Hankey's Clinical Neurology [3 ed.] 2020022754, 2020022755, 9780367280321, 9780367610876, 9780429299476, 9781000210026, 1000210022, 0367280329, 0367610876

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HANKEY’S CLINICAL NEUROLOGY

HANKEY’S THIRD EDITION

CLINICAL NEUROLOGY Edited by

Philip B. Gorelick

MD, MPH, FACP, FAHA, FAAN, FANA Adjunct Professor of Neurology Davee Department of Neurology Northwestern University Feinberg School of Medicine Chicago, Illinois, USA Emeritus Executive Medical Director, Mercy Health Hauenstein Neurosciences at Saint Mary’s Hospital Professor, Translational Neurosciences Michigan State University College of Human Medicine Grand Rapids, Michigan, USA

Fernando D. Testai

MD, PhD, FAHA Associate Professor in Neurology University of Illinois College of Medicine at Chicago Department of Neurology and Rehabilitation University of Illinois–Health Chicago, Illinois, USA

Graeme J. Hankey

MBBS, MD, FRACP, FRCP, FRCPE, FAHA, FESO, FWSO, FAAHMS Professor of Neurology Medical School, Faculty of Health and Medical Sciences The University of Western Australia Consultant Neurologist Department of Neurology, Sir Charles Gairdner Hospital Perth, Australia

Joanna M. Wardlaw

CBE, MBChB, MRCP, FRCR, MD, FRCPE, FAHA, FESO, FWSO, FMedSci, FRSE Professor of Applied Neuroimaging Division of Neuroimaging Sciences Centre for Clinical Brain Sciences and UK Dementia Research Institute University of Edinburgh, Chancellor’s Building, Edinburgh, UK

Third edition published 2021 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 and by CRC Press 2 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN © 2021 Taylor & Francis Group, LLC First edition published by CRC Press 2008 Second edition published by CRC Press 2014 CRC Press is an imprint of Taylor & Francis Group, LLC This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged, please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging‑in‑Publication Data Library of Congress Cataloging-in-Publication Data Names: Gorelick, Philip B., editor. | Testai, Fernando D., editor. | Hankey, Graeme J., editor. | Wardlaw, Joanna M., editor. Title: Hankey’s clinical neurology / edited by Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw. Other titles: Clinical neurology Description: Third edition. | Boca Raton ; London : CRC Press, 2020. | Includes bibliographical references and index. | Summary: “The rapid expansion of clinical knowledge in the field of neurology warrants a new edition of this highly regarded textbook of neurology. In addition to the anchor chapters on major areas such as headache, stroke, developmental disorders, dementia, epilepsy, acquired metabolic disorders and others, several new chapters have been added to meet the clinical demand for those in practice. This edition features new chapters on neurotoxicology, neuroimaging, and neurogenetics including basic and more advanced concepts for the practitioner. Finally, as the health care system continues to evolve, a new chapter on population health and systems of care reflects current practice in team care, patient-centric approaches, and value-based care”-- Provided by publisher. Identifiers: LCCN 2020022754 (print) | LCCN 2020022755 (ebook) | ISBN 9780367280321 (paperback) | ISBN 9780367610876 (hardcover) | ISBN 9780429299476 (ebook) Subjects: MESH: Nervous System Diseases Classification: LCC RC346 (print) | LCC RC346 (ebook) | NLM WL 140 | DDC 616.8--dc23 LC record available at https://lccn.loc.gov/2020022754 LC ebook record available at https://lccn.loc.gov/2020022755 ISBN: 978-0-367-28032-1 (pbk) ISBN: 978-0-367-61087-6 (hbk) ISBN: 978-0-429-29947-6 (ebk) Typeset in Warnock Pro by KnowledgeWorks Global Ltd.

I dedicate this book in honor of my mother for her high moral standards, intellect, and love of family for over 90 years, and to my father in his eternal resting place as a continuous inspiration. Philip B. Gorelick I dedicate this book to my wife, Flavia, whose support is never-ending. To my daughter, Sofia, who is an example of dedication and kindness. To my son, Martin, who taught me what it means to be a true fighter. To my parents, Ruben and Stella, who sacrificed everything to give their children the privilege of an education they couldn’t access. To my unconditional fans, my sisters Alejandra and Naiara. And, in particular, to our patients, who are an endless source of inspiration. Fernando D. Testai I dedicate this book in honor of my mother for her high moral standards, intellect, and love of family for over 90 years. And to my father in his eternal resting place as a continuous inspiration. Graeme J. Hankey I dedicate this work to my family, in gratitude for their unwavering support, to my many colleagues, collaborators and patients for their inspiration to me, and to the brain scientists and medics of the future whom I hope will be inspired by this work. Joanna M. Wardlaw

CONTENTS Preface.....................................................................................................viii Contributors............................................................................................ix Abbreviations..........................................................................................xi 1. Neurologic diagnosis................................................................... 1 John Dunne, Robert Edis 2. Tools for the diagnosis and management of nervous system diseases............................................................ 53 William McAuliffe, Elizabeth Berry-Kravis, Gian D. Pal, Deborah A. Hall 3. Population health and systems of neurological care..........81 Philip B. Gorelick, Jong S. Kim, Hee-Joon Bae 4. Disorders of consciousness...................................................... 89 Rick Gill, Sean Ruland 5. Epilepsy........................................................................................115 Donald C. Barr, Andres M. Kanner 6. Headache..................................................................................... 143 Peter J. Goadsby 7. Vertigo..........................................................................................163 Christopher C. Glisson, Jorge C. Kattah 8. Hyperkinetic movement disorders......................................173 Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson 9. Developmental diseases of the nervous system...............205 James H. Tonsgard, Nikolas Mata-Machado 10. Hereditary and metabolic diseases of the central nervous system in adults.........................................................251 Sho T. Yano, Kenneth Silver 11. Trauma of the brain and spinal cord..................................285 Fernando D. Goldenberg, Ali Mansour 12. Stroke and transient ischemic attacks of the brain and eye..................................................................297 Graeme J. Hankey 13. Neuroinfectious diseases: Infections of the central nervous system................................................409 Jeremy D. Young, Jesica A. Herrick, Scott Borgetti, Michael D. Carrithers

15. Tumors of the nervous system..............................................493 Ugur Sener, Julie E. Hammack 16. Degenerative diseases of the nervous system..................529 James A. Mastrianni, Elizabeth A. Harris, Brandon R. Barton, Roshni Patel, Vikram G. Shakkottai, Sharan R. Srinivasan 17. Nutritional deficiencies.......................................................... 615 Deepa Bhupali, Fernando D. Testai 18. Acquired encephalopathies...................................................629 Herman Sullivan, Muhammad U. Farooq 19. Neurotoxicology........................................................................641 Sean D. McCann, Trevonne M. Thompson 20. Disorders of circulation of the cerebrospinal fluid....................................................................651 Edward A. Michals 21. Cranial neuropathies I, V, and VII–XII.............................667 Carlen Yuen, Helene Rubeiz 22. Cranial neuropathies II, III, IV, and VI.............................693 Tanyatuth Padungkiatsagul, Heather E. Moss 23. Spinal cord disease................................................................... 717 Ryan Jacobson, Allison Osen 24. Autonomic nervous system disorders................................ 749 Robert Henderson, Judy Spies 25. Diseases of the peripheral nerve and mononeuropathies....................................................................757 Diana Mnatsakanova, Charles K. Abrams 26. Neuromuscular junction disorders..................................... 819 Diana Mnatsakanova, Qin Li Jiang 27. Muscle disorders.......................................................................835 Kourosh Rezania, Peter Pytel, Betty Soliven 28. Sleep–wake disorders..............................................................875 Margaret Kay-Stacey, Eunice Torres-Rivera, Phyllis C. Zee Index.......................................................................................................915

14. Inflammatory disorders of the nervous system...........................................................................................473 Neil Scolding

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PREFACE We welcome you to the third edition of Hankey’s Clinical Neurology. Some 7 years have been passed since we published the second edition. A substantial expansion of clinical knowledge in our field has moved us to update the text. The many successes of the second edition have brought the same editors back to the drawing board. Professors Hankey and Wardlaw, the founding editors of the book have had an active hand in guiding the third edition forward. Professors Gorelick and Testai of the second edition have returned as lead editors to clear a pathway for updates and new chapters. The second edition had 24 chapters, but the third edition has been expanded to include 28 chapters. Whereas a number of anchor chapters remain in place such as headache (Goadsby), stroke (Hankey), developmental disorders (Tonsgard), dementia (Mastrianni), epilepsy (Kanner), acquired metabolic disorders (Testai), and others that have been updated and expanded, several new chapters have been added to meet the clinical demand for those in practice. The third edition now features a chapter on neurotoxicology as we find ourselves in the midst of possible worldwide pandemics and bioterrorism. Neuroimaging, a mainstay of the neurologist’s tool box for diagnosis and management, is a separate chapter based on its important role in clinical diagnosis. Neurogenetics, a burgeoning field, is a stand-alone chapter and includes basic and more advanced concepts for the practitioner. Finally, as the health care system continues to evolve, we meet a need for a primer chapter on population health and systems of care as training programs are now emphasizing team care, patient-centric approaches, and value-based care. We have maintained the original style of the first and second editions of the book. The text is a combination of pithy bullet points and standard prose to allow the reader to easily digest concepts and key messages. In addition, the chapters are liberally spiced with summary tables, neuroimages, photomicrographs, neuroanatomic drawings, gross and microscopic neuropathologic specimen photos, and other graphics. The reader is further aided by the presence of summary boxes to capture essential clinical messages. Thus, chapters are crafted in a way to appeal to both the visuospatial and analytic functional centers of the brain, as we stimulate the senses and learn. We hope that you will be stimulated to read on or use the text as an up-to-date reference source in general clinical neurology. We anticipate Hankey’s Clinical Neurology, third edition, will be of value to medical students, physicians in training, neurology fellows, neurologist and neurosurgeon practitioners, and advanced practice professionals (e.g. nurse practitioners and physician assistants) who are faced with neurologic practice challenges. The chapters contain recent literature references and some of the more classic ones to help guide the reader who wishes more information. We wish to thank all the authors who were tasked to bring together up-to-date chapters on a relatively short timeline to allow us to provide current information in a text book format. Our publisher, CRC Press, responded to the challenge with a timely turnaround to have the book ready for circulation while the information was still fresh. It truly took a village to make this happen, and we thank all who participated including our generous patients who agreed to allow their likenesses

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or other neurologic diagnostic results to be utilized in this tome. Finally, and in advance, we thank those who may utilize the text and we welcome your feedback. Philip B. Gorelick Fernando D. Testai Graeme J. Hankey Joanna M. Wardlaw A decade has passed since the first edition of Clinical Neurology. Those who have embraced it have encouraged us to update it. The explosion of rigorous scientific evidence for interventions in clinical neurology, coupled with astonishing advances in the clinical neurosciences, have further inspired us to undertake a second edition. As the initial authors (GJH and JMW) are now a decade older and have gravitated toward greater subspecialization, another couple of fellow enthusiasts (PBG and FDT) from Grand Rapids and Chicago, USA have joined to facilitate a re-energized, comprehensive, and more global, rather than Anglo-Australian, effort. Together we have enlisted the generosity and specialist expertise of our friends and colleagues throughout the world who are recognized leaders in their field and who have kindly agreed to enlighten us with a chapter on the subject to which they are dedicated. The subjects and format of the first edition have been maintained and are complemented by the addition of a new chapter on sleep disorders. The chapter covering degenerative diseases of the nervous system has now been subdivided into three main sections, dementias, Parkinson’s disease and parkinsonian syndromes, and hereditary ataxias. The cranial neuropathies chapter now includes an entirely new section on neuro-ophthalmology. In addition, there are over 440 new illustrations. The perspective for each chapter is also fresh, as each chapter (with the exception of the chapter on stroke) has been written by one or more of our new contributors, in contrast to the first edition which represented the perspective of GJH and JMW. The purpose of the book, nevertheless, continues to focus on the essentials for students of clinical neurology, particularly neurologists-in-training and practicing neurologists, who wish to have ready access to a comprehensive, up-to-date, and evidence-based guide to the understanding, diagnosis, and management of common and important neurologic disorders. Many of the illustrations are images taken from our own patients, whom we would like to thank for allowing us to photograph them or the outcome of their investigations. Furthermore, we would also like to thank all the current and past contributors of figures (too many to list individually here) for providing illustrations, as indicated throughout the book. Finally, we would like to thank our families and colleagues for supporting us in this endeavor. We hope you enjoy it and we welcome any comments and criticisms. Philip B. Gorelick Fernando D. Testai Graeme J. Hankey Joanna M. Wardlaw

CONTRIBUTORS Charles Abrams University of Illinois at Chicago College of Medicine Chicago, IL, USA Annu Aggarwal Centre for Brain and Nervous System Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute Mumbai, India Hee-Joon Bae Department of Neurology Cerebrovascular Disease Center Seoul National University College of Medicine Seoul National University Bundang Hospital Seongnam, Republic of Korea Donald C. Barr Department of Neurology University of Miami, Miller School of Medicine Miami, FL, USA Brandon R. Barton Rush University Medical Center Jesse Brown VA Medical Center Chicago, IL, USA Elizabeth Berry-Kravis Department of Pediatrics Department of Neurological Sciences Department of Integrated Biomedical Sciences Rush University Medical Center Chicago, IL, USA Deepa Bhupali Advocate Christ Medical Center Chicago, IL, USA Scott Borgetti Division of Infectious Diseases University of Illinois at Chicago Chicago, IL, USA Michael D. Carrithers Jesse Brown VA Hospital Department of Neurology and Rehabilitation Physiology and Biophysics University of Illinois at Chicago Chicago, IL, USA

John Dunne University of Western Australia School of Medicine Royal Perth Hospital Unit Perth, WA, Australia Robert Edis Department of Neurology Sir Charles Gairdner Hospital Perth, WA, Australia Muhammad U. Farooq Mercy Health Hauenstein Neurosciences Assistant Professor of Neurology Michigan State University College of Human Medicine and College of Osteopathic Medicine Grand Rapids, MI, USA Victor S.C. Fung Movement Disorders Unit Department of Neurology Westmead Hospital and Sydney Medical School University of Sydney Sydney, NSW, Australia Rick Gill Loyola University Chicago Stritch School of Medicine Maywood, IL, USA Christopher C. Glisson Neuro-Ophthalmology Program Mercy Health Hauenstein Neurosciences Michigan State University Grand Rapids, MI, USA Peter J. Goadsby King’s College London London UK University of California Los Angeles, CA, USA Fernando D. Goldenberg Neuroscience Critical Care Section University of Chicago Chicago, IL, USA Deborah A. Hall Department of Neurological Sciences Department of Integrated Biomedical Sciences Rush University Medical Center Chicago, IL, USA

Julie E. Hammack Department of Neurology Mayo Clinic in Florida Jacksonville, FL, USA Elizabeth A. Harris Department of Neurology University of Chicago Medical Center Chicago, IL, USA Robert Henderson Royal Brisbane & Women’s Hospital UQ Centre for Clinical Research Brisbane, QLD, Australia Jesica A. Herrick Division of Infectious Diseases University of Illinois at Chicago Chicago, IL, USA Morales-Briceno Hugo Movement Disorders Unit Department of Neurology Westmead Hospital and Sydney Medical School University of Sydney Sydney, NSW, Australia Ryan Jacobson Department of Neurological Sciences Rush University Medical Center Chicago, IL, USA Qin Li Jiang Jesse Brown VA Medical Center Chicago, IL, USA Andres M. Kanner Department of Neurology University of Miami, Miller School of Medicine Miami, FL, USA Jorge C. Kattah University of Illinois College of Medicine Illinois Neurologic Institute Saint Francis Medical Center Peoria, IL, USA Margaret Kay-Stacey Northwestern University Feinberg School of Medicine Chicago, IL, USA

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Contributors

x Jong S. Kim Department of Neurology Asan Medical Center University of Ulsan Seoul, South Korea Ali Mansour Neuroscience Critical Care Section University of Chicago Chicago, IL, USA James A. Mastrianni Center for Comprehensive Care and Research on Memory Disorders Department of Neurology University of Chicago Pritzker School of Medicine Chicago, IL, USA Nikolas Mata-Machado University of Illinois at Chicago Chicago, IL, USA William McAuliffe Department of the Neurological Intervention and Imaging Service of WA (NIISWA) Perth, WA, Australia Sean D. McCann Emergency Medicine and Medical Toxicology University of Illinois College of Medicine Chicago, IL, USA Edward A. Michals University of Illinois Chicago, IL, USA Diana Mnatsakanova University of Illinois at Chicago College of Medicine Chicago, IL, USA Heather E. Moss Department of Ophthalmology Department of Neurology and Neurological Sciences Stanford University Palo Alto, CA, USA Allison Osen Department of Neurological Sciences Rush University Medical Center Chicago, IL, USA Tanyatuth Padungkiatsagul Department of Ophthalmology Faculty of Medicine Ramathibodi Hospital Mahidol University, Bangkok, Thailand Department of Ophthalmology, Stanford University Palo Alto, CA, USA

Gian D. Pal Department of Neurological Sciences Rush University Medical Center Chicago, IL, USA Roshni Patel Rush University Medical Center Chicago, IL, USA Peter Pytel Department of Pathology University of Chicago Chicago, IL, USA Kourosh Rezania Department of Neurology University of Chicago Chicago, IL, USA Helene Rubeiz University of Chicago Chicago, IL, USA Sean Ruland Professor of Neurology Loyola University Chicago Stritch School of Medicine Maywood, IL, USA Neil Scolding Learning and Research, Southmead Hospital University of Bristol Bristol, UK Ugur Sener West Virginia University Morgantown, WA, USA Vikram G. Shakkottai University of Michigan Ann Arbor, MI, USA Kenneth Silver Shriners Hospital for Children Chicago Department of Pediatrics and Neurology University of Chicago Chicago, IL, USA Betty Soliven Department of Neurology University of Chicago Chicago, IL, USA Judy Spies Royal Prince Alfred Hospital Central Clinical School University of Sydney School of Medicine Camperdown, NSW, Australia

Sharan R. Srinivasan University of Michigan Ann Arbor, MI, USA Herman Sullivan Mercy Health Hauenstein Neurosciences Michigan State University College of Human Medicine and College of Osteopathic Medicine Grand Rapids, MI, USA Philip Thompson The University of Adelaide Adelaide, SA, Australia Trevonne M. Thompson Emergency Medicine and Medical Toxicology University of Illinois College of Medicine Chicago, IL, USA James H. Tonsgard Pediatric Neurology University of Chicago College Chicago, IL, USA Eunice Torres-Rivera Northwestern University McGaw Chicago, IL, USA Sho T. Yano Pediatric Neurology and Medical Genetics Bethesda, MD, USA Jeremy D. Young Division of Infectious Diseases The Ohio State University Wexner Medical Center Columbus, OH, USA Carlen Yuen University of Chicago Chicago, IL, USA Phyllis C. Zee Benjamin and Virginia Boshes Professor in Neurology Northwestern University Feinberg School of Medicine Chicago, IL, USA

ABBREVIATIONS 5HT AA AAD AASM Aβ AC Aca ACE ACE-R AChE AChR ACTH AD ADAMTS ADC ADCA ADEM ADHD ADL ADLP ADP AED AF AFB AFP AHI AICA AIDP AIDS AION AIP aKGD ALD ALDP ALS ALT AMAN AML AMN (c)AMP AMSAN ANC ANCL AO AOA ApoE APP APS aPTT ARAS ARDS ARI ARR ARSA ARSACS ARX

5-hydroxytryptamine anaplastic astrocytoma atlantoaxial dislocation American Association of Sleep Medicine amyloid-β activated charcoal aceruloplasminemia angiotensin-converting enzyme Addenbrooke’s Cognitive Examination Revised acetylcholinesterase acetylcholine receptors adrenocorticotropic hormone Alzheimer’s disease a disintegrin and metalloproteinase with thrombospondin motif apparent diffusion coefficient autosomal dominant cerebellar ataxia acute disseminated encephalomyelitis attention deficit hyperactivity disorder activities of daily living/adrenoleukodystrophy adrenoleukodystrophy protein adenosine diphosphate antiepileptic drug atrial fibrillation acid-fast bacilli alpha-fetoprotein apnea/hypopnea index anterior inferior cerebellar artery acute inflammatory demyelinating polyradiculoneuropathy acquired immunodeficiency syndrome anterior ischemic optic neuropathy acute intermittent porphyria alpha-ketoglutarate dehydrogenase adrenoleukodystrophy adrenoleukodystrophy protein amyotrophic lateral sclerosis alanine aminotransferase acute motor axonal neuropathy angiomyolipoma adrenomyeloneuropathy (cyclic) adenosine monophosphate acute motor and sensory axonal neuropathy accessory neurenteric canal adult neuronal ceroid lipofuscinoses anaplastic oligodendroglioma oligoastrocytoma apolipoprotein E amyloid precursor protein antiphospholipid syndrome activated partial thromboplastin time ascending reticular activating system adult respiratory distress syndrome absolute risk increase absolute risk reduction arylsulfatase A autosomal recessive spastic ataxia of Charlevoix–Saguenay Aristaless-related homeobox

AS ASA ASD ASO ASP AST AT ATP ATM AVM AVS AZA AZP BAEP BAL BBB BBS BDNGF BF bFGF BFP BFPP BGP BHC BMD BMI BNCT BP BPAP BPP BPPP BPPV BRRS BSE BSK BTX BUN BWSTT BZDs CADASIL

Angelman’s syndrome atrial septal aneurysm atrial septal defect/autism spectrum disorder antisense oligonucleotide amnestic shellfish poisoning aspartate aminotransferase ataxia telangiectasia adenosine triphosphate acute transverse myelitis arteriovenous malformation acute vestibular syndrome azathioprine azaspiracid shellfish poisoning brainstem auditory evoked potential British anti-Lewisite blood–brain barrier Bardet–Biedl syndrome brain-derived nerve growth factor blood flow basic fibroblast growth factor bilateral frontal PMG bilateral frontoparietal PMG bilateral generalized PMG benign hereditary chorea Becker’s muscular dystrophy body mass index boron neutron capture therapy blood pressure/Bereitschaftspotential bilevel positive airways pressure bilateral perisylvian PMG bilateral parasagittal parieto-occipital PMG benign paroxysmal positional vertigo Bannayan–Riley–Ruvalcaba syndrome bovine spongiform encephalopathy Barbour–Stoenner–Kelly botulinum toxin blood urea nitrogen body weight–supported treadmill training benzodiazepines cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CAM computer-assisted myelography CAS carotid artery stenting CBD corticobasal degeneration CBF cerebral blood flow CBS corticobasal syndrome/cystathionine β-synthase deficiency CBT cognitive behavioral therapy CBV cerebral blood volume CDC Centers for Disease Control and Prevention CEA carotid endarterectomy/carcinoembryonic antigen cEEG continuous electroencephalography CE-MRA contrast-enhanced magnetic resonance angiography CGRP calcitonin gene-related peptide CI confidence interval/cholinesterase inhibitor CIDP chronic inflammatory demyelinating polyneuropathy CIM critical illness myopathy xi

Abbreviations

xii CIMT CIP CIS CISC (f/i/s/v) CJD CK CLAM CM CMAP CMD CMT CMV CNS CNVs CO COACH COMT CORS COX CPA CPAP CPEO CPK CPM CPP CPR Cr CRAO CRP CRVO CS CSA CSF CT CTA CTV CV CVA CVT DAI DALY DBP DBS DD DFA DGC DIC DLB DMD DNA DNET DNS DRPLA DSA DSP DSPN DUB DVT DWI EACA

constraint-induced movement therapy critical illness polyneuropathy clinically isolated syndrome clean intermittent self-catheterization (familial/iatrogenic/sporadic/variant) Creutzfeldt–Jakob disease creatine kinase cholesterol-lowering agent myopathy congenital myopathy compound muscle action potential congenital muscular dystrophy Charcot–Marie–Tooth disease cytomegalovirus central nervous system copy-number variants carbon monoxide cerebellar vermis hypo/aplasia, oligophrenia, ataxia congenital, coloboma, and hepatic fibrosis catechol-O-methyltransferase cerebello-oculo-renal syndrome cyclo-oxygenase cerebellopontine angle continuous positive airway pressure chronic progressive external ophthalmoplegia creatine phosphokinase central pontine myelinolysis cerebral perfusion pressure cardiopulmonary resuscitation creatinine central retinal artery occlusion C-reactive protein central retinal vein occlusion Cowden’s syndrome central sleep apnea cerebrospinal fluid computed tomography computed tomography angiography computed tomography venography color vision cerebrovascular accident cerebral venous thrombosis diffuse axonal injury disability-adjusted life year diastolic blood pressure deep brain stimulation developmental delay direct immunofluorescent antibody dystrophin glycoprotein complex disseminated intravascular coagulation dementia with Lewy bodies Duchenne’s muscular dystrophy deoxyribonucleic acid dysembryoplastic neuroepithelial tumor delayed neurologic sequelae dentatorubro–pallidoluysian atrophy digital subtraction cerebral angiography diarrhetic shellfish poisoning distal symmetric polyneuropathy deubiquitinating enzyme deep vein thrombosis diffusion-weighted imaging epsilon-aminocaproic acid

EBRT EBV ECG ECT EDH EEG EGF(R) EIAC EITB ELISA EM EMD EMG EMS EOG EPP EPT ER ERG ESR ESRD ET EV EVD FA FAST FDA FES FFI FHM FIESTA FISH FLAIR FMD FSHD FTA FTD FTLD FVC FXTAS GABA GAD GALC GBM GBS GCI GCS GCSE GCT GFR GI GIST Glut 1 GMP GPi GSS GTN GTP GWAS H&E HAART

external beam radiation therapy Epstein–Barr virus electrocardiogram/electrocardiography electroconvulsive therapy extradural hematoma electroencephalography epidermal growth factor (receptor) enzyme-inducing anticonvulsant enzyme-linked immunoelectrotransfer blot assay enzyme-linked immunosorbent assay erythema migrans Emery–Dreifuss muscular dystrophy electromyography emergency medical services electro-oculogram endplate potential enhanced physiologic tremor extended-release electroretinography erythrocyte sedimentation rate end-stage renal disease essential tremor eustachian valve extraventricular drain Friedreich’s ataxia Functional Assessment Staging Test Food and Drug Administration functional electrical stimulation fatal familial insomnia familial hemiplegic migraine fast imaging employing steady state acquisition sequence florescent in-situ hybridization fluid-attenuated inversion recovery fibromuscular dysplasia facioscapulohumeral muscular dystrophy fluorescent treponemal antibody frontotemporal dementia frontotemporal lobar degeneration forced vital capacity fragile X-associated tremor/ataxia syndrome gamma-aminobutyric acid glutamic acid decarboxylase galactocerebrosidase glioblastoma multiforme group B streptococci/Guillain–Barré syndrome glial cytoplasmic inclusion Glasgow Coma Scale generalized convulsive status epilepticus undifferentiated germinoma glomerular filtration rate gastrointestinal gastrointestinal stromal tumor glucose transporter type 1 (deficiency) guanosine monophosphate globus pallidus internus Gerstmann–Straüssler–Scheinker syndrome glyceryl trinitrate guanosine triphosphate genome-wide association study hematoxylin and eosin highly active antiretroviral therapy

Abbreviations HAM/TSP HTLV-associated myelopathy/tropical spastic paraparesis HANAC hereditary angiopathy, nephropathy, aneurysm, and muscle cramps HARP hypoprebetalipoproteinemia, acanthocytes, retinitis pigmentosa, pallidal degeneration HBO hyperbaric oxygen HCD hepatocerebral degeneration HCG human chorionic gonadotropin HCP hereditary coproporphyria HD Huntington’s disease HDL Huntington’s disease-like HE hepatic encephalopathy HELLP hemolysis, elevated liver enzymes, low-platelet count syndrome HHT hereditary hemorrhagic telangiectasia (Osler– Rendu–Weber syndrome) HHV human herpesvirus HI hypomelanosis of Ito hIBM hereditary inclusion body myopathy HIF hypoxia-inducible factor HIS head impulse sign HIT horizontal head impulse test HIV human immunodeficiency virus HLA human leukocyte antigen HMSN hereditary motor sensory neuropathy HNPP hereditary neuropathy with liability to pressure palsies HPE holoprosencephaly HR hazard ratio/heart rate HRIG human rabies immune globulin HsE Hashimoto’s encephalopathy HSP hereditary spastic paraparesis HSV herpes simplex virus HTIG human tetanus immune globulin HTLV human T-lymphotropic virus hyperPP hyperkalemic periodic paralysis hypoPP hypokalemic periodic paralysis HZV herpes zoster virus IBM inclusion body myositis IBPN immune-mediated brachial plexus neuropathy ICA internal carotid artery ICCA infantile convulsions and choreoathetosis ICH intracerebral hemorrhage ICP intracranial pressure ID intellectual disability ICU intensive care unit ICVT intracranial cerebral venous thrombosis IF intrinsic factor Ig immunoglobulin IGF insulin-like growth factor IGRA interferon-γ release assay IIH idiopathic intracranial hypertension IL interleukin ILAE International League against Epilepsy ILOCA idiopathic late-onset cerebellar ataxia IMS intermediate syndrome INH isoniazid INO internuclear ophthalmoplegia INR international normalized ratio ION ischemic optic neuropathy IOP intraocular pressure

xiii IPC IPV IRIS IVIG JCV JME KBS KD KSS LAA LAM LAST LCMV LDD LDL LEMS LFT LGG LGMD LGV LHON LITAF

intermittent pneumatic compression inactivated poliovirus vaccine immune reconstitution inflammatory syndrome intravenous immune globulin John Cunningham virus juvenile myoclonic epilepsy Klüver–Bucy syndrome Krabbe’s disease Kearns–Sayre syndrome left atrial appendage lymphangiomyomatosis local anesthetic systemic toxicity lymphocytic choriomeningitis virus Lhermitte–Duclos disease low-density lipoprotein Lambert–Eaton myasthenic syndrome liver function testing low-grade glioma limb girdle muscular dystrophy lymphogranuloma venereum Leber’s hereditary optic neuropathy lipopolysaccharide-induced tumor necrosis factor-α factor LLN lower limit of normal LMICs low-middle income countries LMN lower motor neuron LNS Lesch–Nyhan syndrome LNSS linear nevus sebaceous syndrome LMWH low-molecular-weight heparin LOC loss of consciousness LP lumbar puncture LS Leigh’s syndrome LTBI latent tuberculous infection MAO monoamine oxidase MAP mean arterial pressure MAPT microtubule-associated tau gene MBP myelin basic protein MCA middle cerebral artery MCI mild cognitive impairment MCM L-methylmalonyl-CoA mutase MCP middle cerebellar peduncle MCPH microcephaly MCTD mixed connective tissue disease MEG magnetoencephalography MELAS mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes MEP motor evoked potential MERRF myoclonic epilepsy with ragged red fibers MFAP muscle fiber action potential MFS Miller Fisher syndrome MHA-TP microhemagglutination for antibodies to Treponema pallidum MG myasthenia gravis MGMT methylguanine-DNA methyltransferase MIP maximum intensity projection/maximal inspiratory pressure MJD Machado–Joseph disease MLD metachromatic leukodystrophy MLF medial longitudinal fasciculus MMF mycophenolate mofetil MMR mumps, measles, rubella MMSE Mini-Mental State Examination

