients as the disorder appears to be constricted to motor pathways. Speech difficulties are also often present, but correspond with dysarthric presentations, rather than damage to cortical speech areas. Emotional lability (e.g., inappropriate euphoria, depression, anger, and crying) is quite common in these patients, but not present in all cases. DIAGNOSIS

Like many autosomal recessive disorders, prenatal diagnosis of at-risk pregnancies is possible for Troyer’s syndrome. DNA analysis from fetal cells obtained by amniocentesis (amniotic fluid test) around 15–18 weeks of gestation or through chorionic villus sampling, which involves removal and examination of a small piece of placenta tissue, around 10–12 weeks of gestation. Prenatal diagnosis hinges on identification of a mutation in the SPG20 gene, specifically, the 1110delA mutation in exon 4 (Patel et al., 2002).

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If prenatal diagnosis of Troyer’s syndrome is not conducted, genetic testing will likely occur within the 1st decade of life when clinical symptoms begin to appear. The pathognomonic clinical signs of Troyer’s syndrome are spasticity in the lower limbs with hyperreflexia and extensor plantar responses. Prior to this, delayed and dysarthric speech, combined with delayed, unsteady, and wide-based ambulation may be an early indicator of Troyer’s syndrome. Genetic testing will be further warranted upon the presence of distal amyotrophy, choreoathetoid movements, and skeletal abnormalities. Specifically, patients with Troyer’s syndrome appear to regularly have short stature, kyphoscoliosis (spinal curvature), and pes cavus (fixed plantar flexion). Finally, the previously mentioned cerebellar signs, learning difficulties, and emotional lability are also indicative of this disease. In conjunction with mutation in the SPG20 gene, each of these clinical signs is diagnostic of Troyer’s syndrome.

Cross, H. E., & McKusick, V. A. (1967). The Troyer syndrome: A recessive form of spastic paraplegia with distal muscle wasting. Archives of Neurology, 16, 473–485. Patel, H., Cross, H., Proukakis, C., Hershberger, R., Bork, P., & Ciccarelli, F. D., et al. (2002). SPG20 is mutated in Troyer syndrome, a hereditary spastic paraplegia. Nature Genetics, 31, 347–348. Proukakis, C., Cross, H., Patel, H., Patton, M. A., Valentine, A., & Crosby, A. H. (2004). Troyer syndrome revisited: A clinical and radiological study of a complicated hereditary spastic paraplegia. Journal of Neurology, 251, 1105–1110.

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TREATMENT

Currently, there are no treatments available that will prevent or slow the progressive degeneration in Troyer’s syndrome. The current best practice in the management of this disease consists of symptomatic therapy through antispasmodic drugs, physical therapy, and assistive devices to aid in walking. Physical therapy will not be able to combat the skeletal abnormalities or denervation in Troyer’s syndrome, but may be able to help patients maintain and increase muscle strength and range of motion. Medicinal interventions, such as dantrolene or baclofen (orally or intrathecally) to reduce spasticity, zanaflex to treat muscle spasms, or benzodiazepines (i.e., diazepam and clonazepam), and botox injection as muscle relaxants may also be useful. Finally, in patients with a much slower disease progression, lengthening the ankle plantar flexors through orthopedic surgery may be beneficial to reduce equine gait and extensor plantar flexion. Daniel J. Heyanka Charles Golden Auer-Grumbach, M., Fazekas, F., Radner, H., Irmler, A., Strasser-Fuchs, S., & Hartung, H. P. (1999). Troyer syndrome: A combination of central brain abnormality and motor neuron disease? Journal of Neurology, 246, 556–561. Bakowska, J. C., Wang, H., Xin, B., Sumber, C. J., & Blackstone, C. (2008). Lack of spartin protein in Troyer syndrome: A loss-of-function disease mechanism? Archives of Neurology, 65, 520–524.

Tuberous sclerosis complex is an autosomal dominant neurocutaneous, multisystem disorder with a prevalence of 1 in 10,000 (Hunt & Lindenbaum, 1984). Although tuberous sclerosis is predominately reported as an inherited disorder, 60–70% of cases present secondary to spontaneous genetic mutations, most commonly related to anomalies of TSC1 and TSC2 genes that together produce hamartin and tuberin, respectively (Maria, Deidrick, Roach, & Gutmann, 2004; van Slegtenhorst et al., 1997). Although various systemic effects of the presentation can be seen, neurological involvement is common including mental retardation, higher incidence of autistic spectrum features, potential hydrocephalus, and seizures (e.g., infantile spasms). Treatment is usually focused on achieving good seizure control (Wong, 2006) and potential shunting if hydrocephalus presents. Surgical intervention may be employed for severe epileptiform activity and/or systemic issues such as kidney dysfunction. Medicinal intervention remains the most commonly used method of seizure control. Neuropsychological assessment is essential to identifying cognitive or behavioral deficits that are addressed as needed.

NEUROPATHOLOGY/PATHOPHYSIOLOGY

Tuberous sclerosis arises from mutations of TSC1 and TSC2 genes that are thought to be suppressor genes. The mutations lead to abnormalities in cell proliferation, differentiation, and migration that can affect the brain, heart, skin, retina, and kidneys (Ramesh, 2003).

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These mutations arise spontaneously in more than 60% of cases. Neurological features remain the most commonly seen sequelae of tuberous sclerosis. The neuropathology of the presentation corresponds with at least one supratentorial lesion characterized by the combined effects of cortical tubers and transmantle dysplasia, subcortical heterotopias, white-matter abnormalities, corpus callosum agenesis or dysplasia, and/or subependymal giant cell astrocytomas that can cause hydrocephalus and epileptogenic activity (van Slegtenhorst et al., 1997). The tubers that characterize the disorder are composed of poorly delineated mixtures of both neuronal and glial cell elements (Dabora et al., 2001). The cortical tubers and the abnormal tissue surrounding these formations serve as the basis of the seizures that present in conjunction with the disorder and are in many ways dependent upon the number, size, and location (Maeda, Tartaro, Matsuda, & Ishii, 1995). Periventricular and frontal regions may represent those areas with the highest prevalence of abnormalities such as ventricular enlargement in addition to supratentorial features previously discussed. Infratentorial brain lesions may also be seen but are far less common presenting in less than 5% of patients. These lesions include linear and gyriform cerebellar folia calcifications, cerebellar nodular white-matter calcifications, agenesis and hypoplasia of the cerebellar hemispheres and vermis, enlargement of the cerebellar hemispheres, and subependymal nodules and tubers in the brainstem and fourth ventricle (Maria et al., 2004). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The clinical manifestations of tuberous sclerosis vary and include both neurological and physiological features. The type and amount of symptoms correspond with diagnosis. Definitive diagnosis is said to be concluded when two major or one major and two minor features present. If only one major symptom is seen in conjunction with only one minor symptom then diagnosis is said to be probable, whereas a possible diagnosis is noted when only one major feature is seen or two minor symptoms are seen (Maria et al., 2004). Major features include manifestations of the skin, other organs, and brain. Major skin presentations include facial angiofibromas, ungual fibroma, more than three hypomelanotic macules, and shagreen patch. Cardiac rhabdomyoma, lymphangioleiomyomatosis, and renal angiomyolipoma represent major symptoms that involve other organs. Finally, cortical tubers, subependymal nodules, and subependymal

giant cell astrocytomas represent the major brainbased features. Minor symptoms include multiple randomly distributed pits in dental enamel, rectal polyps, bone cysts, cerebral white-matter migration abnormalities on brain imaging, gingival fibromas, nonrenal hamartomas, retinal achromic patches, confetti skin lesions, and multiple renal cysts (Maria et al., 2004). Although central nervous system complications represent the most common sequelae, renal complications are the second most common cause of morbidity including kidney failure, angiomyolipomas, and polycystic kidney disease occurs in 5–8% of patients (Maria et al., 2004). Pulmonary distress may also be seen secondary to lung manifestations including lymphangioleiomyomatosis, multifocal cysts, and multifocal micronodular pneumocyte hyperplasia, which correspond with symptoms including cystic lung disease, dyspnea, cough, hemoptysis, recurrent pneumothoraces, lymphatic obstruction, and retroperitoneal and hilar adenopathy (Maria et al., 2004). Cardiac features may present as ventricular tachycardia and fibrillation, arrhythmia, bradycardia, and heart block (Maria et al., 2004). Neurological degradation remains the most common feature of tuberous sclerosis. The disease is the leading cause of infantile spasms with a third of patients presenting with this type of seizure disorder although other seizure forms have also been noted (Maria et al., 2004). In fact, in upward of 90% of patients with tuberous sclerosis present with seizures. The presence of seizures is largely related to the manifestation of cognitive and/or behavioral deficits. Mental retardation and other neuropsychological deficits, including attention and executive function impairments, present in approximately 45–57% of patients (Hunt & Shepherd, 1993; Jozwiak, Goodman, & Lamm, 1998; Shepherd & Stephenson, 1992; Shepherd, Houser, & Gomez, 1995). One of the more recent investigations demonstrated IQs falling below 70 in 44% of patients assessed (Joinson et al., 2003). Beyond mental retardation, autism or autistic-like behaviors have been noted in as high as 35% of patients; ADHD or ADHD-like symptoms have been noted in approximately 25% of patients; and aggression and destructiveness have been noted 48% of patients (Webb, Fryer, & Osborne, 1991; Webb, Thomson, & Osborne, 1991). Learning disabilities are also commonly seen. DIAGNOSIS

As discussed previously, diagnosis is based on the type and the number of symptoms seen. Definitive

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diagnosis is said to be concluded when two major or one major and two minor features present. If only one major symptom is seen in conjunction with only one minor symptom then diagnosis is said to be probable, whereas a possible diagnosis is noted when only one major feature is seen or two minor symptoms are seen (Maria et al., 2004). Magnetic resonance imaging offers the most detailed view of the majority of brain lesions seen in tuberous sclerosis, although computed tomography scans can better display calcified areas (Maeda et al., 1995). EEG is essential given the high prevalence of seizures. Genetic testing may also be employed but has been reported previously as only 80% accurate (Roach, Gomez, & Northrup, 1998). Dental examinations are also useful as 100% of people with tuberous sclerosis are said to present with dental pits and craters in permanent teeth and a majority have gingival fibromas. Screening of behavioral and neurodevelopmental dysfunction has also been recommended by the National Institutes of Health at the time of diagnosis and at the start of a child’s schooling and then at regular periods in time thereafter. Neuropsychological assessment is an essential component of these initial and follow-up evaluations. TREATMENT

Treatment approaches are symptom based. For seizures that present in more than 90% of all patients with tuberous sclerosis, medication, vagus nerve stimulation, the ketogenic diet, and surgery have all been used (Maria et al., 2004). Medicinal intervention for seizures secondary to tuberous sclerosis is often different than medicinal control of seizures not associated with tuberous sclerosis. Research has demonstrated that children with tuberous sclerosis complex and epilepsy respond poorly to conventional antiseizure therapies (Maria et al., 2004). Rather, Vigabatrin, which is an irreversible 7-aminobutyric acid (GABA) transaminase inhibitor, is the preferred medicinal treatment for infantile. Surgical management of seizures in tuberous sclerosis is used rarely as there are often multiple bilateral lesions. Still, other research has suggested that reduction of lesion sites that correspond with seizure activity can reduce medicinal use and has been linked with improved development, behavior, and quality of life in some children (Romanelli, Najjar, Weiner, & Devinsky, 2002). As noted previously, kidney complications are commonly seen in patients with tuberous sclerosis and are the second most common cause of morbidity.

Treatment can range from regular monitoring to partial or total nephrectomy. The presence of angiomyolipomas increases the risk of renal hemorrhage. In such instances, embolization may be used to prevent hemorrhage and reduce tumor size while maintaining kidney tissue that reduces the risk of dialysis need. Other physiological issues such as cardiac complaints are addressed through standard symptom management practices. For cognitive and behavioral deficits, early intervention with speech-language, physical, and occupational therapies can prove essential. In children with problems in social interaction related to autism, which occurs at higher rates in tuberous sclerosis, behavioral modification can help remediate problem behaviors and improve functional skills (Wong, 2006). Oftentimes this treatment is also dependent upon aforementioned seizure treatment. Jambaque´, Chiron, Dumas, Mumford, and Dulac (2000) note that cognitive and behavioral difficulties in tuberous sclerosis complex can improve with reduction of seizure activity or structural lesions or therapeutic or medical interventions to treat specific disorders and that seizure control is associated with developmental gains. Problematic behaviors that may arise in relation to developmental delays, autism, and/or mental retardation can be addressed with psychotropic medications (Bruni et al., 1995; Romanelli et al., 2002). Jacob M. Goings Chad A. Noggle Bruni, O., Cortesi, F., Giannotti, F., & Curatolo, P. (1995). Sleep disorders in tuberous sclerosis: A polysomnographic study. Brain & Development, 17(1), 52–56. Dabora, S. L., Jozwiak, S., Franz, D. N., Roberts, P.S., Nieto, A., Chung, J., et al. (2001). Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. American Journal of Human Genetics, 68(1), 64–80. Hunt, A., & Lindenbaum, R. H. (1984). Tuberous sclerosis: A new estimate of prevalence within the Oxford region. Journal of Medical Genetics, 21(4), 272–277. Hunt, A., & Shepherd, C. (1993). A prevalence study of autism in tuberous sclerosis. Journal of Autism and Developmental Disorders, 23(2), 323–339. Hunt, A., & Stores, G. (1994). Sleep disorder and epilepsy in children with tuberous sclerosis: A questionnaire-based study. Developmental Medicine and Child Neurology, 36(2), 108–115. Jambaque´, I., Chiron, C., Dumas, C., Mumford, J., & Dulac, O. (2000). Mental and behavioural outcome of infantile

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epilepsy treated by vigabatrin in tuberous sclerosis patients. Epilepsy Research, 38(2–3), 151–160. Joinson, C., O’Callaghan, F. J., Osborne, J. P., Martyn, C., Harris, T., & Bolton, P. F. (2003). Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychological Medicine, 33(2), 335–344. Jozwiak, S., Goodman, M., & Lamm, S. H. (1998). Poor mental development in patients with tuberous sclerosis complex: Clinical risk factors. Archives of Neurology, 55(3), 379–384. Maeda, M., Tartaro, A., Matsuda, T., & Ishii, Y. (1995). Cortical and subcortical tubers in tuberous sclerosis and FLAIR sequence. Journal of Computer Assisted Tomography, 19(4), 660–661. Maria, B. L., Deidrick, K. M., Roach, E. S., & Gutmann, D. H. (2004). Tuberous sclerosis complex: Pathogenesis, diagnosis, strategies, therapies, and future research directions. Journal of Child Neurology, 19(9), 632–642. Ramesh, V. (2003, June). Aspects of tuberous sclerosis complex (TSC) protein function in the brain. Biochemical Society Transactions, 31(Pt 3), 579–583. Roach, K. S., Gomez, M. R., & Northrup, H. (1998). Tuberous sclerosis complex consensus conference: Revised clinical diagnostic criteria. Journal of Child Neurology, 13(12), 624–628. Romanelli, P., Najjar, S., Weiner, H. L., & Devinsky, O. (2002). Epilepsy surgery in tuberous sclerosis: Multistage procedures with bilateral or multilobar foci. Journal of Child Neurology, 17(9), 689–692. Shepherd, C. W., Houser, O. W., & Gomez, M. R. (1995). MR findings in tuberous sclerosis complex and correlation with seizure development and mental impairment. AJNR. American Journal of Neuroradiology, 16(1), 149–155. Shepherd, C. W., & Stephenson, J. B. (1992). Seizures and intellectual disability associated with tuberous sclerosis complex in the west of Scotland. Developmental Medicine and Child Neurology, 34(9), 766–774. van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., et al. (1997). Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science (New York, N.Y.), 277(5327), 805–808. Webb, D. W., Fryer, A. E., & Osborne, J. P. (1991). On the incidence of fits and mental retardation in tuberous sclerosis. Journal of Medical Genetics, 28(6), 395–397. Webb, D. W., Thomson, J. L. G., & Osborne, J. P. (1991). Cranial magnetic resonance imaging in patients with tuberous sclerosis and normal intellect. Archives of Disease in Childhood, 66(12), 1375–1377. Wong, V. (2006). Study of the relationship between tuberous sclerosis complex and autistic disorder. Journal of Child Neurology, 21(3), 199–204.

TURNER’S SYNDROME T DESCRIPTION

Turner’s syndrome (TS) is chromosomal disorder, arising in females, in which one of the X chromosomes is essentially absent. The presentation is thus represented as an XO combination as opposed to XX. The end result of this chromosomal defect is infertility in the affected female due to diminished estrogen levels and underdeveloped ovaries in combination with phenotypical traits of short stature, webbed neck, and cubitus valgus that is when the elbows are turned in slightly causing a wider carrying angle of the arms (Turner, 1938). TS presents in roughly 1 out of every 2,000 live female births (Saenger, 1996) Functionally, hearing problems and ear defects may also be observed with the prior increasing with increasing age. Sensorineural hearing loss begins in adolescence and by age 40, hearing impairment is observed in more than 85% of women with TS (Hederstierna, Hultcrantz, & Rosenhall, 2008). Motor deficits and delays are also common, including hypotonia, delays in ambulation and coordination, and sensorymotor integration (Hagerman, 1999). In addition, neuropsychological deficits have been commonly reported. TS has been associated with a profile indicative of a nonverbal learning disability, including weak visuospatial skills compared with verbal and difficulties in mathematics (Mazzocco, 2009; Pennington et al., 1985). Attentional deficits, executive dysfunction, and working memory deficits have been reported, as has increased prevalence of attention deficit hyperactivity disorder (ADHD) (Bender, Linden, & Robinson, 1990; Russell et al., 2006). Both short-term and long-term memory deficits have also been reported in TS, including impaired visual memory (Ross et al., 2002). Increased risk of psychiatric presentations, such as anxiety and depression have also been reported (Cardoso et al., 2004) Interventions and treatment vary and are multifaceted. Given that the presentation arises from a chromosomal defect there is no cure; rather, treatment seeks to reduce symptoms. NEUROPATHOLOGY/PATHOPHYSIOLOGY

As previously discussed, TS is a chromosomal disorder, characterized by the essential absence of a second X chromosome in females, represented as XO in lieu of XX. More specifically, the most common

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karyotype (49% of cases) is 45,X instead of 46,XX although others have been reported including those with mosaicism and structural defects of the second X (23%), 45,X/46,XX mosaicism (19%), and ill-defined structural defects of the second X not due to mosaicism (9%) (Birkebaek, Cruger, Hansen, Nielsen, & Bruun-Petersen, 2002). Neuropathological alterations have been well researched in association with TS revealing structural and functional differences between these individuals and normal controls (Mullaney & Murphy, 2009). The summation of these studies has revealed abnormalities of the parietal lobe (Ross et al., 2002), thus explaining some of the most salient neurocognitive deficits best described as a nonverbal learning disability. Within this region reduced volume of both gray and white matter. Abnormalities have also been noted in the temporal lobe and limbic system, including the amygdala, hippocampus, and superior temporal gyrus, the cerebellum, and the midbrain (Kesler et al., 2003, 2004). Decreased white matter volume has been suggested on diffusion tensor imaging (DTI) in parietooccipital and frontoparietal regions (Holzapfel, BarneaGoraly, Eckert, Kesler, & Reiss, 2006). PET studies have reiterated anomalies in many of these areas, showing hypometabolism of glucose in parieto-occipital regions as well as medial temporal regions (Murphy et al., 1997). In fMRI studies, decreased functioning in the frontoparietal regions, including the inferior parietal lobe and dorsolateral prefrontal cortex, the caudate, and the left fusiform gyrus have been noted (Kesler et al., 2004; Skuse, 2005). TS has also been associated with significantly higher concentrations of hippocampal Cho, and lower parietal N-acetylaspartate (NAA) (Mullaney & Murphy, 2009), which the authors cite as associated with healthy old age, thus suggesting TS, in some respects, neurochemically mimics aging. Specifically, the authors (i.e., Mullaney & Murphy, 2009) suggested TS anatomically was associated with (1) increased brain aging, (2) differences in neuronal membrane turnover and signal transduction that modify cell survival, and (3) reduced neuronal density/mitochondrial function in the parietal lobe. In terms of the neuropathological and even functional features and deficits exhibited by individuals with TS, research has suggested a role of genetic imprinting outcomes (Skuse, 2000). In other words, outcomes may be related to which parent the defective X chromosome comes from or, the reverse, which parent provided the preserved X chromosome. Preservation of the paternal X chromosome (Xp) has been associated with better social adjustment, verbal skills, and executive functioning as well as better verbal

memory (Bishop et al., 2000); however, it has also been linked with poorer outcomes in visuo-spatial memory and functioning (Bishop et al., 2000). When it comes to neuroanatomical presentation, results are more mixed. Some have suggested a link between genomic imprinting and alterations of the brain, including bilateral temporal lobe white matter volume and midbrain gray matter volume (Cutter et al., 2006; Kesler et al., 2003), whereas others have failed to find any link between anatomical presentation and genomic imprinting (Good et al., 2003; Kesler et al., 2004). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The clinical features of TS can be divided into physical, cognitive, and behavioral traits. Physically, as previously discussed, phenotypical traits of short stature, webbed neck, and cubitus valgus are hallmark of the presentation (Turner, 1938). The short stature observed presents secondary to a combination of mild growth retardation prenatally, slowed growth during infancy, delayed growth onset in childhood, and failed pubertal growth spurt (Taback et al., 1996). A broad chest, epicanthal folds, and low posterior hair line may be noted. Variability can be seen across these features based on the origin of the chromosomal defect. For example, some females will spontaneously enter puberty, but this is more commonly seen in relation to mosaicisms as opposed to the traditional 45,X karotype. Hearing loss is quite common, corresponding with a sensorineural origin. As previously noted, the superior temporal gyrus in the temporal lobes is often a site of volumetric reduction. Similarly, motor deficits are common, including developmental delays in walking, hypotonia, dyscoordination, and poor sensory-motor integration (Hagerman, 1999). Cognitively, TS has been strongly linked with a profile indicative of nonverbal learning disability. That is, TS corresponds with significant deficits in performance IQ in comparison with verbal IQ (Temple & Carney, 1993). Despite this discrepancy, general IQ is often normal as verbal strengths often offer compensation for performance weaknesses. In some instances, TS has even been associated with hyperlexia and even normative strengths in linguistic knowledge and phonological processing (Murphy & Mazzocco, 2008). In comparison, response speed and oral/semantic fluency are areas of difficulty in TS (Mazzocco, 2001) but may be confounded by attention and executive defects. In addition, neuropsychological deficits have been commonly reported. TS has been associated

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with a profile indicative of a nonverbal learning disability, including weak visuospatial skills compared with verbal and difficulties in mathematics (Mazzocco, 2009). Specific strengths in language have been reported in receptive vocabulary, phonemic processing, and lexical storage, whereas syntactic processing and semantic fluency tends to be impaired (Hong, Kent, & Kesler, 2009). As verbal tasks rely on spatial processes or higher level attention or executive functions, performance is impeded. For example, Inozemtseva, Matute, Zarabozo, and Ramı´rez-Duen˜as (2002) found that individuals with TS exhibited impairments navigating maps when instructions were given verbally Executive functioning and visuospatial processing represent those areas of greatest impairment in TS. Cognitive inflexibility may present (Buchanan, Pavlovic, & Rovet, 1998; Romans, Roeltgen, Kushner, & Ross, 1996). Attention and working memory deficits are also commonly reported (Russell et al., 2006). Consistent with these findings, Simon et al. (2008) found that on the WISC-IV and WISC-III, individuals with TS performed significantly worse than controls on both the POI and PRI. Finally, both short-term and long-term memory deficits have also been reported in TS, including impaired visual memory (Ross et al., 2002). Increased risks of psychiatric, social, and adaptive difficulties have been associated with TS. As previously noted, increased risk of anxiety and depression has been associated with TS (Cardoso et al., 2004). However, this most often presents as increased selfreport of anxiety, depression, low-self-esteem, and impaired social competence compared with sameaged peers (McCauley, Feuillan, Kushner, & Ross, 2001; Lagrou et al., 2006). In regard to social competence and functioning, both hearing loss and deficits in facial recognition have been identified as mediators (Bergamaschi et al., 2008). Finally, in regard to academic performance, as noted, mathematics tends to be an area of relative weakness for individuals, potentially requiring special education services. In comparison, reading tends to be a relative strength, presenting as hyperlexia. DIAGNOSIS

Definitive diagnosis of TS is accomplished through genetic testing. Oftentimes it is indicated upon noticing the phenotypical traits associated with the presentation, but not confirmed until such analysis is completed. MRI and functional imaging may be completed, but are not necessary for diagnosis. Rather, neuropsychological assessment is more essential as

it provides a means by which neurocognitive strengths and weaknesses are identified and appropriate interventions may be designed. Audiology evaluations are highly recommended given the high prevalence of sensorineural hearing loss. Motor development assessment should also be carried out. TREATMENT

There is no cure for TS given it is a chromosomal defect. Treatment and intervention is thus directed at addressing symptoms and features of the presentation. Again, treatments fall across physical, cognitive, and behavioral lines. Physically, treatment has sought to address both the short stature and pubertal absence experienced with TS as well as potential hearing loss. Historically, growth hormone has been used to offset the short stature exhibited in TS. As described previously, delay or slowness in growth has been reported across much of infancy, childhood, and adolescence. However, results have been mixed, with increases being reported as ranging from minimal growth (less than 5 cm) to as much as 17 cm (van Pareren et al., 2003). Indications vary in terms of when treatment should be started. Some have suggested that it can be started as early as 2 years of age, whereas others suggest growth itself is the determining factor with treatment starting once individuals drop below the fifth percentile of the normal female growth curve (Ismail et al., 2010). Hormone replacement therapy with estrogen is used to initiate puberty and to counteract gonadal dysgenesis. Still yet, as many as 30% of females enter puberty spontaneously (Birgit et al., 2009; Modi, Sane, & Bhartiya, 2003). Cognitively, variable reports of effectiveness have been reported for psychostimulants in offsetting deficits in attention, processing speed, and features of ADHD (Hagerman, 1999). However, risk is increased with these agents if cardiac defects are present, thus cardiological consultation is often needed first to determine safety. Interestingly, estrogen therapy has also been correlated with improvements in cognition. Ross et al. (1998) found that estrogen led to improvements in motor skills. Special education services are often required to address deficits in mathematics. Oxandrolone, an oral androgen, has shown some utility in improving mathematics deficits in TS when used over a 4-year period (Ross et al., 2009). Chad A. Noggle Bender, B., Linden, M., & Robinson, A. (1990). SCA: In search of developmental patterns. In D. Berch & B. Bender

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(Eds.), Sex chromosome abnormalities and human behavior: Psychological studies, AAAS Selected Symposium. Boulder, CO: Westview Press. Bergamaschi, R., Bergonzoni, C., Mazzanti, L., Scarano, E., Mencarelli, F., Messina, F., et al. (2008). Hearing loss in Turner syndrome: Results of a multicentric study. Journal of Endocrinological Investigation, 31, 779–783. Birgit, B., Julius, H., Carsten, R., Maryam, S., Gabriel, F., Victoria, K., et al. (2009). Fertility preservation in girls with Turner syndrome: Prognostic signs of the presence of ovarian follicles. The Journal of Clinical Endocrinology & Metabolism, 94, 74–80. Birkebaek, N. H., Cruger, D., Hansen, J., Nielsen, J., & BruunPetersen, G. (2002). Fertility and pregnancy outcome in Danish women with Turner syndrome. Clinical Genetics, 61(1), 35–39. Bishop, D. V., Canning, E., Elgar, K., Morris, E., Jacobs, P. A., & Skuse, D. H. (2000). Distinctive patterns of memory function in subgroups of females with Turner syndrome: Evidence for imprinted loci on the X-chromosome affecting neurodevelopment. Neuropsychologia, 38, 712–721. Buchanan, L., Pavlovic, J., & Rovet, J. (1998). The contribution of visuospatial working memory to impairments in facial processing and arithmetic in Turner syndrome. Brain Cognition, 37, 72–75. Cardoso, G., Daly, R., Haq, N. A., Hanton, L., Rubinow, D. R., Bondy, C. A., et al. (2004). Current and lifetime psychiatric illness in women with Turner syndrome. Gynecological Endocrinology, 19(6), 313–319. Cutter, W. J., Daly, E. M., Robertson, D. M., Chitnis, X. A., van Amelsvoort, T. A., Simmons, A., et al. (2006). Influence of X chromosome and hormones on human brain development: A magnetic resonance imaging and proton magnetic resonance spectroscopy study of turner syndrome. Biological Psychiatry, 59, 273–283. Good, C. D., Lawrence, K., Thomas, N. S., Price, C. J., Ashburner, J., Friston, K. J., et al. (2003). Dosage-sensitive X-linked locus influences the development of the amygdala and orbitofrontal cortex, and fear recognition in humans. Brain, 126, 2431–2446. Hagerman, R. J. (1999). Neurodevelopment disorders: Diagnosis and treatment. New York: Oxford University Press. Hederstierna, C., Hultcrantz, M., & Rosenhall, U. (2008). Estrogen and hearing from a clinical point of view; characteristics of auditory function in women with Turner syndrome. Hearing Research, 252, 3–8. December 6 (Epub ahead of print). Holzapfel, M., Barnea-Goraly, N., Eckert, M. A., Kesler, S. R., & Reiss, A. L. (2006). Selective alterations of white matter associated with visuospatial and sensorimotor dysfunction in Turner syndrome. Journal of Neuroscience, 26, 7007–7013.

Hong, D., Kent, J. S., & Kesler, S. (2009). Cognitive profile of turner syndrome. Developmental Disabilities Research Reviews, 15, 270–278. Hovatta, O. (1999). Pregnancies in women with Turner’s syndrome. Annals of Medicine, 31, 106–110. Inozemtseva, O., Matute, E., Zarabozo, D., & Ramı´rezDuen˜as, L. (2002). Syntactic processing in Turner’s syndrome. Journal of Child Neurology, 17, 668–672. Ismail, N. A., Eldin Metwaly, N. S., El-Moguy, F. A., Hafez, M. H., Abd El Dayem, S. M., & Farid, T. M., (2010). Bone age is the best predictor of growth response to recombinant human growth hormone in Turner’s syndrome. Indian Journal of Human Genetics, 16(3), 119–126. Kesler, S. R., Blasey, C. M., Brown, W. E., Yankowitz, J., Zeng, S. M., Bender, B. G., et al. (2003). Effects of Xmonosomy and X-linked imprinting on superior temporal gyrus morphology in Turner syndrome. Biological Psychiatry, 54, 636–646. Kesler, S. R., Garrett, A., Bender, B., Yankowitz, J., Zeng, S. M., & Reiss, A. L. (2004). Amygdala and hippocampal volumes in Turner syndrome: A high-resolution MRI study of X-monosomy. Neuropsychologia, 42, 1971–1978. Lagrou, K., Froidecoeur, C., Verlinde, F., Craen, M., De Schepper, J., François, I., et al. (2006). Pyschosocial functioning, self-perception and body image and their auxologic correlates in growth hormone and oestrogentreated young adult women with Turner syndrome. Hormone Research, 66, 277–284. Mazzocco, M. M. M. (2001). Math learning disability and math LD subtypes: Evidence from studies of Turner syndrome, fragile X syndrome, and neurofibromatosis type 1. Journal of Learning Disabilities, 34(6), 520–533. Mazzocco, M. M. M. (2009). Mathematical learning disability in girls with Turner syndrome: A challenge to defining MLD and its subtypes. Developmental Disabilities Research Reviews, 15, 35–44. McCauley, E., Feuillan, P., Kushner, H., & Ross, J. L. (2001). Psychosocial development in adolescents with Turner syndrome. Journal of Developmental and Behavioral Pediatrics, 22, 360–365. Modi, D., Sane, S., & Bhartiya, D. (2003). Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads. Molecular Human Reproduction, 9, 219. Mullaney, R., & Murphy, D. (2009). Turner syndrome: Neuroimaging findings: Structural and functional. Developmental Disabilities Research Reviews, 15, 279–283. Murphy, D. G. M., Mentis, M. J., Pietrini, P., Grady, C., Daly, E., Haxby, J. V., et al. (1997). A PET study of Turner’s syndrome: Effects of sex steroids and the X chromosome on brain. Biological Psychiatry, 41, 285–298. Murphy, M. M., & Mazzocco, M. M. M. (2008). Rote numeric skills may mask underlying mathematical disabilities in girls with fragile X syndrome. Developmental Neurospychology, 33, 345–364.

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Pennington, B., Heaton, R., Karzmark, P., Pendleton, M. G., Lehman, R., & Shucard, D. W. (1985). The neuropsychological phenotype in Turner syndrome. Cortex, 21, 391–404. Romans, S. M., Roeltgen, D. P., Kushner, H., & Ross, J. L. (1996). Executive function in females with Turner syndrome. Archives of Clinical Neuropsychology, 11, 442. Ross, J. L., Mazzocco, M. M., Krushner, H., Kowal, K., Cutler, G. B., Jr., & Roeltgen, D. (2009). Effects of treatment with oxandrolone for 4 years in the frequency of severe arithmetic learning disabilities in girls with turner syndrome. The Journal of Pediatrics, 155(5), 714–720. Ross, J. L., Roeltgen, D., Feuillan, P., Kushner, H., & Cutler, G. B., Jr. (1998). Effects of estrogen on nonverbal processing speed and motor function in girls with Turner syndrome. The Journal of Clinical Endocrinology and Metabolism, 83(9), 3198–3204. Ross, J. L., Stefanatos, G. A., Kushner, H., Zinn, A., Bondy, C., & Roeltgen, D. (2002). Persistent cognitive deficits in adult women with Turner syndrome. Neurology, 58, 218–225. Russell, H. F., Wallis, D., Mazzocco, M., Moshang, T., Zackai, E., Zinn, A., et al. (2006). Increased prevalence of ADHD in Turner syndrome with no evidence of imprinting effects. Journal of Pediatrics Psychology, 31(9), 945–955.

Saenger, P. (1996). Turner’s syndrome. The New England Journal of Medicine, 335, 1749–1754. Simon, T. J., Takarae, Y., DeBoer, T., McDonald-McGinn, D. M., Zackai, E. H., Ross, J. L., et al. (2008). Overlapping numerical cognition impairments in children with chromosome 22q11.2 deletion or Turner syndromes. Neuropsychologia, 46, 82–94. Skuse, D. H. (2000). Imprinting, the X-chromosome, and the male brain: Explaining sex differences in the liability to autism. Pediatric Research, 47, 9–16. Skuse, D. H. (2005). X-linked genes and mental functioning. Human Molecular Genetics, 14, R27–R32. Taback, S. P., Collu, R., Deal, C. L., Guyda, H. J., Salisbury, S., & Dean, H. J. (1996). Does growth-hormone supplementation affect adult height in Turner’s syndrome? Lancet, 348, 25–27. Temple, C. M., & Carney, R. A. (1993). Intellectual functioning of children with Turner syndrome: A comparison of behavioural phenotypes. Developmental Medicine & Child Neurology, 35, 691–698. Temple, C. M., & Carney, R. (1996). Reading skills in children with Turner’s syndrome: An analysis of hyperlexia. Cortex, 32, 335–345. Turner, H. H. (1938). A syndrome of infantilism, congenital webbed neck and cubitus valgus. Endocrinology, 23, 556–574.

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UV VASCULITIS DESCRIPTION

The term ‘‘vasculitis’’ is derived from the Latin word vasculum meaning vessel and itis, which means inflammation. Although the exact mechanisms of the condition are unknown, it is primarily characterized by an inflammation in the veins, arteries, or capillaries. Many diseases exist — over 30 — that are characterized by vasculitis as the primary symptom including, but not limited to Kawasaki’s disease, Behcet’s disease, polyarteritis nodosa, Wegener’s granulomatosis, cryoglobulinemia, Takayasu’s arteritis, Churg–Strauss syndrome, giant cell arteritis (temporal arteritis), and Henoch– Schonlein’s purpura (Watts & Scott, 2009). Other conditions maintain vasculitis as a secondary or atypical symptom (i.e., infection, cancer, etc.). Prevalence rates vary based on the specific subtype of vasculitis. For example, in the United States, the prevalence for giant cell arteritis in the elderly is approximately 20 per 100,000, 4–15 per 100,000 for Kawasaki’s disease, 6 per 100,000 for allergic angiitis, 3 per 100,000 for Wegener’s granulomatosis, 3 per 100,000 for polyarteritis nodosa, and 1 per 100,000 for Takayasu’s arteritis (Khasnis & Langford, 2009). It is estimated that 100,000 individuals are hospitalized each year in the United States for vasculitis, and may or may not exhibit differences based on race, gender, or age (i.e., giant cell arteritis that tends to occur in those over 50s in Caucasian women and Kawasaki’s disease that tends to occur in children) (Khasnis & Langford, 2009). Prognosis of vasculitis depends upon the organ systems involved and the number of sites affected in the body with systemic vasculitis often leading to debilitating conditions (i.e., stroke, myocardial infarction, blindness, or end stage renal disease) and, at times, fatality (Perez et al., 2004). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The pathophysiology of vasculitis is largely unknown; however, generalities of the disease process can be mentioned. As the blood vessels become inflamed,

they may narrow and eventually close or stretch and weaken, eventually bursting (aneurysm) (Khasnis & Langford, 2009). Although the exact etiology or risk factors of the disease are unknown for the majority of vasculitis subtypes, it is proposed that inflammation is secondary to abnormal immune response where blood vessels are targeted (Perez et al., 2004). Those variants of vasculitis with unknown etiology are referred to as primary vasculitides, whereas the variants where an identified disease is the etiology are referred to as secondary vasculitides (Merkel, Choi, & Niles, 2002). In regard to secondary vasculitides, individuals present with abnormal proteins in their blood, cryoglobulinemia, most commonly seen in individuals with a hepatitis C virus infection or in those with hepatitis B virus infection who develop polyarteritis nodosa (Watts & Scott, 2009). Autoimmune disorders, such as rheumatoid arthritis, lupus erythematosus, and Sjo¨gren’s syndrome, may also result in inflammation, and even allergic reactions to medication may result in vasculitis (Merkel, Choi, & Niles, 2002).