Abbreviations

xiv MND MoCA MOTSA MPR MRA MRI mRS MRSA MRV MS MSA MSLT MSM MSPNST MTHFR MTR MUP MuSK MUT MWT MZ NAAT NAc NAD NADP NAION NARP NBIA NCDs NCL NCS NCSE NDT NF NF-1 NFT NFG NFLE NGGCT NHL NIF NIH-SS NIID NMDA NMJ NMO NMS NO NPC NPDS NPH NPHP NSAIDs NSE NSP NTD O-AA OAA OCD ONH OP

motor neuron disease Montreal Cognitive Assessment multiple overlapping thin-slab acquisition multiplanar reformat magnetic resonance angiography magnetic resonance imaging modified Rankin’s score methicillin-resistant Staphylococcus aureus magnetic resonance venography multiple sclerosis multiple system atrophy Multiple Sleep Latency Test men who have sex with men malignant peripheral nerve sheath tumor methylenetetrahydrofolate reductase methionine synthase motor unit action potential muscle-specific receptor tyrosine kinase methylmalonyl-CoA mutase maintenance of wakefulness test monozygotic/marginal zone nucleic acid amplification test neuroacanthocytosis nicotinamide adenine dinucleotide nicotinamide adenine dinucleotide phosphate nonarteritic anterior ischemic optic neuropathy neurogenic weakness with ataxia and retinitis pigmentosa neurodegeneration with brain iron accumulation noncommunicable diseases neuronal ceroid lipofuscinosis nerve conduction studies nonconvulsive status epilepticus neurodevelopmental therapy neuroferritinopathy neurofibromatosis 1 neurofibrillary tangle nerve growth factor nocturnal frontal lobe epilepsy nongerminomatous germ cell tumor non–Hodgkin’s lymphoma negative inspiratory pressure National Institutes of Health Stroke Scale neuronal intranuclear inclusion disease N-methyl-d-aspartate neuromuscular junction neuromyelitis optica neuroleptic malignant syndrome nitrous oxide Niemann–Pick type C National Poison Data System normal pressure hydrocephalus nephronophthisis nonsteroidal anti-inflammatory drugs neuron-specific enolase neurotoxic shellfish poisoning neural tube defect organic amino aciduria oculomotor apraxia obsessive compulsive disorder optic nerve head opening pressure/organophosphate

OPCA olivopontocerebellar atrophy OPIDP organophosphate-induced delayed polyneuropathy OPV oral poliovirus vaccine OR odds ratio OSA obstructive sleep apnea OTR ocular tilt reaction PA pernicious anemia PACI partial anterior circulation infarct PACS partial anterior circulation syndrome PAF pure autonomic failure PAM potassium-aggravated myotonia PAS para-aminosalicylic acid/periodic acid–Schiff PC phase contrast PCD paraneoplastic cerebellar degeneration PCNSL primary CNS lymphoma PCom posterior communicating artery PCR polymerase chain reaction PCV vincristine PD Parkinson’s disease PDD Parkinson’s disease dementia PDGF platelet-derived growth factor PDHC pyruvate dehydrogenase complex PDW proton density weighted PE plasma exchange/pancreatic encephalopathy PEG percutaneous endoscopic gastrostomy PEM paraneoplastic encephalomyelitis PEO progressive external ophthalmoplegia PET positron emission tomography PFK phosphofructokinase PFO patent foramen ovale PHTS PTEN hamartoma tumor syndrome PION posterior ischemic optic neuropathy Pi-TON posterior indirect traumatic optic neuropathy PKAN pantothenate kinase–associated neurodegeneration PLED periodic lateralized epileptiform discharge PLEX plasmapheresis PLM periodic leg movement PLMD periodic leg movement disorder PMA progressive myoclonic ataxia PME progressive myoclonic epilepsy PMG polymicrogyria PML progressive multifocal leukoencephalopathy PMN polymorphonuclear PMzD Pelizaeus–Merzbacher disease PNET primitive neuroectodermal tumor PNFA progressive nonfluent aphasia PNH-PMG PMG associated with nodular heterotopia POCI posterior circulation infarct POCS posterior circulation syndrome POEMS polyneuropathy, organomegaly, endocrinopathies, M-protein, skin changes including thickening and hyperpigmentation, clubbing of the fingers POST positive occipital sharp transients of sleep POVL postoperative visual loss PP preplate zone/perfusion pressure PPA primary progressive aphasia PPRF paramedian pontine reticular formation PRES posterior reversible encephalopathy syndrome PRG pontine respiratory group PrP prion protein PSC primary stroke center PSN paraneoplastic sensory neuropathy

Abbreviations PSP

progressive supranuclear palsy/paralytic shellfish poisoning PSV peak systolic velocity PSWC periodic sharp wave complex PTH parathyroid hormone PTSD posttraumatic stress disorder PWS Prader–Willi syndrome PWI perfusion-weighted imaging PXA pleomorphic xanthoastrocytoma PXE pseudoxanthoma elasticum QTL quantitative trait loci RBC red blood cell RCCVC Regional Cardiocerebrovascular Center RCT randomized controlled trial RCVS reversible cerebral vasoconstriction syndrome RDA recommended daily allowance RDI respiratory disturbance index REM rapid eye movement RERA respiratory event–related arousal RF resistance to flow rFVIIa recombinant activated factor VII RLS right-to-left shunt/restless legs syndrome RMSF Rocky Mountain spotted fever RNA ribonucleic acid RNS repetitive nerve stimulation ROM range-of-motion RPR rapid plasma reagin RR risk ratio/relative risk RRR relative risk reduction RTK receptor tyrosine kinase (r)-tPA (recombinant) tissue plasminogen activator SAH subarachnoid hemorrhage SAM S-adenosylmethionine SBP systolic blood pressure SC Sydenham’s chorea SCA spinocerebellar ataxia/sex chromosome aneuploidy SCC semicircular canal SCD subacute combined degeneration SCI spinal cord injury SCLC small-cell lung carcinoma SCN suprachiasmatic nucleus ScvO2 central venous oxygen saturation SD semantic dementia SDB sleep-related breathing disorder SDS Shy–Drager syndrome SE status epilepticus SEGA subependymal giant cell astrocytoma SFEMG single-fiber electromyography SGCT subependymal giant cell tumor SIADH syndrome of inappropriate antidiuretic hormone SIBM sporadic inclusion body myositis SIS second impact syndrome SISCOM subtraction ictal SPECT coregistered to MRI SLE systemic lupus erythematosus SMA spinal muscular atrophy SMN survival of motor neuron SNAP sensory nerve action potential SND striatonigral degeneration SNP single-nucleotide polymorphisms SOD septo-optic dysplasia SOREMP sleep-onset REM period SPECT single-photon emission tomography

xv SR SS SSCM SSCP SSEP SSPE SSRI SSS SUDEP SVV SVZ SW SWI TA TAB TACI TACS TAND

system reference serotonin syndrome split spinal cord malformation single-stranded conformational polymorphism somatosensory evoked potential subacute sclerosing panencephalitis selective serotonin reuptake inhibitor superior sagittal sinus/Scandinavian Stroke Scale sudden unexplained death in epilepsy subjective visual vertical subventricular zone Sturge–Weber syndrome susceptibility-weighted imaging temporal arteritis temporal artery biopsy total anterior circulation infarct total anterior circulation syndrome tuberous sclerosis–associated neuropsychiatric disorder TAO thyroid-associated ophthalmopathy TB tuberculosis TBI traumatic brain injury TCD transcranial Doppler ultrasonography TCS tethered cord syndrome TGF transforming growth factor THB tetrahydrobiopterin TIA transient ischemic attack TK transketolase TMJ temporomandibular joint TMP–SMX trimethoprim–sulfamethoxazole TN trigeminal neuralgia TNF tumor necrosis factor TOAST Trial of Org 10172 in Acute Stroke Treatment TOE transesophageal echocardiography TOF time-of-flight TPHA Treponema pallidum particle agglutination assay TS Tourette’s syndrome TSC tuberous sclerosis complex TSE turbo spin echo/transmissible spongiform encephalopathy TSH thyroid-stimulating hormone TST thermoregulatory sweat test TTE transthoracic echocardiography TTR time in therapeutic range/transthyretin TTX tetrodotoxin UBO unidentified bright object UE uremic encephalopathy UFH unfractionated heparin ULN upper limit of normal UMN upper motor neuron UPP unilateral perisylvian PMG VA visual acuity VaD vascular dementia VAPP vaccine-associated paralytic poliomyelitis VLDL very low-density lipoprotein VDRL Venereal Disease Research Laboratory V-EEG video electroencephalography VEGF vascular endothelial growth factor VEMP vestibular evoked potential VEP visual evoked potential VF visual field VGCC voltage-gated calcium channel

Abbreviations

xvi VHL VKA VLCFA VLM VNG VNS VOR VP VPM VR VSGP VSR VTE

von Hippel–Lindau disease vitamin K antagonist very long-chain fatty acid ventrolateral medulla videonystagmography vagal nerve stimulation vestibulo-ocular reflex vascular parkinsonism/variegate porphyria ventral posteromedial volume rendered vertical supranuclear gaze palsy vestibulospinal reflex venous thromboembolism

vWF VWFCP VZ VZV WBC WBRT WD WES WHO WM WNV XLAG XP

von Willebrand’s factor von Willebrand’s factor–cleaving protease ventricular zone varicella-zoster virus white blood cell whole brain radiation therapy Wilson’s disease whole-exome sequencing World Health Organization white matter West Nile virus X-linked with abnormal genitalia xeroderma pigmentosum

1

NEUROLOGIC DIAGNOSIS

John Dunne, Robert Edis

Contents Neurologic Examination and CSF Analysis......................................................................................................................................................................3 Introduction............................................................................................................................................................................................................................3 The Diagnostic Process in Neurology................................................................................................................................................................................4 Diagnostic questions.......................................................................................................................................................................................................4 Important elements of the consultation process.................................................................................................................................................4 How to improve communication............................................................................................................................................................................4 The structure of a neurologic history...........................................................................................................................................................................5 Presenting problem/complaint................................................................................................................................................................................5 Functional neurologic disorders..............................................................................................................................................................................5 Concluding the history..............................................................................................................................................................................................7 Neurologic Examination.......................................................................................................................................................................................................7 First impressions..............................................................................................................................................................................................................8 Mental State (Higher Mental Function)............................................................................................................................................................................8 Screening tests............................................................................................................................................................................................................8 Formal tests.................................................................................................................................................................................................................8 Bedside cognitive testing..........................................................................................................................................................................................9 Frontal lobe functions...................................................................................................................................................................................................10 Attention and behavior abnormality....................................................................................................................................................................10 Verbal fluency............................................................................................................................................................................................................10 Abstraction................................................................................................................................................................................................................10 Response inhibition and set shifting....................................................................................................................................................................10 Frontal release signs.................................................................................................................................................................................................10 Paratonia (“gegenhalten”)........................................................................................................................................................................................10 Right hemisphere function...........................................................................................................................................................................................10 Sensory visual and tactile neglect.........................................................................................................................................................................10 Hemispatial neglect.................................................................................................................................................................................................11 Dressing dyspraxia...................................................................................................................................................................................................11 Facial recognition (prosopagnosia).......................................................................................................................................................................11 Dominant left hemisphere function...........................................................................................................................................................................11 In right-handed patients.........................................................................................................................................................................................11 Language....................................................................................................................................................................................................................11 Praxis...........................................................................................................................................................................................................................11 Calculation.................................................................................................................................................................................................................12 Cranial nerves.................................................................................................................................................................................................................12 Screening tests..........................................................................................................................................................................................................12 Formal tests.....................................................................................................................................................................................................................12 Nerve I (olfactory nerve).........................................................................................................................................................................................12 Nerve II (optic nerve)..............................................................................................................................................................................................12 Nerves III, IV, and VI (oculomotor, trochlear, and abducens nerves)...........................................................................................................16 Testing movements of both eyes (versions)........................................................................................................................................................17 Nystagmus and other ocular oscillations............................................................................................................................................................18 Nerve V (trigeminal nerve)....................................................................................................................................................................................18 Nerve VII (facial nerve)...........................................................................................................................................................................................19 Nerve VIII (auditory and vestibular nerve).........................................................................................................................................................19 Nerves IX and X (glossopharyngeal and vagus nerves)...................................................................................................................................19 Nerve XI (accessory nerve)....................................................................................................................................................................................19 Nerve XII (hypoglossal nerve)...............................................................................................................................................................................20 Motor system..................................................................................................................................................................................................................20 Screening tests................................................................................................................................................................................................................20 Posture of outstretched hands...............................................................................................................................................................................20

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Hankey’s Clinical Neurology

Rapid finger and foot tapping................................................................................................................................................................................20 The forearm and finger-rolling tests.....................................................................................................................................................................20 Power..........................................................................................................................................................................................................................20 Tone.............................................................................................................................................................................................................................20 Formal tests.....................................................................................................................................................................................................................21 Power..........................................................................................................................................................................................................................21 Coordination...................................................................................................................................................................................................................21 Screening tests..........................................................................................................................................................................................................21 Formal tests...............................................................................................................................................................................................................22 Deep tendon reflexes.....................................................................................................................................................................................................22 Screening tests..........................................................................................................................................................................................................22 Formal tests...............................................................................................................................................................................................................22 Sensation..........................................................................................................................................................................................................................23 Screening tests................................................................................................................................................................................................................23 Formal tests.....................................................................................................................................................................................................................23 Proprioception..........................................................................................................................................................................................................23 Vibration sense..........................................................................................................................................................................................................23 Cortical-based discriminative sensation.............................................................................................................................................................24 Stance and Gait...............................................................................................................................................................................................................24 Screening tests................................................................................................................................................................................................................24 Formal tests.....................................................................................................................................................................................................................24 Interpretation of clinical signs.....................................................................................................................................................................................24 Concluding the examination........................................................................................................................................................................................25 A particular diagnosis seems certain....................................................................................................................................................................25 There are several possible diagnoses....................................................................................................................................................................25 You have no idea what is wrong............................................................................................................................................................................25 Lumbar Puncture and Cerebral Spinal Fluid Examination.........................................................................................................................................25 Indications.................................................................................................................................................................................................................26 Contraindications.....................................................................................................................................................................................................26 Technique...................................................................................................................................................................................................................26 Problems.....................................................................................................................................................................................................................27 Complications...........................................................................................................................................................................................................28 Assessing the CSF.....................................................................................................................................................................................................28 References..............................................................................................................................................................................................................................29 Neurophysiologic Examination.........................................................................................................................................................................................30 Electroencephalography.....................................................................................................................................................................................................30 Technique........................................................................................................................................................................................................................30 Normal EEG recordings................................................................................................................................................................................................32 Awake..........................................................................................................................................................................................................................32 Drowsiness and sleep...............................................................................................................................................................................................34 Abnormal EEG recordings...........................................................................................................................................................................................34 Absent brain waves..................................................................................................................................................................................................34 Slow waves (delta or theta).....................................................................................................................................................................................36 Epileptiform activity................................................................................................................................................................................................37 Role...................................................................................................................................................................................................................................38 Interpretation..................................................................................................................................................................................................................39 Nerve Conduction Studies.................................................................................................................................................................................................40 Technique........................................................................................................................................................................................................................40 Motor NCS......................................................................................................................................................................................................................40 Sensory NCS...................................................................................................................................................................................................................41 Pathologies (neuropathology and neurophysiology)..............................................................................................................................................42 Wallerian degeneration...........................................................................................................................................................................................42 Axonal degeneration................................................................................................................................................................................................42 Segmental demyelination........................................................................................................................................................................................42 Neuronopathy or primary nerve cell degeneration...........................................................................................................................................42

Neurologic Diagnosis

3

Late responses.................................................................................................................................................................................................................42 F-wave.........................................................................................................................................................................................................................42 H-reflex.......................................................................................................................................................................................................................43 The long loop reflex.................................................................................................................................................................................................43 Repetitive stimulation studies.....................................................................................................................................................................................43 Electromyography................................................................................................................................................................................................................44 Normal muscle activity.................................................................................................................................................................................................44 Insertional activity....................................................................................................................................................................................................44 At rest with no needle movement (spontaneous)..............................................................................................................................................44 Muscle activation.....................................................................................................................................................................................................44 Abnormal muscle activity.............................................................................................................................................................................................45 Insertional activity....................................................................................................................................................................................................45 At rest (spontaneous)..............................................................................................................................................................................................45 Voluntary muscle activation........................................................................................................................................................................................46 Upper motor neuron lesion....................................................................................................................................................................................46 Lower motor neuron lesion....................................................................................................................................................................................46 Neuromuscular junction disease...........................................................................................................................................................................47 Muscle disease (myopathy)....................................................................................................................................................................................47 Movement disorders................................................................................................................................................................................................47 Role...................................................................................................................................................................................................................................47 Interpretation..................................................................................................................................................................................................................48 Evoked Potentials.................................................................................................................................................................................................................48 Visual evoked potentials...............................................................................................................................................................................................48 Brainstem auditory evoked potentials.......................................................................................................................................................................49 Somatosensory evoked potentials..............................................................................................................................................................................49 Motor evoked potentials...............................................................................................................................................................................................50 Bereitschaftspotential (readiness potential).............................................................................................................................................................51 Role...................................................................................................................................................................................................................................51 References..............................................................................................................................................................................................................................51

NEUROLOGIC EXAMINATION AND CSF ANALYSIS Robert Edis

INTRODUCTION Neurologic diagnosis is now made with greater certainty, facilitated by continually evolving neurodiagnostic tests, especially in imaging, but also in immunology, neurophysiology, and molecular genetics. A reliance on neuroimaging in particular, however, has led to a devaluation and a loss of clinical skills necessary for routine diagnosis in clinical neurology. This realization has created a renewed interest in how to teach a neurologic examination more effectively in a rapidly changing clinical scene fit for the 21st century.1,2 There has been a return to demonstrating the utility of the traditional key clinical skills of the neurologic history, examination, localization, and differential diagnosis at the patient’s bedside. There is also a need for these skills to be learned by the trainee over time by repetition and observed patient presentations under supervision and constructive feedback. Learning from diverse medical mentors, including allied health practitioners and nurses, is integral to a neurologic education, particularly as physicians and neurologists are now often members of multidisciplinary care teams.

Core neurologic curricula have been updated, and the traditional examination techniques have been subject to critique to be more evidence based. 3 Studying compact expert didactic texts remains necessary to refresh one’s knowledge of neurologic disorders, neurologic examination techniques, and the relevant basic neuroanatomy needed for diagnostic localization. These texts are now also in digital format and include videos of abnormal clinical scenarios (see Neurologic Examination section, references 1–4). Internet teaching sites, especially on YouTube, demonstrate examination techniques and show examples of neurologic conditions when “once seen, are easier to recognize a second time around” (e.g. unusual clinical signs, especially in neuro-ophthalmology).4, 5 The roles of Google and Google Scholar as diagnostic tools are now routinely recognized; they can be both educational and helpful in formulating a differential diagnosis. Using online medical literature search engines such as Cochrane Library and PubMed permits rapid access to relevant knowledge and evidence-based guidelines and protocols. A mobile phone video can play a vital diagnostic role, for instance, when an episode of altered behavior or loss of consciousness, other paroxysmal event, or movement disorder is documented by an observer. Photos and videos (with the patient’s signed permission) of clinical scenarios can help in diagnostic discussions with colleagues or in teaching students.6 Tele-neurology, where the neurologist takes a history and may be able to watch an examination by video link, is now being incorporated into outpatient clinics because of increasing demands on

Hankey’s Clinical Neurology

4 resources and as a distance community outreach. This requires a modified approach to the neurologic consultation.7 Requesting appropriate neurophysiology and neuroimaging tests requires a clear diagnostic question to be answered, knowledge of whether the patient can co-operate, and the limits of each modality to address the particular question posed (see further in Neurophysiologic Examination section and Chapter 2 for details about these tests).

TIP • Despite these technological advances, the clinical history remains the most important and productive part of the neurologic assessment as it generates the diagnostic possibilities and directs the examination, any investigations, and information search.

THE DIAGNOSTIC PROCESS IN NEUROLOGY Depending on the presentation, the process is based on two different pathways: • Pattern recognition: this refers to recognizing a pattern of symptoms and signs, which have meaning (such as when diagnosing trigeminal neuralgia, carpal tunnel syndrome, and Parkinson’s disease) based on “book knowledge” or previous clinical exposure. It is intuitively used by experts utilizing the brain’s “fast-thinking” diagnostic shortcut system based on knowledge from a wide experience and therefore more difficult for the inexperienced trainee. In order to deploy this technique successfully, one has to have sufficient clinical experience and enough basic knowledge of the more common neurologic conditions. Goal-orientated questioning is used to gather information in order to distinguish between various diagnostic possibilities, which arise during history taking to aid in localization and in syndromic diagnosis (e.g. which headache syndrome fits best in someone presenting with a headache problem). • Hypothetico-deductive system: clinical reasoning in unfamiliar conditions depends on early hypothesis formation from clues in the history, which may then be modified as new data are collected from the history, examination, and any targeted investigations (using the brain’s “slowthinking” diagnostic system). In the situation of an evolving organic neurologic disorder, the history, repeated examinations, and changing signs lead to an anatomical localization and a differential diagnosis of pathologies and causes, which may then need new targeted investigations to clarify the diagnosis (e.g. a total spinal magnetic resonance imaging (MRI) with gadolinium in an ascending spinal cord syndrome).

Diagnostic questions

There are six basic diagnostic questions to be answered: 1. Is there a neurologic problem present? This requires good internal medicine, psychiatric, and neurologic knowledge.

2. Where is the problem? This requires knowledge of basic clinical anatomy and physiology. • Localization: focal, multifocal, diffuse. • Cortical (supratentorial). • Brainstem (infratentorial). • Spinal cord (extrinsic or intrinsic). • Peripheral (nerve, neuromuscular junction, and muscle). • More than one level. 3. What has caused the problem? • Factors: hereditary/genetic, congenital, infective, inflammatory, autoimmune, mechanical, traumatic, degenerative, neoplastic, vascular, metabolic, toxic, paroxysmal, social/psychiatric. 4. How bad is the problem? This needs an appreciation of how the patient is functioning at home and at work. 5. What is the likely outcome? The prognosis will influence investigation and treatment. 6. What can be done about it? Treatment and management options.

TIP • Answers to the six basic diagnostic questions must be actively sought throughout the history and examination, with early, broad hypothesis generation tested and refined by goal-directed questioning, while simultaneously considering the consequences for the patient.

Important elements of the consultation process

• Be friendly throughout, and after introducing yourself and making sure that the patient knows your role, spend some minutes in general conversation to establish rapport. Use humor when possible and appropriate throughout. • If there is a problem in communication due to a language difference with the patient, then try to book an official interpreter to be present or contact a telephone interpreter to help with the history taking and examination (this is preferable to asking a relative to translate). • Clarify with the patient what he or she expects from the consultation, and this is in accord with what you can deliver, as sometimes inappropriate referral or expectations need to be addressed early. • Ask whether the symptoms are better, worse, or unchanged since the referral, to bring yourself up to date. • A contribution from family members or friends is essential if a presentation suggests dementia, altered behavior, or loss of consciousness. • If necessary, at the time of the interview, telephone to clarify information or to get a witness description. • Write down brief notes (especially verbatim statements) and time lines, as well as diagnostic, investigation, and treatment thoughts as they come to mind.

How to improve communication

Patients are now more informed and demanding, armed with ideas from family, friends, alternative health practitioners, and the Internet. To use the consultation as a positive intervention in its own right requires honest open dialogue with the patient and family. This patient-centered approach means that rather than

Neurologic Diagnosis “taking the history” we want to “build a history” and a joint understanding with the patient through an interactive conversation. Communication skills need to be learned and practiced and they include core skills of (a) appropriate questioning, (b) active listening, (c) facilitating, (d) keeping the patient relevant, and (e) summarizing.8

Questioning

• Use open questions as often as possible, particularly at the beginning of an interview. • For example, “Begin from when you were last perfectly well.” • “Tell me what is worrying you the most.” “Tell me about your headaches.” • Then when necessary, obtain specific information by using focused and goal-directed questions as you formulate hypotheses. • Use probing questions to clarify, for example, “What do you mean by dizziness?” and accuracy of information, for example, “What were you doing exactly at the time your symptoms came on?” “What was the very first thing you noticed?” and “Then what happened next?” • Avoid asking several questions at once or giving multiple options.

Active listening

• Allow the patient to talk about the presenting problem(s) without interruptions (usually takes less than 2 minutes). • Make empathic statements and show sympathy when appropriate, for example, “That must have been difficult for you,” to keep the flow of history going. • Permit pauses and silences to encourage the patient to reveal more.

Facilitating

Encourage more information with verbal (“Tell me more”; “Go on”) and physical (head nodding) cues.

Relevance

It is important to use time effectively and this may involve redirecting the interview at certain times in the history.

Summarizing

Paraphrasing the story back to the patient is helpful at times during and at the end of the consultation. This confirms that you have been listening and allows the patient to agree, clarify, or add further information.

The structure of a neurologic history

Practicing a systematic approach to the interview makes sure that all relevant information has been gathered. Flexibility in how this information is gathered, and the importance of some aspects over others in any one patient, comes with experience. Often some elements of the history cannot be raised during the consultation because of time constraints, new diagnostic thoughts, or because it may be best to seek sensitive information away from an accompanying person.

Presenting problem/complaint

The chief problem(s) should be clear from the referral but must be confirmed with the patient by asking, depending on the context: “I have read the referral from your doctor, but can you tell me in

5 your own words what it is that is most troubling you”; or “Tell me the story of your problem”; or “What is it you hope I will be able to do for you today?”

TIP • It is often helpful early in the consultation to get a sense of the patient and his or her world by briefly enquiring about work, where they live, daily activities, and family responsibilities to provide a context for the symptoms. There may be one or a number of symptoms (“problem list”) that need to be analyzed. For each relevant symptom, find out the circumstances, timing, content, and its relationship to other symptoms through goal-directed questioning related to sorting through your early diagnostic possibilities. • Onset such as “When exactly did it begin?” “What were you doing at the time?” and “Did it begin suddenly/gradually and over what time period?” If long-standing, “Why are you presenting now?” • Constant or intermittent such as “How long does it last for?” “Any particular time of day?” “Is it the same each time or does it vary in content or intensity?” and “How often does it occur?” • Triggering factors such as cough or sneeze-induced limb pain, and paresthesia with radiculopathy; exercise or overheating causing visual blurring in optic neuropathy; situational syncope due to prolonged standing, pain, defecation, micturition, coughing, or swallowing. • Relieving/exacerbating factors such as shaking the hand/ driving car in carpal tunnel syndrome and hand on the head relieving lower cervical nerve root compression pain. • Any associated symptoms such as pallor, sweating, nausea, postictal confusion, and tongue biting when evaluating syncope versus seizure, one of the most common presentations to neurologists where a detailed history in evaluating convulsive syncope is pivotal in making the diagnosis.9 • Timing of the onset and evolution of the problem is often a clue to a cause: • Intermittent or episodic symptoms with full recovery can suggest migraine, syncope, epilepsy, transient ischemic attacks (TIAs), myasthenia gravis, and periodic paralysis. • A fluctuating and chronic course over years may point to multiple sclerosis (MS), autoimmune disorder, or functional symptoms. • A chronic progressive history points to an inflammatory or neurodegenerative disorder. • Acute or subacute progressive course may indicate a neoplastic, inflammatory, paraneoplastic, or infective problem. • Acute-onset single event with recovery may suggest an epileptic, inflammatory, or vascular cause.

Functional neurologic disorders

Functional disorders of the nervous system are common and have been referred to as “the new normal,” as studies show about 30% of new neurology outpatients have main presenting symptoms that are only “somewhat or not at all explained” by disease.

Hankey’s Clinical Neurology

6 This includes patients with a known neurologic disease but with a “functional overlay.”10, 11 About 15% have a primary functional/psychological diagnosis (including pain and fatigue unexplained by disease). About 5% have dissociative seizures, weakness, sensory symptoms, or movement disorders, which are thought by the neurologist to be functional (sometimes called “conversion symptoms”). Diagnosis is based on the two hallmark features of inconsistency of signs and incongruity with any recognized neurologic disease pattern and should never be based alone on any evidence of anxiety or high stress levels that may be present. Investigation and management of functional disorders are within the domain of neurology (although with help in refractory cases from an informed consultation-liaison psychologist/ psychiatrist or a dedicated multidisciplinary team if appropriate and available).

TIP • In diagnostic hypothesis formation, mentally refers to useful criteria sets (syndromes) in your own mind that characterize different conditions (e.g. carpal tunnel syndrome vs. cervical radiculopathy, seizure vs. syncope, trigeminal neuralgia vs. atypical facial pain, functional vs. organic symptoms, different headache and epilepsy syndromes).

Review of body systems

The purpose of this review is to look for further evidence to test a hypothesis already generated or to elicit information that may be overlooked by the patient. Questions briefly probe “whether they have any other health problems,” followed by more specific questions relevant to your current diagnostic hypotheses such as any appetite or weight change; sleep; chest tightness, palpitations, shortness of breath if suspecting chronic hyperventilation or amplification of normal bodily sensations; sphincter function; skin lesions (Figure 1.1); the musculoskeletal system; exercise patterns; and mood as appropriate.

Smoking and alcohol intake

Record the patient’s smoking, alcohol, and other drug habits, and any attempt to modify these habits. Certain clinical presentations raise “red flag” enquiries into drug use (such as an episode of rhabdomyolysis with suspected methamphetamine or heroin use or an ataxic spinal cord syndrome with a Lhermitte’s phenomenon due to chronic nitrous oxide recreational use in “nanging”).

Medications

Record current and recent past medication intake. This is particularly important in patients with epilepsy and headache and should include dose and length of use, side effects, and the patient’s attitude to medication. Patients should be specifically asked about the use of oral contraceptives, complementary and alternative medicines, nutritional supplements, and overthe-counter drugs. These are commonly taken in conjunction with conventional medication and may be relevant to the patient’s symptoms or to a proposed treatment (e.g. direct toxicity from prolonged high-dose vitamin B6 supplements causing a sensory peripheral neuropathy).

Past medical history

Enquiry into previous illness, operations, accidents, and admissions to hospital may give information relevant to the current illness such as history of diabetes mellitus in a patient with peripheral neuropathy, multiple admissions with unexplained illnesses suggesting somatization, and previous skin cancer surgery with a possible incomplete skin cancer removal (see Figure 1.1).

Family history

An inquiry regarding the current family members’ state of health or presence of relevant disease or cause of death may need to be made. Patients may be suffering from an unsuspected genetic disorder (e.g. hereditary spastic paraplegia where a family history of a gait disorder may have been ascribed wrongly to a previous motor vehicle accident injury or to arthritis) or the patient’s concerns may relate to the experience of others in the family (e.g. with dementia or brain tumor). An ever-increasing number of neurologic disorders are being recognized as having genetic associations such as a C9orf gene mutation–positive motor neuron disease patient having a relative with a frontotemporal dementia (FTD) as part of a clinical spectrum of this gene’s expression.

Social history

FIGURE 1.1  Cranial nerve VII nerve palsy due to local spread of a basal cell carcinoma.

Details of the domestic, social, and work background including the patient’s relationship with family, friends, employer, and workmates; attitude to work; when they last took holidays; hobbies; living arrangements; financial state; and sexual preference (especially if syphilis or a human immunodeficiency virus [HIV]associated syndrome is in the differential diagnosis) may be keys to understanding the patient’s presentation. It is often helpful to run through the course of a typical day with the patient. This may also give an insight into unrecognized or denied stress factors, which can relate in particular to functional disorders, chronic tension-type headache, dizziness, and relapse of seizures. Mononeuropathies could be due to hobbies or daily activities that put nerves at risk of pressure or stretch, such as repeated leaning on an elbow while at the computer for prolonged gaming causing a compressive ulnar neuropathy. Neurologic patients often have significant disability, and it is important to know the impact of the illness on other family members.

Neurologic Diagnosis

7

Concluding the history

By the end of the history, make sure you also have the answers to the questions: “What do you think is causing your problem?” and “Is there anything else you would like to discuss?” to make sure patients have had a chance to tell you everything they wanted to say. Answers to these questions may also reveal anxieties and misapprehensions that need to be addressed (e.g. an inappropriate worry about having Lyme disease or MS). You should now most often have a working diagnosis with perhaps several alternatives. It is appropriate to briefly (and broadly, without committing yourself, if uncertain) discuss initial diagnostic thoughts with the patient and what you would now like to examine.

TIP • Not obtaining a sufficient and detailed history is the most common cause of failure to make the correct diagnosis. If time is short, skimp on the examination rather than the history.

NEUROLOGIC EXAMINATION The bedside neurologic examination is a powerful portable lowcost diagnostic tool. It is important to have your own set of familiar instruments for examinations in a small carry bag including a good reflex hammer, ophthalmoscope and penlight (both with well-charged batteries!), and a reading type test card or book; a 128-Hz tuning fork; cotton wool; and items to test language vision and stereognosis (e.g. the “Cookie Thief” picture, coins, key, paper clip). The degree to which the patient needs to disrobe depends on the type of clinical problem being addressed such as arms exposed only, if a probable carpal tunnel syndrome and limbs and trunk fully exposed to underwear only, if looking for fasciculations and muscle wasting in a possible case of motor neuron disease. The specific examination techniques and their interpretation of a patient in stupor or coma is addressed in Chapter 4. A “focused neurologic examination” is designed to look for abnormal signs relevant to a diagnostic hypothesis generated from the history. For example, in a case of an acute ascending paralysis with reduced limb reflexes, attention will be paid to the plantar responses, the pattern of any sensory loss in the limbs and trunk, and weakness including whether there is mild facial weakness, in considering a differential diagnosis of an acute ascending neuropathy of Guillain–Barré syndrome or a spinal cord acute myelitis. A “screening neurologic examination” is employed when examining a patient in whom it is not normally expected to find any neurologic abnormalities and is designed to detect deficits that may not be apparent to the patient, such as mild muscle weakness, pyramidal/extrapyramidal motor signs, gait abnormality, visual field loss, pupillary change, papilledema, cortical sensory loss, and reflex changes (e.g. fundoscopy in all headache patients to detect papilledema in the rare case of idiopathic intracranial hypertension (IIH) mimicking a migraine history). Incorporate a relevant general examination into the sequence of the neurologic examination (e.g. taking pulse and blood pressure in a patient with stroke or headache to detect an arrhythmia or significant hypertension; examining the fingernails for Mee’s white lines across the fingernail due to episodes of arsenic or thallium poisoning as an “unexpected” cause of an

FIGURE 1.2  Mee’s lines in fingernails of a case of a peripheral neuropathy as part of an enigmatic “multisystem disease” but actually due to episodes of acute arsenic poisoning. enigmatic peripheral neuropathy (Figure 1.2); lying and standing blood pressure to detect postural hypotension in syncope, and in parkinsonian syndromes on treatment and as a clue to a multisystem atrophy where postural hypotension due to autonomic system involvement may be asymptomatic).

TIP • Perform an examination focused on functions relevant to the presenting problem, both for diagnosis and because a careful examination helps the therapeutic relationship. It also continually reinforces an appreciation of the range of normal responses. If you do not perform an examination, explain why you do not think it is necessary. In certain diagnostic contexts, look at the skin for a rash (Figure 1.3) or markers of associated neurologic disease

FIGURE 1.3  A left lumbar nerve root (motor and sensory) herpes zoster, presenting with a painful quadriceps weakness and a subtle paraspinal rash.

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FIGURE 1.4  Facial skin angiofibromas associated with tuberous sclerosis. (e.g. tuberous sclerosis and seizures [Figure 1.4]) and in older patients with recent-onset headache for temporal artery tenderness and pulsation to detect temporal arteritis. Auscultate the heart, neck, and orbits for bruits if there is pulsatile tinnitus, a TIA, or stroke. Examination of range of joint motion to detect a restricted arthritic movement at the wrist in a carpal tunnel syndrome or in elbow movement in an ulnar neuropathy can point to contributing factors. Record the patient’s weight at the end of the examination when possible, as this may be relevant as a reference in the future medical history of the patient. The learning of any physical examination involves both the content knowledge (how to perform it) and reasoning skills (why it is performed and what the findings mean). A systematic examination has evolved that demonstrates how to evaluate mental status, cranial nerves, motor function, reflexes, coordination, sensation, and gait. Although there are traditional clinical methods for examining the nervous system, every physician/neurologist develops his or her own style influenced by mentors, clinical experience, and from texts.1–4

First impressions

Some diagnoses are apparent immediately by pattern recognition (e.g. parkinsonism, hypothyroidism, hemifacial spasm, essential head or voice tremor, chorea, a patient sitting crossed-leg in the waiting room or during the history taking presenting with a foot drop due to compression of the common peroneal nerve at the head of fibula). Behavioral hyperventilation may be evident with the patient sighing frequently during the history and is often a clue to the cause of his or her symptoms, such as chronic fatigue or nonspecific dizziness. Looking frequently to the spouse to answer questions points to a cognitive problem.

MENTAL STATE (HIGHER MENTAL FUNCTION) Screening tests

If the presenting complaint is of a worrying change in memory, language or behavior, and personality, then further evaluation requires a cognitive screening test as well as interviewing someone familiar with the patient for corroborative evidence. Observations can be made during the history and examination about the patient’s: • Attention and cooperation. • Language and memory functions reflected by responses to questions. • Behavior and awareness of the consultation purpose and context.

There are now many brief general cognitive screening tests that provide an estimate of overall cognitive function and help identify patients who require a more detailed evaluation.5 The Mini-Mental State Examination (MMSE) is the most established test but is heavily biased toward orientation/attention and memory (70% of available points). It is insensitive to mild cognitive disorders and to deficits found in some dementias such as FTD. It is now also subject to copyright. For these reasons, it has been argued that it is time for it to be replaced by more modern comprehensive tests. The Montreal Cognitive Assessment (MoCA) is recommended as it also tests language, executive function, and visuospatial abilities as well as attention and memory. It is more sensitive in detecting mild cognitive impairment through a cutoff score of 26/30 with a sensitivity of ∼90% and specificity of 87% It has been translated into and validated in many different languages, and the administration time is comparable to that of the MMSE. The MoCA is free to use, and there are Internet-based guidelines for administration/scoring and a YouTube instruction video (Table 1.1).

Formal tests

If the presenting complaint of loss of memory, language errors, behavioral change, or hallucinations are confirmed by a relative and an abnormal screening cognitive test, then do more detailed higher function testing.

TIP • The purpose of the testing must be explained to patients to get them to participate; administer in an encouraging nonjudgmental manner.

• The most useful comprehensive sensitive cognitive battery is the Addenbrooke’s Cognitive Examination version 111 (ACE111), as it is a detailed cognitive screening test in wide clinical usage taking ∼20 minutes to administer. It is scored out of 100 points and a cutoff of 2 mL

Comments + Simultaneous serum sample Larger volumes → ↑ yield 10 mL or more to detect malignant cells Low yield for smaller volumes + Simultaneous serum sample + Simultaneous serum sample + Simultaneous serum sample

PCR: polymerase chain reaction; VDRL: Venereal Disease Research Laboratory.

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• Herniation of the medial temporal lobe through the tentorial opening (transtentorial herniation) or of the medulla through the foramen magnum (coning) leads to medullary compression and death. This rare tragic complication can be avoided by never doing an LP if there is evidence for raised ICP with focal signs, or obstructed CSF flow or brain shift laterally on CT scan. The decrease in pressure in the spinal canal by removal of CSF in these situations will cause downward brain movement with herniation. On the other hand, if there is diffusely raised ICP with free flow of CSF through all parts of the intracranial and spinal CSF compartments, which can be discerned with CT or MRI scan, then LP should be safe (e.g. IIH). • Spinal nerve root damage can be caused, usually, by inserting the needle lateral to the midline. • Post-LP headache occurs in up to 40% of LPs causing morbidity and prolonged hospital stays and is thought to be due to low CSF pressure consequent on leakage from the dura. The headache is characteristically postural (relieved by lying flat), usually occurs within 48 hours of LP (although onset in some is 72 hours later), and rarely lasts more than a week. The incidence decreases with the use of an atraumatic LP needle.

If headache persists, then an autologous epidural blood patch can be used to block the CSF leak, or as a last resort, by open surgery to seal the dural leak. • Infection of the CSF or an epidural abscess can occur if sterile precautions are not taken or if the needle is inserted through infected skin. • Spinal hemorrhage (epidural, subdural, or subarachnoid) may manifest as severe back and/or nerve root pain and nerve root or a spinal cord compression requiring urgent decompression surgery. This is very rare unless there is a low platelet count or a coagulation defect. • Intracranial subdural hemorrhage or VIth nerve palsy may rarely occur.

Assessing the CSF

Decisions on what tests should be done, and with what priority, depend on the clinical situation; discussion with a pathologist and/or infectious disease specialist may be appropriate prior to doing the LP. 3 The following parameters are measured: • Pressure. Less than 250 mm of CSF/water, and usually less than 200 mm if the patient is relaxed (must be measured vertically from the needle hub in the lateral decubitus position or appropriate correction made by the radiologist in the prone position). • Red blood cells. Normally the CSF is clear with no red blood cells. If the CSF is bloody, it should be centrifuged immediately and the supernatant examined by eye and spectrophotometry if a SAH is suspected. Yellow (xanthochromic) pigmentation is due to breakdown of products of hemoglobin (e.g. oxyhemoglobin and bilirubin), and it is seen in SAH at least 12 hours before, in jaundice, and in very high CSF protein (>1.5 g/L [150 mg/dL]).

• White blood cells (WBCs). CSF cell count should be done ideally within 30 minutes of sampling, because cell counts diminish after this time due to settling and lysis. Normally, CSF contains 0.6). It is depressed (usually 800 diabetes Maternal < 45 normal 45–54 gray zone 55–199 premutation, FXTAS, FXPOI 200–1000s FXS

First exon

Expression

Mechanism of Disease

Transcribed into Gain of function: mRNA, not RNA toxicity translated (abnormal RNA processing and splicing in nucleus) In DM2, mRNA does not undergo normal splicing with expanded repeat is retained in mRNA (spliced out in normal) Transcribed and Gain of function: translated into polyglutamine toxicity protein (protein interactions)

Intron

Not transcribed

First exon 5’UTR

Transcribed, not translated

Loss of function: interfere with transcription elongation

Loss of function: silencing of gene Gain of function: RAN translation, sense and antisense RNA toxicity Intron Transcribed, not Gain of function: between translated expanded repeat alternate 5’ stabilizes repeatexons containing mRNA, RAN translation, sense and antisense RNA toxicity

Abbreviations: DM, myotonic dystrophy; HD, Huntington’s disease; FA, Friedreich’s ataxia; FXS, fragile X syndrome; FXTAS, fragile X-associated tremor/ataxia syndrome; FXPOI, fragile X-associated primary ovarian insufficiency; ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; AD, autosomal dominant; AR, autosomal recessive; XL, X-linked; UTR, untranslated region; RAN, repeat-associated non-ATG. Additional details about the information presented in the Table can be found in references 7–12.

varied mechanisms of disease in example repeat-related neurological disorders. An example of mechanisms of trinucleotide repeat-mediated disease is shown for FMR1-asssociated disorders in Figure 2.51. Understanding of the mechanism of repeat expansion disorders has, in some cases, led to new approaches now in development for disease-targeted treatment, particularly antisense oligonucleotide (ASO)-mediated modulation of mutated gene expression (Figure 2.52).12,13

IMPRINTING Certain genes are marked or “imprinted” so as to have different activity on the maternally and paternally derived chromosomes. Usually, the imprinted genes are turned off specifically on either

the maternal or paternal chromosomes. Imprinted genes tend to cluster in specific areas of certain chromosomes, but not all chromosomes have imprinted genes. Imprinting is a genetic mechanism which is thought to maintain sexual reproduction in the species. If a person has a deletion of an imprinted area on one chromosome or inherits both of an imprinted chromosome from the same parent, that person will have a disease defined by specific genes which are inactivated on the chromosomes inherited, as they have no copy of the chromosome from the other parent on which the genes would have been active. A classic example of imprinting is that of Prader Willi syndrome (PWS) and Angelman syndrome.14 PWS is associated with hypotonia, early feeding problems and failure to thrive, later obesity, behavior problems, mild intellectual disability, and mild dysmorphisms including small hands and feet. AS

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FIGURE 2.51  Genetic mechanisms in FMR1-associated disorders provide examples of mechanisms of disease due to trinucleotide repeat expansions. The normal FMR1 (top) contains 10–45 CGG repeats in exon 1 in the promoter region which are transcribed into the FMR1 mRNA but not translated into fragile X mental retardation protein (FMRP). For FMR1 with an expanded repeat sequence in the form of a premutation (55–200 CGG repeats, middle), the expanded repeat sequence in the mRNA interacts with other nuclear proteins and forms potentially toxic inclusions. Antisense mRNA transcripts containing an expanded GCC repeat sequence are also produced and are elevated in premutation carriers and may contribute to toxicity. The long repeat in the mRNA also results in ribosomal stalling during translation in the cytoplasm and aberrant RAN translation from a non-AUG codon which produces polyglutamine from the repeat sequence (also lower amounts of polyalanine and polyarginine depending on the reading frame) that appears to exert cellular toxicity and is also present in inclusions. These toxic products derived from the expanded repeat sequence cause neural and ovarian damage, resulting in fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). Transcription is less efficient from premutation alleles and although FMR1 mRNA levels are increased in premutation carriers, FMRP is made in lower amounts, especially at higher repeat sizes. When the expanded repeat is larger than 200 CGG repeats (full mutation, bottom), FMR1 is methylated and transcriptionally silenced, thus FMRP is substantially reduced or absent, resulting in synaptic regulation and plasticity deficits and fragile X syndrome with intellectual disability, behavioral problems, and autistic traits.

is characterized by severe developmental delay, very delayed motor skills, ataxia, laughing spells, seizures, severe intellectual disability, behavior problems, and variable dysmorphic features. Both syndromes result from identical deletions of an imprinted area at chromosome 15q11-13, but the syndrome that occurs depends on whether the deletion is paternal or maternal in origin. PWS results from paternal deletion, maternal disomy 15, or an imprinting “center” mutation (such that only maternally inherited genes are present in the imprinted area). So PWS in all cases results from loss of activity of a set of genes that is turned off on the maternal chromosome, in a setting of absence of the paternally derived genes. AS results from the opposite problem of maternal deletion or paternal disomy for chromosome 15 (such that only

paternally inherited genes are present in the imprinted area). So AS, in 80% of cases, results from loss of activity of a single gene (UBE3A) in the imprinted area due to absence of the normally active maternal UBE3A, a gene which is imprinted and turned off in the brain only on the paternal chromosome. In AS, 20% of patients have the maternal gene present but have a mutation in the maternal copy of UB3A. Methylation PCR can be used to distinguish the paternal and maternal pattern of gene activation (genes are methylated when inactive) as shown in Figure 2.50c. The mechanism of silencing (imprinting) of the paternal gene in AS has been discovered in recent years and involves trancription of an antisense noncoding RNA (UBE3A-ATS) that interferes with transcription of the UBE3A gene. ASOs targeted to the antisense RNA sequence, designed to prevent transcription

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FIGURE 2.52  Common ASOs mechanisms of action. Uniquely designed ASOs bind to target RNA with base pair complementarity in order to exert their various effects. Mechanisms that are commonly employed in preclinical models of neurodegenerative disease and human clinical trial development, are shown. These mechanisms include: (1) mRNA target degradation via recruitment of the RNase H enzyme, (2) alternative splicing modification to include or exclude exons, and (3) miRNA inhibition to inhibit miRNA binding to its target mRNA.24 of inhibitor RNA have resulted in successful activaton of the paternal copy of UBE3A in human cells and animal models.15 Human trials are underway to determine if genetic correction of the disease can be accomplished. This is not only the first example of therapeutic reversal of imprinting, but it will also begin to answer long-term key questions about at what age sufficient neural plasticity exists to improve function with restoration of normal molecular function in genetic neurodevelopmental disorders.

MITOCHONDRIAL INHERITANCE The mitochondrial DNA (mtDNA) resides within mitochondria in cells and encodes a small percent of mitochondrial proteins (13 critical respiratory chain subunits), 2 mitochondrial rRNAs, and all the mitochondrial tRNAs (Figure 2.53). There can be sporadic mutations in the mitochondrial DNA which are not inherited. These are often structural mitochondrial DNA mutations such as duplications or deletions, which cause diseases such as Kearns– Sayre syndrome (KSS), isolated myopathy, and/or chronic progressive external ophthalmoplegia (CPEO). Point mutations can occur de novo or can be maternally inherited and cause conditions such as mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome (MELAS), mitochondrial encephalopathy and ragged red fibers (MERRF), neuropathy, ataxia and retinitis pigmentosa (NARP), and Leber’s hereditary optic neuropathy (LHON). Mitochondrial diseases can be caused by mtDNA mutations or nuclear DNA mutations in genes that impact mtDNA maintenance or code for mitochondrial proteins not encoded on the mtDNA (the majority of mitochondrial proteins).16 Mutations in mtDNA affect only respiratory chain function. Duplications, deletions, tRNA and rRNA mutations affect

multiple enzymes, while subunit gene mutations affect only the protein coded by that gene. Deleterious mtDNA mutations are often heteroplasmic (only a percent of mitochondrial DNA has the mutation and a percent is normal). The ratio of mutated to normal mtDNA may vary from one tissue to another, which contributes to the variability in presentations of mitochondrial diseases, as symptoms are often dependent on the percent of abnormal mtDNA in a given tissue. Mitochondrial mutations are more frequent in the population and accrue more rapidly during life than genomic mutations because of less sophisticated repair mechanisms for mtDNA. Mitochondrial inheritance is always maternal as the mitochondria are passed only from the oocyte to the zygote upon fertilization. There is an mtDNA “bottleneck” when the zygote is formed, such that only a small number of mitochondria are passed on, so the highly variable mutation content of those mitochondria will then define risk of disease in the offspring. For this reason, there can be very different percentages of abnormal mtDNA in different offspring. However, all children of a mother with a mitochondrial DNA mutation will likely inherit the mutation at some percentage and will be variably symptomatic depending on the tissue threshold for manifesting the effects of the mutation, the percent of mutation inherited, the distribution of the mutation in different tissues, and other factors. This makes genetic counseling extremely difficult. Men with a mitochondrial DNA mutation will never pass it to their children. Mitochondrial DNA diseases are diagnosed by PCR for specific mutations (Figure 2.50b), mitochondrial sequencing, or Southern blot for mitochondrial DNA size (to pick up large deletions and duplications), in cases suspected to have a mitochondrial disease. Although mitochondrial mutations have their largest impact in the nervous system, these conditions are very pleiotropic and variable, and there are many organs that can be affected. Given the

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FIGURE 2.53  Mitochondrial genetics and disease. The circular mitochondrial DNA (mtDNA) and genes for respiratory chain proteins, mitochondrial rRNAs, and mitochondrial tRNAs (shown as the letter representing the amino acid carried) encoded are shown on the left, along with several examples of common mutations seen in mtDNA and the common deletion area where most mtDNA deletions are found. The contribution of these and/or nuclear mutations leads to the illustrated diverse array of symptoms in multiple organs seen in mitochondrial disease, most prominently in brain and muscle. MELAS, mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome; MERRF, mitochondrial encephalopathy and ragged red fibers; NARP, neuropathy, ataxia, and retinitis pigmentosa (this mutation also causes Leigh’s disease when present in a high percent of mtDNA); LHON, Leber’s hereditary optic neuropathy; KSS, Kearns–Sayre syndrome; CPEO, chronic progressive external ophthalmoplegia.

variability and frequent absence of a classic mtDNA disease phenotype, it is often difficult to pin down which patients are likely to have an mtDNA disease and should be tested. Nonetheless, suspicion of mitochondrial disease should occur when several common manifestations of mitochondrial disease (Figure 2.53) occur together. Lactic acid levels can suggest the diagnosis but can be normal frequently, or artifactually high. Muscle biopsy can suggest or confirm a mitochondrial disease, but noninvasive mitochondrial disease genetic panels that test both mtDNA and nuclear gene mutations causing mitochondrial disorders are at this point the most comprehensive and efficient type of testing with the highest yield for patients with a suspected mitochondrial disease who are not characteristic of a specific syndrome such as MELAS. An example of a nuclear gene causing mitochondrial disease in children or adults is POLG, mutations in which affect mitochondrial DNA replication and cause progressive neurological symptoms that vary in different individuals but can include ataxia, seizures, and/or encephalopathy, as well as liver disease, particularly with valproate exposure.

MOSAICISM Mosaicism occurs when chromosomes and/or genes differ in different populations of cells in a single individual. The phenotype is often less severe or nonexistent in persons

who are mosaic for normal and disease-associated genes/ chromosomes (examples are Turner mosaics, Down’s mosaics). Mosaicism is common in unstable trinucleotide repeat disease due to the germline and somatic instability of these mutations (Figure 2.50d,f). Germline mosaicism occurs when a mutation is in the germline (egg and sperm cells) but not in the body. Germline mosaicism has been described in many conditions and is responsible for recurrence of disease in a second child when the parents appear not to be carriers. In this case, a new mutation has been propagated only in germ cells. This problem is relatively common in Duchenne’s/Becker’s dystrophy and a number of other dominant and X-linked diseases.

INSERTION/DELETION FROM UNEQUAL CROSSOVER ”Unequal crossover” occurs at sites where homologous sequences are repeated in DNA near each other on the chromosome. When the chromosomes line up at meiosis, there is mispairing, so the repeated sequence is shifted up or down along one of the chromosomes. A crossover then occurs, but because of the shifted pairing, one chromosome gets an extra piece of DNA, and the other is missing the corresponding piece. The chromosomes separate,

76 and offspring may inherit either the chromosome with the small duplication or the chromosome with the small deletion. The disease inherited often differs depending on differing effects of the duplication versus the deletion. The most well-known example of this is Charcot–Marie–Tooth (CMT) disease or hereditary motor sensory neuropathy (HSMN1) and hereditary neuropathy with tendency to pressure palsies (HNPP).17 Patients with CMT1A (HSMN1) have a progressive hereditary motor and sensory neuropathy and have a duplication that results in three copies of the dose-sensitive PMP20 gene due to an extra small piece of chromosome 17 at p11.2-p12. Family members may have a deletion of the corresponding piece of chromosome 17 (one copy of PMP20) and get HNPP, which is a milder disease in general than CMT, with less chronic neuropathy but a tendency to pressure palsies that usually resolve (see Figure 2.49f for example of microarray result showing the CMT1A duplication and HNPP deletion).

GENE CONVERSION Gene conversion occurs when there are two very similar genes and one is converted to the other. The mechanism for this is unclear but possibly related to mispairing in DNA replication. This process may involve genes which have been duplicated in evolution and one copy is the more functional gene. The most well-known example of this situation is seen in spinal muscular atrophy (SMA).18 In SMA, there is a failure of anterior horn cells to develop leading to failure of muscle cell innervation and development, thus producing hypotonia, weakness, and lack of reflexes. There are three types of SMA based on severity: Type 1 SMA patients never sit independently and are typically deceased or ventilator-dependent by 2 years of age. Type 2 SMA patients sit, but do not walk and live much longer. Type 2 SMA patients have many musculoskeletal comorbidities from their severe chronic weakness. Type 3 SMA patients walk at some point in their life although they may lose this ability as they grow. A variant of type 3 is sometimes called type 4, and this refers to SMA patients who present with weakness in adulthood. SMA is autosomal recessive and results from abnormalities in the survival motor neuron gene (SMN) affecting SMN genes on both chromosomes (Figure 2.54). SMN1 and SMN2 are similar genes arising from an ancient duplication of a region on chromosome 5. SMN1 and SMN2 differ only at 3 nucleotides, but SMN1 is the important copy that makes most of the SMN protein. The chromosome 5 region with the ancient duplication is a common region for deletions and SMN1 can be deleted. Often in SMA (and the normal population), however, there are chromosomes on which SMN1 is not deleted but all or part of SMN1 is converted to SMN2. In this case, the result is similar to but milder than absence of SMN1 because SMN2 does not fully compensate function. Chromosomes with gene conversions have an extra copy of SMN2 or a hybrid combination gene which presumably came from SMN1. SMN2 can also be converted to SMN1, but this is not associated with disease. There is thus much variability in how many copies of SMN1 and SMN2 exist on chromosomes in the population. One of the base pair differences in SMN2 relative to SMN1 changes the splicing pattern of mRNA such that for most but

Hankey’s Clinical Neurology not all of the mRNA transcripts, exon 7 of the mRNA is spliced out such that this RNA produces a nonfunctional SMN protein (Figure 2.54). Only a small percent of functional SMN protein is made from SMN2, but this is enough to modify the phenotype in SMA such that the number of SMN2 copies correlates with the severity of the phenotype. Thus, although all SMA patients are missing SMN1 on both chromosomes (or have one SMN1 gene with a mutation and are missing the other), most type 1 SMA patients have two copies of SMN2, type 2 patients have three copies of SMN2, and type 3 and 4 patients have four or more copies of SMN2. A severe neonatal form of SMA with only one copy of SMN2 has been described. Lack of any copies of SMN1 or SMN2 and thus no SMN protein at all appears to be a situation incompatible with life. Understanding the genetic mechanism of the relationship between SMN1 and SMN2 has led to a dramatic and life-saving treatment for SMA (Figure 2.53). An ASO which binds to the SMN2 mRNA at a splice regulating site in intron 7 and prevents the excision of exon 7 has been developed. This essentially converts SMN2 into a gene that behaves like SMN1 and rescues the phenotype in animal models and more recently in humans with SMA, who receive the ASO by LP infusion every 4 months. The ASO has been FDA approved based on a shamcontrolled clinical trial demonstrating prolongation of survival of infants with SMA type 1. This ASO (Spinraza) appears to improve symptoms of SMA in all types of disease at all ages, but the improvements are most evident when the treatment is started early. Infants treated in the first few months of life with Spinraza when they are still minimally symptomatic are able to walk and climb at age 2 or 3. Later treatment, after 6 months of age, yields less dramatic improvement. Treatment at this age will often prevent respiratory complications and death and may allow the patient to sit but not walk. Early diagnosis and treatment is thus imperative now that an effective treatment is available. A gene therapy for SMA has also just been approved by the FDA and also works best if started early. Further, there is a splice-altering small molecule in development that also modifies SMA type 1. None of these treatments completely normalize SMA type 1 patients even when started early, and it is thought the treatments will work best in combination. Trials are being planned to explore this complex problem of evaluation of combination genetic treatments for a rare disease. SMA has emerged as a model disease exemplifying the value of understanding genetic mechanisms of neurological disease to develop disease-reversing treatments for previously untreatable conditions.

INCOMPLETE PENETRANCE Incomplete penetrance is very common, and there are many examples of this in dominant, recessive, and X-linked neurological diseases. Incomplete penetrance is a situation when not everyone with the mutation or mutations which would be expected to cause the disease actually does get the disease. Affected individuals may also have more or less severe forms of the disease. The term variable expressivity refers to the variable clinical manifestations of a pathogenic genotype. There is often no difference between more affected, less affected, and unaffected family members in terms of specific mutation or protein levels. Unknown factors such as activity of interacting proteins due to polymorphisms

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FIGURE 2.54  Genetic mechanism of spinal muscular atrophy (SMA) and new genetically targeted treatment to reverse the disease. SMN1 differs in a functionally meaningful way from SMN2 only at the one nucleotide in exon 7 shown in the diagram (a C in SMN1 and a T in SMN2). This change results in splicing out of exon 7 in about 90% of transcripts from SMN2 and production of only about 10% of normal SMN protein (filled blue circles), with 90% of an aberrant protein that is missing exon 7 and is nonfunctional (open blue circles). In normal individuals with two copies of SMN1 and carriers with one copy of SMN1, the normal SMN protein is made predominantly from SMN1. Carriers have somewhat lower levels of protein, but this reduction is insufficient to cause symptoms. In SMA, both copies of SMN1 are absent and nonfunctional (represented by X in the figure), due to deletion of the gene, an inactivating point mutation or gene conversion to SMN2. In this case, all available SMN protein is made from SMN2 from the small percent of transcripts that retain exon 7, thus if there are more copies of SMN2 due to the patient having a gene conversion from SMN1 rather than deletion of SMN1, the SMA phenotype is milder. Use of an antisense oligonucleotide to block a splice enhancer site in SMN2 intron 7 just distal to exon 7 (bottom picture) prevents splicing out of exon 7 from SMN2 transcripts and results in a large increase in normal SMN protein, reversing symptoms of SMA.

in other genes and environmental factors likely result in the variability of expression and/or penetrance of effects of a given mutation and impact the clinical severity of disease in different individuals carrying the mutation(s). An example of incomplete penetrance is DYT1-related idiopathic torsion dystonia.19 This is the most common genetic cause of unexplained torsion dystonia and is inherited as autosomal dominant with incomplete penetrance. The condition is due to a single mutation in DYT1, a GAG insertion that leads to gain of function. Only about 30–40% of the mutation carriers get the disease. The mutation can also be associated with depression with or without dystonia, and it is unclear why some

people are protected from manifesting disease. There are no obvious environmental interacting factors, although there are other polymorphisms in the DYT1 gene that may influence penetrance. A variation of incomplete penetrance is when a gene mutation causes both dominant and recessive disease. More severe disease occurs in the recessive condition when both genes are mutated and a milder dominant disease occurs with only one gene mutated. Examples of this are inheritance patterns in Tourette’s syndrome, PARK mutations in Parkinson’s disease, and GTP-cyclohydrolase (GTPCH) deficiency, in which when one gene is mutated, the patient often has DOPA-responsive dystonia

78 (although may not have symptoms), and when both are mutated, the patient has a severe neonatal onset static encephalopathy with movement disorder and seizures.

ENVIRONMENTAL MODIFIER MECHANISM The environmental modifier mechanism is a situation in which a specific genetic abnormality predisposes to disease, but then the disease is triggered by a specific environmental interaction. Although the affected individual has had the mutation, their entire life without problems, usually the onset of disease is rapid. Examples of the environmental modifier mechanism include X-linked adrenoleukodystrophy (ALD), 20 which is associated with rapid onset at around age 4–10 years of ataxia, spasticity, and cognitive and behavioral deterioration, leading over a year or two to complete dependence, feeding, and respiratory compromise and subsequent death. The majority of individuals with a mutation in the ALD-causing ABCD1 gene do not develop disease or get adrenomyeloneuropathy (AMN), which manifests as gradually progressive spasticity, ataxia, and/or neuropathy in adults. AMN is due to chronic neural toxicity of very long-chain fatty acids (VLCFAs), which accumulate in ALD/AMN due to defective adrenoleukodystrophy protein (ALDP) resulting in failure to transport very long-chain fatty acids into the peroxisome to be metabolized. It is thought that ALD appears suddenly with a rapid course after normal development for many years because of an immune response in white matter set off by a virus or autoimmune mechanism due to an environmental exposure, coupled with susceptibility due to the elevated VLCFAs.

MULTIPLE ADDITIVE GENES FOR SAME DISEASE There are some genetic conditions for which multiple genes exist for the same disease. These genes are located in different chromosomal areas, and a person needs some total number of mutations in multiple genes to get the disease. The set of genes involved typically produces proteins that operate in the same cellular pathways. An example of this is Bardet–Biedl disease, 21 which is associated with pigmentary retinal degeneration, obesity, intellectual disability, and progressive spastic ataxia. There are at least six genes for this condition, and frequently, disease occurs when mutations on both chromosomes for one gene plus a third mutation in one of the other genes are present. There are multiple combinations, and some people get the disease with mutations in only one gene.