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Vasculitis may present in many ways given the plethora of variants and distinctive involvement in organ systems. General symptoms for vasculitis may include fever, swelling, headache, and weight loss (Khasnis & Langford, 2009). If the skin system is involved, then palpable pupura and livedo reticularis may be evident (Xu, Esparza, Anadkat, Crone, & Brasington, 2009). When muscles and joints are involved, then myalgia, arthralgia, or arthritis may be observed (Watts & Scott, 2009). Cardiovascular system involvement may result in hypertension, gangrene, or myocardial infarction (Mukhtyar, Brogan, & Luqmani, 2009). Respiratory system involvement may evince lung infiltrates, bloody cough, or nose bleeds (Watts & Scott, 2009). Gastrointestinal system involvement often results in abdominal pain, perforations, or bloody stool (Morgan & Savage, 2005). Renal system involvement often exhibits glomerulonephritis (Samarkos, Loizou, Vaiopoulos, & Davies, 2005).

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Vasculitis may also involve the nervous system resulting in the following common symptoms: confusion, forgetfulness, stroke, or mononeuritis multiplex (Khasnis & Langford, 2009). Given the blood vessel perfusion of the brain, cognitive impairments may likely be diffuse, with impairments being either transient or persisting. DIAGNOSIS

There are more than 30 types of vasculitis that have been named from the primary author who initially identified the condition, the clinical setting where it occurs, the size of the blood vessel involved, or features from the biopsy. Differential diagnosis may be difficult to ascertain because vasculitis resembles many other medical disorders. Common differential diagnoses include: infection, drug toxicity or poisoning, coagulopathy, malignancy, atrial myxoma, multiple cholesterol emboli, congenital collagen disorders, or fibromuscular dysplasia (Khasnis & Langford, 2009). Common tests to elucidate the presence of vasculitis include blood tests, imaging, urinalysis, or biopsy. Specific blood tests may analyze erythrocyte sedimentation rate, C-reactive protein, platelets, white blood cell count, antineutrophyl cytoplasmic antibodies, rheumatoid factor, or antinuclear antibody (Eleftheriou & Brogan, 2009). Imaging may be performed through ultrasound, CT, MRI, or angiogram (Perez et al., 2004). Urine samples may be analyzed to rule out infection or renal involvement. Finally, biopsy is considered the most conclusive test for differential diagnosis (Perez et al., 2004). TREATMENT

In general, vasculitis is considered a rare condition, which requires specialized medical care. Consistent with the variability in diagnosis noted above and the plethora of subtypes of vasculitis, treatment and outcome tend to be complex. Some individuals with vasculitis may experience minor symptoms and full recovery without treatment (i.e., Henoch–Schonlein’s purpura), whereas other cases may be terminal, or even if successfully treated may recur (i.e., giant cell arteritis, Wegener’s granulomatosis, and Takayasu’s arteritis), thereby requiring chronic monitoring and treatment (Merkel, Choi, & Niles, 2002). To further complicate matters, pharmaceutical treatments can be toxic resulting in permanent sequelae in the blood vessel. Although, medication tends to be the primary intervention utilized for vasculitis with common

prescriptions being in the order of increasing severity: nonsteriodal anti-inflamatory drugs (i.e., aspirin and ibuprofen), corticosteroids (i.e., prednisone or methylprednisolone), or — for particularly intractable vasculitis — cytotoxic drugs (i.e., azathioprine or cyclophosphamide) (Eleftheriou & Brogan, 2009; Khasnis & Langford, 2009). Response to medication and disease progression is monitored with routine blood tests, and follow-up with the treating physician is recommended. Javan Horwitz Natalie Horwitz Chad A. Noggle Eleftheriou, D., & Brogan, P. A. (2009). Vasculitis in children. Best Practice & Research Clinical Rheumatology, 23(3), 309–323. Khasnis, A., & Langford, C. A. (2009). Update on vasculitis. The Journal of Allergy and Clinical Immunology, 123(6), 1226–1236. Merkel, P. A., Choi, H. K., & Niles, J. L. (2002). Evaluation and treatment of vasculitis in the critically ill patient. Critical Care Clinics, 18(2), 321–344. Morgan, M., & Savage, C. (2005). Vasculitis in the gastrointestinal tract. Best Practice & Research Clinical Gastroenterology, 19(2), 215–233. Mukhtyar, C., Brogan, P., & Luqmani, R. (2009). Cardiovascular involvement in primary systemic vasculitis. Best Practice & Research Clinical Rheumatology, 23(3), 419–428. Perez, V. L., Chavala, S. H., Ahmed, M., Chu, D., Zafirakis, P., Baltatzis, S., et al. (2004). Ocular manifestations and concepts of systemic vasculitides. Survey of Ophthalmology, 49(4), 399–418. Samarkos, M., Loizou, S., Vaiopoulos, G., & Davies, K. (2005). The clinical spectrum of primary renal vasculitis. Seminars in Arthritis and Rheumatism, 35(2), 95–111. Watts, R. A., & Scott, D. G. (2009). Recent developments in the classification and assessment of vasculitis. Best Practice & Research Clinical Rheumatology, 23(3), 429–443. Xu, L. Y., Esparza, E. M., Anadkat, M. J., Crone, K. G., & Brasington, R. D. (2009). Cutaneous manifestations of vasculitis. Seminars in Arthritis and Rheumatism, 38(5), 348–360.

VON

ECONOMO DISEASE

DESCRIPTION

von Economo disease (VED), commonly known as encephalitis lethargica, was pandemic from 1917 to

VON ECONOMO DISEASE & 747

1926 with affected individuals suffering both acute and chronic symptoms. Originally thought to be related to influenza, there is presently no definitive identifiable etiology and current estimates of the prevalence of VED have not been established. Originally, mortality rates were between 20% and 40%, with survivors developing parkinsonian features and dyskinesias. However, at the present time, the prognosis of VED is highly variable depending upon accompanying complications and disorders (Dale et al., 2003). Common features of VED may include diplopia, lethargy, mutism, facial and cranial nerve palsies, motor disturbances, dyskinesias, and other parkinsonian features.

NEUROPATHOLOGY/PATHOPHYSIOLOGY

The etiology of the original VED epidemic remains a mystery, and the present form of the disease may be entirely different today than the disease originally explained by von Economo (Dale, Webster, & Gill, 2007). Because the original acute form of VED disappeared following the 1920s, a direct study of the disease is not possible. Epidemiological studies of the brain samples from the 1917 epidemic have failed to associate VED with influenza. However, some believe that the samples may have been contaminated or influenced by a myriad of impending factors that may have eliminated any trace evidence of viral encephalitis, if present (McCall, Vilensky, Gilman, & Taubenberger, 2008). Rather than finding evidence of influenza RNA, some studies have found the presence of intrathecal oligoclonal bands and elevated protein suggesting neurotropic viral encephalitis as an unlikely etiology (Dale et al., 2003). Postencephalitic individuals may present similar neuropathology as individuals with idiopathic Parkinson’s disease such as dopaminergic denervation in the caudate nuclei and putamen (CaparrosLefebvre et al., 1998). Furthermore, some individuals with VED display bilateral abnormalities in the substantia nigra, increased signal in the tegmentum and basal ganglia, and lesions to the right striatum during MRI (Dale et al., 2003; Verschueren & Crols, 2001). Although imaging has found deep gray matter lesions in individuals with VED, many have normal MRI scans. The present form of VED may be subsequent to postinfectious autoimmunity in deep gray matter. Individuals with VED have been found to have significantly more autoantibodies that were reactive toward basal ganglia antigens than normal individuals, which results in movement and psychiatric disorders (Dale et al., 2003).

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Visuoconstructional abilities may be impaired as measured by Rey’s figure copy and recall measure. Individuals with VED may present with executive and cognitive impairment, and impairment on measures of concept formation, mental flexibility, verbal abstraction, nonverbal recall and recognition, and verbal associate learning (Dewar & Wilson, 2005). Postencephalitic individuals who have been diagnosed with VED are at a higher risk of developing obsessive-compulsive disorder, depression, or other psychiatric disorders (Caparros-Lefebvre, et al., 1998; Dale et al., 2003; Dale et al., 2007). Individuals may experience diplopia, lethargy, mutism, facial and cranial nerve palsies, motor disturbances, hyperesthesia, dyskinesias (e.g., distonia, stereotypes, motor tics, facial grimacing, chorea, or facial grimacing), and/ or other common parkinsonian features such as bradykinesia with postural instability, tremor, or rigidity (Dale et al., 2003; Taylor, 1921). Differentiation between postencephalitic parkinsonian and idiopathic Parkinson’s disease may be made in part based upon age of onset. VED-related parkinsonian features may manifest as early as childhood, whereas the mean age of onset for idiopathic Parkinson’s disease is approximately 59 years (Li et al., 2003). Sleep disorders are also common including hypersomnolence, insomnia, and sleep inversion (Dale et al., 2003; Ocular palsies in encephalitis lethargica, 1924). Individuals may experience additional symptoms associated with intracranial pathology. In a study by Dale et al. (2003), over half of individuals contracted pharyngitis preceding onset of VED.

DIAGNOSIS

Raghav et al. (2007) suggest that diagnosis can be made based on clinical features, laboratory investigation, exclusion of other disorders, and circumstantial evidence. Specific manifestations of VED that aid in diagnosis include the characteristic parkinsonian signs, which are very common. In fact, many individuals with VED may actually meet the diagnostic criteria for Parkinson’s syndrome (Dale et al., 2003). As noted previously, in contrast to idiopathic Parkinson’s disease, parkinsonian symptoms may develop at an early age. Such features may include, but are not limited to, bradykinesia, resting tremor, or rigidity. Dyskinesias as well as sleep disturbances including hypersomnolence, sleep inversion, and insomnia are of diagnostic utility as they occur frequently in

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individuals with VED. Additional symptomology of diagnostic utility include lethargy, oculogyric crisis, cranial nerve palsies, and diplopia. To make a correct diagnosis, Raghav and colleagues identified clinical features from the original epidemic disease, such as acute encephalitis associated with symptoms from basal ganglia dysfunction, neuropsychiatric signs, respiratory problems, and oculogyric posturing as a comparison for making a present diagnosis. Due to the fact that almost half of the individuals with VED have normal MRIs, the MRI may be used to differentiate between VED and other neuropathological conditions. Although neuropsychological test data exist for VED, due to the lack of replication in the literature it is recommended that the aforementioned neuropsychological signs be used as supplement additional data and independently. Deep gray matter lesions may help identify underlying neuropathology typical of VED. The presence of intrathecal oligoclonal bands and elevated protein may also be useful in making a diagnosis (Dale et al., 2003).

TREATMENT

Treatment for VED is largely symptomatic in nature, and treatment outcomes are mixed. However, some individuals with VED have experienced full recovery following electroconvulsive therapy, which may be due to the treatment’s effect on underlying dopaminergic activity (Delkeva & Husain, 1995). Individuals with VED oftentimes are very reactive to L-dopa, experiencing many side effects. Hypersensitive dopamine receptors may be responsible for the development of dyskinesias during L-dopa treatment. Foster and Hoffer (2003) suggest that accompanying an L-dopa treatment with an antioxidant supplement may reduce oxidative stress, and prolong the benefits of the medication in comparison to subsequent side effects. McAuley, Shahmanesh, and Swash (1999) treated a patient with trials of apomorphine infusion followed by oral L-dopa without the individual experiencing additional dyskinetic problems. Lorazepam may also be useful in improving behavioral agitation that sometimes accompanies VED (Dale et al., 2007). However, full recovery from VED is likely to occur only in a minority of individuals (Dale et al., 2003). Cognitive rehabilitation may be useful for individuals with memory or executive impairment. Compensatory strategies aimed at managing memory impairment such as the use of memory diaries or other memory aids, restructuring the individual’s environment, or providing a problem-solving template may

allow an affected individual to improve memory functioning (Dewar & Wilson, 2005). Anthony P. Odland Charles Golden Caparros-Lefebvre, D., Cabaret, M., Godefroy, M., Seinling, M., Re´my, P., Samson, Y., et al. (1998). PET study and neuropsychological assessment of a long-lasting postencephalitic parkinsonism. Journal of Neural Transmission, 105, 489–495. Dale, R. C., Church, A. J., Surtees, R. A., Lees, A. J., Adcock, J. E., Harding, B., et al. (2003). Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity. Brain, 127(1), 21–33. Dale, R. C., Webster, R., & Gill, D. (2007). Contemporary encephalitis lethargica presenting with agitated catatonia, stereotypy, and dystonia-parkinsonism. Movement Disorders, 22(15), 2281–2284. Delkeva, K. B., & Husain, M. M. (1995). Sporadic encephalitis lethargica: A case treated successfully with ECT. The Journal of Neuropsychiatry and Clinical Neurosciences, 7, 237–239. Dewar, B. K., & Wilson, B. A. (2005). Cognitive recovery from encephalitis lethargica. Brain Injury, 19(14), 1285–1291. Foster, H. D., & Hoffer, A. (2004). The two faces of L-DOPA: Benefits and adverse side effects in the treatment of encephalitis lethargica, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis. Medical Hypotheses, 62, 177–181. Li, Y. J., Oliveira, S. A., Xu, P., Martin, E. R., Stenger, J. E., Scherzer, C. R., et al. (2003). Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Human Molecular Genetics, 12(24), 3259–3267. McAuley, J., Shahmanesh, M., & Swash, M. (1999). Dopaminergic therapy in acute encephalitis lethargica. European Journal of Neurology, 6(2), 235–237. McCall, S., Vilensky, J. A., Gilman, S., & Taubenberger, J. K. (2008). The relationship between encephalitis lethargica and influenza: A critical analysis. Journal of Neurovirology, 14, 177–185. Ocular palsies in encephalitis lethargica. (1924). British Journal of Ophthalmology, 8, 421. Raghav, S., Seneviratne, J., McKelvie, P. A., Chapman, C., Talman, P. S., & Kempster, P. A. (2007). Sporadic encephalitis lethargica. Journal of Clinical Neuroscience, 14, 696–700. Taylor, J. (1921). Some cases of encephalitis lethargica. The British Journal of Ophthalmology, 1–4. Verschueren, H., & Crols, R. (2001). Bilateral substantia nigra lesions on magnetic resonance imaging in a patient with encephalitis lethargica. Journal of Neurology, Neurosurgery and Psychiatry, 71(2), 275.

VON HIPPEL–LINDAU SYNDROME & 749

VON

HIPPEL–LINDAU SYNDROME

DESCRIPTION

von Hippel–Lindau syndrome (VHL) is so named for the two researchers most linked with its discovery and delineation as a syndrome. Eugene von Hippel originally discovered hemangioblastomas (benign tumors that are cystic in nature that occur throughout the central nervous system [CNS]) involving the retina. Twenty years later, Arvid Lindau made the connection between retinal, cerebral, and visceral hemangioblastomas (Morantz & Walsh, 1993). The VHL gene is a tumor suppressor gene commonly found in different areas throughout the body. As a result, tumors commonly occur in many different sites throughout the body. In the brain, hemangioblastomas occupy space and compress the fourth ventricle. The initial effects can be ataxia of gate or ataxia of one side of the body. Other signs might include increased intracranial pressure, retinal angioma, or hepatic and pancreatic cysts. The last two symptoms are normally verified through imaging such as MRI or CT and will be further discussed in association with VHL. VHL is a genetic syndrome that can be traced through familial descent in approximately 75% of cases (Morantz & Walsh, 1993). Through genetic mapping it has been determined that VHL is a problem with the third chromosomal arm. This relatively common (compared with other genetic disorders) autosomal disorder has been estimated to occur in 1 in 35,000 individuals (Greenburg & Cheung, 2005). In many cases, this syndrome presents later in life, but is not isolated to later life. The syndrome presents in different ways and there are a variety of ways to diagnose the disorder. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Diagnosis needs to take into account two different variations when attempting to understand the clinical presentation. The first type of presentation occurs in those who have no familial history of VHL. These patients have the simplex version and are completely diagnosed based on their symptom presentation. This should include at least two of the following: retinal hemangioblastomas, multicystic renal disease, renal cell carcinoma, pheochromocytoma, pancreatic cysts, epididymal cysts, cerebellar hemangioblastomas, and/or hemangioblastomas of other CNS locations (e.g., cortex, brainstem, spinal cord) (Morantz & Walsh, 1993). In the familial version of the syndrome,

the patient only needs to have one of the above-mentioned symptoms and a family member with VHL or gene coding for the disorder. The most common method of diagnosis is through the identification of retinal hemangioblastomas, which occur in a majority of the cases. Presentation of the retinal hemangioblastomas can begin without symptoms but in most cases retinal detachment occurs. Common techniques for establishing the criterion mentioned above involve the use of CT and MRI scans. These types of scans have the ability to view CNS tumors, pheochromocytomas (tumor of the adrenal glands or extra chromaffin cells), and endolymphatic tumors (tumors of the endolymphatic sac inside the ear). Both T-1 and T-2 MRIs are used. The use of ultrasound is also warranted in cases of epididymis and broad ligament or for kidney screening. Other methods used include radioiodine-labeled MIBG, PET, and urinary catecholamine metabolites. Genetic testing has also been used in order to confirm diagnosis by looking for the factors associated with familial version and for prenatal testing. Genetic testing has been advised for all individuals who are thought to have VHL (Rasmussen et al., 2006). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The effects of VHL on neuropsychological assessment have not been formally analyzed due to the semi-rare nature of the disorder. The neurological symptoms associated with VHL occur from the CNS pathology that occurs in concert with the syndrome. VHL has CNS pathology within the cerebellum. Although many of the tumors occur in the CNS, the location and the pressure that they exert cause both peripheral and central symptoms. The location of any tumors in the spinal cord must also be taken into account when looking at the physical symptoms of the syndrome. The cerebellum is associated with coordinated movement; tumors here usually lead to some type of ataxic movement. Neurological signs associated with VHL include various manifestations of ataxia as well as slurred speech and nystagmus. Consequently, these symptoms would be expected to affect the results of neuropsychological testing that require motor movements or visual motor skills. If the ataxia occurs on one side of the body, symptoms of lateralized motor problems can be generated. Furthermore, slurred speech could interfere with any verbal tests, especially those involving expressive speech and verbal fluency. If nystagmus is present, it could be difficult for the person to complete subtests that require any type of fine vision. In cases where hydrocephalus

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develops, there can be diffuse and global changes in cognitive abilities. Within this context, confusional states, feeling cloudy, and memory impairment are all possible symptoms. Agitation and vomiting can also occur, as well as personality change. DIAGNOSIS

As mentioned, the syndrome requires one or two symptoms depending upon the familial status. The patient’s symptoms must include one or two of the following: retinal hemangioblastomas, multicystic renal disease, renal cell carcinoma, pheochromocytoma, pancreatic cysts, epididymal cysts, cerebellar hemangioblastomas, and/or hemangioblastomas of other CNS locations (Morantz & Walsh, 1993). This presentation should be confirmed through either MRI and/or CT in order to better understand the symptom presentation. Furthermore, the confirmation should include genetic testing because it is highly reliable and could also help to take preventative measures in the future for the individual and their family. EEG and ultrasound can also help because of their diagnostic abilities. Ultrasound is an efficacious diagnostic tool as it permits the viewing of the kidneys for different pathologies associated with the disorder. In comparison, EEG will sometimes have nonspecific slowing of the wave patterns that may serve to demonstrate a pathological course. As a hallmark of the disorder, it is important to also note when attempting to diagnose VHL that cysts occur in the viscera of most people and therefore cannot be the sole diagnosing feature. The ability to differentially diagnose this disorder from other similar disorders is apparent. The complexity of the symptoms and the pervasive nature of the VHL tumor suppressor gene make the non-CNSaffected sites look similar to other disorders. Hay, Haywood, Levin, and Sondheimer (2000) noted that there are a wide variety of lethal disorders in children, which can present similar to VHL. However, the likelihood of a person developing VHL before 15 is low. Given the diagnostic complexity surrounding the disorder, in the more complex cases of VHL, it is important to use genetic testing to verify the disorder. Another important marker associated with the disorder is the lack of cutaneous abnormalities.

Although the disorder is listed under the cutaneous class of disorders it has no cutaneous abnormalities. The absence of such symptoms allows VHL to be separated from other disorders like Birt–Hogg–Dube´ (BHD) syndrome and hereditary leiomyomatosis, as well as renal cell cancer (HLRCC), a disorder that overlaps with VHL but will be accompanied by cutaneous malformations.

TREATMENT

Treatment of VHL begins with preventative measures and scans. If an individual has a family history of the disorder it is extremely important to get scanned continually for the different types of hemangioblastomas mentioned above. As mentioned above, the preventative genetic testing allows for knowledge regarding an individual who may develop VHL. Along with the scanning techniques, eye examinations should be conducted because of the high likelihood of retinal hemangioblastomas. These can be treated through surgical intervention or laser removal. These detection methods can help identify the signs of the disorder prior to the physical and psychological symptoms occurring. In the case of cerebral hemangioblastomas the utmost caution must be taken, as symptoms may not develop due to their commonly benign nature. If these symptoms are observed, surgical intervention may be warranted. David M. Scarisbrick Charles Golden Greenburg, A., & Cheung, A. K. (2005). Primer on kidney diseases. Elsevier Health Sciences. Hay, W. W., Haywood, A. R., Levin, M. J., & Sondheimer, J. M. (2000). Current pediatric diagnosis & treatment. McGraw-Hill Professional. Morantz, R. A., & Walsh, J. W. (1993). Brain tumors: A comprehensive text. Informa Health Care. Rasmussen, A., Nava-Salazar, S., Yescas, P., Alonso, E., Revuelta, R., Ortiz, I., et al. (2006). Von Hippel-Lindau disease germline mutations in Mexican patients with cerebellar hemangioblastoma. Journal of Neurosurgery, 104, 389–394.

W WALLENBERG’S SYNDROME DESCRIPTION

Wallenberg’s syndrome (also known as lateral medullary syndrome) is one of the most commonly recognized conditions resulting from brainstem infarction (Rigueiro-Veloso, Pego-Reigosa, Bran˜as-Ferna´ndez, Martı´nez-Va´zquez, & Corte´s-Laı´n˜o, 1997). The condition also commonly involves the posterior cerebellar regions, and therefore is also often characterized as posterior inferior cerebellar artery syndrome. The condition is caused by infarction of the brainstem involving the dorsolateral medulla (Ross, Biller, Adams, & Dunn, 1986), and onset is often progressive, typically occurring after the age of 40, and one study identified a predominance of middle-aged men (age range 30–78 years) among patients presenting with Wallenberg’s syndrome (Rigueiro-Veloso et al., 1997). A variety of cerebrovascular risk factors, including hypertension, hypercholesterolemia, and diabetes are often present prior to the cerebrovascular event resulting in Wallenberg’s syndrome, and arterial hypertension is known to be the primary risk factor (52%; Rigueiro-Veloso et al., 1997). Despite the higher prevalence of Wallenberg’s syndrome due to cerebrovascular accident, cases of symptom emergence resulting from brain tumor have also been reported (Hanyu, Yoneda, Katsunuma, Miki, & Miwa, 1990). Clinical outcome is often favorable, although death secondary to either respiratory or cardiac failure has been previously described but is uncommon (Hanyu at al., 1990; Rigueiro-Veloso et al., 1997). Additional lesions within the cerebellum are possible, as noted above, resulting in a similar pattern of clinical symptoms. However, further complications including acute hydrocephalus resulting from brainstem compression are also common with this combined syndrome type (Ross et al., 1986). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Wallenberg’s syndrome results from infarction within the arterial supply of the medulla. More specifically, the condition results from vertebral artery occlusion

and infarction of the lateral medulla posterior to the inferior olivary nucleus (Nowak & Topka, 2006). Posterior cerebellar infarction is also common. Consequently, the neuropsychiatric and neurocognitive sequelae of Wallenberg’s syndrome appears to be attributable to corticocerebellar circuits connecting the ventral posterior cerebellum to associative (parietal) and paralimbic cortical areas (Exner, Weniger, & Irle, 2004). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Wallenberg’s syndrome manifests in a collection of symptoms including vertigo and dizziness (91%), cerebellar gait ataxia (88%), dysphagia (61%), dysphonia (55%), Horner’s syndrome (73%), and sensory abnormalities including facial (85%) and hemibody (94%) sensory changes (Kim, Lee, Suh, & Lee, 1994; Zhang, Liu, Wan, & Zheng, 2008). Approximately 25% of patients presenting with lateral medullary infarction also later develop central poststroke pain (Kim, 2007). Although investigation fails to suggest a significant role of the medulla in cognitive processing, research has demonstrated the importance of the cerebellum for higher-order cognitive processing, to which deficits in reasoning, executive function, and memory may be attributed. As such, the cognitive symptoms may reach sufficient severity to warrant a diagnosis of dementia (Chafetz, Friedman, Kevorkian, & Levy, 1996). Previous work has also documented a particularly specialized role of the posterior cerebellum in both cognitive and affective processing (Schmahmann & Sherman, 1998; cerebellar cognitive affective syndrome); in contrast, individuals with lesions in the superior or anterior cerebellar regions tend to remain cognitively and behaviorally unaffected. However, infarction of the posterior inferior cerebellar artery results in deficits noted in the areas of executive functioning, visuospatial ability, memory function, and neuropsychiatric/personality changes including affective blunting. More recent work (Exner et al., 2004) has demonstrated a similar pattern of memory impairment, with visuospatial, working, and episodic memories preferentially impaired in combination with emotional

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withdrawal noted in subjects with focal posterior cerebellar lesions (i.e., individuals with lesions in the posterior inferior cerebellar artery territory). This effect appears to be specific to the posterior cerebellar regions, as similar findings were not demonstrated for lesions within the superior cerebellar artery. Lesion size was not responsible for these cognitive findings, and, in fact, subjects with superior cerebellar lesions were virtually identical to control subjects in both cognitive and affective functioning. DIAGNOSIS

The diagnosis of Wallenberg’s syndrome is done by clinical observation (i.e., signs) as well as the patient’s report of physical symptoms, although clinical confirmation using neuroradiological methods are often employed for diagnostic support. CT imaging appears to be insufficient for the evaluation of medullary lesions, although MRI has been found to be a more useful method for correlating neuropathological diagnosis with clinical symptoms (Ross et al., 1986). One prior report (Ross et al., 1986) indicated the presence of medullary infarction using MRI, but not CT, in four patients with clinical diagnosis of Wallenberg’s syndrome. Axial-plane MRI results also revealed cerebellar infarction of three of the four patients without CT or clinical evidence of cerebellar infarction. This latter finding was particularly revealing, as symptoms associated with coexisting cerebellar lesions often mimic medulla infarction, which may obscure clinical diagnosis and prognostic implications as the secondary lesion may provoke serious and life-threatening complications. A second prior MRI study (Kim et al., 1994) found that symptoms of nausea and vomiting as well as Horner’s sign were common regardless of the lesion location. Rostral medullary lesions were often associated with presence of facial paresis, severe dysphagia, and hoarseness, although caudal lateral medullary lesions were observed in the presence of notable vertigo, nystagmus, and gait ataxia. Ventromedially extending lesions often correlated with contralateral facial sensory change. The investigators concluded that rostrocaudal and dorsoventral MRI findings allows foranato micro-clinical correlations in the evaluation of lateral medullary stroke syndrome patients. A final study (Rigueiro-Veloso et al., 1997) that employed a larger sample revealed positive MRI findings for 22 of the 23 subjects studied. More advanced neuroimaging methods, including diffusion-weighted imaging, have been used to image patients presenting with Wallenberg’s lateral

medullary syndrome. In one recent study (Kitis, Calli, Yunten, Kocaman, & Sirin, 2004), 13 patients presenting in acute or subacute clinical stages underwent diffusion-weighed imaging and results indicated posterolateral medullary localization (positive scan) for 12 of the 13 subjects who underwent imaging. The false-negative result occurred in a patient imaged 10 hr following the onset of symptoms. Clinical observation of imaging results indicated improved detection of normal versus infarcted regions for the high b-value images when compared with the apparent diffusion coefficient map. Researchers concluded that diffusion-weighted neuroimaging is an effective method for examining patients presenting with signs and symptoms of Wallenger’s syndrome, although disease detection for patients within the hyperacute stage of the syndrome remains unclear. TREATMENT

In regard to treatment, compensatory strategies for improving cognitive impairment resulting from cerebellar dysfunction have been attempted. Memory strategies might include the use of external memory devices, such as electronic organizers, whereas rehabilitative strategies for higher cognitive functions such as executive functioning may include implementing increased daily/activity structure. For cases in which new learning is impaired, behaviorally based forms of rehabilitation relying upon development of newly conditioned associations may be warranted (Chafetz et al., 1996). Treatment for noncognitive functional deficits has also been attempted. In particular, bulbar pain (dysesthesia on the opposite side of the body) caused by lateral medullary infarct may be attenuated with stimulation therapy. In one study (Katayama, Tsubokawa, & Yamamoto, 1994), four subjects underwent thalamic stimulation and three underwent motor cortex stimulation. Although pain control was not obtained by thalamic stimulation, two of the three subjects treated with motor cortex stimulation reported satisfactory pain control. Researchers concluded that motor cortex stimulation was significantly more useful than thalamic stimulation for controlling deafferentation pain secondary to lesion of the central nervous system. Jessica Foley Charles Golden Chafetz, M. D., Friedman, A. L., Kevorkian, C. G., & Levy, J. K. (1996). The cerebellum and cognitive function: Implications for rehabilitation. Archives of Physical Medicine Rehabilitation, 77, 1303–1308.

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Exner, C., Weniger, G., & Irle, E. (2004). Cerebellar lesions in the PICA but not SCA territory impair cognition. Neurology, 63, 2132–2135. Hanyu, H., Yoneda, Y., Katsunuma, H., Miki, T., & Miwa, T. (1990). Wallenberg’s syndrome caused by a brain tumor — a case report and literature review. Rinsho Shinkeigaku, 30, 324–326 Katayama, Y., Tsubokawa, T., & Yamamoto, T. (1994). Chronic motor cortex stimulation for central deafferentation pain: Experience with bulbar pain secondary to Wallenberg syndrome. Stereotactic and Functional Neurosurgery, 62, 295–299. Kim, J. S. (2007). Medial medullary infarct aggravates central poststroke pain caused by previous lateral medullary infarct. European Neurology, 58, 41–43. Kim, J. S., Lee, J. H., Suh, D. C., & Lee, M. C. (1994). Spectrum of lateral medullary syndrome. Correlation between clinical findings and magnetic resonance imaging in 33 subjects. Stroke, 25, 1405–1410. Kitis, O., Calli, C., Yunten, N., Kocaman, A., Sirin, H. (2004). Wallenberg’s lateral medullary syndrome: Diffusion-weighted imaging findings. Acta Radiologica, 45(1), 78–84. Nowak, D. A., & Topka, H. R. (2006). The clinical variability of Wallenberg’s syndrome: The anatomical correlate of ipsilateral axial lateropulsion. Neurology, 53, 507–511. Rigueiro-Veloso, M. T., Pego-Reigosa, R., Bran˜as-Ferna´ndez, F., Martı´nez-Va´zquez, F., & Corte´s-Laı´n˜o, J. A. (1997). Wallenberg syndrome: A review of 25 cases. Revista de Neurologia, 59, 211–215. Ross, M. A., Biller, J., Adams, H. P., & Dunn, V. (1986). Magnetic resonance imaging in Wallenberg’s lateral medullary syndrome. Stroke, 17, 542–545. Schmahmann, J. D., Sherman, J. C. (1998). The cerebellar cognitive affective syndrome. Brain, 121, 561–579. Zhang, S. Q., Liu, M. Y., Wan, B., & Zheng, H. M. (2008). Contralateral body half hypalgesia in a patient with lateral medullary infarction: Atypical Wallenberg syndrome. European Neurology, 59, 211–215.

WEGENER’S GRANULOMATOSIS DESCRIPTION

Wegener’s granulomatosis is a form of vasculitis, a disorder characterized by inflammation of the blood vessel(s), involving either the arteries or the veins. The inflammation, necrosis, and vasculitis in Wegener’s granulomatosis most frequently targets the upper (sinuses, nose, and trachea) and lower respiratory tracts (lungs) and the kidneys. Other organs that can

be affected include the eyes, skin, or peripheral nerves. Along with inflamed blood vessels, Wegener’s granulomatosis also forms granulomas around the blood vessels that can destroy normal tissue. Granuloma is a collection of inflammatory tissue, often a small nodular aggregation of inflammatory cells or a collection of macrophages resembling epithelial cells. Wegener’s granulomatosis is part of a large group of vasculitic syndromes. This group presents with an abnormal type of circulating antibody, antineutrophil cytoplasmic antibodies (ANCAs), and affect small- to medium-sized blood vessels. Wegener’s usually occurs in middle age, but is found in people of all ages. This disease is typically not often found in children, but there have been some cases. Wegener’s granulomatosis is found within both sexes, but is slightly more prevalent in men. The cause of Wegener’s is unknown, but appears to be due to an inflammation-causing event that triggers an abnormal reaction from the immune system. This combination of events may ultimately lead to vasculitis, inflamed and constricted blood vessels, and tissue masses. NEUROPATHOLOGY/PATHOPHYSIOLOGY

The traditional tissue abnormality associated with Wegener’s granulomatosis is inflammation with granuloma formation against a nonspecific inflammatory background. It has been determined that the ANCAs are responsible for the inflammation in Wegener’s. The ANCAs found in the disease are those that react with proteinase 3, an enzyme prevalent in granulocytes. This particular type of ANCA is distinguished as cANCA, where ‘‘c’’ indicates cytoplasmic. In Wegener’s, the lungs are sometimes afflicted with inflammation of the alveoli. Necrotizing granulomatosis can develop and may initially appear as small pus-filled abscesses or necrosis of irregularly shaped areas. Inflammation of the arterial walls may occur (arteritis) and may include small and medium vessels, both arteries and veins. Inflammation of these arteries has been both chronic and acute. Scarring of the vasculature can be permanent. The kidneys are typically affected by lesions causing necrotizing glomerulonephritis in Wegener’s. Necrotizing glomerulonephritis is a form of kidney disease that causes damage to the inner structures of the kidney (glomeruli) that help filter waste and fluid from the blood. Inflammation in the kidneys can be seen around the glomeruli or the small renal arteries. Neurological involvement is quite common in Wegener’s; however, pathologic reports of neurological involvement are not as prevalent. Some available studies have determined that about one half

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of patients with Wegener’s manifested neurologic involvement prior to beginning treatment with cyclophosphamide. A large series study of the neurological involvement in Wegener’s was completed by Nishino, Rubino, DeRemee, Swanson, and Parisi (1993). In their series of 324 patients, most were affected by peripheral or cranial neuropathies. In these neuropathies, cranial nerves II, VI, and VII are most commonly affected by injury compression or extension of the disease. Tissue ischemia may also occur due to the direct effects of inflammation. Overall nervous system involvement in the series included peripheral neuropathy, cranial neuropathy, mononeuritis multiplex, external ophthalmoplegia, seizures, cerebritis, and stroke syndromes. On rare occasions, neurological disorders such as myopathy, aseptic meningitis, and diabetes insipidus have been noted. MRI studies have shown increased dural enhancement in patients with signs of meningeal inflammation. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Wegener’s granulomatosis presents with upper and lower respiratory tract symptoms including sinusitis, nasal ulceration, coughing up blood, and uncomfortable breathing. There may also be hearing loss due to auditory tube dysfunction, sensorineural hearing loss, ulcerations in the mouth, pseudotumors of the eyes, scleritis, conjunctivitis, and subglottic stenosis of the trachea. Renal involvement may be present but is much less common than respiratory tract symptoms. Symptoms related to kidneys include a rapidly necrotizing glomerulonephritis that leads to chronic renal failure. This manifests itself through excess proteins in the urine (proteinuria), blood in the urine (hematuria), and renal insufficiency. Fever, weight loss, and anorexia may be present in the systemic version of the disease. Neurological presentations are variable and focus on the impact of Wegener’s on the central nervous system. These presentations include seizures, altered cognition, stroke syndromes, and focal motor and sensory complaints. They may involve chronic, acute, or a stepwise deterioration of tissue inflammation and scarring. This may also be seen in peripheral nerve syndromes and cranial neuropathies related to the disease. Presentation of headaches may be a sign of Wegener’s due to parenchymal and meningeal inflammation. DIAGNOSIS

Initial signs of Wegener’s granulomatosis are variable and diagnosis may be delayed due to the nonspecific

nature of the symptoms. Wegener’s is a suspected diagnosis when there is a presentation including upper respiratory tract symptoms such as chronic sinusitis and/or nasal ulceration, or lower respiratory tract symptoms including coughing up blood (hemoptysis), uncomfortable breathing (dyspnea), or cough. Determination of ANCAs can aid in diagnosis, but positive ANCAs are not conclusive to diagnosis and negative ANCAs are not enough to dismiss the diagnosis. In order to determine ANCAs related to Wegener’s, cytoplasmic staining is used. If the ANCAs react with proteinase 3 in neutrophils, they are typically associated with Wegener’s. If a patient presents with renal failure or skin vasculitis, these would be the most obvious organs to biopsy. On a rare occasion, a lung biopsy may be needed. A biopsy will show leukocytoclastic vasculitis and clumps of typically arranged white blood cells. Many biopsies, however, are nonspecific and provide too little information for diagnosis. Criteria for diagnosis include a granulomatous inflammation involving the respiratory tract and a vasculitis of small- to medium-sized vessels. In addition, there must be nasal or oral inflammation (ulcers or nasal discharge), abnormal chest X-ray with nodules, infiltrates or cavities, urinary sediment, and granulomatous inflammation. Differential diagnosis for this disorder is extensive. Other forms of vasculitis can present with very similar symptoms and the antibodies can be positive after certain drug usage. Some differentials include sarcoidosis and neuropathy, complex partial seizures, cerebellar hemorrhage, diabetic neuropathy, multiple sclerosis, cerebellar aneurysms, amyotrophic lateral sclerosis, and acute disseminated encephalomyelitis. Other problems that may need to be differentiated include lymphoma, neurosyphilis, lymphomatoid granulomatosis, carotid disease, and stroke.