COMPLEX MULTIFACTORIAL TRAIT INHERITANCE Complex multifactorial trait inheritance is actually the most common kind of inheritance in man. This type of inheritance defines normal traits as well as abnormal conditions. This is the situation when a disease phenotype results from the sum

Hankey’s Clinical Neurology of activity of many interacting genes. This type of inheritance is involved in many common diseases in which multiple common risk variants with low pathogenicity combine (often with environmental influences as well) to produce conditions such as Alzheimer’s disease, diabetes, Parkinson’s disease, learning disabilities, autism spectrum disorder, intellectual disability (particularly mild ID), behavior disorders, psychiatric diseases (such as depression and schizophrenia), as well as “normal” personality traits, and learning profiles. Progress is being made in understanding this through population studies with techniques such as linkage analysis in which genetic variants known as single-nucleotide polymorphisms (SNPs) in a specific chromosome area are linked to a given trait or disease in order to identify genes that contribute to disease risk. This can be facilitated by studying population isolates with a high frequency of a mutation or through homozygosity mapping followed by linkage in inbred families with a disease. Genome-wide association study (GWAS), another technique to study complex trait inheritance, involves an observational study of a set of SNPs or genetic variants across the entire genome in a population of different individuals to see if one or multiple variants are associated with a trait. GWAS can be used to map quantitative trait loci (QTL), which are loci (sections of DNA) that correlate with variation of a quantitative trait in the phenotype of a population of organisms. Despite progress and increasing refinement of these techniques, the complexity of inheritance of many common diseases and traits continues to be limiting. An example of this type of complex inheritance is seen in the genetics of Parkinson’s disease (PD),22 which is characterized by bradykinesia, rigidity, rest tremor, depletion of dopamine neurons, and a therapeutic response to L-DOPA. There is wide variability in the etiologies of PD and 2–3% of patients have a single genetic cause inherited as an autosomal dominant, recessive, or X-linked mutation. Risk genes for PD typically show incomplete penetrance. Sporadic PD is occasionally caused by a single-gene mutation with high penetrance; some individuals have a risk gene or genes including one copy of an autosomal recessive gene that may cause PD most of the time when present on both chromosomes but acts as a risk gene when present on only one chromosome. Many genetic factors, including direct variants in cellular proteins and regulatory molecules such as small RNAs, that may play a role in PD have been found, involving mitochondrial metabolism, neurotransmitter metabolism, and protein folding and degradation pathways, and probably in many patients, multiple factors are interacting to cause disease. Of known genes, Parkin, DJ-1, and PINK1 may act in synergy on oxidative stress and mitochondrial dysfunction in dopamine neurons, and Parkin, α- synuclein, UCHL1, LRRK2 act on protein processing and degradation. The model of these high pathogenicity less common genes that are associated with PD and low pathogenicity more common genes that combine in multifactorial inheritance is shown in Figure 2.55. Epigenetics, the methylation, and activity level of different genes in the absence of actual mutation likely also plays a role in many common conditions and increases complexity. As new genetic techniques and more powerful bioinformatics become available, study of extremely large disease populations (and corresponding normative populations) will increasingly unravel these complex genetic interactions that define traits and disease.23

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FIGURE 2.55  Overview of effect sizes and frequencies of genetic variants in several known Parkinson’s disease genes. The diagram illustrates the concept of low-frequency, high-penetrance genetic variants and high-frequency, low-penetrance genetic variants contributing to complex multifactorial trait inheritance. Filled ovals indicate homozygosity and/or compound heterozygosity, whereas half-filled ovals depict heterozygosity.22

REFERENCES









1. Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S. (2011) Evidence report: genetic and metabolic testing on children with global developmental delay: report of the quality standards subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 77:1629–35. 2. Miller DT, Adam MP, Aradhya S, et al. (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86: 749–764. 3. Manning M, Hudgins L, Professional Practice and Guidelines Committee. (2010) Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med 12:742–745. 4. Regier DA, Friedman JM, Marra CA. (2010) Value for money? Array genomic hybridization for diagnostic testing for genetic causes of intellectual disability. Am J Hum Genet 86:765–772. 5. Coulter ME, Miller DT, Harris DJ, et al. (2011) Chromosomal microarray testing influences medical management. Genet Med 13:770–776. 6. Bardakjian TM, Helbig I, Quinn C, et al. (2018) Genetic test utilization and diagnostic yield in adult patients with neurological disorders. Neurogenetics 19:105–110. 7. Yum K, Wang ET, Kalsotra A. (2017) Myotonic dystrophy: disease repeat range, penetrance, age of onset, and



relationship between repeat size and phenotypes. Curr Opin Genet Dev 44:30–37. 8. Testa CM, Jankovic J. (2019) Huntington disease: a quarter century of progress since the gene discovery. J Neurol Sci 396:52–68. 9. Koeppen AH. (2011) Friedreich’s ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci 303:1–12. 10. Pattamatta A, Cleary JD, Ranum LPW. (2018) All in the family: repeats and ALS/FTD. Trends Neurosci 41:247–250. 11. Hall DA, Berry-Kravis E. (2018) Fragile X syndrome and fragile X-associated tremor ataxia syndrome. Handb Clin Neurol 147:377–391. 12. Rodriguez CM, Todd PK. (2019) New pathologic mechanisms in nucleotide repeat expansion disorders. Neurobiol Dis 130:104515. 13. Zain R, Smith CIE. (2019) Targeted oligonucleotides for treating neurodegenerative tandem repeat diseases. Neurotherapeutics 16:248–262. 14. Kalsner L, Chamberlain SJ. (2015) Prader-Willi, Angelman, and 15q11-q13 duplication syndromes. Pediatr Clin North Am 62:587–606. 15. Meng L, Ward AJ, Chun S, Bennett CF, Beaudet AL, Rigo F. (2015) Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature 518:409–412. 16. Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW. (2017) The genetics and pathology of mitochondrial disease. J Pathol 1:236–250. 17. Suter U, Patel PI. (1994) Genetic basis of inherited peripheral neuropathies. Hum Mutat 3:95–102.

80 18. Sumner CJ, Crawford TO. (2018) Two breakthrough genetargeted treatments for spinal muscular atrophy: challenges remain. J Clin Invest 128:3219–3227. 19. Dauer W. (2014) Inherited isolated dystonia: clinical genetics and gene function. Neurotherapeutics 11:807–816. 20. Kemp S, Berger J, Aubourg P. (2012) X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta 1822:1465–1474. 21. Khan SA, Muhammad N, Khan MA, Kamal A, Rehman ZU, Khan S. (2016) Genetics of human Bardet-Biedl syndrome, an update. Clin Genet 90:3–15. 22. Lill CM. (2016) Genetics of Parkinson’s disease. Mol Cell Probes 30:386–396.

Hankey’s Clinical Neurology 23. Timpson NJ, Greenwood CMT, Soranzo N, Lawson DJ, Richards JB. (2018) Genetic architecture: the shape of the genetic contribution to human traits and disease. Nat Rev Genet 19:110–124. 24. Schoch KM, Miller TM. (2017) Antisense oligonucleotides: translation from mouse models to human neurodegenerative diseases. Neuron 94:1056–1070. 25. Choi BO, Kim NK, Park SW, et al. (2011) Inheritance of Charcot-Marie-Tooth disease 1A with rare nonrecurrent genomic rearrangement. Neurogenetics 12:51–58.

3

POPULATION HEALTH AND SYSTEMS OF NEUROLOGICAL CARE

Philip B. Gorelick, Jong S. Kim, Hee-Joon Bae

Contents Introduction..........................................................................................................................................................................................................................81 Definition of Population Health........................................................................................................................................................................................82 Approaches to Reducing Population Risk.......................................................................................................................................................................82 Social Determinants of Health..........................................................................................................................................................................................82 Key Components and Drivers of Health Care Transformation..................................................................................................................................83 Leadership.......................................................................................................................................................................................................................83 The triple aim..................................................................................................................................................................................................................83 Strategic development...................................................................................................................................................................................................83 Team or interdisciplinary care.....................................................................................................................................................................................83 Medical waste.................................................................................................................................................................................................................83 Evidence-based medicine and clinical guidelines....................................................................................................................................................84 Payment models.............................................................................................................................................................................................................84 Health Care Spending in the United States and Other Countries and Its Consequences....................................................................................84 Neurological Systems of Care............................................................................................................................................................................................85 United States...................................................................................................................................................................................................................85 Stroke systems of care in the United States..............................................................................................................................................................85 South Korea.....................................................................................................................................................................................................................85 Stroke systems of care in South Korea.......................................................................................................................................................................86 Further Reading....................................................................................................................................................................................................................86

INTRODUCTION The Burden of Disease Study 2016 (GBD) assessed health care access and quality (HAQ) index in 195 countries and territories or locations across the world. GBD results suggested that the HAQ index may be uneven within and between countries. For example, on a 0–100 scale, a high HAQ index was observed in Iceland (97.1) and Norway (96.6) but was low in the Central African Republic (18.6) and Somalia (19.0). Furthermore, whereas Japan had the smallest range in subnational HAQ index performance, countries such as the United States and England had locations whereby the highest and lowest performance on the HAQ index had twofold and threefold differences, respectively. Overall, higher scores and faster gains for noncommunicable diseases (NCDs) were noted in highand high-middle income sociodemographic index countries, and performance on the HAQ index was positively related to higher levels of health care spending. The striking disparities in health care between and within countries has led to a call for improvement and bridging of gaps in population health and health care delivery. In 2013, an international group of 25 economists and health experts created a framework for achieving global health transformation within one generation (Global Health 2035 [GH2035])

according to four principles that could be applied largely to lowand middle-income countries: • Investment in medical and public health tools and technologies to reduce infectious disease and child and maternal mortality. • Apply “best-buy” population-wide interventions (e.g. multidrug generic therapy for cardiovascular disease risk reduction) for NCDs. • Provide universal health coverage in all regions limited to a high-quality, very cost-effective set of interventions to be expanded upon and funded through public financing. • Emphasize the high value of investment in health relative to cost (i.e. intrinsic value of health) to local governments. In this chapter, we discuss population health and systems of neurological care. Emphasis is placed on transformations in health care and factors that are driving the transformation in a largely US-centric approach. In addition, the cost of health care and quality of care based on health care spending are reviewed. Finally, examples of neurological systems of care in the United States and South Korea are discussed with an emphasis on stroke care.

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TIP • Health care access and quality may be distributed unevenly within a country and between countries. Higher levels of health care spending may help to bridge such gaps.

DEFINITION OF POPULATION HEALTH Population health may be defined as the following: • The delivery of health care to groups of people enrolled in a health system. A more comprehensive definition includes the following components: • Policies, programs, and resource distribution that impact a population by changing the underlying risk and reducing health disparities. Population health interventions may include: • Vaccine administration. • Population screening for key diseases (e.g. colonoscopy for colorectal cancer). • Provision of housing and transportation policies to support healthy behaviors. • Taxes and laws to reduce unhealthy behavior (e.g. taxes on smoking and soda drinks high in sugar). It has become increasingly clear that population health must be considered a convergence science (i.e. a transdisciplinary science). The influence of health care on health outcomes may be as low as 10–20%. Beyond biology, physical and engineering sciences, mathematics, and computational sciences, a convergence of research, policy, and implementation stakeholders is needed to fully realize population health. Consideration for future health must include the following nontraditional planning components for: • Cities, housing, and parks • Education and employment • Business and commerce

TIP • Population health should be considered as a convergence science which brings together multiple stakeholders not only from the scientific field but also from the domains of convergence research, policy, and implementation to take into account nontraditional planning components such as housing, education, and commerce.

APPROACHES TO REDUCING POPULATION RISK In The Strategy of Preventive Medicine, Geoffrey Rose discussed the rationale for why we seek to prevent disease. He concluded that the humanitarian argument was the most compelling rationale: • Being healthy is better than being dead is the only real argument and is sufficient.

TABLE 3.1 Complementary Approaches to Chronic Disease Prevention (after Rose G.) 1. Population (mass) approach: move the distribution of a risk in a population in a beneficial direction by health education, and economic and policy changes (e.g. taxes on purchase of cigarettes to reduce use, public education about the dangers of hypertension). A paradox may exist as some persons may stand to benefit more than other persons and shifts in risk may only be modest for some. 2. High-risk approach: screen for persons at high risk for a disease such as what one may achieve in a clinical office practice, and treat them with lifestyle and medication therapies as needed. The high-risk approach may be expensive. An example is screening for hypertension in an office practice and treating those at highest risk.

In addition, Rose discussed the approaches to chronic disease prevention (see Table 3.1 for definitions): • The population (mass) strategy. • The high-risk strategy.

TIP • The population (mass) and high-risk approaches for prevention of NCDs are complementary strategies.

SOCIAL DETERMINANTS OF HEALTH Social determinants of health may be defined as the social conditions that we are born and live in, interact with, and work in. Such factors include, but are not limited to, education, income, employment, working conditions, race/ethnicity, and access to health care and social support, and they are believed to be the single most important determinant of one’s health. Social determinants of health, however, may be impacted by allocation of financial resources (e.g. spending on social programs). In addition, the following key health indicators are predicted by where one lives (e.g. region, state, zip code): • • • •

Life expectancy Healthy life expectancy Mortality rates Years of life lost due to premature mortality

Thus, disadvantaged neighborhoods, hotbeds of health disparities and NCDs, have become geographic targets for health improvement by policy makers, researchers, and clinicians. For marginalized and excluded populations (e.g. those with common adverse life experiences and risks such as poverty and childhood trauma that lead to social isolation), health and social interventions are available and proven to work (Table 3.2).

TIP • Social determinants of health are considered as the single most important predictor of one’s health.

Population Health and Systems of Neurological Care TABLE 3.2  Effective Interventions for Marginalized and Excluded Populations (after Luchenski S, et al..) Pharmacological (e.g. opioid replacement therapy, long-acting injectable antipsychotics) Psychosocial (e.g. combined motivational interviewing, cognitive behavioral therapy, and contingency management) Case management (e.g. coordination and delivery of health care and social care services) Disease prevention (e.g. screening for high-risk blood-borne viruses, vaccination programs, and substance abuse prevention) Housing and social determinants (e.g. provision of housing and mental health services)

KEY COMPONENTS AND DRIVERS OF HEALTH CARE TRANSFORMATION In this section, we review key components and drivers of health care transformation. At the center of this movement is the need to provide better health care, higher patient satisfaction, and health care at a lower cost. The principles discussed in this section are applicable to both general (primary care) and specialty practices such as neurological practice.

Leadership

A new type of leader has been called for in medicine. Traditional academic models, for example, have enlisted persons with strong academic credentials. In a new era of consumerism and practice management, a leader with the following characteristics is desirable: • Emotional intelligence. • Broad knowledge base of both practice, teaching, and science. • Altruism in relation to the home institution and a resultsbased emphasis. • Ability to manage and relate to people at different levels within the administrative organization and departmental workforce.

83 using cumbersome electronic medical records, and high provider burnout rates, means to prevent and combat burnout are being emphasized. Without a healthy provider, it is difficult to carry out the triple aim.

TIP • Future leaders in medicine are being sought who have qualities of high emotional intelligence, broad knowledge base, personal commitment to the institution, and ability to manage and relate to people at different levels in the health care system. The mantra of health care is the triple aim—better patient care and outcomes, higher patient satisfaction, and affordability of health care at population and individual levels.

Strategic development

In accordance with the triple aim, a strategic approach to account for how a health care organization or department may distinguish itself in relation to the customer’s needs must be considered. Traditional strategies emphasizing operational effectiveness, working hard, best practices, and reliance on marketing reputation still hold value but must be viewed in the context of a patientcentered system.

Team or interdisciplinary care

The complexities of modern health care and an expanding need for health care services have led to the development of team care. To achieve accessible, high-quality, safe, and high-value health care, interdisciplinary team care has become an important component of a health system. Advanced practice professionals (APPs) such as physician assistants and nurse practitioners, pharmacists, caseworkers, and therapists now may be team members. Another important aspect is the coordination of health care between primary care providers and specialists to reduce redundancies in care, unnecessary costs of care, and waste in relation to diagnostic testing.

The triple aim

Fundamental to the transformation of health care is the triple aim. The triple aim embodies the constructs of better patient care and outcomes, higher patient satisfaction, and affordability of health care at the population and individual levels. A high-value proposition is being called for by health care insurers and patients. In addition, health care must shed a traditional paternal approach for a patient-centered one. The epicenter of the system is no longer the hospital, the doctor, and the doctor’s office. The center of the population health system is patients. Patients desire to have access to care, high-quality care, and knowledge about their medical or surgical disorder to allow them to make informed decisions about their health care. Access points to care such as through telemedicine rather than the traditional doctor’s office visits, urgent care center visits rather than more expensive emergency department visits, and other online or electronic resources are important to many consumers. The triple aim has been expanded by some pundits to include a fourth component—physician or provider satisfaction. Given the substantial pressures of fast-paced practices, challenges

TIP • The complexity of modern health care and its challenges have created the need for an interdisciplinary team for the care of the patient. Furthermore, proper strategic development is needed to ensure a customer-centric system.

Medical waste

Medical waste accounts for ∼30% of health care costs. Medical waste includes at least in part unnecessary diagnostic studies, therapies, and office visits. Medical waste may include behavioral (e.g. smoking, physical inactivity), clinical (e.g. unnecessary testing), and organizational (e.g. system redundancies) factors. In a fee-for-service reimbursement climate, the higher the volume of diagnostic studies, treatments, and outpatient visits, the greater is the potential financial gain for the practitioner. In a population health system, one of the goals is to provide high-quality accessible care at low cost

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84 (i.e. value-based care). Obvious strategies to reduce clinical medical waste may include: • Reduction in redundancies of care (e.g. an unnecessary office visit for the same medical problem at primary care and specialty care office levels, which only needs to be managed at one of the offices). • Development of care diagnostic and treatment pathways for primary care offices to reduce unnecessary specialty office or emergency department visits. • Utilization of complex care management programs for patients with challenging medical diagnoses (e.g. persons with diabetes mellitus and depression are managed by a team consisting of a primary care provider, psychiatrist, and APP). • Choosing diagnostic tests and treatments judiciously and according to guideline statements. • Informing patients of diagnostic testing and treatment options and allowing them to communicate their preferences for diagnosis and treatment. Medical waste is a major target for containing costs of medical care.

Evidence-based medicine and clinical guidelines

Clinical practice guidelines are best practices based on evidencebased medicine. The highest level of medical evidence is randomized controlled trials and meta-analyses. Evidence-based medicine, however, has limitations: • Exclusion of study of enrollees who may be common in a provider’s practice. • Placebo-controlled studies that may exaggerate the benefit of a given medical intervention. • Outside the primary end point of a study, the lack of definitive results about other outcomes important to patients (e.g. physical, social, and psychological well-being measures). An evolving approach, interpersonal medicine, a strategy of delivering care that incorporates patients’ circumstances, capabilities, and preferences, addresses an effectiveness approach. Clinical guidelines are likely to persist for a long time, will be updated more frequently, and be modified as new strategies for evaluating evidence are established, and will likely be used to assist in the utilization of precision medicine after big data warehouses are developed.

TIP • Medical waste may relate to 30% of decisions made by providers and includes, but is not limited to, unnecessary diagnostic studies, therapies, and office visits. Better coordination of medical care, familiarity with clinical guidelines, patient-centered approaches to evidencebased medicine, and incorporation of patient preferences in relation to diagnosis and therapy hold promise to help reduce medical waste.

Payment models

The United States, as an example, does not have a single-payer or universal health care system. In the United States, the

TABLE 3.3  Select Strategies Being Taken in the United States to Halt or Reduce Cost and Maintain Quality of Care (after Ginsburg PB and Patel KK) Accountable care organization (ACO): groups or networks of health care providers and hospitals providing coordinated care; also, a contract a group has with payers Medicare bundled payments: rather than paying for individual services, providers receive a set payment per patient episode Merit-based incentive payment system: payment for achieving quality, value, and meaningful use (electronic medical record) metrics Center for Medicare and Medicaid Innovation: testing of innovative payment and service delivery models

Affordable Care Act (ACA) was successful in increasing insurance coverage; however, ∼25 million Americans remain uninsured. A major concern in the United States is the increase in health care spending. Factors associated with such elevated spending include increases in health care service cost that may be positively associated with intensity and population growth and aging but negatively associated with disease prevalence and incidence. In an attempt to move away from fee-for-service reimbursement, halt or reduce health care costs and transform into a population health and value-based care system; select strategies to help achieve the goal are listed and defined in Table 3.3.

HEALTH CARE SPENDING IN THE UNITED STATES AND OTHER COUNTRIES AND ITS CONSEQUENCES The cost of health care in the United States approaches 18% of the country’s gross domestic product and is projected to increase. This has led to the conclusion that health care rationing may be inevitable in the United States. Rationing may be implemented by a number of measures: rationing access, by raising out-ofpocket expenses, restricting availability of a service, or by delaying access to care (e.g. long waits for service). The United States spends more on health care than other countries, yet oftentimes ranks low on key health care indicators. Table 3.4 compares health care spending in the United States and other high-income countries (Japan, Germany, the United Kingdom, France, Canada, TABLE 3.4  Summary of Overall Key Health Care Spending Trends in High-Income Countries (after Papanicolas I et al.) 1. The United States spends approximately two times as much on medical care, but utilization rates are similar to other countries 2. Major drivers of the cost disparity are prices of labor and goods (e.g. pharmaceuticals) and administrative costs 3. Spending on social programs is generally lower in the United States than other countries 4. The United States ranks 10th lowest out of 11 countries in population health metrics 5. The United States ranks highest in practically all pharmaceutical use categories but only 6th out of 11 countries in access and quality, and first in inequality of care

Population Health and Systems of Neurological Care Australia, the Netherlands, Sweden, Switzerland, and Denmark) according to key health care quality indicators. Despite the substantial spending on health care in the United States, life expectancy declined to 78.6 years in 2017 from 78.7 years in 2016. Life expectancy in men went from 76.2 to 76.1 years, but women remained at 81.1 years. Data from GBD 2016 show the following key findings when quality of care is compared in 137 low-middle income countries (LMIC) to 23 high-income countries in relation to 61 conditions: • • • •

15.6 million excess deaths in the LMIC. 8.6 million deaths in the LMIC were amendable to health care. 5.0 million deaths were attributable to poor quality of care. 3.6 million deaths were attributable to nonutilization of health care.

Based on these statistics, it was concluded that 8.6 million deaths annually could be avoided by expansion of universal health care coverage and by investing in higher quality health systems.

TIP • US health care ranks at the top in spending, yet there are disparities in relation to quality indicators of care when compared with other high-income countries. The US ACA reduced the number of uninsured citizens in the United States, helped to improve access to care, improve financial security, and improve health, and led to the development of new payment system models such as bundled payments and accountable care organizations. Opportunities remain to improve health care in the United States and globally. Means to reduce medical waste need to be considered.

85 activator [tPA]). A major goal has been to deliver alteplase as soon as possible as more timely administration of alteplase has been associated with better functional outcomes and lower mortality. The stroke center has been organized to include such components as a team to meet the patient in the emergency department to initiate diagnostic processes, care pathways for treatment, time awareness (“time is brain” adage) to allow provision of treatment as soon as possible, proper diagnosis followed by proper acute and recurrent stroke preventatives, a stroke unit, and other aspects. Over time, with the advent of new treatments such as stroke stent retrievers and aspiration devices for treatment of acute ischemic stroke and perfusion diagnostic software, stroke center certification programs have surfaced and stroke centers are designated based on the complexity of care that can be provided: • • • •

Acute Stroke Ready Hospital Primary Stroke Center (PSC) Comprehensive Stroke Center Thrombectomy-Capable Stroke Center

We have argued previously that although clinical neurological practice continues to evolve in the direction of subspecialization and expansion of knowledge in the areas of informatics and technical knowledge, we need to consider a change in the neurology residency training paradigm, as we are not well positioned to establish neurological patient-centered homes. Opportunity for cotraining in primary care for some neurology residents could be useful to assist in the provision of “one-stop” neurological care (i.e. at a neurological patient-centered home) and possibly reduce medical waste in redundancies in care, diagnosis, and treatment for complex neurological patients. APPs, trained in neurological practice, will likely be needed as the US neurological physician workforce is predicted to be insufficient in the future.

South Korea

The health care system in South Korea has two main components:

NEUROLOGICAL SYSTEMS OF CARE United States

The US neurological system is diverse and includes, but is not limited to, single-occupant private outpatient doctor’s offices, system-linked outpatient clinics, neuroscience centers, and networks of neuroscience programs within a larger health care system. Neurologists as members of a specialty-based discipline have become subspecialized over time (e.g. practices restricted to the following disciplines: stroke, epilepsy, dementia, multiple sclerosis, neuromuscular diseases, and other disorder-specific areas). Such subspecialization lends itself well to organized clinical health care initiatives (e.g. development and implementation of guidelines for care, establishment of processes and outcome metrics, and clinical research). However, the latter approach may restrict the diversity of the types of neurology patients that a provider may be able to diagnose and treat, as they may no longer have the general neurology skills to support a general neurology practice base. An advanced model of a neurological system of care pertains to stroke care.

Stroke systems of care in the United States

In the United States, organized stroke systems of care are established around a stroke center for the diagnosis of acute stroke and the delivery of intravenous alteplase (tissue plasminogen

• Finance • Delivery Regarding finance, universal coverage for all citizens was established in 1989, just 12 years after the introduction of social health insurance in the country. About 96% of the total population are covered by the National Health Insurance Program, and the remaining persons are supported by the Medical Aid Program. However, since 2000, South Korea has had a single payer, the National Health Insurance Service. Health care delivery, however, is dependent on support from the private sector. Only a small portion of public health facilities provides medically necessary services (usually not acute care) at the central, regional, and municipal levels. The private market for health care services is very competitive, attributed in part to the lack of barriers among the different levels of health providers. Compared with other members of the Organization for Economic Cooperation and Development (OECD), South Korean patients can easily use any level of medical facilities, from private clinics to tertiary university hospitals, according to their choice. The patient simply needs to present a referral slip issued by a medical practitioner who has first made a diagnosis, and subsequent cost is minimal. However, even the referral slip is exempt from emergent medical care. Although this system may be convenient for the patient, it may result in weakening of the community-based

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86 primary care system. Furthermore, health care delivery by private providers is compulsory, as there is no option for selective contracting between providers and National Health Insurance Service.

TIP • South Korea has a universal health care coverage system from the financial standpoint. Delivery of health care is dependent on private sector participation.

Stroke systems of care in South Korea

In 2012, the Korean Stroke Society initiated a Stroke Unit Certification Program, and 49 hospitals were certified. According to the seventh report of the Acute Stroke Quality Assessment Program conducted in 2016 by the Korean Government, 72 of the 246 acute care hospitals (29.3%) were reported to provide stroke unit care. The percentage was generally lower than that of other OECD countries, but it was expected to increase with the implementation of financial reimbursement for stroke unit care beginning in 2017. In 2008, the Korean government began to designate the regional cardiocerebrovascular disease center (RCCVC), a more extensive stroke center compared with a PSC. Currently, there are 14 hospitals that have been designated with this higher level status for stroke care and are financially supported to cover the cost of such care on a 24-hour a day, 7-day a week basis. The RCCVCs are distributed throughout the country except in Seoul to allow more balanced distribution of qualified centers for stroke and myocardial infarction throughout the country. The RCCVCs are currently playing a central role in the acute care of stroke and acute myocardial infarction regionally. Thus, quality of care and outcomes have improved regionally and nationally. However, the duration of financial support for the program is limited, and without such continued support, maintenance of “24/7” service may not be sustainable. In South Korea, the PSC has been recognized by the Korean Stroke Society only recently. In January 2019, 48 hospitals were under the PSC certification process, and it is hoped that more than 60 hospitals will be certified. The median time from onset to hospitalization is 6.2 hours for ischemic stroke: only 42% of stroke patients are hospitalized within 3 hours from onset, and 56% are transported by ambulance. There is no official prehospital notification for stroke by emergency medical services (EMS), which might explain the relatively low intravenous thrombolysis and endovascular treatment rates of 10.7 and 3.6%, respectively. There is no hospital certification or accreditation system for stroke rehabilitation, no community rehabilitation, and no longterm services for severely disabled patients. Most acute care hospitals have their own in-hospital rehabilitation services, but capacitance is generally limited and available only for several weeks after acute treatment. In South Korea, stroke mortality per 100,000 population has declined from 58.6 in 2006 to 29.6 in 2015, and 30-day case fatality is one of the lowest (1.8% and 9.8% for admitted ischemic and hemorrhagic stroke patients in 2009, respectively) among OECD countries. This may be attributed to effective risk factor control, especially hypertension control, and development/implementation of advanced stroke care in part attributed to the efforts of the Korean Stroke Society and the Korean Government.

However, South Korea is challenged by an increasing incidence of ischemic stroke associated with continuously increasing average life expectancy. For men, the rate increased from 51.1 in the 1960s to 79.7 in 2017, while for women, it increased from 53.7 in the 1960s to 85.7 in 2017. At the same time, the total fertility rate is sharply decreasing, from 1.67 in 1985 to 0.98 in 2018. The country of South Korea anticipates a rapid rise in overall medical expenditures given the rapidly increasing elderly population. Finally, establishment of a more expansive but cost-effective organized stroke care system (e.g. at the level of EMS, rehabilitation, receiving hospitals, physicians, and public sector) is anticipated given the expected population shifts based on life expectancy predictions.

FURTHER READING Global Burden of Disease Study 2016

GBD 2016 Healthcare Access and Quality Collaborators. Measuring performance on the healthcare access and quality index for 195 countries and territories and selected subnational locations: a systematic analysis from the Global Burden of Disease Study 2016. Lancet. 2018;391:2236–2271.

Social determinants of health and disparities in health care

Dickman SL, Himmelstein DU, Woolhandler S. America: equity and equity in Health 1. Inequality and the health-care system in the USA. Lancet. 2017;389:1431–1441. Kind AJH, Buckingham WR. Making neighborhood-disadvantage metrics accessible—the neighborhood atlas. JAMA. 2018;378:2456–2458. Luchenski S, Maguire N, Aldridge RW, Hayward A, Story A, Perri P, et al. What works in inclusion health: overview of effective interventions for marginalized and excluded populations. Lancet. 2018;391:266–280. US Burden of Disease Collaborators. The state of US health 1990-2016. Burden of diseases, injuries and risk factors among US states. JAMA. 2018;319(14):1444–1472.

Population health and transformation of health care

Dzau VJ, Balatbat CA. Reimaging population health as a convergence science. Lancet. 2018;392:367–368. Gorelick PB. Adaptation of neurological practice and policy to a changing US health-care landscape. Lancet Neurol. 2016;15:444–450. Jacobson RM, Isham GJ, Rutten LJF. Population health as a means for health care organizations to deliver value. Mayo Clin Proc. 2015;90(11):1465–1470. Studer Q, Ford G. Healing physician burnout: diagnosing, preventing and treatment. Pensacola: Firestarter Publishing; 2015; pp. 1–259. Watkins DA, Yarney G, Schaderhoff M, Adeyi O, Alleyne G, Alwan A, et al. Alma-Ata at 40 years: reflections from the Lancet Commission on investing in health. Lancet. 2018;392:1434–1460.

Approaches to prevention

Rose G. The strategy of preventive medicine (reprinted 1994). New York: Oxford University Press; 1994; pp. 1–135.

Population Health and Systems of Neurological Care Evidence-based medicine and clinical guidelines

Chang S, Lee TH. Beyond evidence-based medicine. N Engl J Med. 2018;379:1983–1985. Greenfield S, Kaplan SH. When clinical practice guidelines collide: finding a way forward. Ann Intern Med. 2017;9:677–678. Horwitz RI, Hayes-Conroy A, Caricchio R, Singer BH. From evidence based medicine to medicine based evidence. Am J Med. 2017;130:1246–1250.

Payment models and health care spending in the United States and other countries

Dieleman JL, Squires E, Bui AL, Campbell M, Chapin A, Hamavid H, et al. Factors associated with increases in US health care spending, 1996–2013. JAMA. 2017;318:1668–1678. Fuchs VR. Is single payer the answer for the US health care system? JAMA. 2018;319:15–16. Ginsburg PB, Patel KK. Physician payment reform—progress to date. N Engl J Med. 2017;377:285–292. Obama B. United States health care reform. Progress to date and next steps. JAMA. 2016;316:525–532. Papanicolas I, Woskie LR, Jha AK. Health care spending in the United State and other high income countries. JAMA. 2018;319:1024–1039.

Health care spending in the United States and other countries and its consequences

Bauchner H. Rationing of health care in the United States. An inevitable consequence of increasing health care costs. JAMA. 2019;321:751–752. Kruk ME, Gage AD, Joseph NT, Danaei G, Garcia-Saiso S, Salomon JA. Mortality due to low-quality health systems in the universal health coverage era: a systematic analysis of amendable deaths in 137 countries. Lancet. 2018;392:2203–2212. Murphy SL, Xu J, Kochanek KD, Arias E. Mortality in the United States, 2017. NCHS Data Brief. 2018;328:1–7. Papanicolas I, Woskie LR, Jha AK. Health care spending in the United State and other high income countries. JAMA. 2018;319:1024–1039.

87 Neurological systems of care

Gorelick PB. Primary and comprehensive stroke centers. History, value and certification criteria. J Stroke. 2013;15:78–89. Gorelick PB. Adaptation of neurological practice and policy to a changing US health-care landscape. Lancet Neurol. 2016;15:444–450. Gorelick PB, Schneck MJ, Glisson C. A new era of neurological practice, the need to shift the residency training paradigm, and the importance of neurohospitalists. Neurohospitalist. 2013;3:117–119. Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke. Stroke. 2013;44:870–947. The Joint Commission. Discover the most comprehensive stroke certification. [Internet]. March 3, 2019. Available from: www.jointcommission.org/certification/dsc_neuro2.aspx

South Korean health and stroke systems

Lee KB, Park HK, Park TH, Lee SJ, Bae HJ, Lee KS, et al. Policy making committee, the Korean Stroke Society. Current status and problems of stroke units in Korea: results of a nationwide acute care hospital survey by the Korean Stroke Society. J Korean Neurol Assoc. 2015;33:141–155. Kim JY, Kang K, Kang J, Koo J, Kim DH, Kim BJ, et al. Executive Summary of Stroke Statistics in Korea 2018: a report from the epidemiology research council of the Korean Stroke Society. J Stroke. 2018;21:42–59. OECD. OECD Reviews of Health Care Quality: Korea 2012: Raising Standards, OECD Reviews of Health Care Quality. Paris: OECD Publishing; 2012. Song, YJ. The South Korean Health Care System. JMAJ. 2009;52(3):206–209. World Health Organization. Regional Office for the Western Pacific. 2015 [Internet]. Republic of Korea health system review. Manila: WHO Regional Office for the Western Pacific. Available from: http://www.who.int/iris/ handle/10665/208215

4

DISORDERS OF CONSCIOUSNESS

Rick Gill, Sean Ruland

Contents Impaired Consciousness.....................................................................................................................................................................................................91 Definition.........................................................................................................................................................................................................................91 Classification.............................................................................................................................................................................................................91 Pathophysiology.............................................................................................................................................................................................................91 Etiologic classification...................................................................................................................................................................................................93 Hypoxic–ischemic encephalopathy......................................................................................................................................................................93 Toxic metabolic encephalopathy...........................................................................................................................................................................93 Meningoencephalitis...............................................................................................................................................................................................94 Autoimmune encephalitis......................................................................................................................................................................................94 Prion diseases (transmissible spongiform encephalopathies).........................................................................................................................95 Seizures and status epilepticus..............................................................................................................................................................................95 Vascular causes.........................................................................................................................................................................................................95 Nonvascular causes..................................................................................................................................................................................................96 Structural lesions resulting in impaired consciousness..........................................................................................................................................96 Patterns of supratentorial brain shift....................................................................................................................................................................96 Clinical assessment........................................................................................................................................................................................................97 Physical examination...............................................................................................................................................................................................97 Investigations..................................................................................................................................................................................................................99 Laboratory assessment....................................................................................................................................................................................................99 CSF analysis...............................................................................................................................................................................................................99 EEG..............................................................................................................................................................................................................................99 Prognosis..........................................................................................................................................................................................................................99 Brain Death...........................................................................................................................................................................................................................99 Definition.........................................................................................................................................................................................................................99 Etiology and pathophysiology....................................................................................................................................................................................100 Clinical features............................................................................................................................................................................................................100 Diagnosis........................................................................................................................................................................................................................100 Established ancillary tests for brain death confirmation................................................................................................................................100 Communication with family and organ procurement organization............................................................................................................100 Persistent/Permanent Vegetative State..........................................................................................................................................................................101 Definition and clinical features..................................................................................................................................................................................101 Diagnostic criteria..................................................................................................................................................................................................101 Etiology and pathophysiology....................................................................................................................................................................................101 Differential diagnosis...................................................................................................................................................................................................101 Prognosis........................................................................................................................................................................................................................102 Minimally Conscious State..............................................................................................................................................................................................102 Definition.......................................................................................................................................................................................................................102 Clinical criteria.......................................................................................................................................................................................................102 Etiology and pathophysiology....................................................................................................................................................................................102 Prognosis........................................................................................................................................................................................................................102 Locked-In Syndrome.........................................................................................................................................................................................................102 Definition.......................................................................................................................................................................................................................102 Etiology and pathophysiology....................................................................................................................................................................................102 Ventral brainstem (bilateral midbrain or upper pontine) lesion..................................................................................................................102 Polyneuropathy.......................................................................................................................................................................................................102 Clinical features............................................................................................................................................................................................................103 Investigations................................................................................................................................................................................................................103 Diagnosis........................................................................................................................................................................................................................103 Treatment......................................................................................................................................................................................................................103 Prognosis........................................................................................................................................................................................................................103

89

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Syncope................................................................................................................................................................................................................................103 Definition and epidemiology.....................................................................................................................................................................................103 Pathophysiology...........................................................................................................................................................................................................103 Basic neurophysiology...........................................................................................................................................................................................103 Basic vascular physiology.....................................................................................................................................................................................103 Etiology...........................................................................................................................................................................................................................103 Clinical assessment......................................................................................................................................................................................................104 History......................................................................................................................................................................................................................104 Physical examination.............................................................................................................................................................................................104 Differential diagnosis...................................................................................................................................................................................................104 Investigations................................................................................................................................................................................................................105 Cardiologic..............................................................................................................................................................................................................105 Diagnosis........................................................................................................................................................................................................................107 Treatment......................................................................................................................................................................................................................107 Neurally mediated reflex syncope.......................................................................................................................................................................107 Orthostatic hypotension.......................................................................................................................................................................................107 Cardiac arrhythmias..............................................................................................................................................................................................107 Structural cardiopulmonary disease...................................................................................................................................................................107 Cerebrovascular syncope......................................................................................................................................................................................108 Prognosis........................................................................................................................................................................................................................108 Hypoxic–Ischemic Encephalopathy...............................................................................................................................................................................108 Definition and epidemiology.....................................................................................................................................................................................108 Pathophysiology...........................................................................................................................................................................................................108 Acute, global brain hypoxia and/or hypoperfusion.........................................................................................................................................108 Delayed postanoxic encephalopathy..................................................................................................................................................................108 Etiology...........................................................................................................................................................................................................................109 Clinical features............................................................................................................................................................................................................109 Mild hypoxia............................................................................................................................................................................................................109 Moderate hypoxia...................................................................................................................................................................................................109 Severe but not sustained hypoxia........................................................................................................................................................................109 Severe and sustained hypoxia..............................................................................................................................................................................109 Delayed postanoxic encephalopathy..................................................................................................................................................................110 Differential diagnosis...................................................................................................................................................................................................110 Investigations................................................................................................................................................................................................................110 Imaging.....................................................................................................................................................................................................................110 Diagnosis........................................................................................................................................................................................................................110 Hypoxic encephalopathy.......................................................................................................................................................................................110 Carbon monoxide poisoning...............................................................................................................................................................................110 Treatment......................................................................................................................................................................................................................110 Postcardiac arrest...................................................................................................................................................................................................110 Carbon monoxide poisoning...............................................................................................................................................................................111 Prognosis........................................................................................................................................................................................................................111 Clinical factors........................................................................................................................................................................................................111 Neurophysiologic tests..........................................................................................................................................................................................111 Neuroimaging.........................................................................................................................................................................................................111 Biochemical markers.............................................................................................................................................................................................111 Osmotic Demyelination Syndrome................................................................................................................................................................................111 Definition and epidemiology.....................................................................................................................................................................................111 Etiology and pathophysiology....................................................................................................................................................................................111 Risk factors....................................................................................................................................................................................................................112 Clinical features............................................................................................................................................................................................................112 Predisposing illness................................................................................................................................................................................................112 Variable clinical illness..........................................................................................................................................................................................112 Differential diagnosis...................................................................................................................................................................................................112 Investigations................................................................................................................................................................................................................112 Diagnosis........................................................................................................................................................................................................................112 Pathology..................................................................................................................................................................................................................112 Treatment......................................................................................................................................................................................................................113 Prevention......................................................................................................................................................................................................................113 Prognosis........................................................................................................................................................................................................................113 References............................................................................................................................................................................................................................113

Disorders of Consciousness

IMPAIRED CONSCIOUSNESS Definition

Consciousness is a state in which a person is awake, alert, and aware of his or her surroundings.

Classification

Consciousness exists on a continuum ranging from an alert cognitively intact state to complete unresponsiveness to any environmental stimuli (i.e. coma). Many terms have been used to describe impaired consciousness, which may lead to confusion when applied inconsistently. A detailed description of the patient’s clinical state including motor postures and responses to various applied stimuli (e.g. verbal, tactile, noxious, etc.) is preferred. Detailed descriptions may not only prevent misinterpretation but also have localizing value. Impaired arousal and attention define disorders of consciousness. As the level of consciousness declines, increasing intensity of stimulation is required to elicit and maintain attention until coma is encountered. Various terms have been used to describe these stages and are described as follows: • Normal consciousness/alert and awake: a state where consciousness is intact. • Obtundation/drowsiness/lethargy/confusion/clouded consciousness/delirium: decreased responsiveness whereby patients are arousable to minor applied stimuli such as verbal or light tactile. Although arousal may be maintained for varying lengths of time following cessation of the stimulus, difficulty is encountered in maintaining consistent attention. • Stupor/profound somnolence: severely depressed level of consciousness such that vigorous and noxious stimulation is required to achieve arousal. Upon cessation of stimulation, these patients immediately lapse back into a more deeply impaired state. • Coma: complete unresponsiveness with the eyes closed whereby a patient is incapable of any purposeful response to stimuli. However, occasional eye opening, reflex flexion or extension of the limbs, grimacing, grunting, or groaning in response to pain, and primitive reflexes may be present. Standardized scoring systems such as the Glasgow Coma Scale (Table 4.1), originally developed and validated for trauma patients, may have clinical and prognostic value in patients with selected etiologies of impaired consciousness. However, the Glasgow Coma Scale has several limitations, and an alternative coma score called FOUR (Full Outline of UnResponsiveness) score (Table 4.2) incorporates respiratory patterns and brainstem reflexes but does not incorporate verbal responses.1

Pathophysiology

Consciousness depends on an intact and interacting brainstem reticular formation and cerebral hemispheres. The reticular formation (from the Latin word reticulum, meaning a net) consists of a network of small and large cells and their connections throughout the brainstem from the medulla to the thalamus. All major sensory pathways project to the reticular formation where they interact before proceeding to the sensory cortex.

91 TABLE 4.1  Glasgow Coma Scale Eyes Open Nil To pain To verbal stimuli Spontaneously Best Verbal Response No response Incomprehensible sounds Inappropriate words Disorientated and converses Orientated and converses Best Motor Response No response Extension (decerebrate rigidity) Abnormal flexion of upper limbs (decorticate rigidity) Flexion – withdrawal to pain Localizes pain Obeys commands Total

Score 1 2 3 4 1 2 3 4 5 1 2 3 4 5 6 15

The ascending reticular activating system (ARAS) originates in the tegmentum of the upper pons and projects through the intralaminar nuclei of the thalamus bilaterally and diffusely to the cerebral cortex. The ARAS influences arousal

TABLE 4.2 FOUR (Full Outline of Unresponsiveness) Score1 Eye Response Eyelids remain closed with pain Eyelids closed but open to pain Eyelids closed but open to loud voice Eyelids open but not tracking Eyelids open or opened, tracking, or blinking to command Motor Response No response to pain or generalized myoclonus state Extension response to pain Flexion response to pain Localizing to pain Thumbs-up, fist, or peace sign Brainstem Reflexes Absent pupil, corneal, and cough reflex Pupil and corneal reflexes absent Pupil or corneal reflexes absent One pupil wide and fixed Pupil and corneal reflexes present Respiration Breathes at ventilator rate or apnea Breathes above ventilator rate Not intubated, irregular breathing Not intubated, Cheyne–Stokes breathing pattern Not intubated, regular breathing pattern Total

Score 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 16

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92

FIGURE 4.1  Herniation of the brain. Left: Uncal and transtentorial herniation. A mass such as a hemorrhage, infarct, or tumor in one cerebral hemisphere displaces the diencephalon and mesencephalon horizontally and caudally. The cingulate gyrus on the side of the lesion herniates under the falx cerebri (top arrow). The uncus of the ipsilateral temporal lobe herniates under the tentorium cerebelli (lower arrows) and becomes grooved and swollen and may compress the ipsilateral oculomotor (cranial nerve III) nerve causing pupillary dilatation (Hutchinson’s sign). The cerebral peduncle opposite the supratentorial mass becomes compressed against the edge of the tentorium, leading to grooving (Kernohan’s notch) and a paresis homolateral to the cerebral mass lesion. Central downward displacement also occurs but is less marked than in the adjacent figure on the right. Right: Central transtentorial herniation. Diffuse or multifocal swelling of the cerebral hemispheres (or bilateral subdural or epidural hematomas) compresses and elongates the diencephalon from above. The mamillary bodies are displaced caudally. The cingulate gyrus is not herniated. (Adapted from Plum F, Posner JB (1985). The Diagnosis of Stupor and Coma, 3rd ed FA Davis, Philadelphia.)

and maintains wakefulness. When the ARAS pathways in the brainstem and/or the bilateral cerebral hemispheres are disrupted, impaired consciousness occurs. While diffuse brain injuries and dysfunction affect the ARAS in an intuitive manner, focal injuries and dysfunction leading to impaired consciousness are more complex: • A focal injury to the upper brainstem will adversely affect ARAS function at its origin. • Cerebellar mass lesions may cause obstructive hydrocephalus leading to increased intracranial pressure (ICP). Direct brainstem compression, upward herniation through the tentorial notch, and downward herniation through the foramen magnum from cerebellar mass lesions may also occur. • Hemispheric lesions must be bilateral to cause ARAS dysfunction in both hemispheres or have substantial mass effect to cause remote injury to the ARAS within the contralateral hemisphere or brainstem. In the case of spaceoccupying supratentorial lesions, the exact mechanism of remote dysfunction is uncertain and several possibilities alone or in combination may occur: • Direct compression of the contralateral hemisphere or upper brainstem (Figures 4.1–4.3). • Contralateral ischemia due to vascular impingement against the tentorium as the vessels emerge through the tentorial notch. • Brainstem ischemia or hemorrhage due to brainstem displacement and vascular torsion (Figure 4.4). • Large and small isolated hemisphere lesions may impair consciousness due to contralateral spread of convulsive and nonconvulsive seizure activity.

FIGURE 4.2  Herniation of the brain. Coronal section of the brain of a patient with a massive right temporal lobe glioblastoma multiforme who died after developing uncal herniation syndrome.

FIGURE 4.3  Coronal section of the brain of a patient with multiple cerebral metastases causing brain swelling; raised ICP; and compression, elongation, and caudal displacement of the diencephalon and medial temporal lobes.

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93 Endocrine dysfunction

FIGURE 4.4  Axial section through the mid pons showing Duret’s hemorrhages in the central core of the brainstem of a patient who died after rapid expansion of an acute lobar intracerebral hemorrhage causing transtentorial herniation, downward displacement of the midbrain and pons, and stretching of the medial perforating arteries of the basilar artery (which is tethered to the circle of Willis and cannot shift downward).

Etiologic classification

Disorders of consciousness can be categorized in multiple ways. Although helpful for considering a differential diagnosis, these classification schemes may overlap. Categories include: • Diffuse or focal. • Toxic or metabolic, structural, and/or functional. • Transient and brief, protracted but reversible, or permanent. Clinical examination, imaging, laboratory investigations, and electroencephalography (EEG) are essential in differentiating between these. Diffuse etiologies account for up to 70% of all disorders of consciousness.

Hypoxic–ischemic encephalopathy This topic is covered later in this chapter.

Toxic metabolic encephalopathy2

Toxic metabolic encephalopathy may impair consciousness either by direct and diffuse neuronal suppression, seizures, or both, depending on the etiology. Neuroimaging does not typically demonstrate acute pathology. EEG usually demonstrates diffuse theta or delta frequency rhythms.

Electrolyte disturbances

• Severe hyponatremia. The rapid correction may lead to osmotic myelinolysis. • Hypernatremia. • Hypocalcemia: may have tetany on examination (e.g. Chvostek’s sign, carpopedal spasm, etc.). • Hypercalcemia. • Seizures may occur in disorders of sodium, calcium, severe hypomagnesemia, and severe hypophosphatemia. • Iatrogenic hypermagnesemia (e.g. eclampsia treatment) can impair arousal and have associated signs of decreased neuromuscular transmission.

• Hypoglycemia: seizures and focal deficits may occur. • Hyperosmolar hyperglycemia with or without acidosis: breath odor of ketones suggests ketoacidosis. • Hypopituitarism. • Thyroid disorders: • Hypothyroidism/myxedema coma: – It may be precipitated by cold, infection, or abrupt discontinuation of thyroid replacement hormone. – Clinical signs include low body temperature, coarse facies, obesity, bradycardia, nonpitting edema, and delayed relaxation of tendon reflexes. Myxedema coma is a life-threatening severe expression of hypothyroidism. • Hashimoto’s encephalopathy/steroid responsive encephalopathy associated with autoimmune thyroiditis: cerebral symptoms in patients with serologic evidence of an autoimmune thyroid disease. • Thyrotoxic storm: hyperpyrexia, tachycardia, agitation, delirium, and psychosis to stupor and coma and clinical examination findings consistent with hyperthyroidism. • Hypoadrenalism.

Renal failure3

• Hypotension may occur during dialysis. • Severe electrolyte disturbances. • Uremia: • May have asterixis (i.e. flapping tremor) and fetid breath odor. • EEG may reveal prominent frontal triphasic waves. • Metabolic acidosis. • Impaired excretion of drugs and other toxins. • Dialysis disequilibrium syndrome may occur in patients recently started on dialysis causing intracerebral fluid shifts leading to lethargy, seizures, and signs of elevated ICP.

Hepatic failure4

• Decreased drug metabolism and endogenous toxin clearance. • Hyperammonemia. • Cytotoxic and vasogenic cerebral edema. • May have asterixis (i.e. flapping tremor) and fetid breath odor. • EEG may reveal prominent frontal triphasic waves.

Sepsis

• Sepsis-associated encephalopathy is a diffuse progressive obtundation in patients with overt infection. • Cytokine-mediated.5 • Systemic infections may become complicated by secondary central nervous system (CNS) involvement (e.g. septic embolism).

Antibiotics

• Fourth-generation cephalosporins, fluoroquinolones, and carbapenem (particularly imipenem) antibiotics can reduce the seizure threshold resulting in clinical or subclinical status epilepticus.

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94 • Cefepime-related encephalopathy can present with myoclonus and impaired consciousness, particularly in patients with impaired renal function.6 • Penicillin neurotoxicity is characterized by impaired consciousness, generalized hyperreflexia, myoclonus, and seizures.7

Acute thiamine depletion (Wernicke’s encephalopathy)8

• Impaired consciousness or confusion, opthalmoplegia (including nystagmus), and ataxia. The full triad is seldom present. This topic is covered in Chapter 17.

Intoxication and pharmacologic causes

• Alcohol ingestion: • Patient odor may suggest alcohol intoxication. • Alcohol intoxication does not preclude concomitant drug use disorder, seizures, and/or structural brain injury. • Sedative/hypnotic drug use disorder (e.g. benzodiazepines, barbiturates, opiates, phenothiazines, and tricyclic antidepressants alone or in combination): • Elderly and those with mild cognitive impairment (MCI), pre-MCI, and dementia are particularly sensitive. • Naloxone may be given diagnostically and therapeutically in suspected opiate toxicity. However, its half-life is comparatively shorter than most opioids, and prolonged monitoring is required. • Flumazenil may acutely reverse suspected benzodiazepine toxicity although it carries a risk of provoking seizures and should be avoided in most circumstances. • Prescription medications in usual dosages may result in an encephalopathy in those with impaired metabolism or clearance such as in the elderly and those with renal or hepatic dysfunction, or when a new agent is introduced with a drug–drug interaction. • Medications with anticholinergic effects (e.g. antihistamines of the H1 and H2 blocker class) can affect susceptible individuals such as those with cognitive impairment associated with acetylcholine deficiency. • Neuroleptic malignant syndrome9: • Precipitated by medications with dopamine receptor antagonist properties or rapid withdrawal of a dopaminergic medication. • Clinical signs may include fever, tachycardia, rigidity, bradykinesia, elevated creatine kinase, and leukocytosis. • Treatment includes discontinuing the offending agent and fever control. Benzodiazepines and dopamine agonist therapy (e.g. bromocriptine) may be useful. • Serotonin syndrome9: • Can be seen in patients taking serotonergic agents in the past 5 weeks. Implicated agents include selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, opiate analgesics, over-the-counter cough medications, antibiotics, weight-reduction agents, herbal products, antiemetics, antimigraine agents, and illicit drugs. • Clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities such as tremor, myoclonus, and hyperreflexia.

FIGURE 4.5  Ventral surface of the brain of a patient who died from acute meningoencephalitis. • The rapid onset of symptoms and hyperkinesia (in contrast to bradykinesia) can help distinguish this from neuroleptic malignant syndrome. • Management includes removal of the offending agents; supportive measures including management of hyperthermia, agitation, and autonomic instability; and the use of 5-hydroxytryptamine (5-HT) 2A antagonists such as cyproheptadine.

Meningoencephalitis (Figure 4.5)10

• Assess history of sick contacts, insect bites, and recent travel. • Fever may be absent. • Nuchal rigidity may be absent with deep coma. • May present with lateralizing signs due to focal predilection (e.g. herpes simplex virus [HSV]) or secondary cerebral infarction. • Obstructive hydrocephalus may be present and must be excluded prior to performing a lumbar puncture.

Autoimmune encephalitis

• Autoimmune encephalitis (AE) can be paraneoplastic, when associated with an underlying malignancy, or nonparaneoplastic and is an increasingly recognized cause for rapidly progressive cognitive decline, psychiatric symptoms, and seizures and movement disorders. • Cerebrospinal fluid (CSF) may show a lymphocytic pleocytosis, and magnetic resonance imaging (MRI) can demonstrate medial temporal hyperintensity, although these studies can be normal (Figure 4.6).

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FIGURE 4.7  Restricted diffusion in the caudate and putamen nuclei and more than two regions of cerebral cortex in a patient with sporadic CJD.

FIGURE 4.6  Bilateral temporal lobe hyperintensity on FLAIR MRI imaging in autoimmune encephalitis. • Group I antibodies (e.g. anti-Hu associated with small cell lung cancer) often target intracellular antigens, these are paraneoplastic and respond poorly to immunomodulatory therapy; group II antibodies target cell surface markers (e.g. anti-N-methyl-d-aspartate [NMDA] receptor encephalitis) and typically respond better to treatment.

Vascular causes

A summary of vascular causes of impaired consciousness is covered below, see Chapter 12 for a comprehensive review of the topic.

Intracranial hemorrhage

• Subdural, epidural, and intracerebral or subarachnoid hemorrhage (SAH) may cause increased ICP. • Intraventricular hemorrhage, which can be primary or associated with intracerebral hemorrhage or SAH, can lead to obstructive hydrocephalus (see Figure 4.4). • In SAH, increased ICP may also result from diffuse cerebral. • Cerebral perfusion pressure (CPP) is calculated as the difference between mean arterial pressure (MAP) and ICP.

Prion diseases (transmissible spongiform encephalopathies)

• Rare, rapidly progressive neurodegenerative disorders. • Creutzfeldt–Jakob disease (CJD) is a human prion disease which is inevitably fatal typically within 1 year of onset. It can be sporadic, iatrogenic, or familial. • Clinical characteristics include progressive dementia plus myoclonus, visual or cerebellar signs, pyramidal/extrapyramidal signs, and akinetic mutism. • EEG may show periodic sharp wave complexes, and MRI may have high signal in the caudate and putamen or at least two cortical regions (Figure 4.7). • CSF may have a positive 14-3-3 assay or the more specific real-time quaking-induced conversion (RT-QuIC) assay.

Seizures and status epilepticus

• Assess for history of epilepsy, evidence of tongue biting, and incontinence. • Postictal state: transient and resolves over minutes to several days proportionate to seizure duration. • Nonconvulsive status epilepticus due to a primary seizure disorder or from other diffuse and focal etiologies of impaired consciousness has been reported in up to 30% of those monitored with continuous EEG.

CPP  =  MAP  −  ICP



• In intracranial hypertension, the CPP decreases as the MAP approaches ICP (Figure 4.8). • Surgical evacuation and/or ventriculostomy may be lifesaving early in the course.

Cerebral infarction

• Malignant middle cerebral artery infarction: decompressive hemicraniectomy may improve outcome in selected patients. • Brainstem infarction: occlusion of the basilar artery can lead to coma or a “locked-in syndrome” (see later). • Cerebellar infarction: • Typically occurs with posterior inferior cerebellar artery infarction. • Early suboccipital decompressive craniotomy should be considered, and ventriculostomy may be used as a temporizing measure.

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96 Psychogenic causes

Assess for a history of psychiatric disorder: • Conversion disorder. • Catatonia. • Malingering.

Structural lesions resulting in impaired consciousness

These account for up to 30% (15% supratentorial and 15% infratentorial) of all disorders of consciousness.

Patterns of supratentorial brain shift (Figures 4.1–4.4 and 4.9) Cingulate herniation (Figure 4.2)

• Occurs when the expanding hemisphere forces the cingulate gyrus under the falx cerebri. • Compression and displacement of the anterior cerebral arteries may occur that lead to infarction in the territory of the anterior cerebral artery.

Uncal herniation (Figure 4.3)

FIGURE 4.8  Noncontrast head CT with diffuse SAH in the basal cisterns with prominence of the temporal horns of the lateral ventricles consistent with an obstructive hydrocephalus.

Cerebral vein thrombosis

• Superior sagittal sinus (SSS) occlusion may cause bilateral cortical injury (i.e. infarction or hemorrhage) and/or increase ICP. • Occlusion of the vein of Galen or straight sinus may cause bilateral thalamic infarction. • May be associated with seizures.

Reversible cerebral vasoconstriction syndrome

11

• Reversible cerebral vasoconstriction syndrome (RCVS) is associated with serotonergic medication, cannabinoids, and stimulants. • Postpartum vasculopathy. • Posterior reversible encephalopathy syndrome (PRES): • Hypertensive encephalopathy. • Eclampsia. • Chemotherapy (e.g. cyclosporine A, FK506, etc.).

Nonvascular causes

• Occurs when expanding lesions in the temporal fossa cause the basal edge of the uncus and hippocampal gyrus to bulge over the incisural edge and displace the adjacent midbrain contralaterally. • The posterior cerebral artery may be caught between the overhanging uncus and the incisural edge causing ipsilateral medial temporal and occipital lobe infarction. • In addition to impaired consciousness, initial signs include contralateral motor deficits and ipsilateral IIIrd nerve dysfunction (e.g. fixed and dilated pupil), either from direct compression or ischemia due to vascular torsion. • Ipsilateral motor signs may develop if the contralateral cerebral peduncle is compressed against the contralateral incisura (i.e. Kernohan’s notch) (Figure 4.9).

Central or transtentorial herniation (Figure 4.9)

• Occurs when the hemispheres, basal nuclei, and diencephalon are displaced through the tentorial notch into the adjoining midbrain. • The vein of Galen is compressed causing venous congestion, edema, and even infarction which lead to more mass effect and further herniation. • The cerebral aqueduct may be compressed compromising CSF circulation. • Obstructive hydrocephalus may contribute to further herniation. • Torsion and avulsion of the brainstem vascular supply may cause brainstem ischemia and hemorrhage.

Clinical assessment includes: • Normal rate and depth of respiration, pupillary reactions, muscle tone, deep tendon and abdominal reflexes, and downgoing plantar responses. • Forced resistance of eye opening. • Slow, roving eye movements and oculocephalic reflex are not present due to suppression from an intact cortex. • Optokinetic nystagmus may be present. • Irrigation of the ears with ice-cold water is noxious and evokes nystagmus with the fast component beating away from the side of the irrigated ear. Associated nausea with vomiting may occur.

TIPS • While traditional teaching emphasized downward displacement of the brain as being responsible for worsening level of sensorium, more recent evidence suggests that horizontal and torsional displacement of the brainstem correlates better with the level of sensorium than vertical displacement.12,13 • Pupillary changes from supratentorial expanding mass lesions also may be due to distortion of the midbrain rather than compression of the IIIrd nerve by the uncus of the temporal lobe.

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FIGURE 4.10  Section through the pons and cerebellar hemispheres, axial plane, showing massive fatal pontine hemorrhage extending into the fourth ventricle. (Courtesy of Professor BA Kakulas, Royal Perth Hospital, Australia.)

FIGURE 4.9  The undersurface of the forebrain at autopsy in a patient who died after transtentorial herniation, showing swelling and grooving of the uncus of the left medial temporal lobe (arrows), which has herniated through the tentorium cerebelli and compressed the midbrain. (Courtesy of Professor BA Kakulas, Royal Perth Hospital, Australia.)

Infections

• Brain abscess: • A solitary supratentorial abscess may cause mass effect. • Multiple cerebral abscesses are common and may affect both cerebral hemispheres. • Cerebellar abscesses may efface the fourth ventricle and cause obstructive hydrocephalus. • CNS complications of bacterial endocarditis: • Can lead to embolization from endocardial vegetations causing cerebral ischemia or intracerebral hemorrhage, infection of the meninges or cerebral abscess, and mycotic aneurysms (Figure 4.10). • Encephalitis: • Herpetic encephalitis has a predilection for the frontal and temporal lobes. • Impaired consciousness may result from mass effect or seizures.

Intracranial neoplasm

• Brain tumors may be primary or metastatic and affect the hemispheres, cerebellum, and brainstem. • Posterior fossa tumors may obstruct the fourth ventricle leading to obstructive hydrocephalus. • Metastatic tumors may be multiple and affect both hemispheres. • Seizures may occur.

Traumatic brain injury

• Head trauma may cause intracerebral, subarachnoid, subdural, and epidural hemorrhage (see above).

• Clinical signs may be focal or diffuse. • Acute bilateral cerebral cortical, subcortical, and thalamic structural injury may result from shear stress (i.e. diffuse axonal injury [DAI]).

Clinical assessment

While assessing a comatose patient, the diagnostic evaluation and management should occur simultaneously.

TIPS • Subjects with a Glasgow Coma Scale score of ≤8 may be unable to protect their airway, and tracheal intubation should be considered. • Before pharmacologically lowering an elevated blood pressure, the effect on cerebral perfusion in the setting of raised ICP should be considered.

Physical examination

The history and physical examination may often yield important clues to the underlying etiology of impaired consciousness. Obtain history from as many collateral sources as possible (e.g. family, friends, emergency medical services personnel, bystanders, etc.). In addition to a detailed general examination looking for evidence of acute and chronic systemic diseases which may cause or contribute to impaired consciousness, pay particular attention to the following physical examination components.

Respiratory

• Adequacy of airway and respiratory effort. Intubate if necessary. • Breathing rate and pattern may suggest the level of brain injury: • Posthyperventilation apnea: bilateral hemisphere dysfunction.