TREATMENT

Before medication regimens were determined, Wegener’s was uniformly fatal. However, Wegener’s granulomatosis is now typically treated with various medication regimens using immunosuppressants with a much better prognosis. Most often, a combination of steroids and antimetabolites (i.e., cyclophosphamide, azathioprine, or methotrexate) may prove useful in treating Wegener’s. Antimetabolites inhibit cell growth and proliferation and have some immunosuppressant qualities to them. Cyclophosphamide is now the usual drug for bringing about remission. Cyclophosphamide is administered through pulse IV

WERNICKE–KORSAKOFF SYNDROME & 755

as the standard administration due to the toxicity of the oral version of the medication. Azathioprine is used as initial therapy if the patient is unable to tolerate cyclophosphamide; however, it is usually used as maintenance therapy. Cyclophosphamide is an alkylating agent with potential toxicity to bone marrow, liver, and bladder. Azathioprine is an agent that inhibits DNA, RNA, and protein synthesis and antagonizes purine metabolism. This drug may also decrease autoimmune activity by decreasing the spreading of the immune cells in the body. If the disease is in the severe stages, plasmapheresis may be beneficial. This involves removal, treatment, and return of (components of) blood plasma from blood circulation. Due to the possible side effects of the drugs, doctors may prescribe additional drugs to help prevent the side effects from occurring. These drugs include ones such as trimethoprim/ sulfamethoxazole (Bactrim or Septra) to prevent infection of the lungs, bisphosphonates (Fosamax) to prevent osteoporosis associated with prednisone and other steroids, and folic acid (vitamin B) to prevent sores and other depletion of folate in the body. Finally, surgery may be needed if there has been organ failure as a result of Wegener’s granulomatosis (i.e., kidney transplant to restore proper renal function). Erin L. Tireman Charles Golden

WERNICKE–KORSAKOFF SYNDROME DESCRIPTION

Carl Wernicke in 1881 was the first to describe a triad of symptoms observed in three patients including a rapid progression of weakness of eye muscles, abnormal gait, and changes of mood, a syndrome now known as Wernicke’s encephalopathy (WE). Shortly thereafter, S. S. Korsakoff (1887) published of a series of articles that described an amnesic syndrome, now commonly referred to as Korsakoff syndrome (KS) (both cited in Victor, Adams, & Collins, 1989). In a subsequent 1889 article, Korsakoff described symptoms of peripheral nerve damage starting with paralysis beginning in the lower extremities then continuing to the arms, trunk, bladder, and diaphragm as well as psychic symptoms including irritability, confusion, and disturbances of memory, particularly recent memories (cited in Victor & Yakovlev, 1955). It has become evident that WE and

KS are two aspects of the same disease process but manifested at different points along a continuum of severity and chronicity. A majority of alcoholic patients who survive acute WE develop KS; however, nonalcoholic WE rarely develops into Korsakoff psychosis. The mortality rate of WE is 17–20%, and 85% of survivors develop KS (Victor et al., 1989). WE commonly occurs in chronic alcoholics but has also been documented in adults following bariatric surgery, gastrointestinal (GI) carcinoma, HIV/ AIDS, and any disease in which nutrient absorption is compromised. Wernicke–Korsakoff syndrome (WKS) has also been documented in pediatric patients with cancer, GI diseases, food allergy, and malnutrition (Vasconcelos et al., 1999). NEUROPATHOLOGY/PATHOPHYSIOLOGY

In the 1930s, it was established that animals deprived of vitamin B1, thiamine, developed ‘‘biochemical lesions’’ similar to those seen in WE and KS (Peters, 1936). Further studies have confirmed that WE and Korsakoff amnesia are the result of chronic thiamine deficiency. Thiamine is absorbed by the GI tract, and it is possible that chronic alcohol consumption may lead to impairments in the absorption of thiamine. The body stores enough thiamine to last 4–6 weeks after which time symptoms of WE may be seen. Thiamine crosses the blood–brain barrier via active and passive transport. Active transport of thiamine occurs at approximately the same rate at which thiamine is used by the brain (0.3 g/h/g) (Cook, Hallwood, & Thomson, 1998). Two thiamine-dependent enzymes, -ketoglutarate (KGDH) and transketolase (TK), have been implicated in symptoms and lesions of WKS. A reduction in thiamine leads to a subsequent reduction in KGDH, a rate-limiting enzyme of the citric acid cycle involved in glucose metabolism. In addition, reduction of KGDH may be responsible for increased lactate in the brain, which may play an important role in the formation of biochemical lesions that are characteristic of WKS (Butterworth, 1989, 1995, 2003; Hazell & Butterworth, 2009). It has also been suggested that KGDH is associated with increased nitric oxide production that has also been implicated in neuronal damage. TK is a second thiamine-dependent enzyme believed to be involved in symptoms of WKS. TK is involved in the synthesis of components that are essential for the reduction of nicotinamide adenine dinucleotide phosphate (NADPH). Important cellular functions are lost with the reduction of TK (Butterworth, 1995). In one study, investigators found that in rats treated with pyrithiamine, a

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thiamine antagonist, 36% showed a reduction in alphaketoglutarate dehydrogenase and abbreviated (-KGDH) and up to 69% showed a reduction in TK. The animals were then treated with thiamine at which time KGDH activity returned to normal, but TK activity remained 30% lower. The authors suggested that KGDH may be responsible for reversible symptoms and functional lesions by impaling ACh synthesis but that TK is responsible for more permanent lesions (Gibson, Ksiezak-Reding, Sheu, Mykytyn, & Blass, 1984). Glutamatergic neurotransmission has also been implicated in WKS. Alcohol acts as an N-methylD-aspartic acid receptor antagonist disallowing stimulation of the receptor via calcium influx (Tsai, Gastfriend, & Coyle, 1995). Butterworth (2003) suggested that the best current explanation for this degeneration is a down-regulation of glutamate transporters leading to an increase in radical oxygen and nitrous oxide. Wernicke reported autopsy findings showing lesions of the gray matter around the third and fourth ventricles as well as the cerebral aqueduct. Research using MRI shows that WKS is associated with lesions of the diencephalon, particularly the periventricular area of the third ventricle (Zuccoli et al., 2007), the medial thalamus, the periaqueductal region of the midbrain, the mamillary bodies, and the caudate nuclei (Zhong, Jin, & Fei, 2005). Neuroimaging studies have found reduction in the volume of mamillary bodies and thalamus (Reed et al., 2003). Other research has indicated cerebellar atrophy in approximately 26.8% of patients with WKS (Torvik & Torp, 1986). Lesions of the cerebellar vermis found in WKS may be responsible for ataxic symptoms (Zuccoli et al., 2007). In another study of patients with WE, the medial mamillary nucleus showed the greatest neuronal loss, but severe losses in the medial dorsal nucleus were also found. In addition, the authors found damage to the anterior principal nucleus and concluded that damage to this area is a requirement for amnesia to develop (Harding, Halliday, Caine, & Kril, 2000). Another study showed that increased signals or enhancement of the paramedian thalamus or the mamillary bodies on MRIs of patients with WE were associated with significantly worse outcome, with three of four patients developing KS even after thiamine treatment (Weidauer, Nichtweiss, Lanfermann, & Zanella, 2003). Reed et al. (2003) examined fluorodeoxyglucosepositron emission tomography (FDG-PET) scans from Korsakoff patients compared with controls and found significant white matter hypermetabolism, specifically in the frontotemporal lobes, which they suggested may be due to inflammatory process or subsequent glial proliferation. In addition, they found hypometabolism

of the retrosplenial and medial temporal regions with no atrophy in medial temporal volume, suggesting that changes in the metabolism of this region are not solely due to atrophy of the tissue. Finally, they found hypometabolism in the cortical tissue of the frontotemporal lobe that was directly related to atrophy in that area in one-third of the patients they examined. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Crowe and El Hadj (2002) investigated the effects of thiamine deficiency coupled with alcohol exposure in chicks and found permanent and irreversible memory dysfunction that remained even following subsequent thiamine treatment. In a study with rats, animals exposed to thiamine deficiency and alcohol did not meet criteria for a learning task. The authors conclude that this suggests a synergistic effect of alcohol and thiamine deficiency (Ciccia & Langlais, 2000). Wechsler Adult Intelligence Scale (WAIS-III) and Wechsler Memory Scale (WMS-III) scores from 10 participants diagnosed with KS indicated that intelligence quotients remain relatively intact (PIQ ¼ 92.2; VIQ ¼ 94.5; PSI ¼ 88.2) as do working memory scores (97.8); however, the mean general memory score was 57.8 with a range from 45 to 66 and auditory immediate memory scores averaged 73.1. Results suggest that attention and working memory remain relatively intact, but patients with WKS suffer severe deficits in encoding and storage of information (Psychological Corporation, 1997). Another study found that patients with alcoholic KS had deficits in longterm memory and some executive functions including verbal fluency and working memory but that cognitive abilities remained stable over 2 years. Jacobson and Lishman (1987) examined performance of 38 Korsakoff patients on memory and intelligence tests and found that 63% demonstrated marked deficits in memory with small decline of intellectual functioning; 22% showed only mild impairments in memory and IQ scores; and 11% demonstrated marked deficits in both memory and intelligence scores. DIAGNOSIS

WE has classically been recognized by the triad of symptoms first described by Wernicke in 1881: opthalmoplegia, ataxia, and a global confusional state. However, more recent literature has recognized that relying on this full triad of symptoms as the diagnostic marker leads to misdiagnosis of up to 80% of cases (Butterworth, 2003). In one study, researchers found that only 10% of patients presented with all three

WERNICKE–KORSAKOFF SYNDROME & 757

symptoms. A literature review revealed that disorientation is the most common symptom observed in up to 82% of this population, poor memory in 30%, ataxia presented in 23%, and nystagmus or ophthalmoplegia presented in 29% of cases (Harper, Giles, & FinalyJones, 1986). In 1997, Caine, Halliday, Kril, and Harper operationalized the criteria for WKS stating that, in order for WE to be diagnosed, at least two of four criteria must be met: dietary deficiencies, eye signs, cerebellar signs, or memory impairment. They also concluded that for WKS to be diagnosed, patients must fulfill the criteria for WE, and have documented evidence of amnesia or disorientation in the absence of an acute confusional state. Using these criteria, they found that patients with WE shared a progressive course of deterioration with a maximum survival of 3 years; however, patients with WKS lived longer. Differential diagnosis between WKS and Alzheimer’s disease may be made in several ways. One way is that patients with WKS do not have plaques as seen in Alzheimer patients. Also, the operational criteria aforementioned enable clinicians to diagnose WKS with high sensitivity and specificity. Finally, lesions of the areas surrounding the third and fourth ventricles are characteristic of WKS.

TREATMENT

Administration of vitamin B1 has been effective in reversing some of the symptoms of WKS. However, oral administration may not be sufficient because chronic alcohol consumption reduces thiamine transport in the GI tract. Oral and parenteral thiamine are not equally available to the brain, and it is recommended that thiamine be delivered via IM or IV for the treatment of WKS (Tanev, Roether, & Yang, 2009). Thiamine has been effective at not only ameliorating some of the symptoms of Wernick–Korsakoff syndrome, but has also demonstrated effective reduction of lesions (Zhong et al., 2005). In one patient who developed symptoms of WE after bariatric surgery, oral thiamine was not effective in preventing an acute episode of WE from occurring. It is recommended that thiamine be delivered either intramuscularly or intravenously for 6 weeks postsurgery (Loh et al., 2004). One method of prevention proven relatively effective in some countries is the enrichment of thiamine into staple foods such as bread flour (Harper & Matsumoto, 2005). Mandi Musso Alyse Barker William Drew Gouvier

Butterworth, R. F. (1989). Effects of thiamine deficiency on brain metabolism: Implications for the pathogenesis of the Wernicke-Korsakoff syndrome. Alcohol & Alcoholism, 24(4), 271–279. Butterworth, R. F. (1995). Pathophysiology of alcoholic brain damage: Synergistic effects of ethanol, thiamine deficiency and alcoholic liver disease. Metabolic Brain Disease, 10(1), 1–8. Butterworth, R. F. (2003). Thiamine deficiency and brain disorders. Nutrition Research Reviews, 16, 277–283. Caine, D., Halliday, G. M., Kril, J. J., & Harper, C. G. (1997). Operational criteria for the classification of chronic alcoholics: Identification of Wernicke’s encephalopathy. Journal of Neurology, Neurosurgery, and Psychiatry, 62(1), 51–60. Ciccia, R. M., & Langlais, P. J. (2000). An examination of the synergistic interaction of ethanol and thiamine deficiency in the development of neurological signs and long-term cognitive and memory impairments. Alcoholism: Clinical and Experimental Research, 24(5), 622–634. Cook, C. C. H., Hallwood, P. M., & Thomson, A. D. (1998). B vitamin deficiency and neuropsychiatric syndromes in alcohol misuse. Alcohol & Alcoholism, 33(4), 317–336. Crowe, S. F., & El Hadj, D. (2002). Phenytoin ameliorates the memory deficit induced in the young chick by ethanol toxicity in association with thiamine deficiency. Pharmacology Biochemistry and Behavior, 71(1–2), 215–222. Gibson, G. E., Ksiezak-Reding, H., Sheu, K. R., Mykytyn, V., & Blass, J. P. (1984). Correlation of enzymatic, metabolic, and behavioral deficits in thiamin deficiency and its reversal. Neurochemical Research, 9(6), 803–814. Harding, A., Halliday, G., Caine, D., & Kril, J. (2000). Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia. Brain, 123, 141–154. Harper, C. G., Giles, M., & Finaly-Jones, R. (1986). Clinical signs in the Wernicke-Korsakoff complex: A retrospective analysis of 131 cases diagnosed at necropsy. Journal of Neurology, Neurosurgery, and Psychiatry, 49, 341–345. Harper, C., & Matsumoto, I. (2005). Ethanol and brain damage. Current Opinion in Pharmacology, 5, 73–78. Hazell, A. S., & Butterworth, R. F. (2009). Udpate of cell damage mechanisms in thiamine deficiency: Focus on oxidative stress, excitotoxicity and inflammation. Alcohol & Alcoholism, 44(2), 141–147. Jacobson, R. R., & Lishman, W. A. (1987). Selective memory loss and global intellectual deficits in alcoholic Korsakoff’s syndrome. Psychological Medicine, 17(3), 649–655. Loh, Y., Watson, W. D., Verma, A., Chang, S. T., Stocker, D. J., & Labutta, R. J. (2004). Acute Wernicke’s encephalopathy following bariatric surgery: Clinical course and MRI correlation. Obesity Surgery, 14, 129–132. Peters, R. A. (1936). The biochemical lesion in vitamin B1 deficiency. Application of modern biochemical analysis in its diagnosis. Lancet, 1, 1161–1164.

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Psychological Corporation. (1997). Wechsler Adult Intelligence Scale-third edition and Wechsler Memory Scale-third edition technical manual. San Antonio, TX: Author. Reed, L. J., Lasserson, D., Marsden, P., Stanhope, N., Stevens, T., Bello, F., et al. (2003). FDG-PET findings in the Wernicke-Korsakoff syndrome. Cortex, 39, 1027–1045. Tanev, K. S., Roether, M., & Yang, C. (2009). Alcohol dementia and thermal dysregulation: A case report and review of the literature. American Journal of Alzheimer’s Disease and Other Dementias, 23(6), 563–570. Torvik, A., & Torp, S. (1986). The prevalence of alcoholic cerebellar atrophy: A morphometric and histological study of an autopsy material. Journal of the neurological science, 75(1), 43–51. Tsai, G., Gastfriend, D. R., & Coyle, J. T. (1995). The glutamatergic basis of human alcoholism. The American Journal of Psychiatry, 152(3), 332–340. Vasconcelos, M. M., Silva, K. P., Vidal, G., Silva, A. F., Domingues, R. C., & Berditchevsky, C. R. (1999). Early diagnosis of pediatric Wernicke’s encephalopathy. Pediatric Neurology, 20(4), 289–294. Victor, M., Adams, R. D., & Collins, G. H. (1989) The Wernicke-Korsakoff syndrome and related neurologic disorders due to alcoholism and malnutrition (2nd ed.). Philadelphia, PA: F. A. Davis. Victor, M., & Yakovlev, P. (1955). S. S. Korsakoff’s psychic disorder in conjunction with peripheral neuritis: A translation of Korsakoff’s original article with brief comments on the author and his contribution to clinical medicine. Neurology, 5, 394–406. Weidauer, S., Nichtweiss, M., Lanfermann, H., & Zanella, F. E. (2003). Wernicke encephalopathy: MR findings and clinical presentation. European Radiology, 13, 1001–1009. Wernicke, C. (1881). Die acute haemorrhagische polioencephalitis superior. In Lehrbuch der Gehirn Krankheiten Fr Aerzte und studirende (Vol. 2, pp. 229–242). Kassle, Germany: Theodor Fischer. Zhong, C., Jin, L., & Fei, G. (2005). MR imaging of nonalcoholic Wernicke encephalopathy: A follow-up study. American Journal of Neuroradiology, 26, 2301–2305. Zuccoli, G., Gallucci, M., Capellades, J., Regnicolo, L., Tumiati, B., Cabada Giadas, T., et al. (2007). Wernicke encephalopathy: MR findings at clinical presentation in twenty-six alcoholic and nonalcoholic patients. American Journal of Neuroradiology, 28, 1328–1331.

EEG (Akiyama et al., 2005; Asano et al., 2005). In reality, WS is a variant of infantile spasms. The presentation was first described by West in 1841 when he observed a case that he described as a peculiar form of infantile convulsions. The average prevalence is 0.25 per 1,000 children. To date, classification of the core clinical features of WS has been described. The spasms are very brief and usually occur in a series or cluster. The motor involvement is often asymmetric and presents in conjunction with diverted or other pathological eye movements, facial grimaces, or motionless, blank stares (Donat & Wright, 1991; Gaily, Shewmon, Chugani, & Curran, 1995, 1999; Kellaway, Hrachovy, Frost, & Zion, 1979; Watanabe, Toshiko, Tamiko, Kousaburo, & Norihide, 1994). EMG demonstrates a typical diamond-like pattern with a pattern of rapid increasing/decreasing muscle contraction. Over time, psychomotor regression is seen. Symptoms first onset within the first year of life, but cases have been described with a latent onset later in childhood. WS is divided into three groups: symptomatic, cryptogenic and idiopathic (Baselli et al., 1987). The groups are so defined by their etiological roots. When WS arises from identified brain damage it is referred to as symptomatic. Cryptogenic WS is believed to be secondary to brain damage, but the latter has yet to be or is not definitively related to brain damage. Finally, cases are defined as idiopathic when no suggested cause is established and there are no markers of a possible link to brain damage. From a prognosis standpoint, outcomes are mixed. Although spasms dissipate over time with development and maturation, cognitive deficits may persist that stem from the seizure activity and their resulting insults that themselves increase risk of future epileptic disorders (Chugani, 2002). Still yet, some children, particularly those with an idiopathic etiology, may demonstrate remission of seizures in combination with preservation of cognitive deficits (Drury, Beydoun, Garofalo, & Henry, 1995; Dulac et al., 1994). Adrenocorticotropic hormone (ACTH), vigabatrin, and corticosteroids are usually the first line of treatment; however, the presentation can often remain refractory to treatment and these agents often fail to alter outcome (Camfield, Camfield, Lortie, & Darwish, 2003; Chugani & Chugani, 1999).

WEST’S SYNDROME NEUROPATHOLOGY/PATHOPHYSIOLOGY DESCRIPTION

West’s syndrome (WS), often referred to as infantile spasms, is a severe epileptic disease arising in infancy, characterized by spasms and hypsarrhythmia on

WS is characterized by spasms and hypsarrhythmia on EEG (Asano et al., 2005; Avanzini, Panzica, & Franceschetti, 2002). Although hypsarrhythmia is the most commonly noted feature on EEG, asymmetric or hypersynchronous presentations, and the presence

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of consistent epileptic foci may be noted instead (Drury et al., 1995; Panzica-Hrachovy, Frost, & Kellaway, 1984; Hrachovy & Frost, 2006). Seizures and spasms present in the same ictal sequence, suggesting a common pathophysiological substrate. Ictal discharge commonly arises cortically, with focal origin, and presents with an asymmetric EEG pattern involving rhythmic bursts of fast activity preceding symmetric and asymmetric spasms (Avanzini et al., 2002; Panzica et al., 1999). Focal or diffuse, low- amplitude fast rhythms have also been reported on ictal EEG in association with symptomatic and cryptogenic WS (Asano et al., 2005; Kang et al., 2006; Kobayashi et al., 2004). The occurrence of diffuse, low-amplitude rhythms has suggested the potential of concurrent subcortical activity that some have suggested arises from the brainstem (Fusco & Vigevano, 1993; Vigevano, Fusco, & Pachatz, 2001). Although focal cortical origins may be seen, they are not necessarily tied to specific cortical malformations (Avanzini et al., 2002; Kobayashi et al., 2004; Panzica and Chugani, 1999). For example, Chugani and Chugani (1999) demonstrated that while MRI and CT scans in patients with idiopathic WS remained unremarkable, PET revealed focal cortical abnormalities related to glucose utilization. Following resection of the identified tissue, microscopic analysis revealed subtle malformations and dysplastic cortical lesioning. Anatomically, WS has been associated with diffuse atrophy and delayed myelination. Relative prevalence of lesions arising in the right hemisphere versus the left and in the temporal and/or occipital lobes as opposed to frontal have been reported (Hamano et al., 2000; Koo & Hwang, 1996). Hypometabolism and hypoperfusion in parieto-occipito-temporal areas have been noted on PET and SPECT scans. The corpus callosum may appear thinner than normal. Functional imaging has suggested basal ganglion and brainstem involvement secondary to cortical recruitment (Chugani, 2002; Chugani & Chugani, 1999; Mori et al., 2007; Munakata et al., 2004). In the case of symptomatic WS, in which the presentation arises from neurological disturbance, multiple disorders have been associated with the manifestation of WS, including perinatal hypoxia, viral encephalitis, bacterial meningitis, head injury, vascular disorders, cortical dysplasias, and tuberous sclerosis, among others. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

As previously described, WS is a severe epileptic syndrome arising in infancy and marked by brief,

clustered, asymmetric spasms often seen with additional abnormalities of eye movements, facial grimaces, and/or blank stares (Donat & Wright, 1991; Gaily et al., 1995, 1999; Kellaway et al., 1979; Watanabe et al., 1994). Severe EEG derangement (i.e., hypsarrhythmia) is also seen. These spasms may manifest as forward head nodding, jackknife bowing when sitting (bending over forward from the waist when sitting), and rigid extension of the neck, torso, or extremities among others. Neuropsychological and developmental issues are quite common in association with WS. Over time, following onset of the aforementioned spasms and hypsarrhythmia, psychomotor regression and mental deterioration are noted. However, prior to this, there may be soft signs of impairment. Guzzetta, Frisone, Ricci, Rando`, and Guzzetta (2002) noted that as early as 3 months of age and preceding the onset of spasms, the median DQ on Griffiths’ scales in WS infants was borderline. Following onset of spasms, a general deterioration of cognition was observed, particularly in language competencies. At the time of a 2-year follow-up only minor improvements had been noted. Truly, cognitive impairment seems to occur in the majority of patients, yet variability is seen across patients and even within patients. In infancy, visual impairments have been commonly reported (Guzzetta, Crisafulli, & Isaya Crino`, 1993; Jambaque`, Chiron, Dulac, Raynaud, & Syrota, 1993). Within this domain, visual inattention, decreased acuity, ocular motility, decreased eye contact, and impaired visual scanning skills have all been reported (Brooks, Simpson, Leer, Robertson, & Archer, 2002; Castano, Lyons, Jan, & Connolly, 2000; Guzzetta et al., 2002; Rando´ et al., 2004). Auditory functioning is also commonly affected, having been correlated previously with decreased brainstem auditory evoked potential (Kaga, Marsh, & Fukuyama, 1982). Long-term outcomes in cognition suggest deficits present in approximately 80% of individuals (Riikonen, 2001; Trevathan, Murphy, & Yeargin-Allsopp, 1999). Deficits in memory, attention, and learning have all been reported, even in the presence of preserved or normal intelligence (Gaily et al., 1999). Neurological regression in infancy has also included hypotonia, loss of head control and reaching ability, lack of responsiveness, poor smiling, and decrease of alertness (Guzzetta et al., 1993). Deficits in eye-hand coordination are often below age expectations (Rando´ et al., 2005). Behavioral disorders have been reported at higher rates in WS (Riikonen & Amnell, 1981; Thronton & Pampiglione, 1979). Among these presentations,

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increased risk of autism and autistic features has been noted in the literature (Guzzetta et al., 1993; Jambaque´ et al., 1993). From a prognosis and long-term outcome standpoint, idiopathic WS is associated with the most favorable outcomes. Furthermore, outcomes related to cryptogenic WS are more favorable than in symptomatic WS (Hamano, Tanaka, Mochizuki, Sugiyama, & Eto, 2003; Hamano et al., 2006; Ito et al., 2002; Koo, Hwang, & Logan, 1993; Nabbout, 2001; Yanagaki et al., 1999). Still, long-term deficits have been associated with all variants as discussed above; symptomatic and cryptogenic variants being associated with the greatest deficits. Across all variants, only 16% of patients on average exhibit normal development and over 40% present with neurological deficits with mental retardation being among the most common long-term outcomes; moderate to severe deficits being observed in more than half of patients with cryptogenic or symptomatic forms (Hamano et al., 2003; Ito et al., 2002; Koo et al., 1993). In some cases, the long-term outcomes were related to the timing of treatment initiation, with earlier intervention and seizure management being associated with better outcomes (Koo et al., 1993). When no treatment is received, 75% to 96% of patients present with mental retardation (Jeavons & Bower, 1964). Increased mortality rates have been reported in conjunction with WS, with an average of around 12% including heightened susceptibility to infections that can be serious and even fatal during ACTH treatment (Riikonen, 1993, 1995). DIAGNOSIS

Diagnosis of WS is multifaceted, involving a combination of imaging, EEG, and clinical evaluation and history taking. Regarding the latter, a thorough history is necessary including detailed description of the symptoms and their onset. An MRI is critical as it can identify underlying neurological defects. When no such anomalies are identified, yet EEG and history are suggestive of WS, diagnosis is still made and classified as idiopathic or cryptogenic. PET can be quite valuable in the diagnosis of WS, as it permits detection of functional cortical abnormalities as well as indentifying small lesions not clearly identifiable on CT or MRI. SPECT can also be used in the instance that PET even though it is inferior in comparison with PET. An EEG is essential to the diagnostic workup of WS. As noted, WS presents with EEG patterns characterized by spasms and hypsarrhythmia (Asano et al., 2005; Avanzini et al., 2002). Asymmetric or

hypersynchronous presentations, and the presence of consistent epileptic foci may be noted as may ictal discharge commonly arising cortically, with focal origin, and presenting with an asymmetric EEG pattern involving rhythmic bursts of fast activity preceding symmetric and asymmetric spasms (Avanzini et al., 2002; Drury et al., 1995; Panzica-Hrachovy et al., 1984; Hrachovy & Frost, 2006; Panzica et al., 1999). Again, focal or diffuse low amplitude fast rhythms have been associated with ictal EEG in symptomatic and cryptogenic WS (Asano et al., 2005; Kang et al., 2006; Kobayashi et al., 2004). Video-monitored EEG can aid in better evaluating the seizure characteristics. Neuropsychological evaluation should be sought to document the nature and extent of any neurocognitive deficits as they present in most cases. This is essential to treatment as well in terms of setting up proper educational plans for children as services are often needed. Physical and occupational therapy evaluations may also be sought to document potential psychomotor deficits. Optometry examination should be requested given the high prevalence of visual deficits. Consultation with a neuro-ophthamologist may be required. Auditory examinations are also recommended as such deficits present in higher frequency.

TREATMENT

Medicinal treatment is the most common approach to treatment. ACTH, vigabatrin, prednisolone, and tetracosactide have all shown some efficacy in acute treatment (Camfield et al., 2003; Chugani & Chugani, 1999; Lux et al., 2004). They have demonstrated utility in diminishing seizure activity acutely in a short span of time; however, prolonged use is concerning due to significant side effects. For example, vigabatrin can cause loss or reduction of peripheral vision. Antiepileptic drugs may also be useful, but are discussed less. These include topiramate, valproic acidm felbamate, and lamotrigine. Neurosurgical intervention may be considered if individuals are refractory to medicinal treatment. Beyond medicinal intervention, patients may be aided by a ketogenic diet. Physical and occupational therapy may be needed as individuals present with psychomotor regression early in the disorder do not fully resolve always. Special education services will likely be needed in more than 80% of cases. Necessity of services and type of services required should be based off of assessment findings. Chad A. Noggle

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Akiyama, T., Otsubo, H., Ochi, A., Ishiguro, T., Kadokura, G., Ramachandrannair, R., et al. (2005). Focal cortical high-frequency oscillations trigger epileptic spasms: Confirmation by digital video subdural EEG. Clinical Neurophysiology, 116, 2819–2825. Asano, E., Juhasz, C., Shah, A., Muzik, O., Chugani, D. C., Shah, J., et al. (2005) Origin and propagation of epileptic spasms delineated on electrocorticography. Epilepsia, 46, 1086–1097. Avanzini, G., Panzica, F., & Franceschetti, S. (2002). Brain maturational aspects relevant to pathophysiology of infantile spasms. International Review Neurobiology, 49, 353–365. Baselli, G., Cerutti, S., Civardi, S., Lombardi, F., Malliani, A., Merri, M., et al. (1987). Heart rate variability signal processing: A quantitative approach as an aid to diagnosis in cardiovascular pathologies. International Journal of Biomedical Computing, 20, 51–70. Brooks, B. P., Simpson, J. L., Leer, S. M., Robertson, P. L., & Archer, S. M. (2002). Infantile spasms as a cause of acquired perinatal visual loss. Journal of American Association for Pediatric Ophthalmology and Strabismus, 6, 385– 388. Camfield, P., Camfield, C., Lortie, A., & Darwish, H. (2003). Infantile spasms in remission may reemerge as intractable epileptic spasms. Epilepsia, 44, 1592–1595. Castano, G., Lyons, C. J., Jan, J. E., & Connolly, M. (2000). Cortical visual impairment in children with infantile spasms. Journal of American Association for Pediatric Ophthalmology and Strabismus, 4, 175–178. Chugani, H. T. (2002). Pathophysiology of infantile spasms. Advances in Experimental Medicine and Biology, 497, 111– 121. Chugani, H. T., & Chugani, D. C. (1999). Basic mechanisms of childhood epilepsies: Studies with positron emission tomography. Advances in Neurology, 79, 883–891. Donat, J. F., & Wright, F. S. (1991). Unusual variants of infantile spasms. Journal of Child Neurology, 6, 313–318. Drury, I., Beydoun, A., Garofalo, E. A., & Henry, T. R. (1995). Asymmetric hypsarrhythmia: Clinical electroencephalographic and radiological findings. Epilepsia, 36, 41–47. Dulac, O., Chiron, C., Robain, O., Plouin, P., Jambaque, I., & Pinard, J. M. (1994). Infantile spasms: A pathophysiological hypothesis. Seminars in Pediatric Neurology, 1, 83– 89. Fusco, L., & Vigevano, F. (1993). ICTAL clinical electroencephalographic findings of spasms in West syndrome. Epilepsia, 34, 671–678. Gaily, E., Appelqvist, K., Kantola-Sorsa, E., Liukkonen, E., Kyyro¨nen, P., Sarpola, M., et al. (1999). Cognitive deficits after cryptogenic infantile spasms with benign seizure evolution. Developmental Medicine & Child Neurology, 41, 660–664.

Gaily, E. K., Shewmon, D. A., Chugani, H. T., & Curran, J. G. (1995). Asymmetric and asynchronous infantile spasms. Epilepsia, 36, 873–882. Guzzetta, F., Crisafulli, A., & Isaya Crino`, M. (1993). Cognitive assessment of infants with West syndrome: how useful is it for diagnosis and prognosis? Developmental Medicine & Child Neurology, 35, 379–387. Guzzetta, F., Frisone, M. F., Ricci, D., Rando`, T., & Guzzetta, A. (2002). Development of visual attention in West syndrome. Epilepsia, 43, 757–763. Hamano, S., Tanaka, M., Kawasaki, S., Nara, T., Horita, H., Eto, Y., et al. (2000). Regional specificity of localized cortical lesions in West syndrome. Pediatric Neurology, 23, 219. Hamano, S., Tanaka, M., Mochizuki, M., Sugiyama, N., & Eto, Y. (2003). Long-term follow-up study of West syndrome: differences of outcome among symptomatic etiologies. Journal of Pediatrics, 143, 231–235. Hamano, S., Yamashita, S., Tanaka, M., Yoshinari, S., Motoyuki, M., & Eto, Y. (2006) Therapeutic efficacy and adverse effects of ACTH therapy in West syndrome: Differences in dosage of ACTH, onset of age and etiology. Journal of Pediatrics, 148, 485–488. Hrachovy, R. A., & Frost, J. D. (2006). The EEG in selected generalized studies. Journal of Clinical Neurophysiology, 23, 312–332. Ito, M., Aiba, H., Hashimoto, K., Kuroki, S., Tomiwa, K., Okuno, T., et al. (2002). Low-dose ACTH therapy for West syndrome: initial effects and long-term outcome. Neurology, 58, 110–114. Jambaque´, I., Chiron, C., Dulac, O., Raynaud, C., & Syrota, P. (1993). Visual inattention inWest syndrome: A neuropsychological and neurofunctional imaging study. Epilepsia, 34, 692–700. Jeavons, P. M., & Bower, B. D. (1964). Infantile spasms, a review of the literature and a study of 112 cases. In Clinics in developmental medicine (Vol. 82, pp. 8–25). London: Heineman. Kaga, K., Marsh, R. R., & Fukuyama, Y. (1982). Auditory brainstem responses in infantile spasms. International Journal of Pediatrics Otorhinolaryngology, 4, 57–67. Kang, H. C., Hwang, Y. S., Park, J. C., Cho, W. H., Kim, S. H., Kim, H. D., et al. (2006). Clinical and electroencephalographic features of infantile spasms associated with malformations of cortical development. Pediatric Neurosurgery, 42, 20–27. Kellaway, P., Hrachovy, R. A., Frost, J. D., Jr., & Zion, T. (1979). Precise characterization and quantification of infantile spasms. Annals of Neurology, 6, 214–218. Kobayashi, K., Oka, M., Akiyama, T., Inoue, T., Abiru, K., Ogino, T., et al. (2004). Very fast rhythmic activity on scalp EEG associated with epileptic spasms. Epilepsia, 45, 488–496.

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Koo, B., & Hwang, P. (1996). Localization of focal cortical lesions influences age of onset of infantile spasms. Epilepsia, 37, 1068. Koo, B., Hwang, P. A., & Logan, W. J. (1992). Infantile spasms: Outcome and prognostic factors of cryptogenic and symptomatic groups. Neurology, 43, 2322–2327. Koo, B., Hwang, P. A., & Logan, W. J. (1993). Infantile spasms: Outcome and prognostic factors of cryptogenic and symptomatic groups. Neurology, 43, 2322–2327. Lux, A. L., Edwards, S. W., Hancock, E., Johnson, A. L., Kennedy, C. R., Newton, R. W., et al. (2004). The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: A multicentre, randomised controlled trial. Lancet, 364, 1773–1778. Mori, K., Toda, Y., Hashimoto, T., Miyazaki, M., Saijo, T., Ito, H., et al. (2007). Patients withWest syndrome whose ICTAL SPECT showed focal cortical hyperperfusion. Brain Development, 29, 202–209. Munakata, M., Haginoya, K., Ishitobi, M., Sakamoto, O., Sato, I., Kitamura, T., et al. (2004). Dynamic cortical activity during spasms in three patients with West syndrome: a multichannel near-infrared spectroscopic topography study. Epilepsia, 45, 1248–1257. Nabbout, R. (2001). A risk-benefit assessment of treatments for infantile spasms. Drug Safety, 24, 813–828. Panzica, F., Franceschetti, S., Binelli, S., Canafoglia, L., Granata, T., & Avanzini, G. (1999). Spectral properties of EEG fast activity ICTAL discharges associated with infantile spasms. Clinical Neurophysiology, 110, 593–603. Panzica-Hrachovy, R. A., Frost, J. D., & Kellaway, P. (1984). Hypsarrhythmia: Variations on the theme. Epilepsia, 25, 317–325. Rando´, T., Bancale, A., Baranello, G., Bini, M., De Belvis, A. G., Epifanio, R., et al. (2004). Visual function in infants withWest syndrome: Correlation with EEG patterns. Epilepsia, 45, 781–786. Rando´, T., Baranello, G., Ricci, D., Guzzetta, A., Tinelli, F., Biagioni, E., et al. (2005). Cognitive competence at the onset of West syndrome: correlation with EEG patterns and visual function. Developmental Medicine and Child Neurology, 47, 760–765. Riikonen, R. (1993). Infantile spasms: Infectious disorders. Neuropediatrics, 24, 274. Riikonen, R. (1995). In O. Dulac, H. T. Chugani, & B. Dalla Bernardina (Eds.), Infantile spasms and West syndrome (pp. 216–225). London: W.B. Saunders. Riikonen, R. (2001). Long-term outcome of patients with West syndrome. Brain Development, 21, 683–687. Riikonen, R., & Amnell, G. (1981). Psychiatric disorders in children with earlier infantile spasms. Developmental Medicine & Child Neurology, 23, 747–760. Thornton, E., & Pampiglione, G. (1979). Psychiatric disorders following infantile spasms. Lancet 1(8129), 1297.

Trevathan, E., Murphy, C. C., & Yeargin-Allsopp, M. (1999). The descriptive epidemiology of infantile spasms among Atlanta children. Epilepsia, 40, 748–751. Vigevano, F., Fusco, L., & Pachatz, C. (2001). Neurophysiology of spasms. Brain Development, 23, 467–472. Yanagaki, S., Oguni, H., Hayashi, K., Imai, K., Funatuka, M., Tanaka, T., et al. (1999). A comparative study of highdose and low-dose ACTH therapy for West syndrome. Brain and Development, 21, 461–467. Watanabe, K., Toshiko, H., Tamiko, N., Kousaburo, A., & Norihide, M. (1994). Focal spasms in clusters, focal delayed myelination, and hypsarrhythmia: Unusual variant of West Syndrome. Pediatric Neurology, 11, 47–49.

WHIPLASH DESCRIPTION

Whiplash, a term coined in 1928 by Crowe, constitutes soft-tissue damage to the neck following abrupt flexion or extension often secondary to an automobile accident, sports injury, fall, or assault, typically resulting in neck pain and other assorted symptoms (Crowe, 1964). Motor vehicle accidents as low as 3.6 mph (8.0 km/ hr) have been shown to result in whiplash symptoms (Howard, Bowles, Guzman, & Krenrich, 1998). Due to the complex and confusing symptoms, including no overt evidence of injury and longer periods of disabling symptoms than expected, this syndrome has been debated, criticized, and debunked for over a century (Scaer, 2001). During the 19th and early 20th centuries, this seemingly unusual presentation of symptoms was considered by some practitioners to be a result of psychiatric compensation. However, following research demonstrating pendular effects showing forces 3–4 times greater on the head and neck than those exerted on the body, the medical community has come to recognize this collection of symptoms, which appears to be similar among patients, as a legitimate medical condition (Howard et al., 1998). NEUROPATHOLOGY/PATHOPHYSIOLOGY

Tissues often damaged in such an injury include intervertebral joints, disks, ligaments, cervical muscles, and nerves. Velocity-related injuries can result in minor traumatic brain injury with postconcussion symptoms. The shearing of axons during this event may result in some of the cognitive, somatic, or psychological conditions described below (Rodriguez, Barr, & Burns, 2004).