Hankey’s Clinical Neurology

98 • Long-cycle crescendo–decrescendo (i.e. Cheyne– Stokes): diencephalic injury. • Central hyperventilation: midbrain or upper pons injury. • Periodic breathing, yawning, or hiccoughs: brainstem injury. • Ataxic or short-cycle Cheyne–Stokes breathing: medullary injury. • Slow and shallow breathing: drug intoxication. • Deep and rapid breathing: metabolic acidosis (e.g. Kussmaul’s breathing with diabetic ketoacidosis).

Vital signs

• Temperature: • Fever: meningitis, intracranial infection, septic encephalopathy, anticholinergic and neuroleptic medications, and/or seizures. • Hypothermia: environmental exposure, alcohol or sedative intoxication, or hypothyroidism. • Heart rate: • Sinus tachycardia: sepsis, alcohol withdrawal, seizures, neuroleptic malignant syndrome. • Atrial fibrillation: cerebral infarction or intracranial hemorrhage (if receiving anticoagulant medication). • Bradyarrhythmia: global hypoperfusion – intravenous (IV) atropine 0.5–1 mg or pacing may be required. • Blood pressure: • Hypotension: sepsis, hypoxic–ischemic encephalopathy, adrenal crisis, sedative/hypnotic intoxication. Resuscitate with volume expansion and vasopressors as needed. IV hydrocortisone 100 mg q8 hours or 50 mg q6 hours may be required in patients with adrenal insufficiency. • Hypertension may be secondary such as due to seizures or alcohol withdrawal, or it may be primary such as with hypertensive encephalopathy. In patients with hypertensive encephalopathy, judiciously lower MAP by no more than 10% in the first hour and 25% in the first 2–3 hours.

General appearance

• Cyanosis: hypoxemia or shock. • Cherry-red mucous membranes: carbon monoxide poisoning. • Jaundice: hepatic failure. • Petechiae and purpura: bleeding diathesis, intracranial hemorrhage. • Hyperpigmentation: Addison’s disease. • Needle punctures: diabetes or illicit drug use.

Neurologic function

• Position, posture, and spontaneous movements. • Level of consciousness: • Glasgow Coma Scale (see Table 4.1). • Noxious stimuli above (e.g. supraorbital and temporomandibular joint pressure) and below (e.g. sternal rub and nail-bed pressure) the neck: observe for facial grimacing and the amplitude, quality, and symmetry of extremity movement (e.g. localization, flexion, extension, or withdrawal).

• Brainstem function: • Pupillary size and reactivity: – A unilateral dilated and nonreactive pupil is a sign of uncal herniation until proven otherwise. – Nonreactive (fixed) pupils: midbrain dysfunction, anesthesia, anticholinergic (e.g. atropine) medication effect. – Small (pinpoint) pupils: opiate intoxication, pontine injury, pilocarpine ophthalmic drops. – Horner’s syndrome (ptosis, miosis, and anhidrosis): brainstem infarct with or without cerebellar infarction, hypothalamic injury, and carotid dissection. • Fundoscopy: – Papilledema: increased ICP. The absence of papilledema does not exclude raised ICP particularly early after onset, as papilledema may not become manifest for several hours. – Subhyaloid hemorrhages: intracranial hemorrhage. – Retinal emboli, diabetic or hypertensive retinopathy. • Eye position and movement: • A minor degree of ocular divergence is normal in unconscious patients. • Roving eye movements indicate cortical dysfunction with intact brainstem function. • Conjugate horizontal gaze deviation: ipsilateral frontal lobe dysfunction or contralateral low pontine injury or status epilepticus. • Conjugate downgaze: midbrain tectal lesion or compression (e.g. pineal mass and/or hydrocephalus). • Skew deviation: brainstem injury. • Dysconjugate eyes: nuclear or infranuclear oculomotor or abducens nerve injury, or internuclear ophthalmoplegia (i.e. medial longitudinal fasciculus). Bilateral abducens nerve injury may be falsely localizing and due to hydrocephalus or a supratentorial mass lesion causing downward brainstem shift and stretch of the bilateral abducens nerve fibers as they enter the cavernous sinuses. • Ocular bobbing can be seen in low pontine injury. This consists of spontaneous downward jerking eye movement with a slow return to midposition. • Saccadic eye movements suggest functioning frontal cortical gaze centers, vestibular pathways, and oculomotor system. Therefore, spontaneous nystagmus is unlikely in comatose patients. • Oculocephalic reflex (i.e. “doll’s eye” maneuver): rotating an unconscious patient’s head from side to side elicits conjugate eye movement in the opposite direction when the vestibular pathways and oculomotor system are intact. Absence of eye movement(s) suggests brainstem injury. Do not perform this maneuver when cervical spine injury is suspected. • Oculovestibular reflex (i.e. cold caloric testing): instillation of 50 mL of ice-cold water into a patent external acoustic meatus of an unconscious patient with intact vestibular pathways, and oculomotor system elicits tonic conjugate gaze deviation toward the irrigated ear. Conscious patients or those with psychogenic unresponsiveness with intact corticopontine fibers will have a saccadic component that attempts

Disorders of Consciousness

•

•

•

• •

to drive the eyes back to midposition, thus generating the fast phase of nystagmus away from the irrigated side. A dysconjugate or absent response is likely due to brainstem injury. Test both ears independently; testing both ears simultaneously may evoke conjugate downward movement (with upward saccades in a conscious patient). • Corneal responses (mediated by the cranial nerves V and VII): may be suppressed in drug intoxication or deep toxic metabolic coma. Cough and gag reflexes: • Presence indicates intact function of the medulla. • Asymmetric palatal rise indicates ipsilateral medullary injury. • Absence of adequate cough and gag reflexes suggests poor airway protection, and tracheal intubation should be considered. Motor function: • Spontaneous movement: – Purposeful. – Focal or generalized tonic, clonic, or tonic–clonic movements suggests seizures. – Multifocal myoclonus: diffuse cortical irritation due to anoxia or metabolic disturbances; may be induced by tactile stimulation; when not inducible, it may be difficult to distinguish clinically from generalized seizure activity, and EEG may be helpful. Muscle tone: can be increased in neuroleptic malignant syndrome. • Provoked movements: – Localizing noxious stimulation. – Unilateral or bilateral upper extremity flexion (i.e. decorticate posturing) due to unopposed action of the rubrospinal tract due to a lesion above the level of the red nucleus in the midbrain whereby upper extremity flexors predominate. – Unilateral or bilateral extension (i.e. decerebrate posturing) due to predominance of the vestibulospinal tract with impairment of the rubrospinal tract due to a lesion below the red nucleus. – Withdrawal. – Absent. Deep tendon reflexes: amplitude, quality, and symmetry. Plantar responses.

Investigations

• Brain computed tomography [CT] or MRI should be performed in patients with focal neurologic signs or evidence of head injury. • Some structural etiologies may present without lateralizing signs, yet imaging can be diagnostic (e.g. acute obstructive hydrocephalus, SAH, bilateral subdural hematomas, multiple abscesses, and metastases).

Laboratory assessment

• Blood glucose. • Serum electrolytes including sodium, magnesium, phosphorus, and calcium. • Blood urea nitrogen and serum creatinine. • Complete blood count.

99 • Urine analysis and culture, blood, respiratory, and stool cultures when systemic infection suspected. • Prothrombin time and activated partial thromboplastin time (aPTT). • Blood or urine toxicology screening. • Arterial blood gas. • Carboxyhemoglobin level when carbon monoxide exposure suspected. • Serum ammonia and hepatic transaminases. • Whole blood thiamine level when Wernicke’s encephalopathy suspected. • Thyroid function tests. • Plasma and urine osmolality. • Random serum cortisol and cosyntropin stimulation test when adrenal insufficiency suspected.

CSF analysis

• Assess for infection, inflammation, or neoplasm (i.e. carcinomatous meningitis or intracerebral neoplasm with possible shedding of tumor cells into CSF). • Cell count, protein, glucose, Gram stain, cultures, and polymerase chain reaction (PCR) for common microbial infections, and in selected patients, cytology, flow cytometry, paraneoplastic/autoimmune antibodies.

Lumbar puncture is contraindicated in the presence of spaceoccupying lesions that may increase the pressure gradient between intracranial compartments or across the foramen magnum, as it may exacerbate this pressure gradient and precipitate a herniation syndrome, particularly brainstem “coning.”

EEG

• Diffuse or focal slow waves are common. • Frontal triphasic slow waves suggest hepatic, uremic encephalopathy, or fourth-generation cephalosporin (e.g. cefepime) or carbapenem neurotoxicity. • Continuous EEG monitoring may reveal nonconvulsive status epilepticus in up to 30% of patients with impaired consciousness.

Prognosis

The prognosis for patients with impaired consciousness ranges from full recovery to death, and depends on the etiology, duration, and treatment and the presence of comorbid disease states. Patients with toxic metabolic disorders typically show improvement within a few days of correcting the underlying abnormality. However, irreversible brain injury can occur when the metabolic disturbance is severe and/or prolonged. Hypoxic–ischemic and other structural etiologies are more likely to cause permanent brain injury. A detailed discussion of prognosis for each cause of impaired consciousness is beyond the scope of this chapter. However, prognostic indicators for selected disorders will be described in the forthcoming sections.

BRAIN DEATH Definition

The absence of clinically detectable brain functions when the proximate cause is known and demonstrably irreversible. Neuroimaging is necessary in most circumstances to exclude

Hankey’s Clinical Neurology

100 potentially reversible causes. The clinical diagnosis of brain death requires the absence of potentially confounding factors such as neuromuscular blocking agents, deep sedation, severe metabolic disturbances, and hypothermia.

Etiology and pathophysiology

This is a severe injury to the entire brain, including the brainstem, that leads to irreversible whole brain destruction. Etiologies include: • Traumatic brain injury. • Hypoxic–ischemic injury. • Intracranial hemorrhage and malignant hemisphere infarction with brain herniation and elevated ICP. • Intracranial infection: encephalitis, meningitis.

Clinical features

• Coma without cerebral motor response to pain below and above the neck (i.e. sternal rub, nail-bed pressure, pressure over the supraorbital notch, or temporomandibular joint). • Absent pupillary response to bright light. • No oculocephalic and oculovestibular reflexes. Oculocephalic maneuvers should not be performed in patients with suspected cervical spine injury. • Absent corneal reflexes. • Absent jaw jerk reflex. • Absent grimace to noxious stimuli. • Absent pharyngeal reflexes (i.e. gag or cough to deep tracheal suctioning). • Apnea. Apnea must be confirmed by formal testing: • Prerequisites: – Core temperature ≥ 36°C (≥97°F). – Systolic blood pressure ≥ 100 mmHg (may be receiving pharmacologic support). – Normal PO2 (may be in the presence of supplemental oxygen). – PCO2 > 35 mmHg. • Connect a pulse oximeter. • Preoxygenate with 100% O2 for at least 10 minutes, and discontinue ventilator support. • Supplemental oxygen may be administered through a cannula inserted through the endotracheal tube and placed at the level of the carina or T-piece. • Visually monitor for chest wall movement. • Draw a baseline arterial blood gas before beginning the apnea test and after approximately 8–15 minutes off the ventilator, and then reconnect the patient to the ventilator. • If respiratory movements are absent and arterial PCO2 is >60 mmHg, the apnea test supports the diagnosis of brain death. If the patient’s usual baseline PCO2 is ≥40 mmHg (e.g. CO2 retention from chronic obstructive pulmonary disease [COPD]), then the PCO2 must increase by 20 mmHg from usual baseline before the test is deemed positive. • If the PCO2 is kinetic tremor (absent at rest) of upper limbs. • Not associated with other neurological signs.

Epidemiology • • • • •

Most common adult-onset movement disorder. Point prevalence: 300/100,000 (estimates vary widely). Prevalence increases with age. Age of onset: bimodal—young adults and 40–60 years. Gender: M = F.

Pathology

• No characteristic pathological or biochemical findings.

Etiology

• Hereditary: autosomal dominant inheritance (50% of patients). • Responsible gene(s) unknown. • Sporadic: probably the same entity as hereditary ET.

Clinical features

• Postural and kinetic tremor of fingers, hands, and forearms. • When held outstretched. • During specific fine motor tasks (usually visually guided). • In certain arm positions (“position-specific postural tremor”). • Frequency 4–9 Hz. • Bilateral, may be asymmetric. • Amplitude may fluctuate (increased by emotional stress). • Long history of tremor (>5 years) increasing in severity with age. • Improved by alcohol in 50% cases. • Other sites affected: • Head (30–40%), voice (15–20%), legs (15%), jaw, face rest tremor. • Males >50 years. • Female carriers (16–20%) may also develop symptoms.40 • Cerebellar ataxia, parkinsonism, neuropathy, frontal cognitive signs. • Mimics severe ET or MSA cerebellar variant. • MRI brain: middle cerebellar peduncle and corpus callosum T2-hyperintensities.

Symptomatic palatal tremor (myoclonus)

• Regular, continuous, rhythmic (1–3 Hz) contraction of soft palate. • Generated by contractions of levator veli palatini (facial nerve innervated). Other facial innervated muscles may be involved. • Patients can develop a progressive cerebellar syndrome. • Associated with pendular nystagmus. • Movements persist during sleep. • Caused by lesion of the dentato-rubro-olivary pathway (Guillain–Mollaret triangle). • Onset several months after lesion (vascular, inflammatory, traumatic). • Associated with pseudohypertrophy of the ipsilateral olivary nucleus (visible on MRI).

Essential palatal tremor (myoclonus)

• Regular, continuous, rhythmic (1–3 Hz) contraction of soft palate. • Generated by contractions of tensor veli palatini (trigeminal nerve innervated). • Patients present with the complaint of audible clicking due to tensor veli palatini contractions causing opening and closing of the eustachian tube. • Movements stop during sleep. • No olivary hypertrophy. • Many cases now thought to be psychogenic.

Treatment

• Not all patients require treatment. • Propranolol 10–40 mg mane or twice daily (total dose up to 240 mg). • Metoprolol 25 mg twice daily, 50 mg three times daily.

About half of patients experience a reduction in tremor amplitude of up to 50%. The effect is most significant on postural limb tremor. However, not all patients are helped, and the tremor is seldom abolished. Adverse effects and relative contraindications for

192 propranolol include heart failure, bradycardia, hypotension, and asthma. The mechanism of action of propranolol is thought to be a blockade of peripheral skeletal muscle β2-receptors. Selective β1-blockade is less effective than propranolol. • Primidone 62.5–750 mg daily if propranolol is ineffective or contraindicated. May be as useful as beta-blockers, but adverse effects are common. Care is required when introducing primidone because of acute nausea, sedation, and unsteadiness, which may warrant stopping the drug. A low starting dose minimizes adverse effects, particularly if taken in the evening before retiring. There may be no added benefit increasing the daily dose beyond 250 mg. Other drugs that may be helpful but also have adverse effects include gabapentin, topiramate benzodiazepines, and acetazolamide. Patients with alcohol-responsive tremors may find judicious use of alcohol helpful before social engagements. Botulinum toxin may reduce dystonic head tremor but is less effective in upper limb tremor. Stereotactic thalamic surgery targeting the ventral intermediate nucleus of the thalamus is effective in relieving severe tremor refractory to medical therapies in 70–80% of patients. DBS and focused ultrasound lesioning may have fewer side effects than ablative thalamotomy and more significant functional improvement. Bilateral thalamic stimulation may have a lower complication rate than bilateral thalamotomy. Dysarthria and aphonia complicate up to 20–25% of bilateral thalamic lesions (or stimulators).

Prognosis

ET is slowly progressive and tremor becomes disabling in a few patients with age. Other neurological impairments do not occur in ET. Prognosis depends on the tremor of other causes.

MYOCLONUS Definition

Myoclonus is an abrupt, brief, shock-like jerking movements, usually unidirectional, caused by short bursts of muscle activity (positive myoclonus) or brief suppression of volitional muscle contraction leading to a sudden lapse in limb posture (negative myoclonus or asterixis). In most cases it is a symptom of an underlying neurological disease or an encephalopathy.

Classification

• Distribution. • Pattern of occurrence: • Timing: usually irregular, rarely may appear rhythmic and resemble tremor if occurring in runs. • Spontaneous myoclonus—at rest. • Action myoclonus—during voluntary movement. • Reflex myoclonus—in response to a stimulus. – Sound, visual, somatosensory (touch, muscle stretch).

TIP Repetitive action myoclonus may be mistaken for tremor, and intention myoclonus may be difficult to distinguish from intention tremor in cerebellar disease.

Hankey’s Clinical Neurology Physiological classification based on anatomical site of origin

• Cortical myoclonus: • Distal, small amplitude, repetitive. • Often focal. • Stimulus-sensitive reflex (somatosensory), spontaneous, action. • Short duration bursts muscle activity ( childhood > adolescence > adult). Birth, perinatal history, and developmental delay. Evolution of symptoms: onset and progression. Distribution: body parts affected. Precipitating factor: fever, injury, drug or toxin exposure, occupation. • Family history. • Other neurological symptoms, e.g. seizures, ataxia, dystonia, dementia. • Systemic features: organ failure. • • • • •

Examination

• Observe patient at rest with arms relaxed. • Arm outstretched, finger nose, during various tasks (action myoclonus). • Negative myoclonus (asterixis) seen as lapses in sustained postures while patient maintains a tonic muscle contraction such as with the arms outstretched and wrists and fingers extended, or sitting with legs outstretched in front. • While walking (bouncing gait, gait ataxia). • Distribution (focal, generalized), rhythmicity, and amplitude of jerks. • Stimulus sensitivity: • Light touch or gently flicking fingers (reflex myoclonus). • Loud noise or tap nose (brainstem myoclonus, hyperekplexia). • Examine for other neurological signs. • Systemic examination.

Investigations

Investigations including electrophysiological tests help define the site of origin of myoclonus, formulate a differential diagnosis, and guide further investigation.42

Basic tests

• Electrolytes, glucose, renal, hepatic function, drug, toxin screen. • MRI brain, spine. • EEG.

Electrophysiological tests

• EMG: • Cortical myoclonus is characterized by brief jerks caused by EMG bursts of muscle activity (120 ms. • Voluntary jerks are >120 ms and often complex organized contractions of agonist and antagonist muscle groups. • EEG: polyspike and wave discharges suggest cortical origin of myoclonus. Slowing of background rhythms suggests an underlying encephalopathy. Periodic complexes occur in prion disease and SSPE. • Back-averaging EEG prior to jerks: cortical myoclonus is characterized by cortical discharges preceding the myoclonus.

Hyperkinetic Movement Disorders • Cortical SSEP: giant SSEPs in cortical myoclonus. • Measurement of C reflexes in upper limb muscles following median nerve stimulation.

TIP Electrophysiological tests are invaluable in clarifying the presence of myoclonus and identifying the origin.

SPECIAL SYNDROMES Posthypoxic myoclonus (Lance–Adams syndrome)

Follows hypoxia (respiratory arrest > cardiac arrest). Generalized multifocal cortical action myoclonus (typical). Occasionally, stimulus-sensitive cortical reflex myoclonus. Rarely associated with brainstem (reticular reflex) myoclonus. • Myoclonic dysarthria—may be mistaken for stutter or psychogenic speech. • Difficulty standing and walking due to bouncy legs from positive and negative (asterixis) myoclonus and ataxia. • • • •

Startle syndromes

The auditory startle response is a normal brainstem reflex characterized by closure of the eyes; flexion of the neck, trunk, arms; and variable lower limb manifestations. The response in healthy individuals normally habituates quickly on repetitive stimulation. In pathological startle syndromes, the response is exaggerated and does not habituate.

Hereditary hyperekplexia

• Neonatal generalized stiffness when handled. • Exaggerated startle response to auditory stimuli and head retraction reflex to nose taps. • Symptoms decrease during the first years of life. • Noise and surprise elicit generalized myoclonic jerk affecting upper body. • Followed by limb stiffening resulting in a fall if standing. • Startle response does not habituate. • Dominant (80%) or recessive mutations in the α1 subunit of the glycine receptor (GLRA1). • Other genes (rare): SLC6A5, GLRB, GPHN, ARHGEF9. • Treatment: clonazepam, valproate.

Familial cortical tremor and epilepsy

• Autosomal dominant disorder with high penetrance. • Caused by intronic pentanucleotide repeat insertions in several genes. • Onset in the second decade. • Mutations in SAMD12, MARCH6, STARD7, CTNND2, TNRC6A, RAPGEF2, YEATS2. • Cortical tremor affecting mainly the hands. • Frequently associated with generalized myoclonus. • Often associated with generalized or myoclonic seizures that are well controlled with anticonvulsants. • Electrophysiological studies show cortical myoclonus. • Treatment: valproate, levetiracetam, benzodiazepines.

195 Opsoclonus–myoclonus syndrome

• Opsoclonus: involuntary multidirectional saccadic oscillations. • Action myoclonus in limbs or generalized. • Often combined with ataxia. • Antibodies detected in ∼30% of cases.43 • In children women (4:1).

Pathophysiology

• Familial with variable expression but mode of transmission and gene defect not known. • Hypothesis of abnormality in cortico-striato-pallidothalamo-cortical networks causes tics and psychiatric comorbidities. • Enhanced structural connectivity of striatum and thalamus with primary motor and sensory cortices in functional imaging studies.

Diagnosis

• Multiple motor and one or more vocal tics persisting for more than 1 year.44 • Age of onset 5–18 years (usually 4–6 years). • Tics not caused by other neurological condition.

Clinical features

• Onset simple motor tic of face (blink, facial grimace, nose twitch). • Spread from face to neck, shoulder, trunk, limbs. • Vocal tics emerge 1–2 years after motor tics. • Fluctuating course tics wax and wane over time. • Exacerbations (several weeks) interspersed with relative remission. • Peak severity of tics between ages 10 and 12 years. • Tics decrease over time after adolescence but can persist in adulthood. • Echopraxia, echolalia, palilalia common. • Copropraxia, coprolalia (rare, 50, especially females. • Coexisting neurological or medical disease. • Dose and class of neuroleptic. • Duration of drug exposure. • Anticholinergic exposure.

Hyperkinetic Movement Disorders Tardive dystonia

• Less common than tardive dyskinesia. • Tends to occur in men aged 30–40 years. • Cranial, cervical (retrocollis), axial (trunk extension) dystonia. • Remission 10–14% after drug withdrawal. • Commonly associated with: • Akathisia, parkinsonism, tics, stereotypies. • Breathing noises, sniffing.

Treatment

• Stop offending drug: • Consider change of typical to atypical antipsychotic. • Beware of relapse in psychiatric condition. • Transient deterioration in movements may follow cessation. • Stop anticholinergics in tardive dyskinesia. • Symptomatic treatment depending on type of movement disorder: • Vesicular monoamine transporter 2 inhibitor (for dyskinesias). • Botulinum toxin (for craniocervical tardive dystonia). • DBS of the globus pallidus (for tardive dystonia). • Propranolol (for akathisia).

Akathisia

• Sensation of restlessness often associated with anxiety, discomfort, or irritability. • Accompanied by pacing, rocking in place, marching in place, hand rubbing. • Can be acute (onset days or months) or after long-term use of antipsychotic drugs. • Acute akathisia improves after drug withdrawal, but in tardive cases, akathisia worsens.

TIP Anticholinergic drugs do not prevent tardive dyskinesia and may exacerbate established choreiform dyskinesias.

Levodopa-induced dyskinesias in Parkinson’s disease

• Choreic peak-dose dyskinesias. • Dystonic off-period diphasic dyskinesias (lower limbs more affected).

DRUG-INDUCED MOVEMENT DISORDERS Neuroleptic malignant syndrome Definition

A potentially life-threatening condition characterized by fever, severe muscle rigidity, autonomic instability, and changes in mental state induced by initiation or increased dose of dopamine receptor blocking agents or abrupt withdrawal of dopaminergic stimulation.48

Epidemiology

Incidence: 0.01–0.02% of persons on antipsychotics.

199 Etiology

• Neuroleptic antipsychotic drugs (typical and atypical). • Other drugs (nonneuroleptic). • Metoclopramide, prochlorperazine, droperidol, promethazine. • Tricyclic antidepressants, carbamazepine. • Vesicular monoamine transporter 2 inhibitors. • Abrupt withdrawal of dopaminergic medications, amantadine or acute loss of DBS stimulation (parkinsonism– hyperpyrexia syndrome).

Pathophysiology

Profound decrease of central dopaminergic function leading to rigidity and parkinsonism. Sustained muscle contraction causing rigidity results in increased heat production amplified by altered hypothalamic and autonomic thermoregulation, causing fever and rhabdomyolysis.

Clinical features

Gradual onset within a few days of starting treatment with or increasing dose of a dopamine receptor antagonist, rarely after stopping treatment. Risk factors include previous episodes, dehydration, rapid parenteral administration of neuroleptic, pre-existing organic brain disease, psychiatric illness, and taking lithium.

Diagnostic criteria

• Exposure to dopamine antagonist (or dopamine agonist withdrawal) within the past 72 hours. • Hyperthermia (>38°C on at least two occasions). • Autonomic instability (tachycardia, tachypnea, hypertension, hypotension). • Altered mental state—fluctuating level of consciousness and alertness, confusion. • Agitation, restlessness (may precede fever). • Rigidity, parkinsonism, tremor, oculogyric crises. • Akinetic mutism—can manifest as catatonia. • Forms frustes with a milder form or incomplete syndrome can occur. • Elevated creatine kinase. • Can be mistaken for sepsis. • Negative investigations for an alternative cause.

Investigations • • • • •

Leukocytosis. Myoglobinuria. Hypoxia, respiratory, and metabolic acidosis. Dehydration. Urine, blood, CSF examination, cultures to exclude infection.

Differential diagnosis

• CNS disorders: • Infection (viral encephalitis, HIV, postinfectious encephalomyelitis). • Trauma. • Seizures. • Acute dystonic reaction.

Hankey’s Clinical Neurology

200 • Systemic disorders: • Infection (septicemia, tetanus, rabies). • Metabolic encephalopathy. • Endocrinopathy (thyrotoxicosis, pheochromocytoma). • Autoimmune disease (stiff-man syndrome variants especially progressive encephalomyelitis with rigidity, SLE, polymyositis). • Heat stroke (history of physical exertion, no diaphoresis or rigidity). • Drugs/toxins: • Toxins (carbon monoxide, phenols, strychnine). • Food-related allergic reactions. • Drug withdrawal: salicylates, dopamine inhibitors and antagonists, stimulants, MAO inhibitors, anesthetic agents, alcohol, sedatives. • Substance abuse: cocaine, amphetamines. • Central anticholinergic syndrome: fever, dry skin, confusion: – Differentiated from neuroleptic malignant syndrome (NMS) by peripheral signs of atropine poisoning (dry mouth, mydriasis, bowel paresis, urinary retention) and absence of rigidity. • Malignant hyperthermia: autosomal dominant mutation of the ryanodine receptor (RYR1) and other myopathies: – Exposure to volatile anesthetics or depolarizing agents (succinyl choline) triggers persistent muscle contraction, muscle rigidity, rhabdomyolysis, hyperpyrexia, and metabolic acidosis. • Serotonin syndrome (SS): see below. • Catatonia: see below.

Treatment General • • • •

Early recognition. Discontinue offending antipsychotic drugs. Restart dopaminergic drugs (if discontinued). Transfer to intensive care unit: • Hydration, cooling. • Ventilatory assistance if required. • Rhabdomyolysis: alkalinization of urine, renal replacement therapy.

Specific

• Dopamine agonists, levodopa/carbidopa. • Benzodiazepines: midazolam 1–10 mg/h, diazepam 30 mg/ day, lorazepam 3 mg/day. • Dantrolene. • Electroconvulsive therapy (ECT) may be successful in refractory cases.

Prognosis

• The syndrome lasts 7–10 days in uncomplicated cases receiving oral neuroleptics, recovering spontaneously without the need for specific drugs. • Longer course with depot neuroleptics. • Mortality has declined with early recognition and metabolic support. • Medical complications (respiratory, cardiac, renal) in up to 40%. • Contractures may develop.

• Review need for antipsychotics—recurrence in 30% with rechallenge: • If clinically indicated, restart in small dose, titrate slowly. • Use atypical antipsychotics (but can still occur with atypical neuroleptics).

Prevention

• Careful history of prior antipsychotic use and previous complications. • Clear indications for antipsychotic use. • Increases in dose should be made judiciously based on symptom response.

Serotonin syndrome Definition

A potentially life-threatening disorder resulting from excessive stimulation of central and peripheral serotonin receptors by therapeutic or recreational drugs, often when taken in combination.49

Clinical features

• Mental state: fluctuating confusion, restless agitation, akinetic mutism. • Autonomic hyperactivity: mydriasis, tachycardia, diaphoresis, fever, flushed facies. • Hypertonia, hyperreflexia, clonus. • Myoclonus, tremor. • Diarrhea.

Etiology

Drugs associated with the SS: • SSRIs. • Tricyclic antidepressants. • MAO inhibitors. • Lithium. • Anticonvulsants: valproate. • Analgesics: meperidine, fentanyl, tramadol, pentazocine. • Antiemetics: ondansetron, metoclopramide. • Antimigraine drugs (triptans). • Bariatric medications: sibutramine. • Antibiotics: linezolid, ritonavir. • Cough, cold remedies: dextromethorphan. • Amphetamines, cocaine, lysergic acid diethylamide (LSD). • Herbal products: tryptophan, St. John’s wort, ginseng. Drug combinations associated with SS: • • • • • • •

Phenelzine and meperidine. Tranylcypromine and imipramine. Phenelzine and SSRIs. Paroxetine and buspirone. Linezolid and citalopram. Moclobemide and SSRIs. Tramadol, venlafaxine, and mirtazapine.

Diagnosis

• Clinical suspicion. • Serotonergic drug use. • Rule out infections and other causes of hyperthermia.

Hyperkinetic Movement Disorders • Note: overlap in clinical signs of SS and NMS. The onset of SS is more rapid, usually over hours, and CNS hyperexcitability is more prominent.

Investigations

• Elevated creatine kinase. • Raised transaminases. • Leukocytosis.

Treatment

• Stop drug(s)—may resolve rapidly after cessation offending drugs. • Cyproheptadine. • Benzodiazepines (lorazepam). • Propranolol, bromocriptine, dantrolene contraindicated.

Parkinsonism–hyperpyrexia disorder Definition

The syndrome occurs in patients with PD, who abruptly withdraw or reduce dopaminergic medications and is characterized by increased rigidity, hyperthermia, altered mental status,49 clinical features that are similar to NMS.

Etiology

• Acute withdrawal of levodopa or amantadine. • DBS withdrawal (due to battery or device failure). • Also precipitated by an infection or metabolic disturbances.

Investigations • • • • • •

Check DBS settings and battery. Review changes in antiparkinsonian medications. Leukocytosis. Urine, blood cultures to exclude infection. Myoglobinuria. Hypoxia, respiratory, and metabolic acidosis.

Treatment

• Resume antiparkinsonian drugs. • Intermittent or continuous infusion of apomorphine may be required in severe cases. • ECT considered in refractory cases.

Catatonia Definition

A syndrome of abnormal psychomotor behavior characterized by fluctuations from agitation to stupor, involuntary movements, abnormal postures, and autonomic signs. Catatonia is a syndrome first described in psychiatric disorders (schizophrenia, depression), but systemic medical disease accounts for 20% of the cases, 50 and autoimmune disorders are increasingly recognized (anti-NMDAR encephalitis is the most common).

Clinical features • • • •

Prodrome of hyperactivity, restless agitation, distractibility. Delirium, stupor, staring, withdrawn, inertia. Akinetic mutism, “wakeful unresponsiveness.” Abnormal posturing, waxy flexibility, catalepsy, rigidity.

201 • Automatic obedience, echophenomena, utilization behavior. • Stereotypies—repetitive purposeless movements. • Autonomic dysfunction: fever, diaphoresis, tachycardia.

Diagnosis

• Fluctuating clinical state from agitated, hyperkinetic to unresponsive, hypokinetic states is major diagnostic clue. • Improvement with benzodiazepines (especially lorazepam) is supportive of catatonia.

Investigations • • • • • • •

Normal or elevated creatine kinase. Rule our infections (most common cause). EEG (nonconvulsive status epilepticus). Brain MRI (exclude lesions). CSF analysis. Anti-NMDAR and other autoimmune antibodies. Other investigations normal in the absence of medical illness.

Treatment

• Treat underlying etiology. • Supportive therapy (thromboembolism prophylaxis, nutrition). • Benzodiazepines (especially lorazepam)—often dramatic response. • ECT in refractive cases. • High mortality if unrecognized. • May deteriorate with neuroleptic administration.

FUNCTIONAL HYPERKINETIC MOVEMENT DISORDERS Definition

Functional neurological disorders (FND) are characterized by neurological symptoms and signs that are manifestations or expressions of underlying psychological factors rather than organic disease of the nervous system. These factors vary between individuals and are often obscure without features that permit classical psychiatric diagnoses that in the past were labeled under the rubric of conversion disorders, hysteria, or psychogenic disorders. The diagnosis of an FND is made on a clinical basis and relies on the identification of inconsistent and incongruent signs on examination.

Epidemiology

FNDs are estimated to account for up to 20% of patients attending specialist movement disorder clinics. Tremor and dystonia are the most common expressions followed by myoclonus or jerks. Women are more affected than men.

History • • • • • • • • •

Several features are suggestive. Sudden onset and rapid progression. Waxing and waning. Paroxysmal events. Multiple neurological and somatic complaints. Past psychiatric illness. Identifiable stressor(s). Family member with similar neurological illness. Self-inflicted injuries.

Hankey’s Clinical Neurology

202 Examination • • • • • •

Deficits not congruent with known neurological signs. Unexplained variation in examination findings. Disability out of proportion to examination findings. Excessive effort and fatigue. Electrophysiology to characterize movement patterns. Positive signs in PMD:51 • Tremor: – Tremor pauses with contralateral ballistic movements. – Entrainment of tremor rhythm by moving another body part. – Entrainment of rhythm by external cues. – Tremor fully suppressed with mental distraction. – Variability of tremor frequency. – Tonic coactivation of antagonist muscles at tremor onset. • Myoclonus: – Entrainment to external rhythmic cue. – Movement fully suppressed with mental distraction. – Prominent axial jerks. – Variability in jerk distribution and frequency. • Dystonia: – Fixed dystonia at onset (frequently hand or foot). – Lack of overflow phenomenon. – Variable resistance to passive movements. • Tics: – Variable character. – Interference with speech or voluntary actions. – Absence of premonitory urge. – Lack of voluntary transient suppressibility.

Approach to psychogenic movement disorders

• Careful discussion of diagnosis, 52 both with patient and family/caregivers. • Reassure that condition is curable with treatment • Analysis and treatment of triggers. • Rehabilitation, especially physiotherapy. • Psychiatric evaluation to identify and treat underlying psychological disease if present.

REFERENCES

1. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord. 2013;28:863–873. 2. Steeves TD, Day L, Dykeman J, Jette N, Pringsheim T. The prevalence of primary dystonia: a systematic review and meta-analysis. Mov Disord. 2012;27:1789–1796. 3. Balint B, Mencacci NE, Valente EM, et al. Dystonia. Nat Rev Dis Primers. 2018;4:25. 4. Fung VS, Jinnah HA, Bhatia K, Vidailhet M. Assessment of patients with isolated or combined dystonia: an update on dystonia syndromes. Mov Disord. 2013;28:889–898. 5. Meyer E, Carss KJ, Rankin J, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet. 2017;49:223–237. 6. Morales-Briceno H, Mohammad SS, Post B, et al. Clinical and neuroimaging phenotypes of genetic parkinsonism from infancy to adolescence. Brain. 2019;143:751–770.



7. Morales-Briceno H, Chacon-Camacho OF, Perez-Gonzalez EA, et al. Clinical, imaging, and molecular findings in a sample of Mexican families with pantothenate kinaseassociated neurodegeneration. Clin Genet. 2015;87:259–265. 8. Chang FC, Westenberger A, Dale RC, et al. Phenotypic insights into ADCY5-associated disease. Mov Disord. 2016; 31:1033–1040. 9. Gardiner AR, Jaffer F, Dale RC, et al. The clinical and genetic heterogeneity of paroxysmal dyskinesias. Brain. 2015;138:3567–3580. 10. Erro R, Bhatia KP. Unravelling of the paroxysmal dyskinesias. J Neurol Neurosurg Psychiatry. 2019;90:227–234. 11. Tuschl K, Meyer E, Valdivia LE, et al. Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nat Commun. 2016;7:11601. 12. Quadri M, Federico A, Zhao T, et al. Mutations in SLC30A10 cause parkinsonism and dystonia with hypermangnesemia, polycythemia, and chronic liver disease. Am J Hum Genet. 2012;90:467–477. 13. Ortigoza-Escobar JD, Alfadhel M, Molero-Luis M, et al. Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors. Ann Neurol. 2017;82:317–330. 14. Hamilton EM, Polder E, Vanderver A, et al. Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation. Brain. 2014;137:1921–1930. 15. Ha AD, Parratt KL, Rendtorff ND, et al. The phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome. Mov Disord. 2012;27:1034–1040. 16. Kojovic M, Parees I, Lampreia T, et al. The syndrome of deafness-dystonia: clinical and genetic heterogeneity. Mov Disord. 2013;28:795–803. 17. Maas RR, Iwanicka-Pronicka K, Kalkan Ucar S, et al. Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases. Ann Neurol. 2017;82:1004–1015. 18. Riedhammer KM, Leszinski GS, Andres S, StroblWildemann G, Wagner M. First replication that biallelic variants in FITM2 cause a complex deafness-dystonia syndrome. Mov Disord. 2018;33:1665–1666. 19. Eggink H, van Egmond ME, Verschuuren-Bemelmans CC, et al. Dystonia-deafness syndrome caused by a beta-actin gene mutation and response to deep brain stimulation. Mov Disord. 2017;32:162–165. 20. Hayflick SJ, Kurian MA, Hogarth P. Neurodegeneration with brain iron accumulation. Handb Clin Neurol. 2018;147:293–305. 21. Morales-Briceno H, Sanchez-Hernandez BE, Meyer E, et al. Beta-propeller-associated neurodegeneration can present with dominant or isolated parkinsonism. Mov Disord. 2018;33:654–656. 22. Rattay TW, Lindig T, Baets J, et al. FAHN/SPG35: a narrow phenotypic spectrum across disease classifications. Brain. 2019;142:1561–1572. 23. Laganiere S, Boes AD, Fox MD. Network localization of hemichorea-hemiballismus. Neurology. 2016;86:2187–2195. 24. Mencacci NE, Carecchio M. Recent advances in genetics of chorea. Curr Opin Neurol. 2016;29:486–495. 25. Mariani LL, Tesson C, Charles P, et al. Expanding the spectrum of genes involved in Huntington disease using a combined clinical and genetic approach. JAMA Neurol. 2016;73:1105–1114.

Hyperkinetic Movement Disorders 26. Madeo M, Stewart M, Sun Y, et al. Loss-of-function mutations in FRRS1L lead to an epileptic-dyskinetic encephalopathy. Am J Hum Genet. 2016;98:1249–1255. 27. Roulis E, Hyland C, Flower R, Gassner C, Jung HH, Frey BM. Molecular basis and clinical overview of mcleod syndrome compared with other neuroacanthocytosis syndromes: a review. JAMA Neurol. 2018;75:1554–1562. 28. Papandreou A, Danti FR, Spaull R, Leuzzi V, McTague A, Kurian MA. The expanding spectrum of movement disorders in genetic epilepsies. Dev Med Child Neurol. 2019. 29. Baker K, Gordon SL, Melland H, et al. SYT1-associated neurodevelopmental disorder: a case series. Brain. 2018; 141:2576–2591. 30. Srour M, Caron V, Pearson T, et al. Gain-of-function mutations in RARB cause intellectual disability with progressive motor impairment. Hum Mutat. 2016;37:786–793. 31. McMillan HJ, Telegrafi A, Singleton A, et al. Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy. Orphanet J Rare Dis. 2018;13:86. 32. Gauthier J, Meijer IA, Lessel D, et al. Recessive mutations in VPS13D cause childhood-onset movement disorders. Ann Neurol. 2018. 33. Paucar M, Pajak A, Freyer C, et al. Chorea, psychosis, acanthocytosis, and prolonged survival associated with ELAC2 mutations. Neurology. 2018;91:710–712. 34. Traschutz A, Hayer SN, Bender B, Schols L, Biskup S, Synofzik M. TSFM mutations cause a complex hyperkinetic movement disorder with strong relief by cannabinoids. Parkinsonism Relat Disord. 2019;60:176–178. 35. Shanbhag NM, Geschwind MD, DiGiovanna JJ, et al. Neurodegeneration as the presenting symptom in 2 adults with xeroderma pigmentosum complementation group F. Neurol Genet. 2018;4:e240. 36. Costain G, Ghosh MC, Maio N, et al. Absence of ironresponsive element-binding protein 2 causes a novel neurodegenerative syndrome. Brain. 2019;142:1195–1202. 37. Zekeridou A, Kryzer T, Guo Y, et al. Phosphodiesterase 10A IgG: a novel biomarker of paraneoplastic neurologic autoimmunity. Neurology. 2019;93:e815–e822. 38. Morales-Briceno H, Fois AF, Fung VSC. Tremor. Handb Clin Neurol. 2018;159:283–301. 39. Bhatia KP, Bain P, Bajaj N, et al. Consensus statement on the classification of tremors from the task force on tremor

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of the International Parkinson and Movement Disorder Society. Mov Disord. 2018;33:75–87. 40. Hagerman RJ, Hagerman P. Fragile X-associated tremor/ ataxia syndrome—features, mechanisms and management. Nat Rev Neurol. 2016;12:403–412. 41. Balint B, Vincent A, Meinck HM, Irani SR, Bhatia KP. Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology. Brain. 2018; 141:13–36. 42. Zutt R, Elting JW, van Zijl JC, et al. Electrophysiologic testing aids diagnosis and subtyping of myoclonus. Neurology. 2018;90:e647–e657. 43. Armangue T, Sabater L, Torres-Vega E, et al. Clinical and immunological features of opsoclonus-myoclonus syndrome in the era of neuronal cell surface antibodies. JAMA Neurol. 2016;73:417–424. 44. Kurlan R. Clinical practice. Tourette’s syndrome. New Engl J Med. 2010;363:2332–2338. 45. Katherine M. Stereotypic movement disorders. Semin Pediatr Neurol. 2018;25:19–24. 46. Martino D, Hedderly T. Tics and stereotypies: a comparative clinical review. Parkinsonism Relat Disord. 2019;59:117–124. 47. Factor SA, Burkhard PR, Caroff S, et al. Recent developments in drug-induced movement disorders: a mixed picture. Lancet Neurol. 2019;18:880–890. 48. Kipps CM, Fung VS, Grattan-Smith P, de Moore GM, Morris JG. Movement disorder emergencies. Mov Disord. 2005;20:322–334. 49. Rajan S, Kaas B, Moukheiber E. Movement disorders emergencies. Semin Neurol. 2019;39:125–136. 50. Walther S, Stegmayer K, Wilson JE, Heckers S. Structure and neural mechanisms of catatonia. Lancet Psychiatry. 2019;6:610–619. 51. Espay AJ, Aybek S, Carson A, et al. Current concepts in diagnosis and treatment of functional neurological disorders. JAMA Neurol. 2018;75:1132–1141. 52. Stone J, Carson A, Hallett M. Explanation as treatment for functional neurologic disorders. Handb Clin Neurol. 2016;139:543–553.

Recommended reading

Donaldson I, Marsden CD, Schneider S, Bhatia K. Marsden’s book of movement disorders. Oxford, UK: Oxford University Press; 2012.

9

DEVELOPMENTAL DISEASES OF THE NERVOUS SYSTEM

James H. Tonsgard, Nikolas Mata-Machado

Contents Introduction....................................................................................................................................................................................................................... 209 Embryonic Development of the Nervous System...................................................................................................................................................... 209 Formation of the cerebral cortex...............................................................................................................................................................................210 Developmental Malformations of the Nervous System.............................................................................................................................................211 Spinal Dysraphisms...........................................................................................................................................................................................................212 Embryologic classification of spinal dysraphisms.................................................................................................................................................212 Clinical/Radiologic classification of spinal dysraphisms......................................................................................................................................212 Cranial defects..............................................................................................................................................................................................................212 Epidemiology.................................................................................................................................................................................................................212 Etiology and pathophysiology....................................................................................................................................................................................212 Cranial defects..............................................................................................................................................................................................................212 Anencephaly............................................................................................................................................................................................................212 Encephalocele..........................................................................................................................................................................................................212 Cranial meningocele..............................................................................................................................................................................................213 Spinal defects/dysraphisms........................................................................................................................................................................................213 Meningocele............................................................................................................................................................................................................213 Meningomyelocele.................................................................................................................................................................................................213 Spina bifida occulta or isolated vertebral defect..............................................................................................................................................213 Occult spinal dysraphism.....................................................................................................................................................................................214 Diastematomyelia/split spinal cord malformation..........................................................................................................................................214 Clinical Features.................................................................................................................................................................................................................215 Anterior closure defects..............................................................................................................................................................................................215 Anencephaly............................................................................................................................................................................................................215 Cranial encephalocele............................................................................................................................................................................................215 Spinal dysraphisms......................................................................................................................................................................................................215 Meningocele............................................................................................................................................................................................................215 Meningomyelocele.................................................................................................................................................................................................215 Isolated vertebral defect/spina bifida occulta...................................................................................................................................................215 Occult spinal dysraphism.....................................................................................................................................................................................215 Split spinal cord malformation/diastematomyelia..........................................................................................................................................216 Tethered cord syndrome.......................................................................................................................................................................................216 Investigations................................................................................................................................................................................................................216 Cranial encephalocele............................................................................................................................................................................................216 Spinal defects...........................................................................................................................................................................................................216 Diagnosis........................................................................................................................................................................................................................216 Prenatal diagnosis...................................................................................................................................................................................................216 Postnatal diagnosis.................................................................................................................................................................................................216 Treatment......................................................................................................................................................................................................................216 Prognosis........................................................................................................................................................................................................................217 Anterior closure defects........................................................................................................................................................................................217 Spinal and posterior closure defects...................................................................................................................................................................217 Defects in Hindbrain Development...............................................................................................................................................................................217 Definition.......................................................................................................................................................................................................................217 Epidemiology.................................................................................................................................................................................................................217 Etiology and pathogenesis..........................................................................................................................................................................................217 Arnold–Chiari malformations.............................................................................................................................................................................218 Dandy–Walker malformation..............................................................................................................................................................................218 Cerebellar vermis hypoplasia...............................................................................................................................................................................219

205

206

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Joubert’s syndrome.................................................................................................................................................................................................219 Clinical features............................................................................................................................................................................................................219 Arnold–Chiari malformations.............................................................................................................................................................................219 Dandy–Walker malformation............................................................................................................................................................................. 220 Cerebellar vermis hypoplasia.............................................................................................................................................................................. 220 Joubert’s syndrome................................................................................................................................................................................................ 220 Investigations............................................................................................................................................................................................................... 220 Arnold–Chiari malformations............................................................................................................................................................................ 220 Dandy–Walker syndrome and cerebellar vermis hypoplasia....................................................................................................................... 220 Joubert’s syndrome................................................................................................................................................................................................ 220 Diagnosis....................................................................................................................................................................................................................... 220 Treatment..................................................................................................................................................................................................................... 220 Arnold–Chiari malformations............................................................................................................................................................................ 220 Dandy–Walker syndrome.................................................................................................................................................................................... 220 Joubert’s syndrome................................................................................................................................................................................................ 220 Prognosis....................................................................................................................................................................................................................... 220 Arnold–Chiari malformations............................................................................................................................................................................ 220 Dandy–Walker syndrome.....................................................................................................................................................................................221 Joubert’s syndrome.................................................................................................................................................................................................221 Defects in Forebrain and Cerebral Development........................................................................................................................................................221 Definition.......................................................................................................................................................................................................................221 Disorders of Prosencephalic Development...................................................................................................................................................................221 Epidemiology.................................................................................................................................................................................................................221 Etiology and pathophysiology....................................................................................................................................................................................221 Holoprosencephaly................................................................................................................................................................................................221 Agenesis of the corpus callosum.........................................................................................................................................................................222 Septo-optic dysplasia.............................................................................................................................................................................................222 Clinical features............................................................................................................................................................................................................222 Holoprosencephaly................................................................................................................................................................................................222 Agenesis of the corpus callosum.........................................................................................................................................................................222 Septo-optic dysplasia.............................................................................................................................................................................................222 Investigations............................................................................................................................................................................................................... 223 Diagnosis....................................................................................................................................................................................................................... 223 Treatment..................................................................................................................................................................................................................... 223 Prognosis....................................................................................................................................................................................................................... 223 Disorders of Neuronal Proliferation.............................................................................................................................................................................. 223 Primary Microcephaly..................................................................................................................................................................................................... 223 Definition and epidemiology.................................................................................................................................................................................... 223 Etiology and pathophysiology................................................................................................................................................................................... 223 Clinical features........................................................................................................................................................................................................... 223 Investigations............................................................................................................................................................................................................... 223 Treatment..................................................................................................................................................................................................................... 223 Prognosis....................................................................................................................................................................................................................... 223 Disorders of Neuronal Migration.................................................................................................................................................................................. 223 Definition...................................................................................................................................................................................................................... 223 Periventricular nodular heterotopia.................................................................................................................................................................. 223 Lissencephaly 1...................................................................................................................................................................................................... 223 ARX spectrum disorders..................................................................................................................................................................................... 224 Subcortical band heterotopia.............................................................................................................................................................................. 224 Epidemiology................................................................................................................................................................................................................ 224 Periventricular nodular heterotopia.................................................................................................................................................................. 224 Lissencephaly 1...................................................................................................................................................................................................... 224 ARX spectrum disorders..................................................................................................................................................................................... 224 Subcortical band heterotopia.............................................................................................................................................................................. 225 Etiology and pathophysiology................................................................................................................................................................................... 225 Periventricular nodular heterotopia.................................................................................................................................................................. 225 Lissencephaly 1...................................................................................................................................................................................................... 225 ARX spectrum disorders..................................................................................................................................................................................... 225 Subcortical band heterotopia.............................................................................................................................................................................. 225 Clinical features........................................................................................................................................................................................................... 225 Periventricular nodular heterotopia.................................................................................................................................................................. 225

Developmental Diseases of the Nervous System

207

Lissencephaly 1...................................................................................................................................................................................................... 225 ARX spectrum disorders..................................................................................................................................................................................... 225 Subcortical band heterotopia.............................................................................................................................................................................. 225 Investigations and diagnosis..................................................................................................................................................................................... 225 Treatment..................................................................................................................................................................................................................... 225 Prognosis....................................................................................................................................................................................................................... 225 Disorders of Cortical Organization............................................................................................................................................................................... 226 Definition...................................................................................................................................................................................................................... 226 Polymicrogyria....................................................................................................................................................................................................... 226 Schizencephaly....................................................................................................................................................................................................... 226 Epidemiology................................................................................................................................................................................................................ 226 Polymicrogyria............................................................................................................................................................................................................. 226 Bilateral perisylvian polymicrogyria.................................................................................................................................................................. 226 Bilateral frontal polymicrogyria......................................................................................................................................................................... 226 Schizencephaly........................................................................................................................................................................................................227 Etiology and pathophysiology....................................................................................................................................................................................227 Polymicrogyria........................................................................................................................................................................................................227 Schizencephaly........................................................................................................................................................................................................227 Clinical features............................................................................................................................................................................................................227 Polymicrogyria........................................................................................................................................................................................................227 Schizencephaly........................................................................................................................................................................................................227 Investigations and diagnosis......................................................................................................................................................................................227 Treatment......................................................................................................................................................................................................................227 Prognosis........................................................................................................................................................................................................................227 Neurocutaneous Disorders..............................................................................................................................................................................................227 Activation of mTOR pathway....................................................................................................................................................................................227 Neurofibromatosis Type 1............................................................................................................................................................................................... 228 Definition and epidemiology.................................................................................................................................................................................... 228 Etiology and pathogenesis......................................................................................................................................................................................... 228 Clinical features........................................................................................................................................................................................................... 228 Investigations................................................................................................................................................................................................................232 Diagnosis........................................................................................................................................................................................................................232 Treatment......................................................................................................................................................................................................................233 Prognosis........................................................................................................................................................................................................................233 Neurofibromatosis Type 2............................................................................................................................................................................................... 234 Definition and epidemiology.................................................................................................................................................................................... 234 Etiology and pathogenesis......................................................................................................................................................................................... 234 Clinical features........................................................................................................................................................................................................... 234 Hearing loss and vestibular complaints............................................................................................................................................................ 235 Facial weakness...................................................................................................................................................................................................... 235 Motor impairment................................................................................................................................................................................................ 235 Sensory complaints............................................................................................................................................................................................... 235 Seizures.................................................................................................................................................................................................................... 235 Skin........................................................................................................................................................................................................................... 235 Investigations............................................................................................................................................................................................................... 235 Diagnosis....................................................................................................................................................................................................................... 235 Treatment..................................................................................................................................................................................................................... 236 Vestibular tumors.................................................................................................................................................................................................. 236 Meningiomas.......................................................................................................................................................................................................... 236 Ependymomas........................................................................................................................................................................................................ 236 Cataracts and eyes................................................................................................................................................................................................. 236 Hearing loss............................................................................................................................................................................................................ 236 Genetic counseling................................................................................................................................................................................................ 236 Prognosis....................................................................................................................................................................................................................... 236 Tuberous Sclerosis............................................................................................................................................................................................................ 236 Definition and epidemiology.................................................................................................................................................................................... 236 Etiology and pathogenesis......................................................................................................................................................................................... 236 Brain..........................................................................................................................................................................................................................237 Kidney.......................................................................................................................................................................................................................237 Heart........................................................................................................................................................................................................................ 238 Lungs........................................................................................................................................................................................................................ 238

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Clinical features........................................................................................................................................................................................................... 238 Brain......................................................................................................................................................................................................................... 238 Skin........................................................................................................................................................................................................................... 238 Kidney...................................................................................................................................................................................................................... 238 Heart.........................................................................................................................................................................................................................239 Lungs.........................................................................................................................................................................................................................239 Eye.............................................................................................................................................................................................................................239 Investigations................................................................................................................................................................................................................239 Diagnosis........................................................................................................................................................................................................................239 Treatment......................................................................................................................................................................................................................239 Prognosis....................................................................................................................................................................................................................... 240 Sturge–Weber Syndrome................................................................................................................................................................................................ 240 Definition and epidemiology.................................................................................................................................................................................... 240 Etiology and pathogenesis......................................................................................................................................................................................... 240 Clinical features............................................................................................................................................................................................................241 Skin............................................................................................................................................................................................................................241 Eye.............................................................................................................................................................................................................................241 Brain..........................................................................................................................................................................................................................241 Investigations................................................................................................................................................................................................................241 Diagnosis........................................................................................................................................................................................................................241 Treatment......................................................................................................................................................................................................................241 Prognosis........................................................................................................................................................................................................................241 Hereditary Hemorrhagic Telangiectasia.......................................................................................................................................................................241 Osler–Rendu–Weber Syndrome.....................................................................................................................................................................................241 Definition and epidemiology.....................................................................................................................................................................................241 Etiology and pathophysiology................................................................................................................................................................................... 242 Clinical features........................................................................................................................................................................................................... 242 Telangiectases........................................................................................................................................................................................................ 242 Other features........................................................................................................................................................................................................ 243 Investigations............................................................................................................................................................................................................... 243 Diagnosis....................................................................................................................................................................................................................... 243 Treatment..................................................................................................................................................................................................................... 243 Telangiectases........................................................................................................................................................................................................ 243 AVMs....................................................................................................................................................................................................................... 244 Liver......................................................................................................................................................................................................................... 244 Pregnancy............................................................................................................................................................................................................... 244 Prognosis....................................................................................................................................................................................................................... 244 Linear Nevus Sebaceous Syndrome.............................................................................................................................................................................. 244 Definition and epidemiology.................................................................................................................................................................................... 244 Etiology and pathogenesis......................................................................................................................................................................................... 244 Clinical features........................................................................................................................................................................................................... 244 Sebaceous nevus.................................................................................................................................................................................................... 244 Brain......................................................................................................................................................................................................................... 244 Eye............................................................................................................................................................................................................................ 244 Skeletal..................................................................................................................................................................................................................... 244 Investigations............................................................................................................................................................................................................... 244 Diagnosis....................................................................................................................................................................................................................... 244 Treatment..................................................................................................................................................................................................................... 244 Prognosis....................................................................................................................................................................................................................... 244 Cowden’s Syndrome and Lhermitte–Duclos Disease and PTEN Hamartoma Tumor Syndrome................................................................... 245 Definition and epidemiology.................................................................................................................................................................................... 245 Etiology and pathogenesis......................................................................................................................................................................................... 245 Clinical features........................................................................................................................................................................................................... 245 Brain......................................................................................................................................................................................................................... 245 Skin and oral mucosa............................................................................................................................................................................................ 245 Cancer and tumors................................................................................................................................................................................................ 245 Investigations............................................................................................................................................................................................................... 245 Diagnosis....................................................................................................................................................................................................................... 245 Treatment..................................................................................................................................................................................................................... 246 Prognosis....................................................................................................................................................................................................................... 246

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Von Hippel–Lindau Disease........................................................................................................................................................................................... 246 Definition...................................................................................................................................................................................................................... 246 Etiology and pathogenesis......................................................................................................................................................................................... 246 Incontinentia Pigmenti.................................................................................................................................................................................................... 246 Definition and epidemiology.................................................................................................................................................................................... 246 Etiology and pathogenesis......................................................................................................................................................................................... 246 Clinical features........................................................................................................................................................................................................... 246 Skin........................................................................................................................................................................................................................... 246 Brain..........................................................................................................................................................................................................................247 Eye.............................................................................................................................................................................................................................247 Other organ involvement......................................................................................................................................................................................247 Investigations................................................................................................................................................................................................................247 Diagnosis........................................................................................................................................................................................................................247 Treatment......................................................................................................................................................................................................................247 Prognosis........................................................................................................................................................................................................................247 Hypomelanosis of ITO......................................................................................................................................................................................................247 Definition and epidemiology.....................................................................................................................................................................................247 Etiology and pathogenesis......................................................................................................................................................................................... 248 Clinical features........................................................................................................................................................................................................... 248 Skin........................................................................................................................................................................................................................... 248 Noncutaneous abnormalities.............................................................................................................................................................................. 248 Investigations............................................................................................................................................................................................................... 248 Diagnosis....................................................................................................................................................................................................................... 248 Treatment..................................................................................................................................................................................................................... 248 Prognosis....................................................................................................................................................................................................................... 248 References........................................................................................................................................................................................................................... 248

INTRODUCTION This chapter is divided into two sections: (1) developmental malformations of the nervous system and (2) neurocutaneous disorders. Many of the neurocutaneous disorders could easily be considered in a discussion of tumors of the nervous system. However, several of the disorders show significant developmental abnormalities that justify their inclusion in this chapter. Furthermore, as discussed below, the nervous system emerges from the ectoderm of the primitive embryo from which the skin, as well as portions of the skull and face, also develops. As a consequence, germline or early somatic mutations of the ectoderm may produce defects in both the skin and nervous system resulting in neurocutaneous disorders.

EMBRYONIC DEVELOPMENT OF THE NERVOUS SYSTEM In order to understand the diseases in this section, it is essential to have at least some familiarity with developmental biology. By the time of implantation in the uterine wall, the embryonic cell mass produces a bilaminar disk composed of two layers: the epiblast (future ectoderm) and the hypoblast (future endoderm). Gastrulation is the process by which the bilaminar disk is converted into a three-layer disk with the formation of an intervening layer, the future mesoderm. This process begins by day 14–15 when a stripe of thickened epiblast appears – the so-called primitive streak. The cranial end of the primitive streak develops a central

depression, the primitive pit. The primitive streak is an area of intense mitotic activity. Ectodermal cells migrate toward the primitive streak and pass inward through the primitive pit to the interface between the ectodermal and endoderm. These cells then migrate laterally to form the mesoderm. On day 17, mesodermal elements fuse along the midline to form the notochord. The newly formed notochord secretes signaling molecules, which induces the overlying ectoderm to differentiate into a specialized neuroectoderm. The neuroectoderm produces precursor cells on the dorsal surface along the anterior– posterior axis of the disk and form the neural structures while the notochord becomes the axis of the developing vertebral column. As neuronal precursor cells proliferate, they form a neural plate which indents, forming a groove with ridges or folds on either side (Figure 9.1a). As the folds fuse in the midline to form the neural tube, the neural tube separates from the ectoderm. The neural tube forms by day 23 (Figure 9.1b). Cells at the margins of the folds separate from the neural tube and form the neural crest, the precursor of both the autonomic and peripheral nervous systems. Mesenchyme migrates dorsally between the skin and neural tube to form the meninges, neural arches of the vertebrae, and paraspinal muscles. Closure of the anterior end of the neural tube occurs by day 24 and the posterior end by day 29. Closure of the neural tube is a continuous process that proceeds from as many as five different sites along the anterior–posterior axis (Figure 9.2). The caudal end of the neural plate is located near S2. The remaining sacrococcygeal elements of the spinal cord and filum terminale are formed by the process of secondary neurulation when closure of the posterior end of the neural tube is complete. During secondary neurulation, a secondary neural tube is formed caudad to the posterior neuropore. In this process, a

Hankey’s Clinical Neurology

210 Surface ectoderm Neural crest

Neural fold Pericardial bulge (heart) Otic placode Somites

Neural tube Edge of amnion Amnion

Neural groove a

Day 22 Anterior neuropore Pericardial bulge Somites Posterior neuropore

b

Day 23

FIGURE 9.1  Development of the nervous system and closure of the neural tube. (a) Dorsal and transverse section through the embryo at day 22 at the start of closure of the neural tube. (b) Dorsal view at day 23, with closure of the anterior neuropore beginning, while the posterior neuropore remains open. (Adapted with permission of Sinauer Associates, Gilbert SF, Developmental Biology, 6th ed.)

2

2 4

4

3 1

1

5 a

Formation of the mature nervous system is dependent on the induction or formation of precursor cells, followed by the proliferation and maturation of cells within periventricular

Midbrain Mesencephalon

Hindbrain Metencephalon Myelencephalon

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Formation of the cerebral cortex

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mass of undifferentiated mesenchymal cells appears as a result of fusion of the ectoderm with the lower portion of the notochord. The secondary neural tube is formed by a complicated process that involves apoptosis as well as formation of vacuoles or cysts, which coalesce into a tube that then merges with the previously formed spinal canal (formed in primary neurulation). The segments formed in this process become the conus medullaris and the filum terminale. The undifferentiated mesenchymal cells contribute to the notochord, gastrointestinal (GI) tracts, and the blood vessels supplying these structures. The differentiation of the developing cord is guided by a number of signaling molecules secreted by the surrounding structures. These molecules include fibroblast growth factor, the homeobox family (Sax1), paired box family (Pax6), Iroquois family (Irx3), sonic hedgehog and retinoic acid, and prickle-1 protein. Induction of the nervous system is regulated by genes controlling dorsal–ventral longitudinal organization and genes affecting the anterior–posterior axis, creating transverse divisions or segments. Patterning of the dorsal–ventral axis results in four longitudinal domains of the central nervous system (CNS). Patterning along the anterior–posterior axis results in segmentation of the CNS into the forebrain, midbrain, hindbrain, and spinal cord (Figure 9.3). The rostral end of the neural tube undergoes extensive changes, forming three dilations or segments: the prosencephalon or forebrain, the mesencephalon or midbrain, and the rhombencephalon or hindbrain. The prosencephalon divides transversely to form the telencephalon and diencephalon. Lateral division or cleavage of the telencephalon produces two paired structures, which become the cerebral hemispheres. The rhombencephalon eventually divides into the metencephalon, which becomes the pons and cerebellum, and the myelencephalon, which becomes the medulla (Figure 9.3).1

5 c

FIGURE 9.2  Closure of the neural tube. (a) Normal fetus with the putative sites of neural closure numbered with arrows showing the direction of closure; the number of closure sites is debated. (b) Anencephaly caused by failure of fusion of the anterior neuropore. (c) Spina bifida caused by failure of closure of the posterior neuropore. (Adapted with permission of Sinauer Associates, Gilbert SF, Developmental Biology, 6th ed.)