WHIPLASH & 763

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The primary symptom of whiplash typically includes neck pain, which tends to be focal and spreads to contralateral areas. Additionally, neck stiffness, injuries to the muscles in the face and neck (i.e., myofacial injuries), and shoulder and/or back pain are other common musculoskeletal symptoms. With regard to sensory functions, paresthesias consisting of burning or prickling sensations may occur. Neurologic symptoms typically include headaches and dizziness (Rodriguez et al., 2004). Additional less common symptoms may occur. Infrequent neurologic symptoms may include vertigo, balance problems, fainting, or blurred vision. Neurocognitive dysfunctions may occur and typically includes memory loss and/or concentration impairment secondary to axonal shearing similar to that found in traumatic brain injury. Neurocognitive testing of Grade 3 whiplash (see classification system below) will typically reveal impairments in memory and concentration, with other neurocognitive domains generally remaining intact (Randanov & Dvorak, 1996). Psychiatric disturbances may include nervousness, irritability, sleep disturbances, fatigue, or depression (Randanov & Dvorak, 1996). In general, psychological symptoms appear to be significantly exacerbated by disability and restriction from previous work and leisure activities. Conditions that exacerbate whiplash include being young and involved in contact sports, wearing a seatbelt with a shoulder restraint (which prevents other injuries), poor posture, poor head restraints, being female (likely due to less developed neck muscles), and congenital or acquired narrowing of the cervical spinal canal (Lankester, Garneti, Gargan, & Bannister, 2006). High risk factors include age 65 or greater, paresthesia in extremities, and a ‘‘dangerous mechanism of injury,’’ which is defined as ‘‘a fall from a height of greater than 1 meter or 3.28 feet, an axial load to the head, motor vehicle collision of greater than 100 km/hr (45.45 mph) with rollover or ejection, collision involving a motorized recreational vehicle, or a bicycle collision’’ (Lankester et al., 2006). Low risk factors include rear-end collisions, maintaining ambulation, remaining seated rather than prone, delayed onset of neck pain, and absence of midline cervical spine tenderness (Randanov & Dvorak, 1996). DIAGNOSIS

No independent imaging, physiological, or psychological study provides specific diagnostic criteria.

X-Rays, CT or MRI, and EMG are often utilized to rule out injuries, but generally provide little information resulting in normal readings. Recent preliminary and follow-up neuroradiology studies have provided evidence of fatty infiltrates in the cervical extensor muscles, which may allow for a strong MRI diagnostic test in the future (Elliott et al., 2005). A comprehensive clinical interview and neurobehavioral evaluation examining the neurocognitive and sensorimotor domains will help a practitioner identify the pattern of impairments commonly found with whiplash. Whiplash symptoms or whiplash-associated disorders are graded on a scale of 0–4 based on the severity of symptoms: Grade 0 means no complaints of physical signs; Grade 1 indicates neck complaints but no physical signs; Grade 2 indicates neck complaints and musculoskeletal signs; Grade 3 indicates neck complaints and neurological signs; and Grade 4 indicates neck complaints and fracture or dislocation (Verhagen, Scholten-Peeters, de Bie, & Bierma-Zeinstra, 2004). Differential diagnosis of acute neck pain and stiffness include spinal fracture, cervical disc herniation, subarachnoid hemorrhage, meningitis, myocardial infarction, cervical spondylosis, and brain and bone tumors (Rodriguez et al., 2004). TREATMENT

Treatment for whiplash includes pain medications, nonsteroidal anti-inflammatory drugs, antidepressants, muscle relaxants, and a cervical collar (Verhagen et al., 2004). The latter is often worn for 2–3 weeks, but recent research has shown that extended use of a cervical collar may actually prolong the recovery time (Rodriguez et al., 2004). Range of motion exercises, physical therapy, and cervical traction may also be prescribed and tend to result in rehabilitation (Rodriguez et al., 2004). Supplemental heat application may relieve muscle tension. In general, the prognosis for individuals with whiplash is varied, based on the nature of the injury, but generally good with neck and head pain clearing within a few days to weeks (Rodriguez et al., 2004). Typical recovery often follows a slower than expected and unpredictable course compared to other muscle injuries. Researchers have found that the factors that showed significant association with poor outcome on both physical and psychological outcome scales were pre-injury back pain, high frequency of physician attendance, evidence of pre-injury depression or anxiety symptoms, front position in the vehicle, and pain radiating away from the neck after injury (Lankester et al., 2006). Although the majority of patients (70% to 80%) recover completely within 3–6 months

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post-injury, some may experience chronic neck pain and headaches for several years with periods of worsening symptoms (Scaer, 2001).

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Javan Horwitz Natalie Horwitz Chad A. Noggle Crowe, H. (1964). A new diagnostic sign in neck injuries. California Medicine, 100, 12–13. Elliott, J., Galloway, G., Jull, G., Noteboom, J., Centeno, C., & Gibbon, W. (2005). Magnetic resonance imaging analysis of the upper cervical spine extensor musculature in an asymptomatic cohort: An index of fat within muscle. Clinical Radiology, 60(3), 355–363. Howard, R., Bowles, A., Guzman, H., & Krenrich, S. (1998). Head, neck, and mandible dynamics generated by ‘‘whiplash.’’ Accident; Analysis and Prevention, 30(4), 525–534. Lankester, B., Garneti, N., Gargan, M., & Bannister, G. (2006). Factors predicting outcome after whiplash injury in subjects pursuing litigation. European Spine Journal, 15(6), 902–907. Randanov, B., & Dvorak, J. (1996). Spine update. Impaired cognitive functioning after whiplash injury of the cervical spine. Spine, 21(3), 392–397. Rodriguez, A., Barr, K., & Burns, S. (2004). Whiplash: Pathophysiology, diagnosis, treatment, and prognosis. Muscle Nerve, 29(6), 768–781. Scaer, J. (2001). The body bears the burden: Trauma, dissociation, and disease (pp. 23–53). New York: The Haworth Medical Press. Verhagen, A., Scholten-Peeters, G., van Wijngaarden, S., de Bie, R., & Bierma-Zeinstra, S. (2004). Conservative treatments for whiplash. Cochrane Database of Systematic Reviews, 1, CD003338.

WHIPPLE’S DISEASE DESCRIPTION

Whipple’s disease, also referred to as intestinal lipodystrophy, is a rare, chronic, and infectious disease that can affect multiple systems. However, the disease primarily affects the intestinal tract. The disease is caused by an infection of a rod-shaped bacterium, Tropheryma whippelii, and possibly a genetic anomaly in the host. Common symptoms include abdominal pain, diarrhea, fever, weight loss, and malabsorption in the small intestines. Malabsorption may affect the heart, brain, lungs, joints, and eyes. There is

pathological evidence of central nervous system (CNS) involvement in most cases, although only 10% of cases present with neurological symptoms. Such symptoms may include progressive dementia, personality changes, ophthalmoplegia, seizures, and hemiparesis. This is almost exclusively a disease of middle-aged, Caucasian males. NEUROPATHOLOGY/PATHOPHYSIOLOGY

The infecting organism, T. whippelii, is a rod-shaped bacterium. T. whippelii is a common soil and water saprophyte, and those who are infected frequently work at building sites or farms (Anderson, Dalton, & Davies, 1999; McPhee, Tierney, & Papadakis, 2006). T. whippelii is a gram-positive actinomycete that thrives in the phagosomes of the macrophages that aid the digestive tract. The macrophages swell from the infection, and, in turn, block drainage from the lymph nodes and the spaces where the macrophages accumulate. The result is malabsorption and excess fat in the bowels. The vacuoles within the macrophages can be detected with a periodic acid–Schiff (PAS) stain if they do contain the pathogen (Burmester, Pezzutto, Ulrichs, & Aicher, 2003). When an endoscopy is performed on the affected person, the duodenal mucosa will likely have thickened mucosal folds and will have a scattered granular covering of yellowish plaques. Biopsy of the discolored areas will be most helpful in diagnosis. If the biopsy has no discolorations, the person may have been infected mildly. Intestinal villi may be normal or club shaped, which causes distension of the lamina propria, with the characteristic foamy macrophages. A PAS stain will show many positive inclusions that distend the cytoplasm of the macrophages as well. The PAS-positive bacilli and macrophages are most evident at the tips of the villi; however, the entire mucosa may be involved. Mesenteric lymph nodes that are infected will be enlarged and contain many of the macrophages. In addition, there are rare cases where biopsies of organs not involved with the intestines will be positive for the macrophages (Chandrasoma, 1998). As previously noted, involvement of the CNS is seen in the majority of cases of Whipple’s disease. This is usually seen in the early course of the disease, but is also recognized as the most common site of involvement for recurrence (Suzer, Demirkan, Tahta, Coskun, & Cetin). Suzer et al. (1999), in their review of the literature identified cases of Whipple’s disease in which CNS involvement was seen as the primary presentation, which is rare. Synthesis of these reports identified primary neurological involvement of the cortical gray matter (including temporal parietal and

WHIPPLE’S DISEASE & 765

occipital regions), diencephalon (including both the thalamus and hypothalamus), putamen, leptomeninges, pons, midbrain, and both the supratentorial, and infratentorial white matter. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The symptoms of Whipple’s disease can be considerably variable and nonspecific; therefore, it is often the case that a diagnosis is not reached until later stages of the disease. The disease most often presents as a wasting illness with fever, inflamed and painful joints, skin darkening, and diarrhea. Swollen lymph glands are also common. When the small intestine is involved, steatorrhea, or fatty liver, is likely. Other common symptoms include severe weight loss, sluggishness, chronic diarrhea, and malabsorption. Ninety percent of patients will be anemic. Other systems that may be involved include the central nervous, cardiovascular, and respiratory systems. Ten percent of patients will experience neurological difficulties including dementia, seizures, weakness on only one side of the body (hemiparesis), and paralysis of the eyes (ophthalmoparesis). The involvement of the central nervous system is often indicative of long-term morbidity. Chest discomfort, chronic cough, and shortness of breath (dyspnea) are prevalent in most cases. These respiratory symptoms may be confused for sarcoidosis (Anderson et al., 1999; Miskovitz, 2005). DIAGNOSIS

The organism primarily affects the small bowel and therefore, a definitive diagnosis is obtained with a biopsy of the distal duodenum. This biopsy will differentiate Whipple’s disease from other disorders that cause malabsorption. Positive biopsies will show increased numbers of histiocytes within the lamina propria. The cytoplasm will be relatively foamy, and there will be clear intracytoplasmic inclusion. Tissues that have been affected by Whipple’s disease will have PAS-positive granules within the macrophages. The bacilli can sometimes be seen using electron microscopy. When the central nervous system is involved, collections of PAS-positve cells can be found in the brain and spinal cord. It is definitively diagnosed by PCR (polymerase chain reaction) amplification for T. whipplei from a bowel biopsy, brain biopsy, or other appropriate specimen. The bacteria is a grampositive actinomycete (Anderson et al., 1999; McPhee et al., 2006

Examining T. whippelii DNA from a biopsy sample using PCR is the best method of confirming a diagnosis of Whipple’s disease. The PCR will be positive in mucosal areas that have not shown to be positive histologically. PCR testing of cerebrospinal fluid is recommended in all patients to detect neurological involvement. Neurological relapse is a common cause of treatment failure (Chandrasoma, 1998). The biopsy also helps distinguish Whipple’s disease from other disorders that cause malabsorption and that have a similar clinical presentation. These include celiac disease, AIDS patients who have intestinal infection, sarcoidosis, Reiter’s syndrome, systemic vasculitides, intestinal lymphoma, and subacute infective endocarditis (McPhee et al., 2006). TREATMENT

Left untreated, Whipple’s disease will progress and be fatal usually within 1 year. The goal of treatment is to prevent this progression. Treatment with antibiotics is mandatory for successful recovery, and dramatic clinical improvement is evident within several weeks. Relapse is possible, and therefore prolonged antibiotic treatment for at least 1 year is important. For those in an advanced disease state, recommended treatment includes 2 weeks of intravenous ceftriaxone, followed with trimethoprim-sulfamethoxazole taken twice daily for 1 year. Some patients may be resistant or allergic to sulfonamides in which case treatment with doxycycline and hydroxychloroquine may be effective. After the first year of treatment, patients should have duodenal biopsies obtained to ensure no recurrence of the disease (McPhee et al., 2006). For patients who do exhibit recurrence, a cyclic course, rather than a continuous course of antibiotics should be used to avoid antibiotic resistance. Interventions should also aim to reduce fever, correct malabsorption and malnutrition, correct anemia, and replenish fluids and electrolytes. (Escott-Stump, 2007; McPhee et al., 2006). Kelly R. Pless Charles Golden Anderson, S. H. C., Dalton, H. R., & Davies, G., (1999). Key topics in gastroenterology. New York: Informa Health Care. Burmester, G. R., Pezzutto, A., Ulrichs, T., & Aicher, A. (2003). Color atlas of immunology. New York: Thieme. Chandrasoma, P. (1998). Gastrointestinal pathology. New York: McGraw-Hill Professional. Escott-Stump, S. (2008). Nutrition and diagnosis-related care. Philadelphia: Lippincott Williams & Wilkins.

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McPhee, S. J., Tierney, L. M., & Papadakis, M. A. (2006). Current medical diagnosis and treatment. New York: McGraw-Hill Professional. Miskovitz, P. F. (2005). The doctor’s guide to gastrointestinal health: Preventing and treating acid reflux, ulcers, irritable bowel syndrome, diverticulitis, celiac disease, colon cancer, pancreatitis, cirrhosis, hernias and more. New Jersey: John Wiley and Sons. Suzer, T., Demirkan, N., Tahta, K., Coskun, E., & Cetin, B. (1999). Whipple’s disease confined to the central nervous system: Case report and review of the literature. Scandinavian Journal of Infectious Disease, 31, 411–414.

WILLIAMS’ SYNDROME DESCRIPTION

Williams’ syndrome (WS) is a genetic disorder caused by the deletion of approximately 25 genes on chromosome 7q11.23 (Donnai & Karmiloff-Smith, 2000). The genotype corresponds with a mixed phenotypical pattern of physical, cognitive, and behavioral features. Physically, distinct facial appearance, cardiovascular disease, connective tissue abnormalities, and growth deficiency are noted (Mervis & Morris, 2007). Cognitively, the syndrome is often characterized by mild to moderate mental retardation with hallmark impairments in spatial cognition and motor skill learning in the presence of relatively spared language functioning (Brock, 2007; MayerLindenberg, Mervis, & Berman, 2006). Socially, WS has been linked with atypical social features categorized as hypersociability (Doyle, Bellugi, Korenberg, & Graham, 2004). WS presents with a relative prevalence between 1 in 7,500 and 1 in 20,000 (Strømme, Bjørnstad, & Ramstad, 2002). Because it is genetically based, there is no cure. Treatment is symptom based and primarily focused on addressing cognitive and behavioral sequelae. However, as physical symptoms arise (e.g., cardiovascular issues) they must also be addressed as they can have a direct impact on mortality. NEUROPATHOLOGY/PATHOPHYSIOLOGY

Although genetically based, corresponding with an approximate deletion of 25 genes on chromosome 7q11.23, the clinical profile has more defined pathological foundations. Cognitive and behavioral profiles have been associated with specific neurological abnormalities. Broadly, individuals with WS present with

reduced global brain volume (Meyer-Lindenberg et al., 2005). Focal anomalies have also been described and have been linked with the behavioral picture of WS. Particular attention has been paid to the dorsal stream and parietal regions as well as the amygdala. WS has been linked to impeded development of the dorsal visual stream and parietal regions. These regions present structurally with reduced gray matter and sulci depth as well as reduced functional activation (Chiang et al., 2007; Meyer-Lindeneberg, et al., 2004; Van Essenet al., 2006). In comparison, ventral stream regions seem relatively normal. Meyer-Lindenberg et al. (2004) demonstrated this by comparing dorsal and ventral streams via fMRI of individuals with WS and IQ-matched controls. WS was associated with decreased parietal activation bilaterally in comparison with controls as well as decreased gray matter volume in the intraparietal sulci. Similarly, previous literature also indicated dorsal stream regions while demonstrating preservation of ventral stream regions owing to functional profiles of impaired visuospatial processing in the presence of preserved functions such as motion perception and object identification (Jordan, Reiss, Hoffman, & Landau, 2002; Landau, Hoffman, & Kurz, 2006; Paul, Stiles, Passarotti, Bavar, & Bellugi, 2002; Tager-Flusberg, Plesa-Skwerer, Faja, & Joseph, et al., 2003). Consequently, structural anomalies in parietal regions have also led to the interest in mathematical functioning in WS that is discussed in the following. Abnormalities in the amygdala of individuals with WS has also been commonly reported and been linked to the hypersociable behavior exhibited (Jawaid, Schmolck, & Schulz, 2008). Research has demonstrated abnormalities both in the structure and size, but more importantly the nature of amygdala activation in individuals with WS (Plesa-Skwerer et al. 2009; Reiss et al., 2004). Reiss et al. (2004) suggested localized hyperactivity of particular nerve clusters in the amygdala when viewing facial expressions in comparison with controls. In comparison, PlesaSkwerer et al. (2009) demonstrated hypoarousal of autonomic responses in individuals with WS when watching facial expressions compared with normal controls. These discrepancies may suggest that the strength of connection between the amygdale and autonomic nervous system (ANS) in individuals with WS may be weaker owing to the amygdala’s tendency to by hyperactive yet correspond with reduced autonomic responsiveness. Others have suggested that amygdala dysfunction in WS is compounded by their behavioral actions. Specifically, although normal developing children and adults learn to occasionally avert their gaze in

WILLIAMS’ SYNDROME & 767

social settings to reduce cognitive load (DohertySneddon, Bruce, Bonner, Longbotham, & Doyle, 2002), individuals with WS often do not do this. Maintaining direct eye gaze illicits a physiological response of arousal as the autonomic nervous system is activated by the amygdala (Andreassi, 2000). Normal functioning children and adults avert their gaze to reduce heightened physiological arousal caused by prolonged mutual gaze (Field, 1981). It may be the case that the hyperactivity of the amygdala in WS corresponds with their hypersociability, which itself is reinforced by a lack of gaze aversion that is only possible because their reduced ANS activation prevents them from reaching a point of arousal that would otherwise become uncomfortable. Porter, Coltheart, and Langdon (2007) suggestion of frontal lobe disinhibition may also explain some of this presentation although this proposal is still being evaluated. This latter dysfunction may well explain the higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in WS, however. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

The clinical presentation of WS spans physical, cognitive, and behavioral domains. Physically, WS is characterized by fairly distinct facial dysmorphic features. Individuals commonly present with a constellation of a sunken nasal bridge, small papebral fissures (i.e., eye slits), epicathal fold, eye puffiness, long upper lip owning to a wide mouth in comparison with ears, prominent lower lip, small widely spaced teeth (observable in toddlerhood and through childhood), and a small chin (Bellugi, Lichtenberger, Jones, Lai, & St. George, 2001). In addition, their eyes are blue, they have short stature, and commonly present with cardiovascular defects in which supravalvar aortic stenosis is the most frequently seen. From a cognitive and behavioral standpoint, in many respects, one could conceptualize WS as the polar opposite of autism as verbal skills are spared while visuospatial domains are severely impaired and individuals are hypersocial with overly fixed eye contact. Even toddlers with WS show intense looking behavior toward faces (Mervis et al., 2003). Cognitively, individuals with WS most commonly present with mild to moderate mental retardation although low-average to average intellectual ability can be seen in some individuals. Severe mental retardation may also be seen in small percentage of individuals. Beyond this more global impairment of cognition, WS is associated with a fairly distinct profile (in comparison with the predicted capabilities) of

severe visuospatial impairments, mostly construction, and mathematic disabilities in the presence of relatively spared language functioning. Verbal shortterm memory is also spared (Bellugi et al., 2001; Mervis et al., 2000). Of interest, as individuals age, some of their deficits increase. In a longitudinal study of individuals with WS, Jarrold, Baddeley, and Hewes (1998) found that verbal and spatial abilities develop in a divergent way, and the difference between the two abilities increases with age in these subjects. Behaviorally, WS presents with a distinct personality profile that is hallmark of the presentation itself. Individuals often demonstrate overfriendliness, gregariousness, and high levels of empathy, with an undercurrent of anxiety (Klein-Tasman & Mervis, 2003). In addition, high comorbidity rates have been suggested between WS and various psychiatric manifestations including ADHD, specific phobia, and generalized anxiety disorder beginning in early adolescence (Leyfer, Woodruff-Borden, Klein-Tasman, Fricke, & Mervis, 2006). Furthermore, although irritability and low frustration tolerance has been reported in association with WS (Gosch & Pankau, 1997), oppositional and conduct behaviors are rare (Gosch & Pankau, 1994). DIAGNOSIS

Diagnostic consideration often starts in infancy or early childhood in response to noted facial abnormalities that often include a sunken nasal bridge, small papebral fissures (i.e., eye slits), epicathal fold, eye puffiness, long upper lip owing to a wide mouth in comparison with ears, prominent lower lip, small widely spaced teeth (observable in toddlerhood and through childhood), and a small chin. Eyes are blue with a starry pattern. Genetic testing may then be requested with definitive diagnosis determined through identification of the aforementioned profile of 25 deletions on chromosome 7q11.23. Neuropsychological evaluation remains essential in determining the cognitive and behavioral profile of individuals, with particular attention placed on visuospatial and mathematic domains. Cardiovascular evaluation is recommended given the high prevalence of such issues, particularly supravalvar aortic stenosis. The same is true of connective tissue abnormalities and growth deficiencies whose identification does not aid in the diagnosis of WS but should be evaluated for once WS is diagnosed. TREATMENT

Treatment is symptom-based and begins with thorough evaluation of the patient’s neuropsychological

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profile. As suggested, particular attention in assessment should be placed on visuospatial domains and mathematics as well as other domains with a high parietal loading/dependence. Still, as global impairment in the form of mild to moderate mental retardation is seen at higher than average rates, comprehensive evaluation is necessary. Special education services can be utilized with some success to address mathematic difficulties. Depending upon the particular nature of their deficits in this domain, individualized recommendations are necessary. Applied behavior analysis is recommended at the outset to better determine the nature of the individuals behavioral profile so that specific recommendations can be made. Medicinal interventions have been employed with some success depending upon the severity of the behavioral symptoms. Chad A. Noggle Amy R. Steiner Andreassi, J. L. (2000). Psychophysiology: Human behaviour and physiological response (4th ed). Mahwah, NJ: Lawrence Erlbaum Associates. Bellugi, U., Lichtenberger, L., Jones, W., Lai, Z., & St George, M. (2001). The neurocognitive profile of Williams syndrome: A complex pattern of strengths and weaknesses. In U. Bellugi & M. St. George (Eds.), Journey from cognition to brain to gene: Perspectives from Williams syndrome (pp. 1–41). Cambridge, MA: The MIT Press. Bellugi, U., Wang, P., & Jernigan, T. (1994). Williams syndrome: An unusual neuropsychological profile. In S. Broman & J. Grafman (Eds.), Atypical cognitive deficits in developmental disorders: Implications for brain function. Hillsdale, NJ: Lawrence Erlbaum Associates. Brock, J. (2007). Language abilities in Williams syndrome: A critical review. Development and Psychopathology, 19, 97–127. Chiang, M. C., Reiss, A. L., Lee, A. D., Bellugi, U., Galaburda, A. M., Korenberg, J. R., et al. (2007). 3D pattern of brain abnormalities in Williams syndrome visualized using tensor-based morphometry. NeuroImage, 36, 1096–1109. Doherty-Sneddon, G., Bruce, V., Bonner, L., Longbotham, S., & Doyle, C. (2002). Development of gaze aversion as disengagement from visual information. Developmental Psychology, 38, 438–445. Donnai, D., & Karmiloff-Smith, A. (2000). Williams syndrome: From genotype through to the cognitive phenotype. American Journal of Medical Genetics: Seminars in Medical Genetics, 97(2), 164–171. Doyle, T. F., Bellugi, U., Korenberg, J. R., & Graham, J. (2004). ‘‘Everybody in the world is my friend’’ hypersociability in young children with Williams syndrome. American Journal of Medical Genetics Part A, 124A(3), 263–273.

Field, T. (1981). Infant gaze aversion and heart rate during face-to-face interactions. Infant Behaviour and Development, 4, 307–315. Gosch, A., & Pankau, R. (1994). Social-emotional and behavioral-adjustment in children with WilliamsBeuren syndrome. American Journal of Medical Genetics, 53(4), 335–339. Gosch, A., & Pankau, R. (1997). Personality characteristics and behavior problems in individuals of different ages with Williams syndrome. Developmental Medicine & Child Neurology, 39(8), 527–533. Jarrold, C., Baddeley, A. D., & Hewes, A. K. (1998).Verbal and nonverbal abilities in the Williams syndrome phenotype: Evidence for diverging developmental trajectories. Journal of Child Psychology & Psychiatry & Allied Disciplines, 39, 511–523. Jawaid, A. Schmolck, H., & Schulz, P. E. (2008). Hypersociability in Williams syndrome: A role for the amygdala? Cognitive Neuropsychiatry, 13(4), 338–342. Jordan, H., Reiss, J. E., Hoffman, J. E., & Landau, B. (2002). Intact perception of biological motion in the face of profound spatial deficits: Williams syndrome. Psychological Science, 13, 162–167. Klein-Tasman, B. P., & Mervis, C. B. (2003). Distinctive personality characteristics of 8-, 9-, and 10-year-old children with Williams syndrome. Developmental Neuropsychology, 23, 271–292. Landau, B., Hoffman, J. E., & Kurz, N. (2006). Object recognition with severe spatial deficits in Williams syndrome: Sparing and breakdown. Cognition, 100, 483–510. Leyfer, O. T., Woodruff-Borden, J., Klein-Tasman, B. P., Fricke, J. S., & Mervis, C. B. (2006). Prevalence of psychiatric disorders in 4–16-year-olds withWilliams syndrome. American Journal of Medical Genetics Part B, 141B, 615–622. Mayer-Lindenberg, A., Mervis, C. B., & Berman, K. F. (2006). Neural mechanism in Williams syndrome: A unique window to genetic influences on cognition and behaviour. Nature Reviews Neuroscience, 7, 380–393. Mervis, C. B., & Morris, C. A. (2007). Williams syndrome. In M. M. M. Mazzocco & J. L. Ross (Eds.), Neurogenetic developmental disorders: Variation of manifestation in childhood (pp. 199–262). Cambridge, MA: The MIT Press. Mervis, C. B., Morris, C. A., Klein, T., Bonita, P., Bertrand, J., Kwitny, S., et al. (2003). Attentional characteristics of infants and toddlers with Williams syndrome during triadic interactions. Developmental Neuropsychology, 23, 243–268. Mervis, C. B., Robinson, B. F., Bertrand, J., Morris, C. A., Klein-Tasman, B. P., & Armstrong, S. C. (2000). The Williams Syndrome Cognitive Profile. Brain and Cognition, 44, 604–628.

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Meyer-Lindenberg, A., Kohn, P., Mervis, C. B., Kippenhan, J. S., Olsen, R. K., Morris, C. A., et al. (2004). Neural basis of genetically determined visuospatial construction deficit in Williams syndrome. Neuron, 43, 623–631. Meyer-Lindenberg, A, Mervis, C. B., Sarpal, D., Koch, P., Steele, S., Kohn, P., et al. (2005). Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome. The Journal of Clinical Investigation, 115, 1888–1895. Paul, B. M., Stiles, J., Passarotti, A., Bavar, N., & Bellugi, U. (2002). Face and place processing in Williams syndrome: Evidence for a dorsal-ventral dissociation. Neuroreport, 13, 1115–1119. Plesa Skwerer, D., Borum, L., Verbalis, A., Schofield, C., Crawford, N., Ciciolla, L. & Tager-Flusberg, H. (2009). Autonomic responses to dynamic displays of facial expressions in adolescents and adults with Williams syndrome. Social Cognitive and Affective Neuroscience, 4(1), 93–100. Porter, M. A., Coltheart, M., & Langdon, R. (2007). The neuropsychological basis of hypersociability in Williams and down syndrome. Neuropsychologia, 45, 2839–2849. Reiss, A. L., Eckert, M. A., Rose, F. E., Karchemskiy, A., Kesler, S., Chang, M., et al. (2004). An experiment of nature: Brain anatomy parallels cognition and behavior in Williams syndrome. Journal of Neuroscience, 24, 5009– 5015. Strømme, P., Bjørnstad, P. G., & Ramstad, K. (2002). Prevalence estimation of Williams syndrome. Journal of Child Neurology, 17, 269–271. Tager-Flusberg, H., Plesa-Skwerer, D., Faja, S., & Joseph, R. M. (2003). People with Williams syndrome process faces holistically. Cognition, 89, 11–24. Van Essen, D. C., Dierker, D., Snyder, A. Z., Raichle, M. E., Reiss, A. L., & Korenberg, J. (2006). Symmetry of cortical folding abnormalities in Williams syndrome revealed by surface-based analyses. Journal of Neuroscience, 26, 5470–5483.

WILSON’S DISEASE DESCRIPTION

Wilson’s disease (WD) is a rare (1 in 30,000–100,000 worldwide), autosomal recessively inherited deficiency of copper metabolism. The result is excessive deposits of copper in the liver, brain, and other organs. WD is often categorized as neurologic or liver depending upon presenting symptoms, and as juvenile or adult depending upon the age at onset. It is named after S. A. K. Wilson, a neurologist who described

the syndrome as ‘‘hepatolenticular degeneration’’ in the early 20th century (Wilson, 1912). NEUROPATHOLOGY/PATHOPHYSIOLOGY

When foods rich in copper are ingested (e.g., liver, shellfish, nuts), copper is absorbed in the small intestine, bound to circulating proteins, with excess copper deposited in the liver for out-processing via the bile (de Bie, Muller, Wijmenga, & Klomp, 2007). Copper as a trace mineral assists in the transfer of electrons and is necessary for healthy bones, nerves, and skin. Too little copper (hypocupremia) may result in anemia, bone lesions, kinky hair syndrome, and so forth (Cordano, 1978). In WD excessive amounts of copper can begin to accumulate in the liver as early as birth, with onset of observed symptoms as early as 5 (juvenile-onset type), but more typically as the patient approaches middle age (adult-onset type). Juvenile onset is associated with a more virulent course than is adult-onset WD (Mendez & Cummings, 2003). Age of observable symptom onset in the literature ranges from younger than 2 into the 70s (Roberts & Schilsky, 2008). Concentrations of copper in WD become excessive first in the liver and then in the brain, eyes, kidneys, and joints (Ala, Walker, Ashkan, Dooley, & Schilsky, 2007; Roberts & Schilsky, 2008). Symptoms can include signs of liver damage including cirrhosis (e.g., abdominal pain, jaundice, anemia, vomiting blood, ascites, lower extremity edema, enlarged spleen), neurological involvement (e.g., ‘‘wing-beating’’ tremor, unsteady gait, muscle spasms and/or stiffness, dysarthria, drooling), endocrine problems (e.g., hypoparathyroidism), cardiac (e.g., cardiomyopathy, arrhythmias), corneal (Kayser–Fleischer’s rings — copper deposited in the cornea, typically first observed during slit-lamp eye exam), renal problems (including renal stones), and osteoporosis. Psychosis as well as behavior and personality changes have been documented (e.g., mood swings and affective disorders, agitation; Shanmugiah et al., 2008), including confusion, forgetfulness, and aggression and paranoid-driven violence (Dening & Berrios, 1989; Wynkoop, 1994). In fact, psychiatric symptoms are the first manifestation in 20% to 24% of WD cases (Dening & Berrios, 1989; Shanmugiah et al., 2008). Left untreated, liver failure via cirrhosis or fulminating hepatitis can be debilitating and/or fatal (Scheinberg & Sternlieb, 1984). However, early detection and treatment can lead to a fairly normal life. The genetic mutation for WD is found on chromosome 13 and affects a protein (ATP7B) that assists in the transport of copper in bile and also in the

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bloodstream via the incorporation of copper into ceruloplasmin. Essentially, both parents have to carry the mutated gene and have a 1-in-4 chance of having a child with the disease with each pregnancy. One in 90 persons carry the genetic mutation. WD’s autosomal recessive pattern of inheritance places carrier families and some consanguineous groups at higher risk and results in equal incidence across sexes. The presence of the APOE-3 genotype is believed to contribute to delayed onset of symptoms in WD for reasons that are unclear (Mendez & Cummings, 2003). The neurologic form of adult-onset WD has also been known as Westphal–Strumpell’s pseudosclerosis. In neurologic WD, the areas of the brain believed to be most susceptible to copper deposition are the globus pallidus and putamen (lenticular formation; de Bie et al., 2007). Abnormalities of these structures are observed on CT (Medalia, Isaacs-Glaberman, & Scheinberg, 1988), and the basal ganglia are known to be more sensitive to copper than the thalamus (via MR spectroscopy; Tarnacka, Szeszkowski, Golebiowski, & Czlonkowska, 2009). SPECT has implicated dysfunction in a variety of brain regions including superior frontal, prefrontal, parietal, occipital, select temporal gyri, caudate, and putamen (Piga et al., 2008). Cortical and subcortical regions have been implicated. MRI is the standard of neuroimaging care for WD patients with neurological symptoms at present (Roberts & Schilsky, 2008).

NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

There is no clear pattern of neurocognitive test results in WD. Some of the factors responsible for this include variability in copper deposition in the brain, age at onset, degree of liver involvement (e.g., hepatic encephalopathy), presence of psychiatric symptoms, and severity of the patient’s neurocognitive decline when tested. As above, in addition to the lenticular formation, a variety of cerebral regions may be affected in any given patient and across patients (Piga et al., 2008). Counterintuitively, there may not be a direct linear relationship between level of copper toxicity and neurocognitive deficits (Rathbun, 1996). Decline in general psychometric intelligence, problematic concentration, slowed mentation, apathy, forgetfulness, and problems with abstraction, concept formation, mental flexibility, arithmetic, and spatial orientation have been observed in different patients at different times during the course and treatment of WD (cf. Mendez & Cummings, 2003; SzutkowskaHoser, Seniow, Czlonkowska, & Laudanski, 2005).

DIAGNOSIS

In all likelihood, WD will not be initially diagnosed by the neuropsychologist. However, WD’s neurologic and/or behavioral symptoms often result in referral to characterize neurocognitive functioning. If not already diagnosed, but suspected by the neuropsychologist, a gastroenterology consultation is prudent. A neurology consultation may also be appropriate, given that the patient will likely be experiencing neurological symptoms by virtue of having been referred to neuropsychology. Suspicion of WD is the first step in its diagnosis. Patients with liver disease who are members of consanguineous groups and/or those with biological relatives who have been diagnosed with WD or who have died of undiagnosed liver failure should be suspected. Diagnostic tests include urine copper, serum copper, serum ceruloplasmin, slit-lamp examination (for Kayser–Fleischer’s rings, which occur in 66% of WD cases; Merle, Schaefer, Ferenci, & Stremmel, 2007), liver copper needle biopsy, radio copper ceruloplasmin incorporation test, and DNA analysis of linked markers (Mendez & Cummings, 2003). Not all tests need to be conducted, and diagnostic recommendations have been promulgated (e.g., Roberts & Schilsky, 2008). Regarding genetic testing, the Wilson’s Disease Association (WDA) suggests that all siblings and children of WD patients and other relatives with symptoms or lab tests suggestive of liver or neurological disorder be tested genetically for WD (a description of various genetic tests for WD is provided at the WDA Web site). TREATMENT

The goal of treatment is to eliminate excess copper (acute intervention) and then to prevent excessive reaccumulation (maintenance therapy; Mendez & Cummings, 2003). Chelating agents (e.g., trientine, penicillamine) are most effective at rapidly reducing the amount of stored copper, whereas preventing further absorption of copper in the stomach and small intestine (via zinc acetate) is a second-line therapy for those who cannot tolerate chelation therapy. Copper reducing therapy is required for life in addition to minimizing dietary intake of copper (e.g., avoiding water containing more that 100 mcg of copper per liter; avoiding supplements containing copper; avoiding chocolate, nuts, liver, shellfish, bran, etc.). Liver transplantation as a cure for WD is rarely used (typically in instances of fulminant liver failure or in which the patient does not respond to other therapies) because of the risks involved. The neuropsychologist

WOLMAN’S DISEASE & 771

can provide the patient and family support in addition to serial assessments as needed. Timothy F. Wynkoop Ala, A., Walker, A. P., Ashkan, K., Dooley, J. S., & Schilsky, M. L. (2007). Wilson’s disease. Lancet, 369, 397–408. Cordano, A. (1978). Copper deficiency in clinical medicine. In K. M. Hambidge & B. L. Nichols (Eds.), Zinc and copper in clinical medicine (pp. 119–122). New York: Spectrum. de Bie, P., Muller, P., Wijmenga, C., & Klomp, L. W. (2007). Molecular pathogenesis of Wilson and Menkes disease: Correlation of mutations with molecular defects and disease phenotypes. Journal of Medical Genetics, 44, 673–688. Dening, T. R., & Berrios, G. E. (1989). Wilson’s disease: Psychiatric symptoms in 195 cases. Archives of General Psychiatry, 46, 1126–1134. Medalia, A., Isaacs-Glaberman, K., & Scheinberg, I. H. (1988). Neuropsychological impairment in Wilson’s disease. Archives of Neurology, 45, 502–504. Mendez, M. F., & Cummings, J. L. (2003). Dementia: A clinical approach. Philadelphia: Butterworth/Heinemann. Merle, U., Schaefer, M., Ferenci, P., & Stremmel, W. (2007). Clinical presentation, diagnosis and long-term outcome of Wilson’s disease: a cohort study. Gut, 56, 115–120. Piga, M., Murru, A., Satta, L., Serra, A., Sias, A., Loi, G., et al. (2008). Brain MRI and SPECT in the diagnosis of early neurological involvement in Wilson’s disease. European Journal of Nuclear Medicine and Molecular Imaging, 35, 716–724. Rathbun, J. K. (1996). Neuropsychological aspects of Wilson’s disease. International Journal of Neuroscience, 85, 221–229. Roberts, E. A., & Schilsky, M. L. (2008). Diagnosis and treatment of Wilson’s disease: An update. Hepatology, 47, 2089–2111. Scheinberg, I. H., & Sternlieb, I. (1984). Wilson’s disease. In L. H. Smith (Ed.), Major problems in internal medicine (Vol. 23). Philadelphia: W. B. Saunders. Shanmugiah, A., Sinha, S., Taly, A. B., Prashanth, L. K., Tomar, M., Arunodaya, G. R., et al. (2008). Psychiatric manifestations in Wilson’s disease: A cross-sectional analysis. Journal of Neuropsychiatry and Clinical Neurosciences, 20, 81–85. Szutkowska-Hoser, J., Seniow, J., Czlonkowska, A., & Laudanski, K. (2005). Cognitive functioning and life activity in patients with hepatic form of Wilson’s disease. Polish Psychological Bulletin, 36, 234–238. Tarnacka, B., Szeszkowski, W., Golebiowski, M., & Czlonkowska, A. (2009). Metabolic changes in 37 newly diagnosed Wilson’s disease patients assessed by magnetic resonance spectroscopy. Parkinsonism & Related Disorders, 15, 582–586.

Wilson, S. A. K. (1912). Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain, 34, 295–509. Wynkoop, T. F. (1994). Psychiatric symptomatology and type of treatment in Wilson’s disease: A retrospective case analysis. Advances in Medical Psychotherapy, 7, 181–190.

Online Resources Wilson’s Disease Association (WDA; http://www.wilsons disease.org) provides a wide variety of educational materials for patients, families, and medical professionals in pdf format, as well as advocacy updates (go to Patients Õ WDA Publications). National Institutes of Health’s National Institute of Neurological Disease and Stroke provides the NINDS Wilson’s Disease Information Page (http://www.ninds. nih.gov/disorders/wilsons/wilsons.htm). The ‘‘Additional resources from MEDLINEplus’’ link offers additional links and a wealth of information to share with patients and their families.

WOLMAN’S DISEASE DESCRIPTION

Wolman’s disease is a rare autosomal recessive lysosomal storage disease due to a lysosomal lipase deficiency (Uniyal, Colaco, Bharath, Pradhan, & Murthy, 1995) that results in a toxic accumulation of triglycerides and cholesterol esters throughout major organs. Though effecting less than 200,000 people in the United States, it is a fatal disorder in which most of the patients die during the first year of life (BenHaroush, Yogev, Levit, Hod, & Kaplan, 2003). Infants will initially present with failure to thrive, persistent vomiting, and abdominal distension (Hoeg, Demosky, Pescovitz, & Brewer, 1984). As the disease progresses, the symptoms worsen and additional symptoms appear including anemia, hypotonia, inanition, and hepatosplenomegaly (enlargement of the liver and spleen). NEUROPATHOLOGY/PATHOPHYSIOLOGY

A malfunction of chromosome 10, in which the acid lipase enzyme is located, is the putative causal factor of Wolman’s disease (Uniyal et al., 1995). The paucity of the acid lipase enzyme results in the accumulation of cholesterol esters and triglycerides at a toxic level, causing death in the first year. The pathognomonic pathophysiological aspects of Wolman’s

W

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disease include bilateral adrenal gland enlargement and calcification (Hill, Hoeg, Dwyer, Vucich, & Doppman, 1983), vacuolated lymphocytes, hepatosplenomegaly, and foam cells within the patient’s bone marrow, which owe to accumulation of cholesterol esters and are dangerous as build-up may cause atherosclerosis (Uniyal et al., 1995). The adrenal calcification is primarily confined to the outer edges of the glands, and though they enlarge, the glands retain natural shape. This calcification results in adrenocortical insufficiency, and is similar in process to that found in a milder form of acid lipase deficiency, cholesteryl ester storage disease (CESD), but is more devastating to the patient with Wolman’s disease. An increase in the adrenal cortex is the causal factor of the gland enlargement, and CT scans are the most sensitive neuroradiological modality for identifying this pathognomonic characteristic. Another essentially pathognomonic sign of Wolman’s disease is hepatosplenomegaly, an enlargement of the spleen and liver. According to Crocker, Vawter, Neuhauser, and Rosowsky (1965), the cholesterol levels in the liver are 15–20 times higher than that seen in normal infants and 4–5 times higher than normal in the spleen. This due to the lack of degradation of triglycerides and cholesterol esters from acid lipase enzyme deficiency. In addition to enlargement, the liver loses density (Hill et al., 1983) due to vacuolation of the hepatic parenchymal cells (Uniyal et al., 1995). Interestingly, fibroblast cultures of the skin from patients with Wolman’s disease show increased lipid and cholesterol levels, thus lending further support for deficient triglyceride and cholesterol degradation (Kyriakides, Filippone, Paul, Grattan, & Balint, 1970). Density loss, coupled with gross enlargement due to lipid deposits, contribute to the subsequent liver failure. NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

Assessing for neurocognitive impairments is not feasible as the disease is fatal in infancy without treatment (Stein et al., 2007). Patients show failure to thrive syndrome, which is one of the diagnostic phenotypes of the disorder. This lack of growth results in muscular deficiencies that cause hypotonia and motor delays. In late-onset Wolman’s disease, the muscle tone may initially develop, though there will be deterioration. The enlargement and calcification of the adrenal glands result in adrenocortical insufficiency. This leads to the hypotonia, nausea, vomiting, and gastrointestinal difficulties. Though the adrenal medulla

maintains its shape, it is reduced in size (Ozmen et al., 1992) due to gland expansion and calcification that results in a reduction in the release of epinephrine and norepinephrine as hormones into the blood stream. DIAGNOSIS

A diagnosis of Wolman’s disease first requires an examination of patient symptomatology. The essential symptom presentation is failure to thrive, vomiting, diarrhea, anemia, hypotonia (low muscle tone), and abdominal distension due to an enlarged liver and spleen. In the presence of these symptoms, there are two definitive pathognomonic signs of Wolman’s disease: bilateral adrenal gland enlargement and calcification and dermal fibroblast cultures that demonstrate deficient acid esterase activity (Wolman, 1995) with a substantial elevation in cholesterol levels compared with normals (Kyriakides et al., 1970). Other diagnostic signs of Wolman’s disease are hepatosplenomegaly with diminished liver density as identified through a CT scan (Ozmen et al., 1992), vacuolated lymphocytes, and foam cells in bone marrow (Uniyal et al., 1995). Research has also demonstrated the ability for a prenatal diagnosis of Wolman’s disease in at-risk pregnancies (Coates, Cortner, Mennuti, Wheeler, & Kaback, 1978; Patrick, Willcox, Stephens, & Kenyon, 1976; van Diggelen et al., 1988). Patrick et al. (1976) found severe deficiency of acid esterase activity in cultured amniotic fluid cells (amniocentesis) in the 15th week of pregnancy, suggesting a diagnosis of Wolman’s disease. Van Diggelen et al. (1988) supported the ability to diagnose Wolman’s disease in the first trimester by identifying acid lipase deficiency in the chorionic villi. Finally, Coates et al. (1978) identified deficient acid lipase. The primary differential diagnosis of Wolman’s disease is its milder version, CESD, which does not lead to early death. CESD presents with deficient acid esterase-lipase activity that is less severe (Wolman, 1995). CESD patients are generally asymptomatic in childhood and are eventually diagnosed due to less severe hepatomegaly (Hoeg et al., 1984). The pathognomonic sign of Wolman’s disease is rarely present (Hill et al., 1983; Ozmen et al., 1992). CESD patients have higher lysosomal acid lipase activity (Ozmen et al., 1992) and the lipid deposition is more widespread. TREATMENT

Wolman (1995) posited that the disease process may be slowed by avoiding the introduction of nontransportable

WOLMAN’S DISEASE & 773

and noncatabolizable lipids to the infant from breast milk or formula containing lipid esters. Though effective in slowing the process, reducing lipid intake is unsuccessful in curing the disease. Recent research has suggested that it may indeed be remedied through umbilical cord blood (UCB) transplantation from an unrelated donor, an optimal source of stem cells (Stein et al., 2007). These authors reported successfully restoring acid lipase levels through UCB transplantation at 3 months, with cells engrafting within a few weeks and complete platelet transfusion independence in just over 2 months. Normal levels of acid lipase were identified 7 weeks after UCB transplantation. A follow-up MRI at 18 months noted ageappropriate myelinization 6 months later (Stein et al., 2007). Four years after UCB transplantation, the patient no longer suffered from hepatosplenomegaly, was growing at the normal rate, and motor and intellectual achievements were age appropriate. Hematopoietic cell transplantation (HCT), the transplantation of blood cells derived from bone marrow, has also been found effective in the treatment of Wolman’s disease (Tolar et al., 2008). Tolar et al. (2008) reported that this method was successful in preventing hepatic failure in Wolman’s disease patients, and improves hepatosplenomegaly, and sometimes adrenal function. The authors reported mild to moderate psychomotor developmental delay in one of the patients treated with HCT, but were unable to determine whether the neurocognitive deficits owed to treatment or other medical problems. The patients treated by these authors at an earlier age displayed age-appropriate neurodevelopment. Both HCT and UCB transplantations are best implemented in the first few months of life, and decreasing lipid intake enhances treatment efficacy. Long-term survival rates, and neurocognitive or medical sequelae are not available as both Stein et al. (2007) and Tolar et al. reported these therapies as some of the first known successes, with the eldest surviving patients under the age of 5 at study completion. Daniel J. Heyanka Charles Golden

Ben-Haroush, A., Yogev, Y., Levit, O., Hod, M., & Kaplan, B. (2003). Isolated fetal ascites caused by Wolman

disease. Ultrasound in Obstetrics and Gynecology, 21, 297–298. Coates, P. M., Cortner, J. A., Mennuti, M. T., Wheeler, J. E., & Kaback, M. M. (1978). Prenatal diagnosis of Wolman disease. American Journal of Medical Genetics, 2, 397–407. Crocker, A. C., Vawter, G. F., Neuhauser, E. B. D., & Rosowsky, A. (1965). Wolman’s disease: Three new patients with a recently described lipidosis. Pediatrics, 35, 627–640. Hill, S. C., Hoeg, J. M., Dwyer, A. J., Vucich, J. J., & Doppman, J. L. (1983). CT findings in acid lipase deficiency: Wolman disease and cholesteryl ester storage disease. Journal of Computer Assisted Tomography, 7, 815–818. Hoeg, J. M., Demosky, S. J., Jr., Pescovitz, O. H., & Brewer, H. B., Jr. (1984). Cholesteryl ester storage disease and Wolman disease: Phenotypic variants of lysosomal acid cholesteryl ester hydrolase deficiency. American Journal of Human Genetics, 36, 1190–1203. Kyriakides, E. C., Filippone, N., Paul, B., Grattan, W., & Balint, J. A. (1970). Lipid studies in Wolman’s disease. Pediatrics, 46, 431–436. Ozmen, M. N., Aygiin, N., Kilic, I., Kuran, L., Yalcin, B., & Besim, A. (1992). Wolman’s disease: Ultrasonographic and computed tomographic findings. Pediatric Radiology, 22, 541–542. Patrick, A. D., Willcox, P., Stephens, R., & Kenyon, V. G. (1976). Prenatal diagnosis of Wolman’s disease. Journal of Medical Genetics, 13, 49–51. Stein, J., Garty, B. Z., Dror, Y., Fenig, E., Zeigler, M., & Yaniv, I. (2007). Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation. European Journal of Pediatrics, 166, 663–666. Tolar, J., Petryk, A., Khan, K., Bjoraker, K. J., Jessurun, J., & Dolan, M., et al. (2008). Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease. Bone Marrow Transplant. [EPub ahead of print]. Uniyal, K. J., Colaco, M. P., Bharath, N. S., Pradhan, M. R., & Murthy, A. K. (1995). Indian Pediatrics, 32, 232–235. Van Diggelen, O. P., Von Kuskull, H., Ammala, P., Vredeveldt, G. T. M., Janse, H. C., & Kleijer, W. J. (1988). First trimester diagnosis of Wolman’s disease. Prenatal Diagnosis, 8, 661–663. Wolman, M. (1995). Wolman disease and its treatment. Clinical Pediatrics, 34, 207–212.

W

XYZ ZELLWEGER’S SYNDROME DESCRIPTION

Zellweger’s syndrome is a progressive developmental metabolic disease attributable to deficient biogenesis of peroxisomes and resulting in a generalized loss of peroxisomal functions (Poll-The et al., 2004). The condition manifests in a distinctive dysmorphic phenotype despite a highly variable range of severity levels (Weller, Rosewich, & Ga¨rtner, 2008). All peroxisomal biogenesis disorders are associated with similar clinical, biochemical, pathological, and genetic findings (Folz & Trobe, 1991; Poll-The et al., 2004). Zellweger’s syndrome is part of a group of three peroxisomal disorders, resulting in defective biogenesis of the peroxisome; others included within this category are neonatal adrenoleukodystrophy and infantile Refsum disease (Folz & Trobe, 1991) — all syndromes are collectively known as Zellweger’s spectrum. Zellweger’s syndrome constitutes the most severe variant of the three peroxisomal biogenesis disorders and has been found to be associated with seizures, infantile hypotonia, and death within the first year (Folz & Trobe, 1991), although a significant subset of patients live beyond the age of 4. When it does occur, death is most often attributable to the consequences of respiratory dysfunction, dehydration, renal or liver failure, and gastrointestinal hemorrhage. There is a 77% probability that a nonprogressive child living past the age of 1 will continue to live to school age (Poll-The et al., 2004). NEUROPATHOLOGY/PATHOPHYSIOLOGY

The peroximal biogenesis disorders reflect malformation syndromes resulting from metabolic error and highlight the important role that biochemical pathways play in human development. Zellweger’s spectrum disorders are caused by the inability to import peroxisomal matrix proteins into peroxisomes, which are targeted to peroxisomes by one of two different peroxisome targeting signals (i.e., PTS1 and PTS2). The failure to form peroxisomes, as is the case in

these conditions, leads to impairment of many peroxisomal functions including the formation of polyunsaturated Zellweger’s syndrome, and prior investigation has revealed MRI to be particularly useful for this purpose (Barkovich & Peck 1997; Barth et al., 2001, 2004; van der Knaap & Valk, 1991). More recently, Weller et al. (2008) evaluated 18 patients presenting with Zellweger’s syndrome using conventional MRI and documented a variety of abnormal findings, including an atypical gyration pattern, delayed myelination leukoencephalopathy, and brain atrophy. Polymicrogyria and pachygyria were more common in patients presenting with a more severe variant of the condition, whereas abnormal gyration appears to be more frequent in the milder conditions. Leukoencephalopathy was also found to increase with age in longer-surviving patients. One study of six cases of Zellweger’s syndrome revealed polymicrogyria in both cerebral and cerebellar cortices, neuronal heterotopia in the cerebral white matter, and dysplasia of the inferior olivary nucleus and subependymal cyst (Takashima et al., 1992). Diffuse dysmyelination and neuronal migratory dysfunction also occur in this condition: Although diffuse dysmyelination is likely related to abnormal development of oligodendrocytes, migration dysfunction is due to abnormal endothelial cells or radial glial cells (Takashima et al., 1992). Neurodevelopmentally, neuronal migratory processes are strikingly abnormal, and there are areas of polymicrogyria, Purkinje cell heterotopic and olivary nucleus abnormalities (Steinberg et al., 2006). Molecularly, 21 of 31 patients in a relatively recent investigation showed mutations in the PEX1 gene, and the most common mutations included the G843D (c.2528G Õ A; improved outcome and milder phenotype) missense mutation, and the c.2097insT frameshift mutation (severe phenotype). Intermediate severity is shown in patients heterozygous for G843D/c.2097insT (Poll-The et al., 2004). NEUROPSYCHOLOGICAL/CLINICAL PRESENTATION

A recent investigation conducted on 31 patients (aged 1.2–24 years) with biochemically confirmed

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peroxisome biogenesis disorders presenting with prolonged survival revealed overlapping cognitive and motor dysfunction, retinopathy, sensorineural hearing impairment, eye abnormalities, craniofacial abnormalities, and hepatic involvement. Postnatal growth failure was present among many subjects, and hyperoxaluria was found in 10 subjects. Despite notable cognitive and motor deficits, a range of severity was revealed. In particular, speech ranged from nonverbal communication to grammatically correct speech and comprehensive reading, and motor skills ranged from supported sitting to normal gait (Poll-The et al., 2004). For peroxisome biogenesis disordered patients surviving past age 4, early developmental skills (e.g., unsupported sitting, intentional hand use, unsupported walking, hearing, and purposeful vocalization) were attained by greater than 75% of the individuals studied. Unsupported sitting occurred between 9 and 30 months of age and unsupported walking occurred between 14 and 66 months of age. In contrast, more advanced developmental milestones such as grammatical language (21%) and reading (4%) were seen only in a minority of subjects. Seizures have been observed in 23% of cases, with an average seizure onset between 0 and 2.7 years of age; presentations may vary considerably and include automatisms, myoclonic, atonic, tonic–clonic, and infantile spasms. All subjects studied exhibited severe visual disturbance, which ranged from total blindness originating at birth to corrected vision with prescription glasses; common symptoms included refractive anomalies, strabismus, nystagmus, retinopathy, cataracts, optic nerve atrophy, corneal clouding, glaucoma, and failure to achieve pursuit eye movements. All 31 patients in the study demonstrated hearing impairment. Liver, spleen, and kidney dysfunction were also common. Finally, peroxisome biogenesis disorder has been associated with facial dysmorphic features, including high forehead, epicanthic folds, and abnormal and attached ear lobules (Poll-The et al., 2004; Steinberg et al., 2006).

DIAGNOSIS

Diagnosis of Zellweger’s syndrome is determined by clinical presentation and the biochemical evaluation of peroxisomal metabolites, and is confirmed based upon mutation detection in 1 out of 12 genes coding for proteins involved in the biogenesis of peroxisomes. Biochemical studies are performed in the blood and urine to screen for the peroxisome biogenesis disorders. DNA testing is also possible (Steinberg et al., 2006).

However, in some cases, clinical symptoms are less readily detectable and MRI may prove useful in diagnostic confirmation. Positive MRI findings include abnormal gyration patterns including polymicrogyria and pachygyria, leukoencephalopathy, germinolytic cysts, and heterotopias (Weller et al., 2008).

TREATMENT

The myriad of biochemical abnormalities resulting from peroxisome assembly failure, as detailed above, lead to significant developmental disturbances that present at birth and progress further postnatally. Therapeutic approaches for Zellweger’s syndrome are primarily supportive in nature as effective treatments for attenuating the primary effects of the condition remain to be discovered (Poll-The et al., 2004). Currently available treatments are intended to target seizure disorder, liver dysfunction, sensory abnormalities (e.g., hearing via external aids), ophthalmologic conditions, and other related developmental dysfunction, as described above (Steinberg et al., 2006). Cognitive and motor treatments have not yet been investigated for individuals diagnosed with Zellweger’s syndrome. For milder cases of individuals surviving until school age, treatments may involve participation in schools targeting developmentally disabled students, as well as educational plans aimed at increasing accommodation to cognitive and sensory difficulties (Poll-The et al., 2004). Jessica Foley Charles Golden Barkovich, A. J., & Peck, W. W. (1997). MR of Zellweger syndrome. AJNR American Journal of Neuroradiology, 18, 1163–1170. Barth, P. G., Gootjes, J., Bode, H., Vreken, P., Majoie, C. B., & Wanders, R. J. (2001). Late onset white matter disease in peroxisome biogenesis disorder. Neurology, 57, 1949– 1955. Barth, P. G., Majoie, C. B. L. M., Gootjes, J., Wanders, R. J. A., Waterham, H. R., van der Knaap, M. S., et al. (2004). Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival. Neurology, 62, 439–444. Folz, S. J., & Trobe, J. D. (1991). The peroxisome and the eye. Survey of Ophthalmology, 35, 353–368. Poll-The, B. T., Gootjes, J., Duran, M., De Klerk, J. B., Wenniger-Prick, L. J., Admiraal R. J., et al. (2004). Peroxisome biogenesis disorders with prolonged survival: Phenotypic expression in a cohort of 31 patients.

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American Journal of Medical Genetics. Part A, 126A, 333–338. Steinberg, S. J., Dodt, G., Raymond, G. V., Braverman, N. E., Moser, A. B., & Moser H. W. (2006). Peroxisome biogenesis disorders. Biochimica et Biophysica Acta, 1763, 1733–1748. Takashima, S., Houdou, S., Kamei, J., Hasegawa, M., Mito, T., Suzuki, Y., et al. (1992). Neuropathology of peroxisomal disorders: Zellweger syndrome and neonatal

adrenoleukodystrophy. No To Hattatsu. Brain and Development, 24, 186–193. van der Knaap, M. S., & Valk, J. (1991). The MR spectrum of peroxisomal disorders. Neuroradiology, 33, 30–37. Weller, S., Rosewich, H., & Ga¨rtner, J. (2008). Cerebral MRI as a valuable diagnostic tool in Zellweger spectrum patients. Journal of Inherited Metabolic Disease. [Epub ahead of print].

XYZ

INDEX

-Galactosidase A deficiency, 299 -Interferon, 594 -Ketoglutarate, dehydrogenase (KGDH), 755

-Aminobutyric acid type A (GABAA), 367 3,4-Diaminopyridine, 232 5-HT, 196 5-HT1A, 196 5-HT1B, 196 24-hr urinary free cortisol (UFC) test, 242, 243 46XY/47XXY chromosomal anomaly, 400 48-hr low-dose dexamethasone suppression test, 244

ABCD (age [A], blood pressure [B], clinical features [C], and duration of symptoms [D]) scale, 723 Abnormal Involuntary Movement Scale (AIMS), 703 Academic Competence Evaluation Scales (ACES), 445 Academic Performance Rating Scale (APRS), 445 Acalculia, 328 Acanthocytosis, 519 Acanthosis nigricans, 562 Acenocoumarol, 305 Acetazolamide, 308, 572, 574 Acetylcholine receptor (AChR), 229, 230, 504, 717 Acetylcholinesterase (AChE), 229, 414 Acetylcholinesterase inhibitors, 427, 612, 688 Achilles’ reflex, 348 Aciclovir, 451 Acid ceramidase deficiency. See Farber’s disease Acid maltase. See Acid -glucosidase (GAA) Acid sphingomyelinase (ASM), deficiency of, 540 Acid alpha-glucosidase (GAA), 597

Acquired epileptic aphasia. See Landau–Kleffner syndrome (LKS) Acrocallosal syndrome, 28 Acroparesthesia, 299, 300 Action dystonia, 274 Acute brain syndrome. See Delirium Acute cerebral damage, 453 Acute complete transverse myelitis (ACTM), 725 Acute disseminated encephalomyelitis (ADEM) classification, 1 versus CNS disorders, 1 diagnosis, 2 neuropathology/pathophysiology, 1 neuropsychological/clinical presentation, 1–2 recurrent ADEM, 2 versus Schilder’s disease, 642 symptoms, 1 treatment, 2–3 Acute febrile mucocutaneous lymph node syndrome. See Kawasaki’s disease (KD) Acute febrile vasculitic syndrome, 388 Acute hemiplegia, 656 Acute hemorrhagic leukoencephalopathy (AHLE), 283, 284 Acute idiopathic polyradiculoneuritis. See Miller Fisher syndrome (MFS) Acute inflammatory demyelinating polyneuropathy. See Miller Fisher syndrome (MFS) Acute inflammatory demyelinating polyradiculoneuropathy, 335 Acute motor and sensory axonal neuropathy, 335 Acute motor axonal neuropathy, 335 Acute pain versus chronic pain, 212 Acute partial transverse myelitis (APTM), 725 Acute stress disorder (ASD), 6, 9, 198 Acyclovir, 246, 285, 654 Adiadochokinesia, 271, 272 ADIS-IV (Anxiety Disorders Interview Schedule for DSM-IV), 195

Adnexal atrophy, 576 Adrenal calcification, 772 Adrenocorticotropic hormone (ACTH), 242–244, 253, 397, 431, 551, 758, 760 Adrenoleukodystrophy (ALD) classification, 3 diagnosis, 4–5 neuropathology/pathophysiology, 3–4 neuropsychological/clinical presentation, 4 treatment, 5 Adult anxiety disorders acute stress disorder (ASD), 6, 9 agoraphobia, 6 diagnosis, 9–11 generalized anxiety disorder (GAD), 6–7 neuropathology/pathophysiology, 7–8 neuropsychological/clinical presentation, 8–9 obsessive-compulsive disorder (OCD), 6 panic disorder (PD), 6, 7, 8, 10 panic disorder with agoraphobia (PDA), 6 posttraumatic stress disorder (PTSD), 6 social anxiety disorder (SAD), 6 specific phobias (SPs), 6 treatment, 11–13 Adult criminality diagnosis, 18 neuropathology/pathophysiology, 17 neuropsychological/clinical presentation, 17–18 treatment, 18 Adult, lead intoxication, 417 Adult mood disorders. See Mood disorders, in adult Adult-onset AD (AOAD), 52 Adult-onset Huntington’s disease, 356 Adult Refsum’s disease (ARD) diagnosis, 27 neuropathology/pathophysiology, 27 neuropsychological/clinical presentation, 27 treatment, 27

780 & INDEX

Adult subtype, 460 Adynamia, 86 Agency for Healthcare Research and Quality (AHRQ), 279 Agenesis of the corpus callosum (ACC) Apert syndrome, associated with, 238 diagnosis, 29 neuropathology/pathophysiology, 28 neuropsychological/clinical presentation, 28–29 treatment, 29 Agnosia, 251, 328 apperceptive visual agnosia, 31–32 associative visual agnosia, 32 astereognosis, 35 auditory agnosia, 34 auditory sound agnosia, 34–35 auditory verbal agnosia, 34 autotopagnosia, 36 color agnosia, 33 finger, 37 paralinguistic agnosias, 35 prosopagnosia, 33–34 recognition model, 30 simultanagnosia, 32–33 somatosensory agnosia, 35 stage model, 30 symptoms, 30 tactile, 35–36 visual agnosia, 31 visual recognition model, 30 Agoraphobia, 6, 193, 197–198 Agrammatism, 86 Agraphia with alexia, 44 Agraphias, 305 with alexia, 44 aphasic agraphia, 43–44 apraxic apgaphia, 44 central agraphias, 43 classification, 42–43 linguistic components, disorders of deep agraphia, 46 lexical agraphia, 45 phonological agraphia, 45–46 semantic agraphia, 46 motor components, disorders of allographic agraphia, 47 apraxic agraphia, 46–47 spatial agraphia, 47 primary types, 43 pure agraphia, 43 spatial agraphia, 44–45 test for, 43 treatment, 47 AHI1 gene, 384 Aicardi’s syndrome diagnosis, 50 neuropathology/pathophysiology, 50–51 neuropsychological/clinical presentation, 51 treatment, 51

Akinesia, 682 Akinetic-rigid syndrome, 235, 500 Aldolase muscle enzymes, elevated levels of, 261 ALDP gene, 4 Alemtuzumab, 596 Alexander’s disease (AD) adult-onset form, 52 diagnosis, 53 infantile form, 52 juvenile form, 52 neuropathology/pathophysiology, 52 neuropsychological/clinical presentation, 53 treatment, 53 Alexia attentional alexia, 54 deep alexia, 56 neglect alexia, 54 phonological alexia, 55–56 pure alexia, 54–55 semantic alexia, 56 surface alexia, 55 treatment, 56–57 Alien hand syndrome callosal variant, 59 diagnosis, 59 frontal variant, 59 neuropathology/pathophysiology, 58–59 neuropsychological/clinical presentation, 59 treatment, 59–60 Allergic angiitis. See Churg–Strauss syndrome (CSS) Allergic granulomatosis. See Churg– Strauss syndrome (CSS) Allographic agraphia, 47 Allographic conversion, 47 Allopurinol, 424 Alobar holoprosencephaly, 349–350 Alpers’s disease diagnosis, 61 neuropathology/pathophysiology, 60 neuropsychological/clinical presentation, 60–61 treatment, 61 Alpha-adrenergic agonists, 271 Alpha fetoprotein (AFP), 669 Alphasynuclein pathology, 270 Alternating hemiplegia in childhood (AHC) diagnosis, 62–63 neuropathology/pathophysiology, 62 neuropsychological/clinical presentation, 62 symptoms, 63 treatment, 63 Alzheimer’s disease (AD) versus cerebral arteriosclerosis, 169 diagnosis, 65–66 versus LBD, 426

neuropathology/pathophysiology, 64–65 neuropsychological/clinical presentation, 65 symptoms, 64 treatment, 66–67 Amantadine, 527 Amenorrhea, 280 American Association on Mental Retardation, 455–456 American College of Cardiology/ American Heart Association, 392 American College of Rheumatology (ACR), 215, 594, 646 American Congress of Rehabilitation Medicine, 728 American Psychiatric Association (2000), 264 American Spinal Injury Association (ASIA) Standards, 671 Amimia, 589–590 Amitriptyline, 568 Amniocentesis, 266, 669, 735, 772 Amphetamine, 324, 399 Amphetamine sulfate, 366 Amphotericin B, 451 Ampicillin, 451 Amygdala, 7, 12, 428, 766 Amyotrophic lateral sclerosis (ALS), 483 diagnosis, 70–71 versus Kennedy’s disease, 395 neuropathology/pathophysiology, 68–69 neuropsychological/clinical presentation, 69–70 primary lateral sclerosis, 608 sporadic and familial forms, 68–69 treatment, 71 Anarthria, 91 Ancillary tests, nondystrophic myotonia of, 512 Andersen–Tawil syndrome (ATS), 307, 308 Anderson–Fabry disease. See Fabry’s disease (FD) Androgen receptor (AR) protein, 394 Anemic hypoxia, 167 Anencephaly diagnosis, 75 neuropathology/pathophysiology, 75 neuropsychological/clinical presentation, 75 treatment, 75 Aneurysms diagnosis, 78 neuropathology/pathophysiology, 76–77 neuropsychological/clinical presentation, 77–78 treatment, 78–79 types of, 76

INDEX & 781

Angelman syndrome (AS), 80 diagnosis, 81–82 neuropathology/pathophysiology, 81 neuropsychological/clinical presentation, 81 treatment, 82 Angiokeratoma, 300 Angioma, 173, 684 Angioosteohypertrophy syndrome. See Klippel–Trenaunay’s syndrome (KTS) Angular gyrus, 55 Anhedonia, 202 Anomia, 31, 86 Anomic aphasia, 90 Anorexia nervosa, 279, 280 Anosmia, 27 Anosodiaphoria versus anosognosia, 36 Anoxic encephalopathy, 288 Anoxic/hypoxic brain injury, 167 Anterior cingulate cortex (ACC), 7 Anterior communicating artery (ACoA), 77–78 Anti-epileptic drugs, 708 Anti-GM ganglioside antibodies, 483 Anti-Parkinson medication, 501 Anticoagulation therapy, for deep vein thrombosis treatment, 305 Anticonvulsant medications, 82, 131, 207, 251–252, 294, 333, 482, 534, 584, 640, 731 Antidepressant medications, 12, 24, 25, 110, 123, 213, 568, 591 Antiepileptic drugs (AEDs), 135, 192, 525 Antiglycemics, 688 Antihypertensives, 688 Antilirium, 119 Antimicrobial drugs, 450 Antineutrophil cytoplasmic antibodies (ANCAs), 753 Antiphospholipid antibodies (aPLs), 353, 697 Antiphospholipid syndrome (APS). See also Hughes’ syndrome classification, 83 diagnosis, 84 feature, 83 neuropathology/pathophysiology, 83 neuropsychological/clinical presentation, 84 thrombotic events, 83 treatment, 84–85 Antipsychotics, 621 Antipyretics, febrile seizure, treatment of, 314 Antisocial personality disorder (APD), 17, 18, 224 Antithyroid drugs, 713 Anxiety disorders. See also Adult anxiety disorders in children, 193–199 definition, 193

infancy and toddlerhood, 193 Anxiety Disorders Interview Schedule for DSM-IV (ADIS-IV), 195 Anxiolytics, 213 Apallic syndrome, 223 Apathy, behavioral manifestations, 615 Apert’s syndrome, 238 Aphasia, 236 anomic aphasia, 90–91 aphemia, 91 atrophy, 87 clinical signs and symptoms, 86 diagnosis, 92–93 extrasylvian aphasias, primary types of, 89–90 neuropathology/pathophysiology, 86–87 neuropsychological/clinical presentation, 87 perisylvian aphasias, primary types of, 87–89 pure word deafness, 91 subcortical aphasia, 91–92 treatment, 93–94 Aphasia with convulsive disorder. See Landau–Kleffner syndrome (LKS) Aphasic agraphia, 43–44 Aphasic dysgraphia, 263 Aphemia, 76 Apneic episodes, 661 APOE gene, 64 Apolipoprotein E-e4 (APOE-e4), 64 Apomorphine, 570, 748 Apoptosis, 570 Apparent diffusion coefficient (MD), 490 Apperceptive visual agnosia, 31–32 Apraxia. See also Hallucinations conceptual apraxia, 104 conduction apraxia, 104 constructional apraxia, 104 diagnosis, 104–105 neuropathology/pathophysiology ideational apraxia, 103 ideomotor apraxia, 102 limb-kinetic apraxia, 103 neuropsychological/clinical presentation ideational apraxia, 103 ideomotor apraxia, 102–103 limb-kinetic apraxia, 103 orofacial/buccofacial apraxia, 103–104 speech apraxia, 104 tactile apraxia, 104 treatment, 105 Apraxia of the eyelid (AEO), 142 Apraxic agraphia, 46–47 Apraxic dysgraphia, 263–264 Aqueductal stenosis, 360 Arachnoid cysts, 644, 706 cognitive dysfunction, 106 diagnosis, 107 neuropathology/pathophysiology, 105–106

neuropsychological/clinical presentation, 106–107 treatment, 107 Arachnoiditis classification, 109–110 diagnosis, 110 neuropathology/pathophysiology, 109–110 neuropsychological/clinical presentation, 110 treatment, 110–111 Areflexia, 210, 347, 466 Aripiprazole, 427 Armadillo syndrome. See Isaac’s syndrome Arnold-Chiari malformations. See Chiari malformations Arousal, 10 Arrhythmia, 694 Arteriovenous malformations (AVMs) diagnosis, 112 neuropathology/pathophysiology, 111 neuropsychological/clinical presentation, 111–112 treatment, 112 Artherothrombotic ischemic stroke, 181 Arylsulfatase A (ARSA), lysosomal enzyme, 459 Ashkenazi Jews, 707 ASPA gene, 155 Asparagines substitution (D178N), 312 Aspartoacylase deficiency, 155 Asperger’s syndrome. See also Autism diagnosis, 115–116 neuropathology/pathophysiology, 114–115 neuropsychological/clinical presentation, 115 treatment, 116 Aspirin, 84, 317, 389, 568, 574, 686, 689 Associative visual agnosia, 32 Astereognosis, 35 Ataxia, 27, 312, 320, 557, 682 Ataxia telangiectasia (AT) in children, 117–118 diagnosis, 118–119 neuropathology/pathophysiology, 118 neuropsychological/clinical presentation, 118 symptoms, 117 treatment, 119 Ataxia-telangiectasia mutated (ATM), 118 Ataxic cerebral palsy, 175 Ataxin-3, 437 Atherosclerosis, 209 Atrophy, 509 Attention deficit hyperactivity disorder (ADHD), 193, 224, 264, 661, 739 diagnosis, 122–123 neuropathology/pathophysiology, 120–121

782 & INDEX

Attention deficit hyperactivity disorder (ADHD) (cont.) neuropsychological/clinical presentation, 121–122 symptoms, 120, 123 treatment, 123–124 Attention skills, 443 Attentional alexia, 42, 54 Auditory agnosia, 34, 415 Auditory sound agnosia, 34–35 Auditory verbal agnosia, 34 Autism assessment of, 115 diagnosis, 126–127 neuropathology/pathophysiology, 125 neuropsychological/clinical presentation, 126 spectrum disorders, 319 symptoms, 125 treatment, 127 Autoimmune myasthenia gravis (AMG), childhood, 229–232 Autonomic dysfunction, 339, 500 Autonomic dysregulation, 312 Autonomic failure neuronal loss, associated with, 682 symptoms, 682 Autonomic neuropathy, 565–566 Autosomal-dominant genetic alteration, 341 Autosomal-recessive genetic alteration, 341 Autotopagnosia, 36 Avonex, 496 Axon loss, 488 Azathioprine, 484, 596, 701, 754

Babinski response, 709 Baclofen, 310, 340, 343, 369, 424, 580, 609, 681, 731, 736 Bacterial meningitis, 450 Balloon test occlusion (BTO), 78 Barium swallow, 261 Basal ganglion, 86, 142, 162, 245, 306, 330, 367, 682, 716, 770 Battenin, 529 Batten’s disease diagnosis, 130–131 mutations, 129 neuropathology/pathophysiology, 129 neuropsychological/clinical presentation, 129–130 symptoms, 129 treatment, 131 Beck Anxiety Inventory, 10, 604 Beck Depression Inventory, 23, 661 Becker muscular dystrophy (BMD) characterization, 502 Becker’s disease, 515 Behavior Assessment System for Children (BASC), 206

Behavioral activation system (BAS), 21 Behavioral deficits, Angelman syndrome, 81 Behavioral therapy for anxiety disorders, 11 for mood disorders, 24 Behaviorally inhibited children, 194 Behçet’s disease (BD) diagnosis, 132 neuropathology/pathophysiology, 132 neuropsychological/clinical presentation, 132 treatment, 132–133 Bell’s palsy diagnosis, 134 neuropathology/pathophysiology, 133–134 neuropsychological/clinical presentation, 134 treatment, 134 Benign focal seizure disorder, 135 Benign Rolandic epilepsy (BRE) diagnosis, 137 neuropathology/pathophysiology, 136 neuropsychological/clinical presentation, 136–137 seizures, 135 symptoms, 135 treatment, 137 Benzodiazepine, 220, 241, 244, 271, 314, 343, 527, 603, 632, 731, 736 Benztropine, 277 Bernhardt–Roth syndrome diagnosis, 139 neuropathology/pathophysiology, 138–139 neuropsychological/clinical presentation, 139 symptoms, 138–139 treatment, 139 Betainterferon, 643 Betaseron, 496 Bielschowsky’s disease, 530 Bilateral frontal lobe dysfunction, 158 Bilateral temporal ablation, 406 Binswanger’s disease diagnosis, 141 neuropathology/pathophysiology, 140 neuropsychological/clinical presentation, 140–141 treatment, 141 Biochemical lesions, 755 Biofeedback, 465 Biological glue, 428 Bipolar Disorder (BD) BD I, 21, 23, 202 BD II, 21, 202 clinical presentation, 205–206 versus major depressive disorder, 202–203 NMDA (N-methyl-D-aspartate), hypofunction of, 204

spectrum of, 20–21 symptoms of, 204 treatment of, 25 Biting, 424 Blacklegged ticks, 434 Blatant problems, 106 Blepharospasm (BEB), 275 diagnosis, 142–143 neuropathology/pathophysiology, 141–142 neuropsychological/clinical presentation, 142 symptoms, 141 treatment, 143 Blindness, 246 Bloch–Sulzberger syndrome diagnosis, 144–145 neuropathology/pathophysiology, 144 neuropsychological/clinical presentation, 144 treatment, 145 Blood tests creatine kinase (CK) level measurement, 503 rheumatoid arthritis, 637 Blood transfusions, 657 Blue rubber bleb nevus syndrome, 173 Body dysmorphic disorder (BDD), 577, 664 Bone marrow transplantation, 409, 460 Borrelia burgdorferi, 434 Boston Diagnostic Aphasia Examination (BDAE), 92 Boston Naming Test, 183 Botulinum toxin, 277, 369 Botulinum toxin type A (BoNT-A) treatment, 143 Botulism toxin type A (Botox), 343, 550 Brachial MMA (BMMA), 476 Brachial plexus paralysis. See Erb’s palsy Bradykinesia, 570, 682 Brain aneurysm. See Cerebral aneurysm Brain biopsy, for Rasmussen’s encephalitis, 624 Brain calcifications, 685 Brain, cortical Lewy bodies, 426 Brain-derived neurotropin factor (BDNF), 356, 703 Brain tumors diagnosis, 150 neuropathology/pathophysiology, 146 neuropsychological/clinical presentation, 146, 150 treatment, 150–151 Brainstem, 222 Branched chain amino acids (BCAA), 663 Branched-chain l-2-keto acid dehydrogenase complex (BCKD) activity, 440 Broca’s aphasia, 44, 86, 87, 182, 282 Brody’s disease, 511

INDEX & 783

Bromocriptine, 93–94, 282, 527, 570 Brown metachromatic bodies, 460 Brown-Se´quard syndrome diagnosis, 152–153 neuropathology/pathophysiology, 152 neuropsychological/clinical presentation, 152 symptoms, 152 treatment, 153 Buccofacial apraxia. See Orofacial/ buccofacial apraxia Bulbar pain, 752 Bulimia nervosa, 279, 280 Bursitis, 630

Cafe´-au-lait spots, 524 CAG repeats in Huntington’s disease, 356 in Kennedy’s disease, 394 Calcification, 429 Calcitonin gene-related peptide (CGRP), 573–574 Calcium metabolism, 306 California Verbal Learning Test, 183, 191, 496 California Verbal Learning Test II, 66, 345, 457 Canavan’s disease diagnosis, 156 neuropathology/pathophysiology, 155 neuropsychological/clinical presentation, 155–156 treatment, 156 Capgras’s syndrome, 628 diagnosis, 158 neuropathology/pathophysiology, 157–158 neuropsychological/clinical presentation, 158 treatment, 158 Capsaicin, 654 Carbamazepine, 137, 192, 207, 268, 294, 333, 407, 515, 550, 572, 574, 686, 689, 692, 731 Carbidopa, 427 Carbidopa-levodopa, 554. See also Sinemet Carbon dioxide laser surgery, 429 Carbon monoxide (CO) poisoning, 166 Cardiac and pulmonary weakness, polymyositis, 595 Cardiac arrhythmias, 27 Cardiac conduction abnormalities, 469 Cardiologist, 662 Cardiomyopathy, 469 Carditis, 691 Carotid sinus syncope, 694 Cataplexy, 220 Catastrophic antiphospholipid syndrome (CAPS), 83, 353 Catechol-O-methyl transferase (COMT), 570

Catecholamines, attention deficit hyperactivity disorder, 121 Cathepsin D (CTSD), 530 Causalgia diagnosis, 159–160 neuropathology/pathophysiology, 159 neuropsychological/clinical presentation, 159 treatment, 160 CCM2 gene, 173 Cefotaxime, 451 Ceftriaxone, 451, 537 Celecoxib, 574 Celexa (Citalopram), 199 Cell migration, lead toxicity, 417 Center for disease control and prevention (CDC), 727 Center for Epidemiologic Studies-Depression Scale and Neuropsychiatric Inventory, 183 Central achromatopsia, 33 Central agraphias, 43 Central cord syndrome (CCS) diagnosis of, 161 neuropathology/pathophysiology of, 161 neuropsychological/clinical presentation of, 161 treatment of, 161–162 Central core disease, 233 Central neuropathy, 532 Central pontine myelinolysis (CPM) diagnosis of, 164 neuropathology/pathophysiology of, 163 neuropsychological/clinical presentation of, 163–164 treatment of, 164 Central sleep apnea, 660 Centronuclear myopathy, 234 CEP290 gene, 384 Cephalic disorders, 74 Cephalocervical fibromuscular dysplasia, 317 Ceramide, 310–311 Ceramide trihexosidase, 299 Cerebellar ataxia, 553 Cerebellar atrophy, 707 Cerebellar cognitive affective syndrome (CCAS), 118 Cerebellar hypoplasia, 475 diagnosis, 166 neuropathology/pathophysiology, 165 neuropsychological/clinical presentation, 165–166 treatment, 166 Cerebellar purkinje cell layer, 437 Cerebellar vermis, normal lobulation of, 249 Cerebellum attention deficit hyperactivity disorder, 121

lead intoxication, 417 Cerebral aneurysm, 76 Cerebral angiography, 478–479 Cerebral anoxia diagnosis, 168 neuropathology/pathophysiology, 167 neuropsychological/clinical presentation, 167–168 treatment, 168 Cerebral arteriosclerosis diagnosis, 169–170 neuropathology/pathophysiology, 169 neuropsychological/clinical presentation, 169 treatment, 170 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) diagnosis, 171–172 neuropathology/pathophysiology, 171 neuropsychological/clinical presentation, 171 treatment, 172 Cerebral cavernous malformations (CCMs) diagnosis, 173 neuropathology/pathophysiology, 172–173 neuropsychological/clinical presentation, 173 treatment, 173 Cerebral cortex, 251 Cerebral gigantism. See Sotos’ syndrome Cerebral ischemia, 84 Cerebral palsy (CP), 290 diagnosis, 176 neuropathology/pathophysiology, 175 neuropsychological/clinical presentation, 175–176 treatment, 176–177 Cerebral perfusion pressure (CPP), 373 Cerebral thrombosis, 169 Cerebral venous hypertension, 618 Cerebro-oculo-facio-skeletal (COFS) syndrome diagnosis, 179 neuropathology/pathophysiology, 179 neuropsychological/clinical presentation, 179 treatment, 179–180 Cerebromedullospinal disconnection, 433 Cerebrovascular accident (CVA) definition, 180 diagnosis, 183 neuropathology/pathophysiology, 180–181 neuropsychological/clinical presentation, 181–183 treatment, 183–184 Cervical rib, 710 Cervicogenic headaches, 550

784 & INDEX

CHAC gene, 519 Chapel Hill Consensus Conference (CHCC) criteria, 594 Charçot–Marie–Tooth (CMT) diagnosis, 186 neuropathology/pathophysiology, 185–186 neuropsychological/clinical presentation, 186 treatment, 186–187 Chariot’s sign, 142 Chelating agents, 770 Chelation therapy, lead intoxication, 418 Chemotherapy for cancer treatment, 150–151 neurofibromatosis (NF), 525 Chiari malformations diagnosis, 189 neuropathology/pathophysiology, 188 neuropsychological/clinical presentation, 188–189 subtypes, 188 treatment, 189 types, 188–189 Child Behavior Checklists (CBCL), 206 Childhood absence epilepsy diagnosis, 191–192 neuropathology/pathophysiology, 190 neuropsychological/clinical presentation, 190–191 seizure, 190 treatment, 192 Childhood anxiety disorders anxiety definition, 193 development of, 193–194 diagnosis, 194, 197–198 negative temperaments, 194 neuropathology/pathophysiology, 195–196 neuropsychological/clinical presentation, 196–197 treatment, 198–199 Childhood autoimmune myasthenia gravis (AMG) diagnosis, 231–232 neuropathology/pathophysiology, 229–230 neuropsychological/clinical presentation, 230–231 treatment, 232 Childhood epilepsy Lennox–Gastaut’s syndrome (LGS), 421 Childhood mood disorders diagnosis, 206 neuropathology/pathophysiology, 203–205 neuropsychological/clinical presentation, 205–206 treatment, 206–207 Children chelation therapy, 418

dietary calcium, 418 lead intoxication, 417 Lennox–Gastaut’s syndrome (LGS), 421 opsoclonus–myoclonus syndrome (OMS), 556–558 pica, 417 verbal IQ, 418 Children’s Depression Rating Scale-Revised (CSDRS-R), 206 Children’s Depressive Inventory (CDI), 130, 206 Chloramphenicol, 451 Chloride channel disorders, 512 Cholesteryl ester storage disease (CESD), 772 diagnosis, 209 neuropathology/pathophysiology, 208–209 neuropsychological/clinical presentation, 209 treatment, 209 Choline acetyltransferase, 229 Chorea, 355, 356 Chorea-acanthocytosis (ChAc), 519 Chorea minor. See Sydenham chorea Choreoathetoid movements, 735 Choreoathetosis, 423 Chorionic villus sampling (CVS), 431 Chromosomal deletion in Angelman syndrome, 81 in brain tumors, 146 Chromosomal disorder. See Turner’s syndrome Chromosome 7q11.23, 766 Chronic cluster headache, 216 Chronic fatigue syndrome (CFS), 270 Chronic inflammatory demyelinating polyneuropathy (CIDP), 483 diagnosis, 211 neuropathology/pathophysiology, 210 neuropsychological/clinical presentation, 210–211 treatment, 211 Chronic pain syndrome versus acute pain, 212 diagnosis, 213 neuropathology/pathophysiology, 213 neuropsychological/clinical presentation, 213 treatment, 213–214 Chronic paroxysmal hemicranias (CPH), 338, 573 Chronic traumatic encephalopathy. See Dementia pugilistica Churg–Strauss syndrome (CSS) diagnosis, 215 neuropathology/pathophysiology, 214 neuropsychological/clinical presentation, 214–215 treatment, 215 Cincinnati Pre-hospital Stroke Scale (CPSS), 722

Cingulate gyrus, cortical Lewy bodies, 426 Circle of Willis, 76 Circumlocution, 86 Citalopram. See Celexa (Citalopram) ‘‘Clasp-knife,’’ 368 Classic Hirayama’s disease. See Brachial MMA (BMMA) Classic Pelizaeus–Merzbacher’s disease, 579 Clavicle rib, 710 Clefts, formation of, 643 CLN1, 529, 530 CLN2, 529, 530 CLN3, 129, 529, 530 CLN4, 529, 530 CLN5, 529, 530 CLN6, 529, 530 CLN7, 529–530 CLN8, 530 CLN9, 530 CLN10, 530 Clobazam, 51 Clofazimine, 449 Clomipramine, 717 Clonazepam, 82, 143, 268, 294, 310, 340, 422, 508, 572 Clonidine, 717 Clonopin (Clonazepam), 294 Clorazepate (Tranxene), 294 Closed neural tube defect, 668 Clozapine, 427 Cluster headache (CH), 550 characterization of, 216 chronic form, 216 diagnosis, 217 episodic form, 216 neuropathology/pathophysiology, 216–217 neuropsychological/clinical presentation, 217 treatment, 217–218 CMT1, 185 CMT2, 185 CMT3. See Dejerine–Sottas’s disease CMT4, 186 Cobblestone dysplasia. See Lissencephaly Cockayne syndrome, 179 Coffin–Lowry syndrome diagnosis, 220 neuropathology/pathophysiology, 219–220 neuropsychological/clinical presentation, 220 treatment, 220 Cognitive-behavioral intervention models, 445 Cognitive behavioral therapy (CBT) anxiety disorders, 11, 198 chronic pain syndrome, 214 somatoform disorders and conversion, 664–665 Cognitive domains, 257

INDEX & 785

Cognitive hypothesis-testing (CHT) model, 265 Cognitive impairments Gerstmann–Strau¨ssler–Scheinker (GSS) disease, 330 in myotonia, 512 reduplicative paramnesia, 629 Color agnosia, 33 Color anomia, 33 Colpocephaly diagnosis, 222 neuropathology/pathophysiology, 221 neuropsychological/clinical presentation, 222 treatment, 222 Coma and persisting vegetative state diagnosis, 223 neuropathology/pathophysiology, 222 neuropsychological/clinical presentation, 222–223 treatment, 223 Coma grade, Reye’s syndrome, 635 ‘‘Communicating’’ hydrocephalus, 545 Communication Effectiveness Index (CETI), 92 Communication skills development, in Angelman syndrome, 82 Complete blood count (CBC), 656 Complex regional pain syndrome Type 2. See Causalgia Complicated spastic paraplegia type 2, 579 Compulsions, defined, 10 Conceptual apraxia, 104 Conduct disorder (CD) classification, 224 diagnosis, 226 neuropathology/pathophysiology, 225 neuropsychological/clinical presentation, 225–226 treatment, 226–227 Conduction aphasia, 43, 88–89, 104 Conduction apraxia, 104 Conduction block (CB), 472, 483 Congenital and childhood myasthenias. See Myasthenic syndromes Congenital dysplastic angiectasia. See Klippel–Trenaunay’s syndrome (KTS) Congenital fiber-type disproportion, 234 Congenital hydrocephalus, 360 Congenital muscular dystrophy (CMD), 375, 502 Congenital myasthenias (CMs) diagnosis, 231–232 neuropathology/pathophysiology, 230 neuropsychological/clinical presentation, 231 treatment, 232 Congenital myopathy, 509 diagnosis, 234–235 neuropathology/pathophysiology, 234

neuropsychological/clinical presentation, 234 symptoms of, 234 treatment, 235 Connatal Pelizaeus–Merzbacher’s disease, 579 Connexin, 186 Constructional apraxia, 104 Constructional dysgraphia, 263, 264 Constructive apraxia, 182 Continuous motor nerve discharges. See Isaac’s syndrome ‘‘Continuous muscle-fiber activity,’’ 382 Continuous positive airway pressure (CPAP), 688 Controlled Oral Word Association Test, 183, 608 Conventional catheterization angiography, 701 Conversion disorder. See Somatoform disorders Copaxone (Glatiramer acetate), 496 Copper metabolism, deficiency of, 769 Copper transporting adenosine triphosphatase (ATPase; ATP7A), 452 Corpus callosum, agenesis of. See Agenesis of the corpus callosum (ACC) Cortical amyloid plaques, 426 Cortical atrophy, 647 Cortical dysfunction, 557 Cortical Lewy bodies, 426 Cortical reflex myoclonus, 507 Corticobasal degeneration (CBD) diagnosis, 237 neuropathology/pathophysiology, 235–236 neuropsychological/clinical presentation, 236–237 treatment, 237 Corticobasal degenerative syndrome (CBDS), 616 Corticosteriods acute disseminated encephalomyelitis, 2 arachnoiditis, 110 for Behçet’s disease (BD), 132–133 Bell’s palsy, 134 chronic inflammatory demyelinating polyneuropathy, 211 Cushing’s syndrome (CS), 244 dermatomyositis, 262 Melkersson–Rosenthal’s syndrome, 449 muscular dystrophy, 503–504 neurosarcoidosis treatment, 536 for polymyositis, 596 Rasmussen’s encephalitis, 624 Schilder’s disease, 643 systemic lupus erythematosus, 698 vasculitis, 746 West’s syndrome (WS), 758

CRAFTS trail, 723 Cranial encephalocele, 286 Cranial meningocele, 286 Cranial nerve anomalies, 475 Cranial pressure, 642 Cranial vault remodeling, 239 Craniosynostosis diagnosis, 238–239 neuropathology/pathophysiology, 238 neuropsychological/clinical presentation, 238 treatment, 239 Creatine kinase (CK), 261, 394, 713 Creutzfeldt–Jakob disease (CJD), 329–330 diagnosis, 241 neuropathology/pathophysiology, 240–241 neuropsychological/clinical presentation, 241 treatment, 241 variants of, 240 Criminality, adult. See Adult criminality Crouzon’s disease, 238 Cryoglobulinemia, 745 Cryptogenic West’s syndrome, 758 CT scans olivopontocerebellar atrophy (OPCA), 553–554 Cumulative trauma disorders. See Repetitive motion disorders (RMDs) Curriculum-based measurement (CBM), 444 Cushing’s syndrome (CS), 560–561 diagnosis, 243–244 neuropathology/pathophysiology, 243 neuropsychological/clinical presentation, 243 treatment, 244 Cutaneous pan, 594 Cyanide nitroprusside, 352 Cyclophosphamide, 232, 484, 559, 701, 754 Cyclopia, 350 Cyclosporine, 232 Cyclothymia, 21 Cyclothymic disorder, 203 Cyst formation, 705 Cystathione -synthase (CBS) deficiency, 351–352 Cystic tumors, 146 Cystica. See Spina bifida Cytokines, 697 Cytomegalovirus (CMV), 455 diagnosis, 246 neuropathology/pathophysiology, 245–246 neuropsychological/clinical presentation, 246 treatment, 246 Cytoplasmic inclusions, 682 Cytotoxic drugs, vasculitis, 746 Cytotoxic necrosis, 595

786 & INDEX

D-penicillamine, 647 Daclizumab, 733 Dactylitis, 656 Daily restless legs syndrome, 632 Danazol, 733 Dandy–Walker syndrome (DWM) diagnosis, 250 neuropathology/pathophysiology, 249 neuropsychological/clinical presentation, 249 treatment, 250 ‘‘Dangerous mechanism of injury,’’ 763 Dantrolene, 310, 343, 369, 527, 736 ‘‘Darting tongue,’’ 691 Dawson’s disease definition, 250 diagnosis, 251 neuropathology/pathophysiology, 251 neuropsychological/clinical presentation, 251 treatment, 251–252 Dawson’s fingers, 489 De Morsier’s syndrome diagnosis, 253 neuropathology/pathophysiology, 252–253 neuropsychological/clinical presentation, 253 treatment, 254 Deep agraphia, 46 Deep alexia, 56 Deep brain stimulation (DBS), 177, 570 Deep vein thrombosis, 304–305 Dehydrated blood vessels, 658 Dejerine Thomas type, 552 Dejerine–Klumpke Palsy definition, 254 diagnosis, 255–256 neuropathology/pathophysiology, 255 neuropsychological/clinical presentation, 255 treatment, 256 Dejerine–Sottas’s disease, 185–186 Deletion. See Gene deletion Delinquency, 385 Delirium definition, 256 diagnosis, 257–258 neuropathology/pathophysiology, 257 neuropsychological/clinical presentation, 257 treatment, 258 Delusional misidentification, 157, 158, 628 Dementia, 170, 181, 182, 537 cognitive impairments, 270 differential diagnosis, 257 questionnaire, 456 scale, 456 Dementia pugilistica diagnosis, 259 neuropathology/pathophysiology, 259

neuropsychological/clinical presentation, 259 pharmacologic agents, 259 punch drunk, 258 treatment, 259 Dental abnormalities Bloch–Sulzberger syndrome, 144 tuberous sclerosis, 738 Dentatorubral-pallidoluysian atrophy (DRPLA), 675, 677 Depression Self-Rating Scale, 206 Dermatological symptoms, in incontinentia pigmenti (IP), 144 Dermatomyositis, 562 diagnosis, 261 Gottron’s papules, 260 heliotrope rash, 260 neuropathology/pathophysiology, 261 neuropsychological/clinical presentation, 261 rashes characteristics, 260 Reynaud’s syndrome, 260 shawl rash, 260 treatment, 262 Detrusor tone, 669 Devic’s disease, 725 Dexamethasone, 2, 451 Diabetes, 472, 532 Diabetic microangiopathy, 429 Diabetic neuropathy, 534 Diagnostic and Statistical Manual for Mental Disorders (DSM-IV-TR), 18, 120, 122, 202, 203, 205, 224, 226, 366, 486, 585, 662, 664, 717 Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 6, 16–17, 115, 195, 197, 198, 486, 518, 603, 728 Diagnostic dyspraxia, 58 Diagnostic Interview Schedules for Children (DISC), 206 Diazepam, 268, 294, 310, 369, 383, 424, 681 Diffuse muscular hypotonia, 265 Diffuse myelinoclastic sclerosis. See Schilder’s disease Diffuse scleroderma, 646 Diffusion-tensor imaging, 490 Diffusion-weighted imaging (DWI) in multiple sclerosis (MS), 490 in transient global amnesia, 719 in transient ischemic attacks, 722 in Wallenberg’s syndrome, 752 Digits (WAIS-III) test, 183 Diltiazem, 689 Diphehydramine, 277 Diplegic cerebral palsy, 175 Diplopia. See Visual disturbances Direct bypass methods, 479 Disabilities Education Act, 445 Disease modifying antirheumatic drugs (DMARDs), 637 Disorders of linguistic components, 45–46

Disorders of motor components, 46–47 Disorders of written language (DWL) agraphia, 262 diagnosis, 264 neuropathology/pathophysiology, 263 neuropsychological/clinical presentation, 263–264 treatment, 264 written expression, 262 Disruptive behavior disorders, 224 Distal muscular dystrophy, 502 DISTAR arithmetic program, 446 Divalproex, 207 DNA methylation analysis, 81 DNA testing, Tay–Sachs’s disease, 81 Docosahexanoic acid, 5 Donepezil, 66, 172, 184 Dopa-responsive dystonia (DRD), 274, 275–276 Dopamine agonists, 93 Dopamine beta hydroxylase (DBH), 453 Dorsal simultanagnosia, 32 Dorsomedial prefrontal cortex (DMPFC), 114 Double depression, 20 Down’s syndrome diagnosis, 266–267 neuropathology/pathophysiology, 266 neuropsychological/clinical presentation, 266 treatment, 267 Doxycycline, 765 Dravet’s syndrome diagnosis, 268 neuropathology/pathophysiology, 267–268 neuropsychological/clinical presentation, 268 treatment, 268–269 Dressing apraxia, 182 Drug-induced neuropathy, 532 DSM-V somatic symptoms, 664 Duchenne’s dystrophy, 509 Duchenne muscular dystrophy (DMD) complications, 502–503 intellectual disability, 503 motor delays, 503 symptoms, 502 verbal IQ, in children, 502 Duloxetine, 25 Dynamic Indicators of Basic Early Literacy Skill (DIBELS), 626 Dysarthria, 423, 557 Dysautonomia diagnosis, 270–271 neurasthenia, 269 neuropathology/pathophysiology, 270 neuropsychological/clinical presentation, 270 parasympathetic nervous system, 269 sympathetic nervous system, 269 treatment, 271

INDEX & 787

Dyscalculia diagnosing methods, 444 screener, 444 Dysdiadochokinesia, 735 Dysesthesia, 139 Dyskinesia Identification System, Condensed User Scale (DISCUS), 703 Dyskinesias, 570 Dyskinetic cerebral palsy, 175 Dyslexia, 54, 136, 263, 442, 625, 626, 648. See also Reading disorders Dysmetria, 396 Dysphagia, 162, 595, 682 Dysphasia, 210, 251 Dysphonia, 231 Dyspnea, 754, 765 Dyssynergia cerebellaris myoclonica characterization of, 271 diagnosis, 272 features, 271 neuropathology/pathophysiology, 272 neuropsychological/clinical presentation, 272 treatment, 272–273 Dysthymic disorder, 20, 202, 204, 205 Dystonia-plus syndrome, 275 Dystonias, 367 diagnosis, 276 genetic classification of, 274 Lesch–Nyhan syndrome (LNS), 423 neuropathology/pathophysiology, 273–274 neuropsychological/clinical presentation, 274–276 storm, 273 treatment, 276–277 Dystrophic myotonias (DM) diagnosis, 512 type 1 and 2, 512 Dystrophin, 503 DYT1gene, 273

Early infantile epileptic encephalopathy with suppression-bursts. See Ohtahara’s syndrome Early neurosyphilis, 536 Early onset stage, in Rett syndrome (RS), 633 Eating disorders (ED) diagnosis, 280 neuropathology/pathophysiology, 279 neuropsychological/clinical presentation, 280 prevalence of, 279 risk factors for, 281 treatment, 280–281 Echocardiography, 300 Echolalia, 86 Eculizumab, 596

Ekman facial emotional recognition test, 428 Electrical stimulation treatment, for arachnoiditis, 111 Electroconvulsive therapy (ECT), 22 Electrodiagnostic measures, 255 Embolic ischemic stroke, 180–181 Embolization, in arteriovenous malformations, 112 Emery–Dreifuss muscular dystrophy, 502 Emotional disturbances, 493–494 Empty sella syndrome (ESS) diagnosis, 282 neuropathology/pathophysiology, 282 neuropsychological/clinical presentation, 282 treatment, 282–283 types of, 282 Enabling synkinesis, 59 Encapsulated tumors, 146, 151 Encephalitis, 245, 246 acute and chronic stages, 283 causative agents, 283 diagnosis, 285 neuropathology/pathophysiology, 283–284 neuropsychological/clinical presentation, 284–285 treatment, 285–286 Encephalitis lethargica. See von Economo disease (VED) Encephalitis subcorticalis chronica progressiva, 140 Encephalocele diagnosis, 287 forms of, 286 neuropathology/pathophysiology, 286–287 neuropsychological/clinical presentation, 287 surgery, goals of, 287 treatment, 287 Encephaloduroarteriosynangiosis, 479 Encephalomyelitis. See Acute disseminated encephalomyelitis (ADEM) Encephalopathy diagnosis, 289–290 neuropathology/pathophysiology, 288–289 neuropsychological/clinical presentation, 289 treatment, 290 Encephalophaloplastic porencephaly, 600 Endolymphatic tumors, 749 Endoscopic strip craniectomy, 239 Enoxaparin, 354 Enzyme replacement therapy (ERT), 482 familial dysautonomia (FD), 300 neuronal ceroid lipofuscinoses treatment, 531 Eosinophilia, in paraneoplastic syndromes, 561

Ephedrine, 232 Epidural/extradural hemorrhage, 181 Epilepsia partialis continua (EPC), 623 Epilepsy and seizures diagnosis, 293 division of, 291 neuropathology/pathophysiology, 291 neuropsychological/clinical presentation, 291–293 seizure types, 292–293 treatment, 293–294 Epileptic hemiplegia, 714 Episodic paroxysmal hemicrania (EPH), 573 Erb’s palsy anhydrosis, 296 diagnosis, 296 neuropathology/pathophysiology, 295 neuropsychological/clinical presentation, 295–296 treatment, 296 Ergotamine, 217, 574 Erythrocyte sedimentation rate (ESR), 658 Erythroderma, 563 Escitalopram (Lexapro), 199 Etanercept, 596 Ethosuximide (Zarontin), 192, 294 Ethylmalonic encephalopathy, 288 Evoked potentials, 490–491 Exacerbations, 420 Excitatory:inhibitory ratio (EIR) model, 270 Executive functions, 493 Exner’s area, 42, 263 Expanded Disability Status Scale (EDSS), 493, 496 Exposure therapy, for social anxiety disorder (SAD), 11–12 Extradural cysts, 706 Extraocular movements, 361 Extrapontine myelinolysis (EPM) diagnosis of, 164 neuropathology/pathophysiology of, 163 neuropsychological/clinical presentation of, 163–164 treatment of, 164 Extrapyramidal dyskinesia, 251 Extrapyramidal system damage, 175 Extrasylvian aphasias, primary types of, 89–90 ‘‘Eye of the tiger’’ sign, 522, 523

F2-isoprostanes, 290 F4-neuroprostanes, 290 Fabry’s disease (FD) diagnosis, 300 neuropathology/pathophysiology, 299 neuropsychological/clinical presentation, 299–300 treatment, 300

788 & INDEX

Facial edema, 449 Facial-oral apraxia. See Orofacial/buccofacial apraxia Facial trauma, 576 Facioscapulohumeral muscular dystrophy, 502 Factitious disorder (FD) diagnosis, 302–303 neuropathology/pathophysiology, 302 neuropsychological/clinical presentation, 302 signs and symptoms, 301–302 treatment, 303 Factor V Leiden diagnosis, 304–305 neuropathology/pathophysiology, 304 neuropsychological/clinical presentation, 304 symptoms, 305 treatment, 305 Factor X, 304 Fahr’s syndrome diagnosis, 306 neuropathology/pathophysiology, 306 neuropsychological/clinical presentation, 306 treatment, 306 Famciclovir, 654 Familial periodic paralysis (FPP) diagnosis, 307–308 neuropathology/pathophysiology, 307 neuropsychological/clinical presentation, 307 symptoms, 307, 308 treatment, 308 Familial spastic paraplegia classification, 308 diagnosis, 309–310 neuropathology/pathophysiology, 309 neuropsychological/clinical presentation, 309 treatment, 310 Family therapy, for childhood mood disorders, 207 Farber’s disease diagnosis, 311 neuropathology/pathophysiology, 310–311 neuropsychological/clinical presentation, 311 symptoms, 788 treatment, 311 Farber’s lipogranulomatosis. See Farber’s disease FAST (Face, Arm, Speech, Time) test, 722 Fatal familial insomnia (FFI), 329–330 clinical features of, 311 diagnosis, 312 neuropathology/pathophysiology, 312 neuropsychological/clinical presentation, 312 treatment, 312

Fatigue in multiple sclerosis (MS), 494 Febrile seizure diagnosis, 314 neuropathology/pathophysiology, 313 neuropsychological/clinical presentation, 313–314 symptoms, 314 treatment, 315 Feedback-based learning deficits, 78 Felbamate, 760 Fetal akinesia-hypokinesia deformation sequence (FADS), 179 Fetal alcohol syndrome (FAS) diagnosis, 315 neuropathology/pathophysiology, 315 neuropsychological/clinical presentation, 315 treatment, 315–316 Fetal alcohol syndrome deficits (FASD), 315 Fetal loss, in Hughes’ syndrome, 354 Fetal ultrasound iniencephaly, 381 macrencephaly, 439 Fibromuscular dysplasia (FMD) diagnosis, 317 neuropathology/pathophysiology, 317 neuropsychological/clinical presentation, 317–318 treatment, 317–318 Finger agnosia, 37 Finger tapping test, 191 First-thoracic (T-1) regions, 254 Fisher’s syndrome, 335 Flaccid paralysis, 472 FLAIR (fluid attenuation inversion recovery), 489, 688 ‘‘Floppy,’’ 233 Floppy infant syndrome, 369. See also Infantile hypotonia Fluconazole, 451 Flucytosine, 451 Fluent aphasia, 86. See also Semantic dementia (SD); Wernike’s aphasia Flunarizine, 63, 689 Fluorescent antibody test, 654 Fluorescent in situ hybridization (FISH), 81–82 Fluoxetine, 199, 232, 281, 407, 665, 717 Fluphenazine, 357 Fluvoxamine, 199, 717 Focal cranial dystonia, 141 Focal dystonia, 275 Focal limb paralysis, 472 Focal myoclonus, 507 Focal neurological deficits, 593 Fogginess, of mentation, 603 Folic acid, insufficient intake of, 668 Fondaparinux, 305 Fontanelles, 238 ‘‘Foot drop,’’ 185 Foreign accent syndrome, 91

Foscarnet, 246 Fragile X mental retardation protein (FMRP), 319 Fragile X syndrome, 667 diagnosis, 319–320 neuropathology/pathophysiology, 319 neuropsychological/clinical presentation, 319 symptoms, 319 treatment, 320 Frataxin, 322 Free radical hypothesis, 703 ‘‘Freedom from Distractibility’’ test, 23 French polio. See Miller Fisher syndrome (MFS) Friedreich ataxia, 676, 677–678 diagnosis, 322 neuropathology/pathophysiology, 320–321 neuropsychological/clinical presentation, 321–322 symptoms, 320 treatment, 322 Frontal variant of FTD (fv-FTD), 324 Frontostriatal circuit, 120 Frontotemporal dementia (FTD), 69, 70, 590 diagnosis, 324 neuropathology/pathophysiology, 323 neuropsychological/clinical presentation, 323–324 symptoms, 324 treatment, 324 Functional hemispherectomy treatment, in Rasmussen’s encephalitis, 624 Functional Independence Measure, 671 Fungal meningitis, 450 Fussy-difficult children, 194

GABAergic systems, 190 Gabapentin (Neurontin), 333, 550, 558, 689, 731 Gadolinium-enhanced (T1) images, 489 Gait ataxia, 437 Gait disturbance, in NPH, 545 Galactocerebrosidase deficiency, 408 Galantamine, 66, 184 Ganciclovir, 246 Gangliosides, 466 Gastroesophageal reflux disease (GERD), 661 Gastrointestinal problems, 472 Gastrostomy, COFS syndrome treatment, 179–180 Gaucher’s disease diagnosis, 327 neuropathology/pathophysiology, 327 neuropsychological/clinical presentation, 327 treatment, 327–328 Gegenhalten, 367

INDEX & 789

Gelineau’s syndrome. See Narcolepsy Gene deletion, 766 Gene therapy for Sandhoff disease, 640 Generalized anxiety disorder (GAD), 6–7, 8, 193, 197, 198 Generalized dystonia, 275 Generalized myokymia. See Isaac’s syndrome Genetic counseling, 267, 470, 513, 674 Genetic testing, for tuberous sclerosis, 738 Genetic workup, 268 Geniculate ganglion, 344 Genitourinary problems, 500 Geranylgeranylacetone (GGA), 395 Geriatric Depression Scale, 23 Germinal matrix, early focal destruction of, 643 Gerstmann’s syndrome. See Finger agnosia Gerstmann’s syndrome, 182 diagnosis, 329 neuropathology/pathophysiology, 328–329 neuropsychological/clinical presentation, 329 treatment, 329 Gerstmann–Strau¨ssler–Scheinker (GSS) disease diagnosis, 330–331 neuropathology/pathophysiology, 330 neuropsychological/clinical presentation, 330 treatment, 331 Geste antagoniste, 275 GFAP gene, 52 Giant cell arteritis, 745 Glasgow coma scale (GCS), 728 Glatiramer acetate (Copaxone), 496 Glaucoma, 685 Glial cell growth, by lead toxicity, 417 Gliomas, 146 Global aphasia, 89 Global atrophy, 158 Glossopharyngeal neuralgia (GN) diagnosis, 333 neuropathology/pathophysiology, 332 neuropsychological/clinical presentation, 332–333 symptoms, 332 treatment, 333 Glutamic acid decarboxylase (GAD), 679 Glycogen storage disease, 375 Glycogenosis type-II. See also Pompe’s disease Glycosaminoglycans (GAG), 480 GM2-ganglioside, 640, 707 Gonadotrophins, 395 Gottron’s papules, 260 Granulocytosis, in paraneoplastic syndromes, 561 Granuloma, 754

Granulomatous neuropathy, 532 Grapheme–phoneme approach, 45 Grasp reflex, 59 Gross Motor Functional Classification Scale, 175 Guillain–Barre´ syndrome (GBS), 1, 211. See also Miller Fisher syndrome (MFS) diagnosis, 336 neuropathology/pathophysiology, 335 neuropsychological/clinical presentation, 335–336 plasmapheresis, 534 subtypes, 335 symptoms, 556 treatment, 336 Gyri/convolutions, 429

Haldol, 427 Hallervorden–Spatz disease (HSD), 377–378, 521–522 diagnosis, 338 neuropathology/pathophysiology, 337 neuropsychological/clinical presentation, 337–338 treatment, 338 Hallucinations, 251, 427 Haloperidol, 227, 258, 340, 357, 407, 692, 708 Halstead Category Test (HCT), 493 Halstead–Reitan Battery, 661 Hamilton Anxiety Rating Scale, 10 Hamilton Depression Rating Scale, 23 Happy puppet syndrome. See Angelman syndrome (AS) Harlequin syndrome, 348–349 Hashimoto’s encephalopathy, 289 Head trauma, 576 Headaches paroxysmal hemicranias, 573 secondary symptom of seizures, 685 Hearing loss, 740 Heart transplantation, in mitochondrial cardiomyopathy, 470 Heliotrope rash, 260 Hemangiectatic hypertrophy. See Klippel–Trenaunay’s syndrome (KTS) Hemangioblastomas/angiomas, 173, 749 Hematopoietic cell transplantation (HCT), 482, 773 Hematuria, 754 Hemicrania continua chronic paroxysmal hemicranias, 339 diagnosis, 339 neuropathology/pathophysiology, 339 neuropsychological/clinical presentation, 339 treatment, 339 Hemifacial spasm (HFS) diagnosis, 340

neuropathology/pathophysiology, 340 neuropsychological/clinical presentation, 340 treatment, 340 Hemiparesis, 415, 685, 765 Hemiplegia, 685 Hemiplegic cerebral palsy, 175, 685 Hemispherectomy, 601, 686 Hemodynamic ischemic stroke, 180–181 Hemoglobin, 655 Hemorrhagic strokes, 181 Heparin, 305 Heparin-induced extracorporeal LDL/ fibrinogen precipitation (HELP), 486 Hepatic encephalopathy, 288 Hepatitis B, 593 Hepatolenticular degeneration syndrome, 769 Hepatomegaly, 209 Hepatosplenomegaly, 481, 772 Hereditary neuropath, 532 Hereditary spastic paraplegias (HSPs), 734 classification, 341 diagnosis, 342–343 neuropathology/pathophysiology, 341–342 neuropsychological/clinical presentation, 342 pure versus complicated forms of, 341 treatment, 343 Heredodegenerative dystonia, 276 Herpes zoster (HZ) oticus. See also Shingles diagnosis, 344 neuropathology/pathophysiology, 344 neuropsychological/clinical presentation, 344 treatment, 344 Hesx1 gene, 252 Heterotopias, 644 Hexosaminidase, 640 High-performance liquid chromatography (HPLC), 656 Highly active antiretroviral therapy (HAART) HIV, management of, 345 progressive multifocal leukoencephalopathy treatment, 613 Hippocampal damage, 167 Hippocampus, 7, 417 Hirayama disease. See Monomelic amyotrophy (MMA) HIV/AIDS dementia (HAD) complex diagnosis, 346 neuropathology/pathophysiology, 345 neuropsychological/clinical presentation, 345–346 treatment, 346

790 & INDEX

HLA-DR3 gene, 657 Hoarseness, in vocal projection, 428 Hoffman’s disease, 511 Holmes–Adie syndrome (HAS) diagnosis, 348 neuropathology/pathophysiology, 347 neuropsychological/clinical presentations, 347–348 treatment, 348–349 Holoprosencephaly, 50, 644 diagnosis, 350 neuropathology/pathophysiology, 349–350 neuropsychological/clinical presentation, 350 treatment, 350–351 Homocystinuria diagnosis, 352 neuropathology/pathophysiology, 352 neuropsychological/clinical presentation, 352 treatment, 352 Hopkins Verbal Learning Test, 183, 661 Horner’s syndrome, 256, 695 Hughes’ syndrome clinical features, 353 diagnosis, 354 neuropathology/pathophysiology, 353–354 neuropsychological/clinical presentation, 354 treatment, 354–355 Human leukocyte antigen (HLA), 132, 488, 517, 680 Human mitochondria, 390 Human T-cell lymphotropic virus type-I- (HTLV-I), 732 Human T-cell lymphotropic virus type-I- (HTLV-I)-associated myelopathy (HAM), 732 Humidifiers, 659 Hunter’s disease, 480 Huntington’s disease (HD), 355–356 -like 2 (HDL2), 519, 520 diagnosis, 357 neuropathology/pathophysiology, 355–356 neuropsychological/clinical presentation, 356–357 treatment, 357 Hyaline body myopathy, 234 Hyalinosis cutis et mucosae. See Lipoid proteinosis Hyaluronidase deficiency, 480 Hydranencephaly, 644 cause of, 358 diagnosis, 359 neuropathology/pathophysiology, 358–359 neuropsychological/clinical presentation, 359 treatment, 359

Hydrocephalus, 287 in children, 444 classification, 360 diagnosis, 362 neuropathology/pathophysiology, 360–361 neuropsychological/clinical presentation, 361–362 symptoms of, 249 treatment, 362 Hydromyelia and syringomyelia diagnosis, 364 neuropathology/pathophysiology, 363–364 neuropsychological/clinical presentation, 364 treatment, 364 Hydroxychloroquine, 355, 659, 765 Hyperbaric oxygen therapy, 177 Hypercalcemia, in paraneoplastic syndromes, 560 Hypercapnic patients, 660 Hypercortisolism, 242 Hyperekplexia, 220 Hypereosinophilic stage, in Churg–Strauss syndrome, 214 Hypergammaglobulinemia, 214 Hyperhidrosis, 382 Hyperkalemic periodic paralysis (HPP), 307 Hypermetamorphosis, 407 Hypernatremic encephalopathy, 289 Hyperosmolar therapy, for increased intracranial pressure, 374 Hyperpnea, 383, 384 Hypersomnia diagnosis, 366 neuropathology/pathophysiology, 365 neuropsychological/clinical presentation, 365 treatment, 366 Hypertelorism, 220, 666 Hypertensive encephalopathy, 289 Hyperthyroid myopathy. See Thyrotoxic myopathy Hyperthyroidism, 713 Hypertonia diagnosis, 368 neuropathology/pathophysiology, 367 neuropsychological/clinical presentation, 367–368 spasticity and rigidity, 367, 368 treatment, 368–369 Hypertrophic osteoarthropathy, 563 Hypertrophied limb, 404 Hyperventilation, for increased intracranial pressure, 191, 374 Hypesthesia, 705 Hypochondriasis, 664 Hypocupremia, 769 Hypoglycemia, in paraneoplastic syndromes, 561

Hypoguanine phosphoribosyltransferase (HPRT) enzyme, 423 Hypokalemic paralysis, 308 Hypomania, 21 Hyponatremia, rapid correction of, 163 Hyponic-hyperkinetic syndrome. See Sydenham chorea Hypoparathyroidism, 306 Hypoperfusion, 693 Hypopigmentation, 453 Hypopnea, 660 Hyporeflexia, 477 Hypothalamic–pituitary–adrenal (HPA) axes, 203, 204 Hypothalamic–pituitary–gonadal (HPG) axes, 203, 204 Hypothalamic–pituitary–thyroidal (HPT) axes, 203, 204 Hypothalamus, role of, 573 Hypotonia, 179, 431, 666, 772 diagnosis, 370 neuropathology/pathophysiology, 369–370 neuropsychological/clinical presentation, 370 treatment, 370 Hypoxemia, 166–167 Hypoxia, 166 Hypoxic encephalopathy, 288 Hypoxic-ischemic encephalopathy, 288 Hypsarrhythmia, 758

Ibuprofen, 410, 568, 689 Ichthyosis, 27 Idazoxan, 324 Ideational apraxia, 103 Ideomotor apraxia neuropathology/pathophysiology, 102 neuropsychological/clinical presentation, 102–103 Ideomotor dysgraphia, 263, 264 Idiopathic etiology, 291 Idiopathic hypersomnia, 365 Idiopathic NPH (iNPH), 545 Idiopathic West’s syndrome, 758, 760 Immunomodulation, 285 Impairment of speech, 42 Inappropriate sinus tachycardia (IST), 270 Inattention, features of delirium, 257 Incontinentia pigmenti (IP). See Bloch–Sulzberger syndrome Increased intracranial pressure (ICP) causes of, 373 diagnosis, 374 in healthy adults, 373 neuropathology/pathophysiology, 373 neuropsychological/clinical presentation, 374 treatment, 374 Indomethacin, 339, 689

INDEX & 791

Infantile acquired aphasia. See Landau– Kleffner syndrome (LKS) Infantile form, of Alexander’s disease (AD), 52 Infantile hypotonia description, 374–375 diagnosis, 375–376 neuropathology/pathophysiology, 375 neuropsychological/clinical presentation, 375 treatment, 376 Infantile neuroaxonal dystrophy (INAD) diagnosis, 377–378 neuropathology/pathophysiology, 376–377 neuropsychological/clinical presentation, 377 treatment, 378 Infantile Refsum disease (IRD) diagnosis, 379 neuropathology/pathophysiology, 378–379 neuropsychological/clinical presentation, 379 treatment, 379 Infantile spasms. See West’s syndrome (WS) Infants, dietary calcium in, 418 Infarctive crisis, 656 Infective neuropathy, 532 Infiltrating tumor, 146 Inflammatory encephalopathies, 283 Inflicted traumatic brain injury. See Shaken baby syndrome (SBS) Infliximab, 449, 596 Informant Questionnaire for Cognitive Decline in the Elderly, 183 Infracerebellar fluid collection, 250 Iniencephaly diagnosis, 381 neuropathology/pathophysiology, 380–381 neuropsychological/clinical presentation, 381 treatment, 381 Insomnia, 213 Instructional Hierarchy (IH), The, 627 Insula, 7 Insular cortex, proliferation of cortical Lewy bodies, 426 Intellectual abilities, 493 Interferon therapy multiple sclerosis, 484 Rasmussen’s encephalitis, 625 Intermittent restless legs syndrome, 632 International Classification of Diseases (ICD) ICD-10, 181, 195, 580, 603 ICD-9, 115 International Classification of Headache Disorders, 573 International Headache Society, 730

International RLS Study Group (IRLSSG), 631 Interpersonal therapy childhood mood disorders, 207 chronic pain syndrome, 214 Intestinal lipodystrophy. See Whipple’s disease Intracerebral/intracranial hemorrhage, 181 Intracranial hypertension, 364 Intracranial pressure, signs of increased, 415. See also Increased intracranial pressure (ICP) Intracranial recording, 293 Intravenous gama-globulin, 416 Intravenous immunoglobulin (IVIg), 689 Kawasaki’s disease, 389 Miller Fisher syndrome, 467 paraneoplastic syndrome, 559 Intravenous venography, for deep vein thrombosis diagnosis, 304–305 Ipsilateral cranial autonomic features, 689 Irregular words, 55 Irritable bowel syndrome (IBS), 270 Isaac-Mertens’ syndrome. See Isaac’s syndrome Isaac’s syndrome diagnosis, 383 neuropathology/pathophysiology, 382 neuropsychological/clinical presentation, 382–383 treatment, 383 Ischemic compression, in piriformis syndrome, 592 Ischemic hypoxia, 167 Ischemic paresthesia, 568 Ischemic Score, 486 Ischemic strokes, classification of, 180 Isoelectric focusing (IEF), 656 Ixodes pacificus, 434 Ixodes scapularis, 434

Jargon, 86 Jaundice, 253 JC virus, 612 Joubert’s syndrome, 383 diagnosis, 384 neuropathology/pathophysiology, 384 neuropsychological/clinical presentation, 384 treatment, 384–385 Junctophilin 3 gene, 520 Juvenile delinquency diagnosis, 386–387 neuropathology/pathophysiology, 385–386 neuropsychological/clinical presentation, 386 treatment, 387

Juvenile form, 52, 458, 598, 640 Juvenile Huntington’s disease, 356 Juvenile myasthenia gravis (JM) diagnosis, 231–232 neuropathology/pathophysiology, 230 neuropsychological/clinical presentation, 231 Juvenile neuronal ceroid lipofuscinoses. See Batten’s disease Juvenile subtype, 459

K-schedule for affective disorders and schizophrenia for school-aged children — present and lifetime version (K-SADS-PL), 195 Karyotype test, for infantile hypotonia, 375 Kawasaki’s disease (KD) diagnosis, 389 epidemiology, 388 neuropathology/pathophysiology, 389 neuropsychological/clinical presentation, 389 treatment, 389 Kearns–Sayre’s syndrome (KSS) cardiac involvement, 469 diagnosis, 391–392 MRI findings, 469 neuropatholgy/pathophysiology, 390–391 neuropsychological/clinical presentation, 391 stroke, 469 treatment, 392 Kennedy’s disease (KD) diagnosis, 394–395 neuropathology/pathophysiology, 394 neuropsychological/clinical presentation, 394 treatment, 395 Keratoconjunctivitis sicca, 658 Ketamine, 160 Ketogenic diet, utilization of, 268, 392 Kidney complications, tuberous sclerosis patients, 738 dysfunction, symptom of, 658 Kinky hair syndrome. See Menkes’s disease Kinsbourne’s syndrome diagnosis, 396–397 neuropathology/pathophysiology, 396 neuropsychological/clinical presentation, 396 treatment, 396–397 Kleine–Levin syndrome (KLS) diagnosis, 399 neuropathology/pathophysiology, 398 neuropsychological/clinical presentation, 398–399 treatment, 399

792 & INDEX

Klinefelter’s syndrome diagnosis, 400–401 neuropathology/pathophysiology, 400 neuropsychological/clinical presentation, 400 treatment, 401 Klippel–Feil’s syndrome (KFS), 249 diagnosis, 403 neuropathology/pathophysiology, 402 neuropsychological/clinical presentation, 402 treatment, 403 Klippel–Trenaunay’s syndrome (KTS) diagnosis, 404–405 neuropathology/pathophysiology, 404 neuropsychological/clinical presentation, 404 treatment, 405 Klumpke’s palsy, 296. See also Dejerine–Klumpke Palsy Kluver–Bucy’s syndrome, 590 diagnosis, 407 human examples of, 406 neuropathology/pathophysiology, 406 neuropsychological/clinical presentation, 406–407 treatment, 407 Korsakoff syndrome (KS), 755 Krabbe’s disease diagnosis, 409 neuropathology/pathophysiology, 408 neuropsychological/clinical presentation, 408–409 treatment, 409 Kretschmer’s syndrome, 223 KRIT1 (Krev interaction-trapped 1 protein) gene, 173 Kuf’s disease, 530 Kuru classification, 410 diagnosis, 410 neuropathology/pathophysiology, 410 neuropsychological/clinical presentation, 410 treatment, 410 ‘‘Kuru plaques,’’ 410 Kyphoscoliosis, 736 Kyphosis, 220

Labor-intensive process, 264 Lactate level, 420 Lactate stress test (LST), 473 Lactobacillus-fermented milk, 733 Lacunar infarcts, 140 Lacunar ischemic stroke, 181 Lake’s disease, 530 Lambdoid synostosis, 238 Lambert–Eaton myasthenia syndrome (LEMS), 505, 565 diagnosis, 414

neuropathology/pathophysiology, 230, 413 neuropsychological/clinical presentation, 231, 413–414 treatment, 414 Lamivudine, 733 Lamotrigine, 192, 268, 333, 572, 689, 731, 760 Landau–Kleffner syndrome (LKS) definition, 415 diagnosis, 415 neuropathology/pathophysiology, 415 neuropsychological/clinical presentation, 415 treatment, 415–416 Landry–Guillain–Barre´ syndrome. See Miller Fisher syndrome (MFS) Landry’s ascending paralysis. See Miller Fisher syndrome (MFS) Language deficits, 126 Language/verbal fluency, 493 LAPSS (Los-Angeles Pre-hospital Stroke Scale), 722 Laser treatment procedures, 686 Late infantile variant, 459 Late motor deterioration stage, in Rett syndrome (RS), 633 Late neurosyphilis, 536 Lateral femoral cutaneous nerve, 138 Lateral medullary syndrome. See Wallenberg’s syndrome Latissimus dorsi muscle, 296 Lead encephalopathy, 289 Lead intoxication children, 417 diagnosis, 418 neuropathology/pathophysiology, 417 neuropsychological/clinical presentation, 417–418 rates, 417 treatment, 418 ‘‘Lead-pipe’’ posture, 368 Learning deficits, 78, 350 Learning disabilities, 441 Leigh’s syndrome, 453–454 diagnosis, 420–421 neuropathology/pathophysiology, 419–420 neuropsychological/clinical presentation, 420 subacute necrotizing encephalomyelopathy, 419 treatment, 421 Lennox–Gastaut’s syndrome (LGS) diagnosis, 422 neuropathology/pathophysiology, 421–422 neuropsychological/ clinicalpresentation, 422 treatment, 422 Lesch–Nyhan syndrome (LNS) diagnosis, 424

neuropathology/pathophysiology, 423 neuropsychological/clinical presentation, 423–424 treatment, 424–425 Lesions, with locked-in syndrome, 433 Leukocytoclastic vasculitis, 563 Leukodystrophy, 408, 579. See also Adrenoleukodystrophy (ALD) Leuprorelin, 395 Levetiracetam, 268, 686 Levodopa, 237, 424, 427, 570, 572 Lewy bodies, 569, 683 Lewy body dementia (LBD) clinical symptoms, 426 diagnosis, 426–427 neuropathology/pathophysiology, 426 neuropsychological/clinical presentation, 426 treatment, 427 Lexapro (Escitalopram), 199 Lexical agraphia, 45 Lexical processing, 43 Lexical–semantic spelling route, 45 Libersky hypothesis, 330 Lidocaine, 217, 654, 689 Limb ataxia, 117 Limb-girdle muscular dystrophy, 502 Limb-kinetic apraxia, 103 Limbic encephalitis, 564 Linguistic component disorders, 45–46 Linguistic skills, 443 Lioresal (Baclofen), 550 Lipase enzyme deficiency, 772 Lipoid proteinosis diagnosis, 428–429 neuropathology/pathophysiology, 427–428 neuropsychological/clinical presentation, 428 treatment, 429 Urbach–Wiethe disease, 427 Lissauer’s model, 30 Lissencephaly definition, 429 diagnosis, 431 neuronal migration, 429 neuropathology/pathophysiology, 430 neuropsychological/clinical presentation, 431 treatment, 431–432 Lithium, 515 Lobar holoprosencephaly, 350 Locked-in syndrome, 163, 164 diagnosis, 433 neuropathology/pathophysiology, 433 neuropsychological/clinical presentation, 433 treatment, 433 Logopenic progressive aphasia (LPA), 610, 648 Logorrhea, 86 Long-term memory, 492

INDEX & 793

Lorazepam, 268, 748 Lorenzo’s oil therapy, 5 Loss of consciousness, 694 Lou Gehrig’s disease, 395 Louis–Bar’s syndrome. See Ataxia telangiectasia (AT) Low-dose dexamethasone overnight suppression screening test (LDDST), 242 Lumbar puncture, 364, 451, 696 Lumboperitoneal shunt, Tarlov cysts in, 706 Lumizyme, 598 Luria–Nebraska Neuropsychological Battery, 661 Luvox (Fluvoxamine), 199, 717 Lyme disease diagnosis, 435 neuropathology/pathophysiology, 434 neuropsychological/clinical presentation, 434–435 treatment, 435 Lysosomal acid lipase, 209 Lysosomal enzyme, 597 Lysosomal storage diseases (LSDs), 208–209, 327, 458, 531, 640, 771

Machado–Joseph’s disease (MJD) diagnosis, 438 neuropathology/pathophysiology, 437 neuropsychological/clinical presentation, 437–438 treatment, 438 Macrencephaly diagnosis, 439 megalencephaly, 438 neuropathology/pathophysiology, 439 neuropsychological/clinical presentation, 439 treatment, 439 ‘‘Mad cow’’ disease, 240 Magnetic resonance neurography in piriformis syndrome, 592 Magnetic resonance spectroscopy in multiple sclerosis (MS), 489–490 Major depressive disorder (MDD) versus bipolar disorder, 202–203 characterization, 20, 202 clinical presentation, 205 hypothalamic–pituitary axes dysregulation, 203 neurotransmitter studies, 204 symptoms of, 202 Malcavernin, 173 Mannitol, 374 Maple syrup urine disease (MUSD) diagnosis, 441 neuropathology/pathophysiology, 440 neuropsychological/clinical presentation, 440–441 treatment, 441

Maroteaux–Lamy disease, 480 Maternal serum alpha fetoprotein (MSAFP) screening, 669 Maternal uniparental disomy (mUPD), 606 Mathematical skills, 443 Mathematics disorders diagnosis, 444–445 neuropathology/pathophysiology, 443 neuropsychological/clinical presentation, 443–444 teaching methods, framework of, 445 treatment, 445–446 McArdle’s disease, 511 McLeod syndrome (MLS), 476, 519 Mebaral (Mephobarbital), 294 Mecamylamine, 717 MECP2 gene, 632 Medial lemniscus fibers, 695 Megalencephaly. See Macrencephaly Megalocephaly, 238 Melancholia, 20 Melatonin therapy, 290, 482 Melkersson–Rosenthal’s syndrome (MRS) diagnosis, 449 neuropathology/pathophysiology, 448 neuropsychological/clinical presentation, 448–449 treatment, 449 Melodic intonation therapy, 93 Memantine, 66, 688 Membranous sac, 358 Memorial Sloan–Kettering rating scale, 346 Memory, 492–493 Memory and learning deficits, in hydrocephalus, 361 Meningeal disease, 618 Meningitis diagnosis, 451 neuropathology/pathophysiology, 450 neuropsychological/clinical presentation, 450–451 prevention, 153 treatment, 451 Meningocele, 668 Menkes’s disease diagnosis, 453–454 neuropathology/pathophysiology, 452–453 neuropsychological/clinical presentation, 453 treatment, 454 Mental retardation diagnosis, 455–457 neuropathology/pathophysiology, 455 neuropsychological/clinical presentation, 455 treatment, 457 Menzel type, 552 Mephobarbital (Mebaral), 294 Mertens’ syndrome. See Isaac’s syndrome

Metabolic encephalopathy. See Delirium Metabolic neuropathy, 532 Metachromasia, 459 Metachromatic leukodystrophy (MLD) diagnosis, 460 neuropathology/pathophysiology, 458–459 neuropsychological/clinical presentation, 459–460 treatment, 460 Metastatic tumor, 145 Methimazole, 713 Methionine diet, 352 Methotrexate, 596, 701 Methylphenidate (Ritalin), 123, 227, 366, 717 Methylprednisolone, 2, 449, 557, 596, 672 Metopic synostosis, 238 Mexiletine, 515 Microcephaly, 179, 287, 431, 643 diagnosis, 462 neuropathology/pathophysiology, 462 neuropsychological/clinical presentation, 462 treatment, 462–463 Microdysgenesis, 190 Micrognathia, 179 Micrographia, 682 Microphthalmia, 350 Microvascular decompression (MVD) for glossopharyngeal neuralgia, 332 hemifacial spasm, treatment of, 340 for trigeminal neuralgia, 332, 731 Middle frontal gyrus, 263 Midfacial hypoplasia, 350 Migraine aura, 463 Migraine headache, 550, 603 Migraines criteria for, 465 diagnosis, 465 migraine aura, 463 neuropathology/pathophysiology, 463–464 neuropsychological/clinical presentation, 464–465 treatment, 465 Migrainous symptoms, 339 Mikulicz’s syndrome, 659 Mild cognitive motor disorder (MCMD), 345 ‘‘Milkmaid’s grip,’’ 691 Miller Fisher syndrome (MFS) diagnosis, 467 neuropathology/pathophysiology, 466–467 neuropsychological/clinical presentation, 467 treatment, 467 Miller–Dieker syndrome (MDS), 430 Mindfulness meditation, 12 Minimal Assessment of Cognitive Function in MS (MACFIMS), 495

794 & INDEX

Minnesota Multiphasic Personality Inventory (MMPI), 23, 213 Minnesota Multiphasic Personality Inventory-2 (MMPI-2), 663 Minnesota Test for Differential Diagnosis of Aphasia (MTDDA), 92 Mirror movements, 59 Mitochondrial cardiomyopathy diagnosis, 470 mtDNA, 467–469 neuropathology/pathophysiology, 468–469 neuropsychological/clinical presentation, 469–470 treatment, 470 Mitochondrial DNA (mtDNA) depletion in liver, 60 Leigh’s syndrome, 420 polyplasmy, 467 properties, 390 Mitochondrial encephalomyopathy, 272, 289 Mitochondrial myopathies, 509 diagnosis, 472–473 neuropathology/pathophysiology, 472 neuropsychological/clinical presentation, 472 progressive external ophthalmoplegia (PEO), 472 symptoms of, 472 treatment, 473 Mitoxantrone, chemotherapeutic agents, 496 Mixed (complex) apnea, risk factors, 660 Mixed dysgraphia, 263 Modafinil, 366, 518 Moebius syndrome characterization of, 474 diagnosis, 475 neuropathology/pathophysiology, 475 neuropsychological/clinical presentation, 475 treatment, 475–476 Molecular mimicry, 1 Molindone, 227 Monoamine oxidase inhibition (MAOI) drugs for adult mood disorders, 24 childhood mood disorders, 207 tardive dyskinesia, 703 Monomelic amyotrophy (MMA) diagnosis, 477 neuropathology/pathophysiology, 476–477 neuropsychological/clinical presentation, 477 treatment, 477 Mononeuropathy multiplex, 532 Monosynaptic reflex activity, 348 ‘‘Monroe–Kellie’’ doctrine, 373 Mood disorders, in adult in children, 202–207

diagnosis, 23–24 neuropathology/pathophysiology, 21–22 neuropsychological/clinical presentation, 22–23 symptoms, 20 treatment, 24–25 Moquiro’s disease, 480 Morphometric MRI, 663 Motor abnormalities, progression of, 259 Motor act of writing, 42 Motor component disorders, 46–47 Motor cortex stimulation, Wallenberg’s syndrome treatment, 752 Motor dysfunction, 481 Motor dysgraphia, 264 Motor impairment, in Asperger’s syndrome, 115 Motor tics, 716 Motor/ideokinetic apraxia. See Ideomotor apraxia Movement formulas, 102 Moyamoya’s disease (MD) characterization, 173 diagnosis, 478–479 neuropathology/pathophysiology, 478 neuropsychological/clinical presentation, 478 treatment, 479 mRNA, mutations in, 502 mtDNA. See Mitochondrial DNA Mucopolysaccharidoses (MPS) diagnosis, 481–482 MPS II. See Hunter’s disease MPS III. See Sanfilippo’s disease MPS IV. See Moquiro’s disease MPS IX. See Hyaluronidase deficiency MPS VI. See Maroteaux–Lamy disease MPS VII. See Sly syndrome neuropathology/pathophysiology, 480–481 neuropsychological/clinical presentation, 481 treatment, 482 Multi-infarct dementia (MID), 182 diagnosis, 486 neuropathology/pathophysiology, 485 neuropsychological/clinical presentation, 485–486 treatment, 486–487 Multi-system atrophy with orthostatic hypertension diagnosis, 500–501 neuropathology/pathophysiology, 499–500 neuropsychological/clinical presentation, 500 treatment, 501 Multifocal dystonia, 275 Multifocal motor neuropathy (MMN) diagnosis, 483–484 neuropathology/pathophysiology, 483

neuropsychological/clinical presentation, 483 treatment, 484 Multifocal myoclonus, 507 Multilingual Aphasia Examination (MAE), 92–93 Multiminicore disease, 234 Multiparity, risk factors, 255 Multiple sclerosis (MS) diagnosis, 494–496 neuropathology/pathophysiology diffusion-tensor imaging, 490 diffusion weighted imaging, 490 evoked potentials, 490–491 magnetic resonance spectroscopy, in MS, 489–490 neurobiological markers, 488–489 neuroimaging techniques, 489 spinal tap, 490 neuropsychological/clinical presentation, 491–492 emotional disturbances, 493–494 executive functions, 493 fatigue in MS, 494 intellectual abilities, 493 language/verbal fluency, 493 memory, 492–493 processing speed, 493 sensorimotor functions, 492 visuoconstructive abilities, 492 visuospatial skills, 492 treatment, 496–497 Multiple sleep latency test (MLST), 366 Multiple sulfatase deficiency, 480 Multiple system atrophy (MSA), 553, 681. See also Multi-system atrophy with orthostatic hypertension Multiple tendon reflexes, 348 Muscle biopsy, 261 Muscle diseases, 514 Muscle fiber antigens, 261 Muscle hypertrophy, 382 Muscle-specific receptor tyrosine kinase (MuSK), 229 Muscle stiffness, 382 Muscle weakness, polymyositis symptoms, 595 Muscular dystrophies (MDs) in children. See DMD diagnosis, 503 genetic diseases, 501 neuropathology/pathophysiology, 502 neuropsychological/clinical presentation, 502–503 subtypes, 501 treatment, 503–504 Musculoskeletal symptoms, 646 Music therapy, 633–634 Mutism, 433 Myasthenia gravis (MS), 565. See also Myasthenic syndromes diagnosis, 505

INDEX & 795

neuropathology/pathophysiology, 504–505 neuropsychological/clinical presentation, 505 treatment, 505 Myasthenic syndromes. See also Lambert–Eaton myasthenia syndrome (LEMS) diagnosis, 231–232 neuropathology/pathophysiology, 229 neuropsychological/clinical presentation, 230 treatment, 232 Myelin protein zero (MPZ) gene, 185 Myelin sheath, 483 Myelogram, 696 Myelomeningocele, 668 Myoblast transfer therapy, 504 Myoclonic encephalopathy of infants. See Kinsbourne’s syndrome Myoclonus, 272, 426 diagnosis, 507–508 neuropathology/pathophysiology, 506–507 neuropsychological/clinical presentation, 507 treatment, 508 Myopathy characterization, 508 diagnosis, 509 muscular dystrophies, 508 neuropathology/pathophysiology, 508–509 neuropsychological/clinical presentation, 509 treatment, 509–510 Myotonia classification, 511 demonstration, 510 diagnosis, 512–513 neuropathology/pathophysiology, 511–512 neuropsychological/clinical presentation, 512 in tongue, 512 treatment, 513 Myotonia congenita clinical subtypes of, 515 diagnosis, 514–515 neuropathology/pathophysiology, 514 neuropsychological/clinical presentation, 514 treatment, 515 Myotonic dystrophy, 502 Myotubular myopathy, 234 Myozyme, 598 Mysolin (Primidone), 294, 572

N-acetylaspartate (NAA), 155, 489 N-methyl-D-aspartate (NMDA) receptor, 12, 204, 714

Naproxen, 574, 647, 689 Narcolepsy, 366, 399 with cataplexy, 517 diagnosis, 518 neuropathology/pathophysiology, 517–518 neuropsychological/clinical presentation, 518 treatment, 518 National Down Syndrome Society, 266 National Institute of Neurological Disorders and Stroke (NINDS), 165, 166, 180, 506, 517, 518 National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy (NINDS-SPSP), 615 National Institute on Alcohol Abuse and Alcoholism (NIAAA) (2002), 316 Nationwide Inpatient Sample, 223 Neck pain, 763 Necrotizing granulomatosis, 753 Negative myoclonus, 507 Negative stimulus tests, 255 Neglect alexia, 54 Nemaline myopathy, 234 NEMO (NF-Kappa-B Essential Modulator) gene, 144 Neologism, 86 Neoplastic neuropathy, 532 Neostigmine, 232 Nerve conduction velocity (NCV) tests, 414, 467, 533, 582 Nerve grafting, 296 Neurasthenia, 269 Neuro-BD, 131 Neuro-mineral disease, 306 Neuroacanthocytosis (NA) diagnosis, 520 neuropathology/pathophysiology, 519–520 neuropsychological/clinical presentation, 520 treatment, 520–521 Neurobiological markers, 488–489 Neuroblastoma paraneoplastic syndrome. See Kinsbourne’s syndrome Neuroblastomas, 396, 397 Neurodegeneration with brain iron accumulation (NBIA) diagnosis, 523 ‘‘eye of the tiger’’ sign, 522 neuropathology/pathophysiology, 522 neuropsychological/clinical presentation, 522–523 treatment, 523 Neurodegenerative diseases, aphasia, 87 Neurofibromatosis (NF) characterization, 524

diagnosis, 525 neuropathology/pathophysiology, 524 neuropsychological/clinical presentation, 524–525 treatment, 525 Neurofibromatosis 1 (NF-1) cafe´-au-lait spots, 524 characterization, 524 gene mutations, 524 MRI, 525 nervous system tumors, 524 Neurofibromatosis 2 (NF-2) characterization, 524 gene mutations, 524 MRI, 525 neoplasms of CNS, 524 Neurogenic muscular atrophy, 673 Neuroimaging techniques multiple sclerosis (MS), 489 Neuroleptic malignant syndrome (NMS), 511 diagnosis, 526–527 neuropathology/pathophysiology, 526 neuropsychological/clinical presentation, 526 treatment, 527–528 Neuroleptics frontotemporal dementia, 324 Lewy body dementia, 427 Neurologic syncope, 694 Neurologic variants, 424 Neurological sequelae, 440 Neurolysis, 296 Neuromyotonia. See Isaac’s syndrome Neuron-specific enolase (NSE), 331 Neuronal ceroid lipofuscinoses (NCLs). See also Batten’s disease clinical forms of, 529 diagnosis, 531 genetic subtypes of, 529 neuropathology/pathophysiology, 529–530 neuropsychological/clinical presentation, 530–531 treatment, 531 Neuronal migration, 429 Neuronopathic variations, Gaucher disease, 327 Neuronophagia, 623 Neurontin (Gabapentin), 550 Neuropathy characterization, 532 demyelination, 532, 581 diagnosis, 533 neuropathology/pathophysiology, 532 neuropsychological/clinical presentation, 532–533 treatment, 533–534 Neuropsychiatric SLE (NPSLE), 697 Neuropsychological test battery, 345, 456 Neuropsychological tools, 608

796 & INDEX

Neurosarcoidosis diagnosis, 535 neuropathology/pathophysiology, 534–535 neuropsychological/clinical presentation, 535 symptoms, 534 treatment, 535–536 Neurosyphilis diagnosis, 537 neuropathology/pathophysiology, 536 neuropsychological/clinical presentation, 536–537 stages, 537 treatment, 537 Neurotonia. See Isaac’s syndrome Neurotoxicity diagnosis, 538–539 neuropathology/pathophysiology, 538 neuropsychological/clinical presentation, 538 phenylketonuria, 587 treatment, 539 Neurotransmitter disturbance, 440 Niemann–Pick disease (NPD) diagnosis, 540 neuropathology/pathophysiology, 540 neuropsychological/clinical presentation, 540 treatment, 540–541 Type A, 540 Type B, 540 Type C, 540 Nifedipine, 689 ‘‘Noncommunicating’’ hydrocephalus, 545 Nondystrophic myotonias chloride channel disorders, 512 diagnosis, 512–513 Nonfluent aphasia, 86 Nonfluent aphasia. See Broca’s aphasia Noninflammatory vasculopathy, 1 Nonneuronopathic variations, Gaucher disease, 327 Nonsteriodal anti-inflammatory drugs (NSAIDs), 110, 271, 450, 563, 657, 746 Nonverbal learning disability (NLD), 740 diagnosis, 542–543 identification of younger children, 543 neuropathology/pathophysiology, 542 neuropsychological/clinical presentation, 542 treatment, 543–544 Nonverbal processing, aspects of, 443 Norepinephrine, 24 Normal pressure hydrocephalus (NPH), 545 diagnosis, 546 neuropathology/pathophysiology, 545–546

neuropsychological/clinical presentation, 546 treatment, 546 NOTCH3 gene, 171 NPHP1 gene, 384 Nuclear-encoded respiratory chain subunits, mutations types, 420 Nutritional neuropathy, 532 Nystagmus, 165, 179

Obsessions, defined, 10 Obsessive-compulsive disorder (OCD) characterization, 6 prevalence of, 274 symptoms, 691 Obstructive sleep apnea, risk factors of, 660 Occipital horn syndrome, 454 Occipital neuralgia diagnosis, 549–550 neuropathology/pathophysiology, 549 neuropsychological/clinical presentation, 549 treatment, 550 Occupational therapy dyssynergia cerebellaris myoclonica, 272–273 goal of, 256 Ocular symptoms, in Bloch–Sulzberger syndrome, 144 Oculomotor ataxia, 117 Oculopharyngeal muscular dystrophy, 502 Offenders, criminal. See Adult criminality Ohtahara’s syndrome, 550 diagnosis, 551 neuropathology/pathophysiology, 551 neuropsychological/clinical presentation, 551 treatment, 551 Olanzapine, 357, 704 Oligoarthritis, 132 Olivary dysplasia, 475 Olivopontocerebellar atrophy (OPCA) diagnosis, 553–554 neuropathology/pathophysiology, 552–553 neuropsychological/clinical presentation, 553 treatment, 554 Ophthalmoparesis, 765 Ophthalmoplegia, 466 Opioids, 657, 696 Opipramol, 665 Oppositional defiant disorder (ODD), 224–227, 268 Opsoclonic encephalopathy dancing eyes syndrome. See Kinsbourne’s syndrome Opsoclonus myoclonus ataxia. See Kinsbourne’s syndrome

Opsoclonus–myoclonus syndrome (OMS), 566 diagnosis, 557 neuropathology/pathophysiology, 556–557 neuropsychological/clinical presentation, 557 treatment, 557–558 Optic nerve dysplasia, 253 Optometry examination, for periventricular leukomalacia, 584 Oral calcitrol, 577 Oral dimethyl sulphoxides, 429 Oral doxycycline, 435 Oral noncaseating granulomatous lesions, 448 Orbicularis oculi, spasms of, 1 Orofacial/buccofacial apraxia, 103–104 Oromandibular dystonia, 275 Orthopedic brace, 187 Orthostatic hypertension, multisystem atrophy with diagnosis, 500–501 neuropathology/pathophysiology, 499–500 neuropsychological/clinical presentation, 500 treatment, 501 Orthostatic hypotension, 682, 683 Orthostatic intolerance, 604 Orthostatic syncope, 694 Osteoblasts, 220 Osteopenia, 234 Osteoporosis, 637 O’Sullivan–McLeod syndrome, 476 Otolaryngologist, 662 Overflow dystonia, 274 Overuse syndrome. See Repetitive motion disorders (RMDs) Oxandrolone, 741 Oxcarbazepine, 137, 572, 686, 731 Oximetry, 661 Oxybutynin, 343

Paced Auditory Serial Addition Test (PASAT), 492 Pain disorder, 664 Pain, meaning of, 110 Pain medications, neurofibromatosis (NF), 525 Palatal myclonus, 507 Pallidotomy. See also Thalamotomy for Parkinson’s disease, 570 Palmitoyl protein thioesterase-1 (PPT1), 529 Palpable tendon friction rub, 646 Palpebral fissures, 220 Pancreatic encephalopathy, 289 Panic disorder (PD), 6, 7, 8, 10 Panic disorder with agoraphobia (PDA), 6

INDEX & 797

Pantothenate-kinase 2 gene (PANK2), 337, 522 Pantothenate kinase-associated neurodegeneration (PKAN), 519, 520. See also Hallervorden–Spatz disease (HSD) Paradoxical dystonia, 275 Paragrammatism, 86 Parahippocampal gyrus, cortical Lewy bodies, 426 Paralinguistic agnosias, 35 Paramyotonia, 511 Paraneoplastic cerebellar degeneration, 540 Paraneoplastic dermatologic and rheumatologic syndromes acanthosis nigricans, 562 dermatomyositis, 562 erythroderma, 563 hypertrophic osteoarthropathy, 563 leukocytoclastic vasculitis, 563 paraneoplastic pemphigus, 563 polymyalgia rheumatics, 563 sweet syndrome, 563 Paraneoplastic hematologic syndromes cushing syndrome, 560–561 eosinophilia, 561 granulocytosis, 561 hypercalcemia, 560 hypoglycemia, 561 pure red cell aplasia, 561 syndrome of inappropriate secretion of antidiuretic hormone (SIADH), 560 thrombocytosis, 562 Paraneoplastic limbic encephalitis, 285 Paraneoplastic neurologic syndromes autonomic neuropathy, 565–566 Lambert–Eaton syndrome, 565 limbic encephalitis, 565 myasthenia gravis, 565 opsoclonus-myoclonus syndrome, 566 paraneoplastic cerebellar degeneration, 564 subacute sensory neuropathy, 566 Paraneoplastic pemphigus, 563 Paraneoplastic stiff-person syndrome, 680 Paraneoplastic syndromes diagnosis, 559 neuropathology/pathophysiology, 559 neuropsychological/clinical presentation, 559 treatment, 559–567 types and features, 560–566 Paraproteinemic neuropathy, 532 Parasympathetic nervous system, 269 Paratonia, 367, 368 Paraventricular nucleus, 606 Parenchymal hemorrhage, 181 Parent bibliotherapy, in anxiety disorders, 199 Paresthesia, 139, 705 diagnosis, 568

neuropathology/pathophysiology, 567 neuropsychological/clinical presentation, 567–568 treatment, 568 Parietal lobe, 121 ‘‘Parkinsonian facies,’’ 570 Parkinsonian symptoms, 306 Parkinson’s disease (PD), 289, 426, 615, 747 diagnosis, 570 neuropathology/pathophysiology, 569 neuropsychological/clinical presentation, 569 treatment, 570 Parkinson’s plus. See Orthostatic hypertension Paroxetine, 12, 199, 717 Paroxysmal choreoathetosis (PC), 570 diagnosis, 571–572 neuropathology/pathophysiology, 571 neuropsychological/clinical presentation, 571 treatment, 572 Paroxysmal EEG abnormalities, 415 Paroxysmal hemicrania (PH) clinical phenotype, 573 diagnosis, 574 neuropathology/pathophysiology, 573–574 neuropsychological/clinical presentation, 574 treatment, 574–575 Paroxysmal kinesigenic choreoathetosis (PKC), 571 Parry–Romberg’s syndrome diagnosis, 576–577 neuropathology/pathophysiology, 575–576 neuropsychological/clinical presentation, 576 symptoms, 575, 576 treatment, 577 Paxil (Paroxetine), 199 PDCD10 genes, 173 Pectus carinatum, 220 Pectus excavatum, 220 Pediatric aneurysm, 76 Peer-assisted learning strategies (PALS), 446 Pelizaeus–Merzbacher disease (PMD), 578 diagnosis, 579 neuropathology/pathophysiology, 579 neuropsychological/clinical presentation, 579 treatment, 579–580 Pena–Shokeir II. See Cerebro-oculofacio-skeletal (COFS) syndrome Penicillin, 537, 656, 692 Pentoxifylline, 733 Perceptual skills, 443 Percutaneous endoscopic gastrostomy (PEG), 71, 609

Percutaneous transluminal angioplasty, 317 Pergolide, 570, 717 Perineural cysts, 706 Periodic acid–Schiff (PAS) stain, 459, 764 Periodic paralysis (PP), 307–308 Peripheral agraphias, 43 Peripheral neuropathy, 27, 532 classification, 580 diagnosis, 582 neuropathology/pathophysiology, 580–581 neuropsychological/clinical presentation, 581–582 treatment, 582 Perisylvian aphasias, primary types of Broca’s aphasia, 87–88 conduction aphasia, 88–89 global aphasia, 89 Wernicke’s aphasia, 88 Periventricular leukomalacia (PVL) diagnosis, 584 neuropathology/pathophysiology, 583 neuropsychological/clinical presentation, 583–584 treatment, 584 Permanent vegetative state, 223 Pernicious anemia, autoimmune disorder, 680 Peroxisomal biogenesis factor 7 (PEX7) gene, 27 Peroxisome biogenesis disorder, 775 Persistent stupor, 312 Persisting vegetative state. See Coma and persisting vegetative state Personality Assessment Inventory (PAI), 664 Personality disorder cluster A, 585 cluster B, 585 cluster C, 585 diagnosis, 586 neuropathology/pathophysiology, 585 neuropsychological/clinical presentation, 585–586 treatment, 586 Personality traits, 585 Pervasive developmental disorders (PDDs), 115, 686 Pes cavus, 736 Petit mal epilepsy. See Childhood absence epilepsy Pfaundler–Hurler disease (MPS I-H/S), 480 PHACE, 249 Pharmacotherapy chronic pain syndrome, 213 Lambert–Eaton syndrome, 414 mood disorders, 24–25 Phenobarbital, 294, 314, 572 Phenothiazines, 708 Phenotypes, of Farber’s disease, 311

798 & INDEX

Phenprocoumon, 305 Phenylketonuria (PKU), 454 definition of, 587 diagnosis, 588 neuropathology/pathophysiology, 587 neuropsychological/clinical presentation, 587 treatment, 588 Phenytoin (Dilantin), 268, 294, 422, 515, 550, 572, 689, 741 Pheochromocytomas, 749 Phonemic paraphasia, 86 Phonic tics, 716 Phonological agraphia, 45–46 Phonological alexia, 55–56 Phonological dysgraphia, 263 Phonological processing, 43 Phonophobia, 689 Phototherapy, for Parry–Romberg’s syndrome, 577 Physostigmine, 487 Phytanic acid, 27 Phytanoyl-CoA hydroxylase (PAHX) enzyme, 27, 378–379 Pial-ependymal cells, 644 Pica, 417 Pick, Arnold, 590 Pick’s cells, 590 Pick’s disease diagnosis, 590 neuropathology/pathophysiology, 590 neuropsychological/clinical presentation, 590 treatment, 590–591 Piracetam, 94 Piriformis syndrome diagnosis, 592 neuropathology/pathophysiology, 591–592 neuropsychological/clinical presentation, 582 treatment, 582–593 Piroxicam, 574, 689 Pituitary gland, empty sella syndrome, 282 PKAN2 gene, 520 PLA2G6 gene, 376, 377 Placebo effects, in anxiety disorders, 12 Plasma catechol, 453 Plasma exchange, 594 Plasmapheresis, 27, 211, 336, 414, 467, 557, 755 Plateau/pseudo stationary stage, in Rett syndrome (RS), 633 Plumbism. See Lead intoxication PMP22 gene, 185, 186 Polyarteritis nodosa (PAN) clinical features of, 593 diagnosis, 593–594 neuropathology/pathophysiology, 593 neuropsychological/clinical presentation, 593

treatment, 594 Polyarthritis, 691 Polyglutamine triplet-repeat disease, 393 Polymerase chain reaction (PCR) encephalitis, diagnosis of, 285 shingles, diagnosis of, 654 Whipple’s disease, diagnosis of, 765 Polymerase gene polymerase gamma (POLG1), 60 Polymicrogyria, 643 Polymyalgia rheumatica, 563 Polymyositis (PM), 261 diagnosis, 595–596 neuropathology/pathophysiology, 595 neuropsychological/clinical presentation, 595 treatment, 596 Polyneuropathies, 532 Polyplasmy, 467 Pompe’s disease diagnosis, 598 infantile form, 598 juvenile form, 598 neuropathology/pathophysiology, 597 neuropsychological/clinical presentation, 597–598 treatment, 598–599 Porch Index of Communicative Ability (PICA), 92 Porencephalic cysts, 601 Porencephaly, 644 diagnosis, 601 neuropathology/pathophysiology, 600–601 neuropsychological/clinical presentation, 601 treatment, 601 Port wine stain, 684 Portable cardiorespiratory testing, 661–662 Positive myoclonus, 507 Positive stimulus tests, 255 Positron emission tomography (PET), 663 Binswanger disease, 140 Dawson’s disease, 251 Lewy body dementia (LBD), 426 Postconcussion disorder/syndrome (PCD), 728 diagnosis, 603 neuropathology/pathophysiology, 602–603 neuropsychological/clinical presentation, 603 symptoms, 602 treatment, 603 Posterior fossa decompression, 189 Posterior inferior cerebellar artery syndrome, 752 Postherpetic neuralgia (PHN), 653 Postischemic paresthesia, 568 Postsyncopal phase, 694 Posttraumatic amnesia, 728

Posttraumatic stress disorders (PTSDs), 6, 195, 387, 680 Posttreatment chronic Lyme disease (PCLD), 434 Postural orthostatic tachycardia syndrome (POTS) diagnosis, 605 neuropathology/pathophysiology, 604 neuropsychological/clinical presentation, 604–605 treatment, 605 Potentially riluzole, 674 Prader–Willi syndrome (PWS), 82 diagnosis, 606–607 neuropathology/pathophysiology, 606 neuropsychological/clinical presentation, 606 phenotypic expressions of, 606 treatment, 607 Pramipexole, 570 Prednisolone, 596, 760 Prednisone, 133, 211, 574, 689, 692 Pregabalin, 333 Pregnancy loss, Hughes’ syndrome, 354 Pregnant women, lead intoxication, 418 Preimplantation genetic diagnosis (PGD), 656 Primary brain damage, 727 Primary dystonias, 275 Primary lateral sclerosis (PLS) diagnosis, 608–609 neuropathology/pathophysiology, 608 neuropsychological/clinical presentation, 608 symptoms, 607 treatment, 609 Primary piriformis syndrome, 591 Primary progressive aphasia (PPA), 87 diagnosis, 611 neuropathology/pathophysiology, 610 neuropsychological/clinical presentation, 610–611 treatment, 611–612 Primary tumor, definition of, 145 Primary types of alexia, 54–56 Primidone (Mysolin), 294, 572 Prion disease, 329–330. See also Gerstmann–Strau¨ssler–Scheinker (GSS) disease Prion protein, 240 PRNP gene, 240, 311, 312 Problem Validation Screening (PVS), 626 Probst bundles, 28 Procaine, 515 Procedural errors, 444 Prodrome symptoms, 694 Progressive ataxia, 272 Progressive encephalomyelitis with rigidity and myoclonus (PERM), 680 Progressive external ophthalmoplegia (PEO), 469

INDEX & 799

Progressive facial hemiatrophy (PFH). See Parry–Romberg’s syndrome Progressive multifocal leukoencephalopathy (PML) diagnosis, 613 neuropathology/pathophysiology, 613 neuropsychological/clinical presentation, 613 treatment, 613 Progressive nonfluent aphasia (PNFA), 610, 648 Progressive supranuclear palsy (PSP), 500 diagnosis, 615–616 neuropathology/pathophysiology, 614–615 neuropsychological/clinical presentation, 615 treatment, 616 Promoting Aphasics Communication Effectiveness (PACE), 93 Propylthiouracil, 713 Prosody, lack of, 86 Prosopagnosia, 33–34, 157 Proteinase 3, 753 Proteinuria, 754 Proteolipid protein-1 (PLP1) mutation, 579 Prothrombinase complex, 304 Proximal scleroderma, 646 Prozac, 199. See also Fluoxetine PrP gene, 240, 330 Pruritus (Itching), 647 Pseudocoma, 433 Pseudocramps, 568 Pseudodeficiency allele, 459 Pseudomyotonia, 382 Pseudotumor cerebri diagnosis, 618 neuropathology/pathophysiology, 618 neuropsychological/clinical presentation, 618 treatment, 619 Psychiatric syncope, 694 Psychogenic nonepileptic seizures (NES), 663 Psychomotor slowing, 687 Psychotherapy attention deficit hyperactivity disorder, 123–124 nonverbal learning disability, 544 Psychotic disorders diagnosis, 620–621 neuropathology/pathophysiology, 619–620 neuropsychological/clinical presentation, 620 treatment, 621 Ptosis, 472 Ptosis props, 473 Puberty, 740 Pulmonary distress, 737 Pulmonary impairment, 646

Punch drunk, 258 Pure agraphia, 43 Pure alexia, 54–55 Pure red cell aplasia, in paraneoplastic syndromes, 561 Pure word deafness, 34, 91 PURPLE Crying program, 652 Pyramidal signs, 552 Pyramidal system damage, 175 Pyridostigmine, 232 Pyruvate dehydrogenase metabolism, 420

Quadriplegia, 433 Quadriplegic cerebral palsy, 175 Quantal squander. See Isaac’s syndrome Quercetin, 53 Quetiapine, 427 Quinidine, 515 Quinine, 515

Radiation, for cancer treatment, 150, 150–151 Radiofrequency thermocoagulation, occipital neuralgia treatment, 550 Radioiodine, 713 Radiosurgery, in arteriovenous malformations, 112 Radiotherapy, Brown-Se´quard syndrome, 153 Ragged red fibers, 473 Ramsay Hunt’s syndrome. See Dyssynergia cerebellaris myoclonica Rao’s Brief Repeatable Battery (BRB), 492 Rapid destruction stage, in Rett syndrome (RS), 633 Rapid eye movement (REM) sleep, 4, 135, 517 Rapsyn, cytoplasmic protein, 229 Rasmussen’s encephalitis ‘‘active and remote’’ stage, 623 ‘‘active disease’’ stage, 623 in children, 626 diagnosis, 624 neuropathology/pathophysiology, 623–624 neuropsychological/clinical presentation, 624 ‘‘nonspecific change’’ stage, 624 ‘‘remote stage,’’ 623–624 treatment, 624–625 Reading disorders diagnosis, 626–627 neuropathology/pathophysiology, 625–626 neuropsychological/clinical presentation, 627 treatment, 627 Rebif, 496 Receptive amusia, 34 Recidivism, reducing, 18

Reciprocal inhibition, 274 Rectal diazepam, serial tonic seizures and status epilepticus, 422 Recurrent depression, in mood disorders, 20 Reduplicative paramnesia (RP) diagnosis, 629 neuropathology/pathophysiology, 628 neuropsychological/clinical presentation, 628–629 treatment, 629 Reflex-mediated syncope, 694 Reflex sympathetic dystrophy, 159 Refractory restless legs syndrome, 632 Regional musculoskeletal disorders. See Repetitive motion disorders (RMDs) Regular words, 55 Regularization errors, 55 Reiss Screen, 456 Relapsing–Remitting MS (RRMS), 488, 492 Relaxation training, 465 Remissions, 420 Repetitive motion disorders (RMDs) diagnosis, 630 neuropathology/pathophysiology, 630 neuropsychological/clinical presentation, 630 treatment, 630 Repetitive strain injuries (RSIs). See Repetitive motion disorders (RMDs) Response to intervention (RTI), 445, 627 Resting tremor, 426 Restless legs syndrome (RLS) diagnosis, 632 neuropathology/pathophysiology, 631 neuropsychological/clinical presentation, 631–632 treatment, 632 Reticular reflex myoclonus. See Spinal/ segmental myoclonus Retinitis, 245 pigmentosa, 27 Retrieval-based memory deficits, 587 Retrieval errors, 443–444 Rett syndrome (RS), 82 diagnosis, 633 neuropathology/pathophysiology, 632–633 neuropsychological/clinical presentation, 633 treatment, 633–634 Reversible dementia, 544–545 Rey Complex Figure Test, 183 Reye’s syndrome (RS) diagnosis, 635 neuropathology/pathophysiology, 634 neuropsychological/clinical presentation, 634–635 treatment, 635 Reynaud’s syndrome, 260

800 & INDEX

Reynolds Child Depression Scale, 206 Rheumatic chorea. See Sydenham chorea Rheumatoid arthritis (RA), 532, 581 diagnosis, 637 neuropathology/pathophysiology, 636–637 neuropsychological/clinical presentation, 637 treatment, 637–638 Riluzole, 8, 71, 609 Risperidone, 227, 407 Ritalin (Methylphenidate), 366 Rituximab, 557 Rivastigmine, 66, 486 Ropinirole, 570 Rose Bengal Staining Test, 658 Rosenthal fibers, 52 ROSIER (Recognition of Stroke in the Emergency Room) tool, 722 RSK2 gene, 219, 220 Ruptured aneurysms diagnosis, 78 neuropathology/pathophysiology, 77 neuropsychological/clinical presentation, 77–78 treatment, 78–79

Saccular aneurysm, 76 Sacral perineural cysts. See Tarlov cysts Sagittal synostosis, 238 Salivary cortisol levels, severity of GAD symptoms with, 8 Sandhoff disease adult form of, 640 diagnosis, 640 infantile form of, 640 juvenile form of, 640 neuropathology/pathophysiology, 639 neuropsychological/clinical presentation, 639–640 symptoms, 639 treatment, 640 Sanfilippo’s disease, 480 Santavuori’s disease, 530 Sarcoidosis, 534. See also Neurosarcoidosis Sarcolemma, 515 Saxitoxin, 500 Schedula Monitoria de Noval Febris Ingressa (Sydenham, Thomas), 690 Schilder’s disease diagnosis, 642–643 neuropathology/pathophysiology, 641–642 neuropsychological/clinical presentation, 642 treatment, 643 Schirmer’s eye test, 658 Schizencephaly diagnosis, 644 neuropathology/pathophysiology, 643–644

neuropsychological/clinical presentation, 644 treatment, 644 Schwartz–Jampel’s syndrome, 511 Sclerodactyly, 646 Scleroderma diagnosis, 646 neuropathology/pathophysiology, 645–646 neuropsychological/clinical presentation, 646 treatment, 646–647 SCN1A gene, 267 Scoliosis, 220, 321 Scrotal skin biopsy, 394 Seasonal affective disorder, 20, 25 Secondary brain damage, 727 Secondary dystonia, 275, 276 Secondary normal pressure hydrocephalus, 545 Secondary piriformis syndrome, 591–592 Secondary/metastatic tumor, 145 Secondary/symptomatic narcolepsy, 517 Segmental dystonia, 275 Segmental myoclonus, 507 Seitelberger’s disease. See Infantile Neuroaxonal Dystrophy (INAD) Seizures and epilepsy. See Epilepsy and seizures febrile seizure. See Febrile seizure Selective dorsal rhizotomy cerebral palsy (CP) treatment, 176 Selective serotonin reuptake inhibitors (SSRIs), 12, 207, 271, 303, 407 Selegiline, 324 Sella turcica, 281–282 Semantic (direct) dysgraphia, 263 Semantic agraphia, 46 Semantic alexia, 56 Semantic dementia (SD), 87, 610 diagnosis, 648 neuropathology/pathophysiology, 647–648 neuropsychological/clinical presentation, 648 treatment, 648–649 Semantic paralexias, 56 Semantic paraphasia, 86 Semantic processing, 43 Semilobar holoprosencephaly, 350 Seminiferous tubule dysgenesis, 400, 401 Semiquantitative spot test, 482 Sensorimotor functions, 492 Sensorineural hearing loss, 391 Sensory trick. See Geste antagoniste Separation anxiety disorder (SAD), 193 Septic encephalopathy, 289 Septo-optic dysplasia (SOD). See De Morsier’s syndrome Seroquel, 12

Serotonin, 196, 465 Serotonin-specific-reuptake inhibitors (SSRIs), 649 Serotonin–norepinephrine reuptake inhibitors (SNRIs), 12 Sertraline, 199, 407, 717 Serum tests, antiphospholipid syndrome, 84 Sexually transmitted disease, neurosyphilis, 536 Shaken baby syndrome (SBS) diagnosis, 651 neuropathology/pathophysiology, 650 neuropsychological/clinical presentation, 650 potential risk factor, 651–652 treatment, 651–652 Shawl rash, 260 Shingles diagnosis, 654 neuropathology/pathophysiology, 653 neuropsychological/clinical presentation, 653–654 treatment, 654 Short-term memory, 492 Shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). See SUNCT headache syndrome Sickle cell disease (SCD) diagnosis, 656 neuropathology/pathophysiology, 655–656 neuropsychological/clinical presentation, 656 treatment, 656–657 Sickle cell trait (SCT), 655 Simultanagnosia, 32–33 Sinemet, 501 Single fiber electromyography, 505 Single-photon emission computed tomography (SPECT) alternating hemiplegia in childhood, 63 Dawson’s disease, 251 Lewy body dementia, 426–427 paroxysmal choreoathetosis (PC), 571, 572 Situational syncope, 694 Sjaastad syndrome. See Chronic paroxysmal hemicranias Sjo¨gren-Batten disease. See Batten’s disease Sjo¨gren’s syndrome diagnosis, 658–659 neuropathology/pathophysiology, 657 neuropsychological/clinical presentation, 657–658 treatment, 659 Sleep apnea diagnosis, 661–662 neuropathology/pathophysiology, 659–660

INDEX & 801

neuropsychological/clinical presentation, 660–661 treatment, 662 Sleep disorders, 747 Sleep wake cycle, 257 Slit lamp examination, 348 Sly syndrome, 480 Smoking, aneurysm, 77 Snoring, 660 Social anxiety disorder (SAD), 6 Social phobia, 193, 195 SOD1 gene, 69 Sodium butyrate, 674 Sodium channel disorders, 512 Soft spots, on infant’s head. See Fontanelles Somatic Conversion Scale (SOM-C), 664 Somatic Health Concerns Scale (SOM-H), 664 Somatization disorder, 664 Somatoform disorders diagnosis, 664 neuropathology/pathophysiology, 663 neuropsychological/clinical presentation, 663–664 treatment, 665–666 Somatoform illnesses, 303 Somatosensory agnosia, 35 Somatosensory evoked potentials (SSEP), 255 Somatostatin scintigraphy test, 244 Sotos’ syndrome diagnosis, 667 neuropathology/pathophysiology, 666 neuropsychological/clinical presentation, 666–667 treatment, 667 Spaeth–Barber’s spot test, 352 SPAST gene, 341 Spastic cerebral palsy, 175 Spastic dysphonia, 275 Spastic paraplegia gene (SPG), 341–342 Spastin gene, 309 Spatial agraphia, 44–45, 47 Specific phobias (SPs), 6 Speech apraxia, 104 Speech, impairment of, 42 Speech therapy aphasia, treatment of, 93–94 familial spastic paraplegia, 310 Speed of processing, in multiple sclerosis (MS), 493 SPG. See Spastic paraplegia gene (SPG) SPG20 gene, 735 Sphincter muscle, 348, 669 Spielberger State-Trait Anxiety Inventory (STAI), 10 Spike-wave discharge, 190 Spina bifida in children, 444 diagnosis, 669

neuropathology/pathophysiology, 668 neuropsychological/clinical presentation, 669 treatment, 669 ‘‘Spinal and bulbar muscular atrophy’’ (SBMA). See Kennedy’s disease (KD) Spinal Cord Independence Measure (SCIM), 671 Spinal cord injury (SCI) diagnosis, 671–672 neuropathology/pathophysiology, 670–671 neuropsychological/clinical presentation, 671 treatment, 672 Spinal cord stimulators, 160 Spinal muscular atrophies (SMA), 378 diagnosis, 674 homozygous deletion of, 674 neuropathology/pathophysiology, 673 neuropsychological/clinical presentation, 673–674 treatment, 674–675 Spinal tap, 490 Spinal/segmental myoclonus, 507 Spinocerebellar ataxia (SCA) types SCA1, 676, 677 SCA2, 676, 677 SCA3, 437, 676, 677 SCA6, 676, 677 SCA7, 676, 677 SCA17, 676, 677 Spinocerebellar degenerative disorders diagnosis, 678 neuropathology/ pathophysiology, 675–676 neuropsychological/clinical presentation, 676–678 treatment, 678 Spinothalamic fibers, 695 Spleen, 656 Splinting, 256 Splints, 630 Spoken Language Quotient scores, 191 Spongiosis, 240 Sporadic amyotrophic lateral sclerosis, 68 Sporadic genetic syndrome, 250 Sporadic microcephaly, 462 Sporadic type, 552 St. Johannis chorea. See Sydenham chorea Steatosis, 60 Stem cell transplant, 311 Stereotypes, 86 Steroid treatment, acute disseminated encephalomyelitis, 2 Stiff limb syndrome (SLS), 680 Stiff-person syndrome diagnosis, 681 neuropathology/pathophysiology, 679–680

neuropsychological/clinical presentation, 680 treatment, 681 Stimulator implantation, occipital neuralgia treatment, 550 Stretch therapy, piriformis syndrome, 592 Striatonigral degeneration diagnosis, 683 neuropathology/pathophysiology, 682 neuropsychological/clinical presentation, 682–683 treatment, 683 String of beads, 317 Strip craniectomy, 239 Stroke, 169 Stroke-like symptoms, 472 Stroop Test, 661 Structured Clinical Interview for DSM-IVTR (SCID), 9, 23 Stru¨mpell–Lorrain syndrome. See Familial spastic paraplegia Stuart–Prower factor, 304 Sturge–Weber syndrome, 404 diagnosis, 686 neuropathology/pathophysiology, 684–685 neuropsychological/clinical presentation, 685–686 treatment, 686 Subacute necrotizing encephalomyelopathy. See Leigh’s syndrome Subacute sclerosing panencephalitis. See Dawson’s disease Subacute sensory neuropathy, 566 Subarachnoid hemorrhage, 180, 181 Subcortical aphasia, 91–92 Subcortical band heterotopia (SBH), 430 Subcortical dementia, 306 Subcortical vascular dementia diagnosis, 687–688 neuropathology/pathophysiology, 687 neuropsychological/clinical presentation, 687 treatment, 688 Subdural hemorrhage, 181 Subscapularis muscle, 296 Substantia nigra, 569, 571 Suicidal ideation, 25 Sulci, 429 Sumatriptan, 217, 689 SUNCT headache syndrome, 339, 573, 574 cranial autonomic features, 689 diagnosis, 689 neuropathology/pathophysiology, 688–689 neuropsychological/clinical presentation, 689 treatment, 689 Supine hypotension, 499 Supplementary motor aphasia, 89–90 Supportive counseling, 267

802 & INDEX

Suppression-bursts, 551 Supramaximal motor nerve stimulation, 348 Surface (orthographic) dysgraphia, 263, 264 Surface alexia, 55 Surgical revascularization, 479 ‘‘Surround inhibition,’’ 274 Survival motor neuron gene (SMN1), 673 Sweet syndrome, 563 Sydenham chorea diagnosis, 692 neuropathology/pathophysiology, 691 neuropsychological/clinical presentation, 691–692 treatment, 692 Symbol Digit Modalities Test (SDMT), 492 Sympathetic nervous system, 269 Sympathomimetic agents, 683 Symptomatic etiology, 291 Symptomatic therapy, 496 Symptomatic West’s syndrome, 758 Synaptogenesis, lead toxicity, 417 Syncope diagnosis, 693–694 neuropathology/pathophysiology, 693 neuropsychological/clinical presentation, 693 versus nonsyncopal, 693 treatment, 694 Syndrome of inappropriate secretion of antidiuretic hormone (SIADH), 560 Synovectomy, 637–638 Synovium, 636 Syringobulbia, 696 Syringomyelia. See also Hydromyelia and syringomyelia diagnosis, 696 neuropathology/pathophysiology, 695 neuropsychological/clinical presentation, 695–696 treatment, 696 Syrinx. See Syringomyelia Systemic lupus erythematosus (SLE) diagnosis, 698 neuropathology/pathophysiology, 697–698 neuropsychological/clinical presentation, 698 treatment, 698 Systemic scleroderma, 645

Tacopherol, 704 Tactile agnosia, 35–36 Tactile apraxia, 104 Tactile paresthesias, 567, 568 Takayasu’s disease diagnosis, 701 neuropathology/pathophysiology, 701 neuropsychological/clinical presentation, 701 treatment, 701–702

Tandem mass spectrometry, 482 Tardive dyskinesia (TD) diagnosis, 703–704 neuropathology/pathophysiology, 702–703 neuropsychological/clinical presentation, 703 symptoms, 702 treatment, 704 Tarlov cysts diagnosis, 706 neuropathology/pathophysiology, 705 neuropsychological/clinical presentation, 705–706 treatment, 706 Task-specific dystonia, 274–275 Tay–Sachs’s disease, 640 in Ashkenazi Jews, 707 diagnosis, 707–708 in infants, 707 neuropathology/pathophysiology, 707 neuropsychological/clinical presentation, 707 treatment, 708 Teacher rating of academic performance (TRAP), 445 Teacher referral (TR), 626 Technetium-99m-HMPAO SPECT imaging, 714 Tegretol (Carbamazepine), 294, 550 Telangiectasias, 117 Telegraphic speech, 86 Telegraphic writing, 44 Temporal lobe damage, 121, 406 Temporal lobe epilepsy (TLE), 291 Temporal variant of FTD (tv-FTD), 324 Tendinitis, 630 Tensilon test, 414 Tension headaches, 550 Teratogen, 315 Teratogenic exposure, 380, 475 Terminal dymetria, 735 Test of Language Development, 191 Test of Word Reading Efficiency, 626 Test of written language (TOWL), 264 Testosterone hormone therapy, 401 Tetanus, 511 Tethered spinal cord syndrome diagnosis, 710 neuropathology/pathophysiology, 709 neuropsychological/clinical presentation, 709 treatment, 710 Tetrabenazine, 424, 572, 717 Tetracosactide, 760 Tetraplegia, 671, 672 Thalamotomy, 277 Theory of mind, 115 Thiamine deficiency, 419–420, 755 Thiamine-dependent enzymes, 755 Thioridazine, 227 Thomsen’s disease, 515

Thoracic outlet syndrome (TOS) diagnosis, 712 neuropathology/pathophysiology, 711 neuropsychological/clinical presentation, 711–712 treatment, 712 Thrombocytosis, in paraneoplastic syndromes, 562 Thrombotic ischemic stroke, 180 Thyroidectomy, 713 Thyroiditis, autoimmune disorder, 680 Thyrotoxic myopathy diagnosis, 713 neuropathology/pathophysiology, 713 neuropsychological/clinical presentation, 713 treatment, 713 Thyrotoxic periodic paralysis (TPP), 307 Thyrotoxicosis, 713 Tic disorders, 716 ‘‘Tic douloureux’’. See Trigeminal neuralgia (TN) Tick-borne disease. See Lyme disease Timed Gate Test, 345 Tinnitus, 300 Tissue plasminogen activator (tPA), 721 Tizanidine, 310, 343, 681 Tocainide, 515 Todd’s paralysis diagnosis, 715 neuropathology/pathophysiology, 714 neuropsychological/clinical presentation, 715 treatment, 715 Tonic spasm, 551 Topiramate, 268, 689, 731, 760 TorsinA, 273–274 Torticollis, 275 Tourette Syndrome Classification Study Group (TSCSG) (1993), 717 Tourette’s syndrome (TS), 142 diagnosis, 717 neuropathology/pathophysiology, 716 neuropsychological/clinical presentation, 716 treatment, 717 Toxic neuropathy, 532 Toxic psychosis. See Delirium Toxicity encephalopathy, 417 Trafficking protein kinesin binding 1 (Trak1), 367 Trail Making Test, 183, 345 Transcortical aphasia. See Extrasylvian aphasias Transcortical mixed aphasia, 90 Transcortical motor aphasia, 89 Transcortical sensory aphasia, 90 Transcranial magnetic stimulation, 276 Transforming growth factor (TGFb), 645 Transient global amnesia (TGA) diagnosis, 719–720 neuropathology/pathophysiology, 719

INDEX & 803

neuropsychological/clinical presentation, 719 treatment, 720 Transient ischemic attacks (TIAs), 169, 180, 317, 478 diagnosis, 722 neuropathology/pathophysiology, 721 neuropsychological/clinical presentation, 721–722 symptoms, 721 treatment, 722–723 Transient neonatal myasthenia (TNM) diagnosis, 231–232 neuropathology/pathophysiology, 229 neuropsychological/clinical presentation, 230 treatment, 232 Transient paresthesia, 568 Transketolase (TK), 755 Transmissible spongiform encephalopathy (TSE), 288, 289, 409–410 Transphenoidal selective adenomectomy, 244 Transverse myelitis (TM) ACTM. See Acute complete transverse myelitis APTM. See Acute partial transverse myelitis diagnosis, 726 neuropathology/pathophysiology, 725 neuropsychological/clinical presentation, 725–726 treatment, 726 Traumas, examples, 255 Traumatic brain injury (TBI), 86–87, 464, 650 diagnosis, 728–729 neuropathology/pathophysiology, 727 neuropsychological/clinical presentation, 727–728 treatment, 729 Trazodone, 324, 558 Tremors, 272, 397 Treponema pallidum, 536 Triad of ataxia, 467 Tricyclic antidepressants (TCAs), 71, 207, 271, 339 Trigeminal autonomic cephalalgias (TACs), 573 Trigeminal neuralgia (TN) diagnosis, 730–731 microvascular decompression, 332, 731 neuropathology/pathophysiology, 730 neuropsychological/clinical presentation, 730 treatment, 731 Trigger point injections, piriformis syndrome, 592 Trigonocephaly, 239 Trihexyphenidyl, 143, 277, 572 Trimethoprim-sulfamethoxazole, 755, 765

Trimethylglycine, 352 Triplet repeat diseases, 437 Trisomy, 455 Tropheryma whippelii, 764 Tropical spastic paraparesis (TSP) diagnosis, 733 neuropathology/pathophysiology, 732 neuropsychological/clinical presentation, 732–733 treatment, 733 Troyer syndrome diagnosis, 735–736 neuropathology/pathophysiology, 734–735 neuropsychological/clinical presentation, 735 treatment, 736 Truncal ataxia, 117 TSC1 gene, 736 TSC2 gene, 736 Tuberous sclerosis diagnosis, 737–738 neuropathology/pathophysiology, 736–737 neuropsychological/clinical presentation, 737 treatment, 738 Tumors. See also Brain tumors classification of, 145 locations of, 149 Turkish saddle, 281 Turner’s syndrome (TS) diagnosis, 741 neuropathology/pathophysiology, 739–740 neuropsychological/clinical presentation, 740–741 treatment, 741 Type I sacral cysts, 706 Type II cysts, 706 Type-II glycogenosis. See Pompe’s disease Type III cysts, 706 Tzanck test, 654

UBE3A gene, 81, 82 Umbilical cord blood (UCB) transplantation, 773 ‘‘Umbrella term,’’ 174 Unified Batten Disease Rating Scale (UBDRS), 130 Unilateral coronal synostosis, 238 Uniparental disomy (UPD), 81 Upper airway resistance syndrome, 366 Urbach–Wiethe disease. See Lipoid proteinosis Utilization behavior, 59 Uveitis, 132

Vacuolar myopathy, 597 Vagus nerve stimulators, 268

Valganciclovir, 246 Valium (Diazepam), 119, 294 Valproate, 207, 268, 272, 531 Valproic acid (Depakene/Depakote), 61, 192, 294, 422, 550, 572, 674, 692, 733, 760 Vancomycin, 451 Varicella zoster virus (VZV), 344, 652, 653 Varicose veins, 404 Varivax (Merck), 654 Vascular cognitive impairment, 486 Vascular dementia (VD), 180, 181, 182, 486, 687 Vasculitis, 214, 754 diagnosis, 746 neuropathology/pathophysiology, 745 neuropsychological/clinical presentation, 745–746 treatment, 746 Vasodilator hydergine, 688 Vasogenic oedema, 453 Vasovagal syncope, three specific phases of, 694 Vegetative state, 223 Ventral pons, 433 Ventral pontine syndrome, 433 Ventral simultanagnosia, 32–33 Ventricular hemorrhage, 181 Ventriculoperitoneal/ventriculoatrial shunt, 546 Ventriculostomy method, for increased intracranial pressure, 374 Verapamil, 218, 689 Verbal memory, 107 Verbal overflow, 102 Very long chain fatty acids (VLCFAs), 3, 4 VHL gene, 749, 750 Vigabatrin, 268, 681, 760 Vinpocetine, 487 Viral encephalitis, 284 Viral meningitis, 450 Viral pathogens, 450 Visible papules and nodules, 429 Visual action therapy, 93 Visual agnosia, 31, 182, 406 Visual disturbances, 499 Visual expressive. See Disorders of written language (DWL) Visual hallucinations, 257, 426 Visual impairments, 252 Visual loss, in pseudotumor cerebri, 618 Visuoconstructive abilities, 492 Visuospatial functions, 291, 492 Visuospatial skills, 492 Vitamin B12, 532, 581 Vocal/phonic tics, 716 Vogt-Spielmeyer disease. See Batten’s disease Voltage-gated potassium channels (VGKCs) antibodies, 382 Voltage-gated sodium channel Nav1.1, 267

804 & INDEX

Voluntary movement disturbance, 369 von Economo disease (VED) diagnosis, 747–748 neuropathology/pathophysiology, 747 neuropsychological/clinical presentation, 747 treatment, 748 von Hippel–Lindau disease (VHL), 173 diagnosis, 750 neuropathology/pathophysiology, 749 neuropsychological/clinical presentation, 749–750 treatment, 750 VPS13A gene, 519

Wallenberg’s syndrome diagnosis, 752 neuropathology/pathophysiology, 751 neuropsychological/clinical presentation, 751–752 treatment, 752 Warfarin, 84, 305, 354 ‘‘Warm-up phenomenon,’’ 511 Watermelon stomach, 646 Wechsler adult intelligence scale-III (WAIS-III), 756 Wechsler adult intelligence scale-IV (WAIS-IV), 264 Wechsler intelligence scale for children-IV (WISC-IV), 264 Wechsler Intelligence Scale for ChildrenRevised (WISC-R), 130, 191 Wechsler Memory Scale, 23 Wechsler Memory Scale-III (WMS-III), 66, 457, 756 Wegener’s granulomatosis diagnosis, 754 neuropathology/pathophysiology, 753–754 neuropsychological/clinical presentation, 754 treatment, 754–755 Wernicke–Korsakoff syndrome diagnosis, 756–757 neuropathology/pathophysiology, 755–756 neuropsychological/clinical presentation, 756 treatment, 757

Wernicke’s aphasia, 86, 88, 182 Wernicke’s encephalopathy (WE), 289, 755 Wernike’s aphasia, 43–44 Western Aphasia Battery (WAB), 92 Western blacklegged ticks, 434 Westphal–Strumpell pseudosclerosis, 770 West’s syndrome (WS), 422 classification, 758 diagnosis, 760 neuropathology/pathophysiology, 758–759 neuropsychological/clinical presentation, 759–760 treatment, 760 Whiplash diagnosis, 763 neuropathology/pathophysiology, 762 neuropsychological/clinical presentation, 763 treatment, 763–764 Whiplash-associated disorders (WAD) grading system, 763 Whipple’s disease diagnosis, 765 neuropathology/pathophysiology, 764–765 neuropsychological/clinical presentation, 765 treatment, 765 White-matter dysfunction, 542 White matter hyperintensities (WMH), 171 Williams’s syndrome (WS) diagnosis, 767 neuropathology/pathophysiology, 766–767 neuropsychological/clinical presentation, 767 treatment, 767–768 Wilson’s disease (WD), 276 diagnosis, 770 neuropathology/pathophysiology, 769–770 neuropsychological/clinical presentation, 770 treatment, 770–771 Wisconsin Card Sorting Test (WCST), 8–9, 493

Wolman’s disease, 208–209 diagnosis, 772 neuropathology/pathophysiology, 771–772 neuropsychological/clinical presentation, 772 treatment, 772–773 Word deafness. See Auditory agnosia Word fluency test, 191 Work-related disorders. See Repetitive motion disorders (RMDs) Working memory, 492 World Federation of Neurology (WFN), 70 World Health Organization (WHO), cerebrovascular accident (CVA), 180 Writer’s cramp, 275 Writing, motor act of, 42 Written language, disorders of. See Disorders of written language (DWL)

X-linked bulbospinal neuropathy, 394 X-linked recessive genetic alteration, 341 Xerostomia, 658 XLIS/DCX gene, 430, 431

Young Mania Rating Scale, 24

Zanaflex, 736 Zarontin (Ethosuximide), 192, 294 Zellweger spectrum, 775 Zellweger syndrome diagnosis, 776 neuropathology/pathophysiology, 775 neuropsychological/clinical presentation, 775–776 treatment, 776 Zidovudine, 733 Zoloft (Sertraline), 199 Zolpidem, 168 Zonisamide, 51, 268 Zostavax (Merck), 654 Zoster, 343. See also Herpes zoster (HZ) oticus Zung Depression Scale, 23