Forebrain Diencephalon Telencephalon

FIGURE 9.3  The early embryonic brain is divided into three segments: forebrain, midbrain, and hindbrain. Cleavage of the telencephalon of the forebrain produces two paired structures that become the cerebral hemispheres. The metencephalon becomes the pons and cerebellum, while the myelencephalon becomes the medulla.

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germinal centers and finally, migration to their intended sites. A cross section of the developing brain shows that it is initially organized into an outer pial (preplate) or marginal zone (MZ) and inner ventricular zone (VZ) (Figure 9.4a). Stem cells proliferate and differentiate into immature neurons and glial precursors within the VZ and subventricular zone (SVZ). Starting in the seventh fetal week, neuroblasts in the VZ migrate upward to form a subpial preplate zone (PP). Subsequently, neurons migrate into the PP (Figure 9.4c1). These neurons divide, with some forming the superficial molecular layer or MZ (layer I) and others moving to the deep subplate. Thereafter, waves of neurons pass through the subplate, successively forming layers VI, V, IV, III, and II in an inside-out pattern, with the last neurons moving into layer II (Figure 9.4b, c3). The majority of primitive neurons migrate radially or upward along glial fibers that extend from the VZ to the outer molecular layer. However, some neurons move tangentially or laterally within the VZ and SVZ, and intermediate zone (the future white matter [WM]). Radial and tangential movements are determined by characteristics of the radial glial fibers as well as a number of molecules (BLBP, ErbB4 receptor, and Notch receptors). The molecules that contribute to movement include cytoskeletal proteins (filamin A, doublecortin, Lis 1, ARFGEF2), signaling molecules (reelin), molecules modulating glycosylation that provide stop signals, neurotransmitters, neural cell adhesion molecules, and growth factors. Toxins such as alcohol and cocaine may also affect this process. Migration of neurons primarily occurs between the 12th and 24th fetal weeks.

Neurons within the subplate are transient and proliferate between 22 and 34 weeks’ gestation, form synaptic connections between the deep nuclei of the brain and the cortex, and express regulatory protein receptors, neurotransmitter receptors, and growth factor receptors. Cells that remain within the VZ become the ependyma lining the ventricles. The relatively cell-free area between the cortical plate and the VZ becomes the WM of the mature brain. Myelination is under the control of the glial elements and occurs during the first 2 years of postnatal life and beyond.2 Thus, the development of the brain can be understood as a complicated series of processes that includes induction, fusion, bending, proliferation, patterning, segmentation, cleavage, differentiation, migration, mitotic arrest, and finally myelination. Blood vessel formation and vascular proliferation are also of critical importance.

DEVELOPMENTAL MALFORMATIONS OF THE NERVOUS SYSTEM Malformations of the nervous system may be broadly classified into: • Spinal dysraphisms. • Brain malformations: • Cranial defects. • Abnormal segmentation and sulci formation.

a

3 I

Lateral ventricles Ventricular zone (VZ) Subventricular zone (SVZ) Neocortex c b

MZ CP SP

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III CP

1

IV

II/III IV

SP PP

V VI

II MZ

V IZ

IZ

VI SVZ

IZ SVZ VZ

VZ

VZ

WM

FIGURE 9.4  Development of the cortex. (a) An axial section of the immature brain. (b) Successive waves of neuron migration beginning with the deepest cortical layers. (c) 1: The first immature neurons migrate from the ventricular zone (VZ) through the intermediate zone (IZ), to form the preplate (PP). 2: Subsequently, migrating neurons (green), moving along radial glial fibers (brown), split the PP into the marginal zone (MZ) and the subplate (SP) and begin to form the cortical plate (CP). The MZ contains Cajal–Retzius cells (white) that control the position of the migrating neurons. 3: The mature CP has six defined layers (I–VI), while the MZ, SP, and VZ have disappeared and the IZ has become the white matter (WM).

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212 • Abnormal proliferation and migration of neuronal cells and precursors. • Agenesis–hypoplasia.

SPINAL DYSRAPHISMS The spinal dysraphisms can either be classified embryologically or by their clinical/radiologic manifestations.

Embryologic classification of spinal dysraphisms

• Anomalies of gastrulation/disorders of notochord development: • Neurenteric cysts. • Split spinal cord malformations (SSCM; diastematomyelia). • Dermal sinus. • Disorders of primary neurulation: • Myelomeningocele. • Myeloschisis. • Lipomas with dural defects (lipomyelomeningocele and lipomyeloschisis). • Anomalies of secondary neurulation: • Filar lipoma. • Tight filum terminale. • Elongated spinal cord. • Persistent termina ventricle. • Anomalies of unknown origin: • Cervical myelocystocele. • Meningocele.

Clinical/Radiologic classification of spinal dysraphisms

• Open spinal dysraphisms: • Myelomeningocele, myeloschisis, hemimyelomeningocele, hemimyelocele. • Closed spinal dysraphisms: • With subcutaneous mass: – Lumbosacral: – Lipomas with dural defect and lipomyeloschisis. – Terminal myelocystocele and meningocele. • Cervical: – Cervical myelocystocele, cervical myelomeningocele. – Meningocele. • Without subcutaneous mass: • Doral enteric fistula. • Split cord malformation. • Dermal sinus. • Intradural lipoma, filar lipoma. • Tight filum terminale. • Elongated spinal cord. • Persistent terminal ventricle, neurenteric cysts. • Spinal segmental dysgenesis.

Cranial defects

• Anencephaly. • Encephalocele, cephalocele

Epidemiology

The incidence varies widely in different populations. In the United States, neural tube defects (NTDs) occur in 1 of every 1000 pregnancies. The recurrence risk in siblings is 2–5%, representing as much as a 50-fold increased risk over the general population. Defects in closure of the cranium are more frequent than closure defects of the spine. The incidence of anencephaly is 9.4 per 100,000 births and is more common in Hispanic infants and girls. The incidence decreased 20% with the mandatory fortification of foods with folic acid.

Etiology and pathophysiology

Defects in folding, fusion, or closure of the neural tube occur between days 20 and 29 of gestation. Defects involve a variable portion of the dorsal midline structures of the primitive neural tube including its covering of meninges, bone, and skin. Defects can occur anywhere along the neural axis. Defects can also result in the formation of the notochord and secondary neurulation. Both genetic and environmental factors are known to play a role in NTDs. NTDs are associated with a number of genetic syndromes and chromosomal abnormalities, but no one single gene has been implicated as a causative agent. Several of the genes involved in folate-dependent pathways have been implicated in NTDs, although the exact mechanism is unknown. Some mothers with NTDs during pregnancy appear to have autoantibodies to folate receptors. Folate supplementation is thought to bypass competitive blocking autoantibodies. NTDs also can be induced by toxins such as retinoic acid and valproic acid, and there is an increased incidence in infants of diabetic mothers.

Cranial defects Anencephaly

Anencephaly is a lethal condition in which there is an absence of both cerebral hemispheres and the cranial vault. The undeveloped brain lies in the base of the skull as a small vascular mass of neural tissue (Figure 9.5). Anencephaly is clearly caused by a defect in the anterior neuropore. • Most anencephalic infants are stillborn. • There is a striking variation in prevalence with the highest prevalence in the United Kingdom and Ireland, and the lowest in Asia, Africa, and South America. • Females are more affected than males. • It is the most frequent of the cranioschises.

Encephalocele

Encephalocele is a herniation of intracranial contents including the brain and meninges. It is a mass protruding from the skull, most commonly in the occipital area (Figure 9.6). Frontal encephaloceles are much less common, but are more frequent in the Asian population. Basal defects involving the sphenoid or ethmoid sinuses also are seen. The amount of herniated neural tissue in the defect is variable and in part determines severity of the deficits. The cause of encephaloceles is unclear although they are clearly defects in closure of the anterior neural tube. Nasofrontal lesions are thought to be due to defective separation of the neural and surface ectoderm at the site

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213 nervous tissue. The mass appears as a fluid-filled protrusion covered either by a membrane or skin in the midline, and it is not associated with any neurologic deficit. Meningoceles may occur anywhere along the neuroaxis. Their embryologic origin is unclear.

TIP • Encephaloceles are defects in the skull, commonly associated with Dandy–Walker and Klippel–Feil syndromes, Arnold–Chiari malformation, porencephaly, agenesis of the corpus callosum, cleft palate, and several chromosomal disorders. These associations affect outcome.

Spinal defects/dysraphisms Meningocele

FIGURE 9.5  Sagittal section of a pathologic specimen of a dead fetus with anencephaly showing absence of the cranial vault and its contents. of closure of the anterior neuropore. Occipital encephaloceles may be due to defective segmentation of the bones of the posterior cranium.

Cranial meningocele

Cephalocele is a herniation of intracranial contents through a defect in the skull. It is classified depending on the contents. A cranial meningocele is a protrusion of meninges without any

FIGURE 9.6  Encephalocele. Sagittal T1-weighted MRI of the brain showing a defect in the suboccipital area in a patient with a Chiari III malformation, and herniation of hypoplastic cerebellar tissue (yellow arrow) and meninges (red arrow) through the bony defect.

Meningocele is a protrusion of meninges without accompanying neural tissue through a spina bifida. It is most commonly in the lumbar or sacral spine but also can occur in the thoracic or cervical area. Meningoceles are covered by normal skin and are thought to arise from ballooning of the meninges through a posterior spina bifida due to pressure from cerebrospinal fluid (CSF), but their embryologic origin is unclear. Meningoceles in cranial and upper cervical spine can be associated with aqueductal stenosis, Arnold–Chiari malformations, and hydromyelia (Figure 9.6).

Meningomyelocele

Meningomyelocele is a cystic protrusion in the midline that involves the spinal cord, nerve roots, meninges, vertebral bodies, and skin. Myelomeningocele is due to a failure of closure of the neural tube, which results in malformation of the vertebrae and spinal cord. There is sometimes a split cord malformation in which case the dorsal portion is a hemicord and other portion of the cord is ventral to the lesion. Meninges and spinal cord or roots protrude through the defect in the neural arch as a dural sac containing spinal cord or roots closely applied to the body of the sac (Figure 9.7). Meningomyeloceles are commonly associated with hydrocephalus due to an accompanying Arnold– Chiari malformation (Figure 9.8) (see the section Defects in Hindbrain Development). Aqueductal stenosis is a less common cause of hydrocephalus in meningomyeloceles. Characteristics of meningomyelocele include: • The lumbosacral area is the most common location. • Thoracic defects are less frequent and associated with more complications. • The lumbosacral and thoracic defects account for 90% of meningomyeloceles. • When the cervical spinal cord is involved, two distinct types of abnormalities are seen: a myelocystocele herniating posteriorly into a meningocele (Figure 9.8) and a meningocele without an underlying cord defect.

Spina bifida occulta or isolated vertebral defect

This is the most common form of closed spinal dysraphism. It is characterized by failure of fusion of the vertebral body dorsal to

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FIGURE 9.9  Diastematomyelia. Tl-weighted axial MRI of the lumbar spine showing the neural tissue (yellow arrows) passing around the bony bar (red arrow) with a misshapen vertebral body.

Occult spinal dysraphism

An occult spinal dysraphism is spina bifida occulta associated with: FIGURE 9.7  Sagittal T1-weighted MRI of the lumbosacral spine showing a lumbosacral meningomyelocele (red arrow) and narrowing of the elongated lumbar cord with cord tethering (yellow arrow). the spinal cord. Radiologic findings in addition to the defect in the posterior vertebral arch may include widening of the spinal canal, fusion of vertebral bodies, and fused or malformed lamina. Abnormalities of overlying skin are common including nevi, dermal sinus, dimple, hemangioma, lipoma, or hair. It commonly involves the lamina of L5 and S1. The incidence is about 5% of the population. When there is any associated neurologic deficit, it is called an occult spinal dysraphism.

FIGURE 9.8  Chiari II malformation. T1-weighted MRI midline sagittal view of the brain and upper cervical cord showing elongated brainstem with downward displacement of the cerebellum and obliteration of the fourth ventricle (arrows).

• • • • • •

Fibrous bands causing distortion of the cord. Intraspinal lipoma. Dermoid or epidermoid cyst. Fibrolipoma, subcutaneous lipoma. Diastematomyelia. Commonly results in the tethered cord syndrome (TCS).

Diastematomyelia/split spinal cord malformation

SSCM is the currently preferred term for what was previously called diastematomyelia. The embryologic origin is related to the persistence of the accessory neurenteric canal (ANC). Embryologically, the endodermally derived yolk sac is initially connected to the ectodermally derived amnion through a primitive neurenteric canal. This structure exists only transiently. However, persistence of adhesions between the endoderm and ectoderm, called the ANC can result in abnormal development of vertebrae and spinal cord, as well as anomalies of the GI tract, enteroenteric fistula, and genitourinary abnormalities. The spinal lesions due to the persistence of the ANC include split notochord syndrome, neurenteric cysts, dorsal dermal sinus tracts and cysts, sacral meningeal cysts, and SSCM. In SSCM, there is a splitting or duplication of the spinal cord. In SSCM, there is a midline longitudinal division of the spinal cord due to a septum (Figures 9.9, 9.10). The septum is made of bone, cartilage, or fibrous tissue attached posteriorly to the vertebrae or dura and may extend for as many as 10 spinal segments (thoracic or lumbar). In type 1 SSCM, each hemicord has a full thecal sac and meningeal and nerve roots covering with a a double spinal canal. In type 2 SSCM, the two hemicords are surrounded by one thecal sac and there is a single spinal canal. Terminal SSCM anomaly is thought to have a different embryologic origin related to abnormal secondary neurulation. SSCM is usually associated with a hairy patch, dimple hemangioma, lipoma, or teratoma overlying the defect (Figure 9.11).

Developmental Diseases of the Nervous System

215 to stimuli that are purely spinal reflexes. Neuroendocrine defects are frequent due to pituitary hypoplasia.

Cranial encephalocele

Small frontal encephaloceles protruding into the nasal cavity may cause no neurologic signs; trauma to frontal defects may result in CSF rhinorrhea or infection. Occipital encephaloceles are associated with mental retardation, seizures, motor dysfunction, and visual defects. The degree of disability depends both on the amount of neural tissue in the encephalocele and the other conditions associated with the defect.

Spinal dysraphisms Meningocele

A meningocele in the thoracic or lumbar cord that is covered by skin is unlikely to be associated with any deficits. Cervical meningoceles are associated with hydrocephalus, and severe motor deficits due to the associated defects mentioned above.

Meningomyelocele FIGURE 9.10  Diastematomyelia. T2-weighted MRI, midline sagittal view showing a bony bar (arrow) across the center of the spinal canal.

CLINICAL FEATURES Anterior closure defects Anencephaly

Anencephaly is incompatible with life; most fetuses are stillborn. Some infants survive for several days and demonstrate responses

The location determines the type and severity of complications; lumbosacral defects are the most common, and thoracic and cervical lesions tend to be more complicated. Characteristics include: • • • • • • •

Variable weakness of the legs. Loss of bowel and bladder control. Sensory defects that can result in skin ulceration. Deep tendon reflexes are absent. Dislocation of the hips may occur. Hydrocephalus is common. Infection may complicate closure of the defect or treatment of the hydrocephalus. • Growth of child stretches the spinal cord causing the tethered cord syndrome (TCS).

Isolated vertebral defect/spina bifida occulta

This is not associated with any clinical deficits, and it is often associated with changes in the overlying skin, such as hyperpigmentation, hair, discoloration, dimple, or dermal sinus (Figures 9.11, 9.12).

Occult spinal dysraphism

This is associated with clinical deficits; the degree of deficits is variable and sometimes severe: • • • • FIGURE 9.11  Photograph of the lower back of a patient with spina bifida occulta showing a tuft of hair over the site of the spinal defect and a vertical surgical scar.

Absent Achilles’ tendon reflexes. Incontinence, sensory loss in the feet or legs. Gait abnormalities. Static deficits and progressive dysfunction can be seen with growth. • Sometimes the defect goes unnoticed until late childhood when increase in height results in stretching of the cord. • A common presentation is the TCS.

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• Plain spine X-rays to look for a Klippel–Feil defect. • Chromosome studies for chromosomal abnormalities, genetic diseases, or syndromes.

Spinal defects

Including meningocele, meningomyelocele, spina bifida occulta, occult spinal dysraphisms, and SSCM. • X-rays of the spine delineate the vertebral abnormalities: failure of fusion of one or more vertebral arches, hemivertebrae, block vertebrae, or a bony spur. • MRI of the spine is essential to delineate these defects. • Ultrasound is useful to investigate sacral dimples or dermal sinus tract and can demonstrate intradural lipomas as well as low-lying conus in infants. • Urodynamic studies are helpful in patients with TCS.

Diagnosis Prenatal diagnosis FIGURE 9.12  Sagittal postcontrast T1 MRI of lumbar spine showing a dermal sinus tract extending from the skin to the sacral canal (arrow) with associated intraspinal infection.

Split spinal cord malformation/diastematomyelia This is always associated with clinical symptoms, including: • Progressive scoliosis. • Overlying cutaneous abnormality. • TCS.

Tethered cord syndrome

TCS is caused by stretch-induced injury to the caudal spinal cord due to attachment of the filum terminale to caudal structures. This may occur independently or be associated with other dysraphisms. Embryologically, it is due to abnormal development of the caudal mass in secondary neurulation. In TCS, the spinal cord is attached to inelastic structures caudally such as fibrous or fatty filum, tumor, meningocele, myelomeningocele, or septum (as in SSCM). In TCS, the conus fails to ascend within the spinal canal/dural sac as the child increases in height. Onset of symptoms occurs in late childhood or later, including: • Progressive sensorimotor deficits in the legs or feet (most patients especially young children). • Severe pain in the perineum, gluteal region, or legs (common in older children). • Midline cutaneous lesions (many but not all patients). • Bowel and bladder dysfunction (frequent). • Upper motor neuron signs coexist with symptoms of conus dysfunction (rare).

Investigations Cranial encephalocele

• Magnetic resonance imaging (MRI) of the brain defines the amount of neural tissue contained in the defect and shows other associated defects such as agenesis of the corpus callosum, Dandy–Walker malformation, and Arnold–Chiari malformation.

Enhanced birth defect screen or AFP3/AFP4, measuring alpha fetoprotein, dimeric inhibin A, beta human chorionic gonadotropin, and unconjugated estradiol, is commonly used at 15–20 weeks’ gestation to evaluate the potential for NTDs and chromosomal anomalies. Based on the results of this screening, pregnant women may be referred for amniocentesis. Maternal gene MTHFR 677T is a risk factor for meningomyelocele.

TIPS • Elevated levels of amniotic fluid alpha fetoprotein and acetyl cholinesterase are found in patients with open NTDs. • Prenatal ultrasound is effective in diagnosing the NTDs with the exception of the occult dysraphisms.

Postnatal diagnosis

Ultrasound, plain X-rays, and MRI as discussed above.

Treatment Prevention

Because of the markedly increased risk for recurrence of NTDs in subsequent pregnancies, mothers of children with NTDs should receive appropriate genetic counseling and screening. Mandatory folate supplementation of foods has helped to reduce the incidence of some NTDs. Because NTDs are associated with exposure to seizure medicines, women with seizures should receive appropriate counseling and evaluations regarding their seizure medicines.

TIPS • Folic acid supplementation of at least 4 mg/day reduces the risk of NTDs by as much as 70%. • Folic acid is a water-soluble B vitamin that is essential for cell function, division, and differentiation.3

Prenatal treatment

Intrauterine repair of a myelomeningocele reduces spinal fluid leakage in the back and prevents or reverse herniation of the hindbrain (Chiari II malformation) in patients prior to 25 weeks’

Developmental Diseases of the Nervous System gestation, although there are maternal and fetal risks.4 A randomized controlled trial of fetal surgery showed a substantial reduction in need for CSF shunting in the treated group as well as improved developmental quotient. Intrauterine surgery is, however, associated with a higher risk of preterm delivery, pulmonary complications in infants and obstetrical complications, and a higher infant mortality rate.

Postnatal treatment

• Prompt closure of meningomyeloceles reduces the risk of infection and improves subsequent function. • Ventriculoperitoneal shunting is required for patients with hydrocephalus. • Patients with loss of sphincter control require a daily regimen of catheterization and bowel emptying. • Patients with meningomyeloceles should have a coordinated multidisciplinary team to deal with urologic, orthopedic, neurologic, and neurosurgical complications. • Treatment of tethered cord depends on the cause. Surgical intervention is required in patients with progressive deficits, severe pain, or progressive scoliosis.

Prognosis Anterior closure defects

• Anencephaly is a universally lethal condition. • Occipital encephaloceles are associated with mental retardation, seizures, variable motor dysfunction, and frequent visual impairment.

Spinal and posterior closure defects

• Meningoceles and spina bifida occulta are not associated with any neurologic sequelae. • Meningomyelocele: • Overall, long-term mortality rate has improved and approaches zero in recent series for sacral and lumbar lesions. Outcome is largely dependent on the need for ventriculoperitoneal shunting. • 65% require ventricular peritoneal shunting. • 50% are ambulatory and 50% attend regular school and achieve at an age-appropriate level. • Patients do face a lifetime of disability with potential motor problems, shunt infections and shunt failures, and chronic urinary catherization. • Occult spinal dysraphisms, SSCM, and TCS have a variable response to surgical intervention: • Pain is relieved or improved in almost all patients. • Motor function is improved in 25–80%. • Bowel and bladder function improves in 16–67%. • Scoliosis is improved or stabilized in 43–67%.5

DEFECTS IN HINDBRAIN DEVELOPMENT Definition

Arnold–Chiari malformations are the most common of the defects involving the lower hindbrain or medulla. The central feature of all of the Chiari malformations is downward

217 displacement of the cerebellar tonsils and brainstem through the foramen magnum: • Chiari type I malformation is the most common cause of syringomyelia. It is defined by downward displacement of the cerebellar tonsils by at least 5 mm in adults or adolescents. • Chiari type II is more severe than type I and is almost invariably associated with myelomeningocele. In type II, the tonsils protrude into the spinal canal, and there is obstruction of CSF outflow causing obstructive hydrocephalus. • Chiari type III is rare and associated with a cervical encephalocele and meningocele. • Chiari type IV consists of cerebellar hypoplasia, and there is no herniation of the brain. It is probably unrelated to the other types. • In Chiari type 0, there is minimal to no herniation of the cerebellar tonsils, but there is often syringomyelia and symptoms suggestive of obstruction of CSF outflow. • Dandy–Walker syndrome is the best known of the defects affecting the cerebellum. In this syndrome, there is hypoplasia of the cerebellar vermis and cystic dilation of the fourth ventricle. • Cerebellar vermis hypoplasia is hypoplasia of the cerebellar vermis without a posterior fossa cyst. • Malformations associated with the “molar tooth” sign, including Joubert’s syndrome, are a group of malformations affecting the midbrain.

TIPS • Chiari type I malformation consists of downward displacement of the cerebellar tonsil and brainstem in isolation. • Chiari type II consists of elongation of the medulla, often associated with kinking or folding of the medulla, and it is invariably associated with a meningomyelocele.

Epidemiology

Arnold–Chiari type I malformations are common incidental finding; the exact incidence is unknown. It is frequently discovered in late childhood or adolescence. Chiari type II malformations are by definition associated with meningomyelocele and are apparent at birth. The Dandy–Walker malformation is primarily a sporadic condition. The incidence varies widely: 1 in 5000 to 1 in 50,000 live births. The Dandy–Walker malformation has been reported in association with a number of chromosomal anomalies. Cerebellar vermis hypoplasia is a rare disorder that is X-linked in some patients and apparent in infancy. Inferior cerebellar vermian hypoplasia appears to be a distinct entity that may be due to a defect in chromosome 8q13. Joubert’s syndrome is a rare autosomal recessive disorder associated with multiple genetic mutations.

Etiology and pathogenesis

Development of the posterior fossa is a complicated process that begins after neural tube closure and after the brain has divided into three primary structures: the prosencephalon, mesencephalon, and rhombencephalon. The pons, cerebellum, and medulla

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218 are derived from the rhombencephalon; the cerebellum is derived from the most rostral portion of the hindbrain, the pons from the next portion of the hindbrain or metencephalon, and the medulla from the lower portion of the hindbrain or myelencephalon. Only the midbrain is derived from the mesencephalon. A number of genes have been identified in the subdivision, bending, and patterning process that forms the structures of the midbrain and hindbrain. The first parts of the cerebellum develop between 6 and 7 weeks’ gestation. The cerebellar vermis is fully developed by 4 months’ gestation, and the cerebellar hemispheres develop between 5 and 7 months of fetal life. However, the cerebellum is not fully developed until 20 months of life.6

Arnold–Chiari malformations Type I

• Elongation of the medulla. • Downward displacement of the medulla and cerebellar tonsils through the foramen magnum (Figure 9.13). • Hydromyelia and syringomyelia occur in 30–70% of patients. This is a cystic dilation of the central canal of the spinal cord that can be progressive and extend for several vertebral segments (Figure 9.14). Syringobulbia, i.e. fluid within the brainstem, is also sometimes seen (Figure 9.15).

Type II

• The medulla is elongated and sometimes folded, causing thinning of the upper cervical cord and upward displacement of cervical roots (Figure 9.16). • Vascular injury to the medulla may also occur. • The pons is often thin. • Aqueductal stenosis or compression of outflow of the fourth ventricle causes hydrocephalus. • Hydromyelia and syringomyelia of the cervical cord also occur. • Meningomyelocele is invariably associated. • Increased gyri, heterotopias of the brain, and Klippel–Feil syndrome can be associated with type II malformation.

FIGURE 9.13 Chiari I malformation. Midline sagittal T1-weighted MRI showing displacement of the cerebellar tonsils (arrow).

FIGURE 9.14  Syringomyelia. Sagittal T1-weighted MRI of the cervical spine showing displacement of cerebellar tonsils (red arrow) and a large bead-like syrinx (blue arrows) extending into the thoracic cord.

Type III

• Cerebellar herniation. • High cervical or occipital–cervical meningomyelocele. • Open, dystrophic posterior fossa.

Dandy–Walker malformation

• Posterior fossa is enlarged. • Tentorium and lateral sinuses are displaced upward. • Cerebellar vermis is hypoplastic or absent and upwardly displaced.

FIGURE 9.15  Syringomyelia and syringobulbia. T1-weighted sagittal MRI of the brain and brainstem and upper cervical cord showing herniated cerebellar tonsils (red arrow), cervical syrinx (yellow arrows), and syringobulbia (blue arrow) extending to the level of the pontomedullary junction.

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219 Cerebellar vermis hypoplasia

• The vermis is small but in a normal position relative to the brainstem. • There is a retrocerebellar fluid collection, not a cyst, which does communicate with the fourth ventricle. Inferior cerebellar vermis hypoplasia appears to be a distinct entity.

Joubert’s syndrome • • • •

There is an abnormally deep interpeduncular fossa. Hypoplasia of the vermis. Elongated superior cerebellar peduncles. Fourth ventricle is also enlarged so that axial views of the midbrain have a molar tooth appearance (Figure 9.18).

Clinical features Arnold–Chiari malformations Type I

FIGURE 9.16  Chiari II malformation. Sagittal Tl-weighted MRI of brainstem and cervical cord showing elongation of the medulla, with downward displacement of the medulla and cerebellar tonsils. • Cerebellar hemispheres are simplified and displaced upward. • Fourth ventricle is enlarged and deformed and cyst like (Figure 9.17). • Third and lateral ventricles are usually enlarged, and hydrocephalus is frequently present. • Associated other defects include agenesis of the corpus callosum, a variety of cortical malformations, aqueductal stenosis, Klippel–Feil syndrome, and a variety of somatic malformations.7

FIGURE 9.17  Dandy–Walker malformation. CT of the brain shows absence of the midline cerebellar vermis and a large posterior fossa cyst communicating with the fourth ventricle (red arrow) and dilated lateral ventricles (yellow arrows).

• May be noted incidentally on MRI imaging and remain asymptomatic. • Symptoms may appear in late childhood or adolescence. • Headaches, neck pain, ataxia, and problems with gag or swallowing; sometimes headache will be worse with coughing or Valsalva’s maneuver. • Ataxia, nystagmus (particularly downbeat nystagmus), extensor plantar responses, posterior column signs, and scoliosis can be seen.

Type II

• Meningomyelocele. • Hydrocephalus.

Type III

• Cervical meningomyelocele. • Not usually compatible with life.

FIGURE 9.18  Joubert’s syndrome. Axial FLAIR MRI of the brainstem shows distortion of the fourth ventricle (red arrow) and prominent, elongated superior cerebellar peduncles (yellow arrows) forming a molar tooth sign.

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220 Dandy–Walker malformation

Diagnosis

Cerebellar vermis hypoplasia

Treatment Arnold–Chiari malformations Type I

• • • •

Presentation is in infancy. Large head, back of the head is large and flattened. Hypotonia, and developmental delay. Hydrocephalus often brings these children to clinical attention. • Nystagmus, apnea, and seizures are frequent. • Rarely, patients die suddenly from uncal herniation. • Mental impairment is frequent, but as many as 50% have normal intelligence.

• Similar presentation to the Dandy–Walker malformation. • X-linked form appears to be associated with severe mental retardation, seizures, choreoathetosis and spasticity, and coarse facial features. Inferior cerebellar vermian hypoplasia is a distinct entity that is associated with mild motor and language deficits.

Diagnosis is made by MRI of the brain. Chiari malformation is pathologic if the tip of the cerebellar tonsils is more than 5 mm below the foramen magnum after the first decade of life. Prior to that, the tonsils may need to be more than 6 mm below the foramen magnum. Dandy–Walker syndrome is diagnosed by the presence of all of the features on MRI. Joubert’s syndrome and other midbrain malformations are readily recognized by the presence of the molar tooth sign on MRI.

• Intervention is not without controversy, because patients may be found to have the MRI finding incidentally. • It is important not to intervene unless the patient is symptomatic. • Some symptoms such as headache, neck pain, incontinence, or difficulties with coordination are nonspecific and may not respond to treatment.

Joubert’s syndrome • • • •

Hypotonia, developmental delay. Nystagmus or oculomotor apraxia. Apnea and seizures. Wide spectrum of severity, with some patients severely retarded. • Somatic defects including retinal dystrophy, coloboma, renal disease, and hepatic fibrosis.

Investigations Arnold–Chiari malformations

• MRI of the brain. • MRI of the spine is essential to look for a syrinx of the cord as well as to assess the meningomyelocele that accompanies types II and III. • Dynamic CSF flow studies can be useful in assessment of the adequacy of posterior fossa CSF flow around the cerebellar tonsils. • Plain X-rays are helpful in diagnosing associated vertebral anomalies.

Dandy–Walker syndrome and cerebellar vermis hypoplasia

• MRI of the brain is essential in diagnosing and evaluating these syndromes. • MRI of the brain is also important in identifying other potentially associated brain abnormalities. • Genetic testing is indicated as it is linked to multiple gene defects.

Joubert’s syndrome

• MRI of the brain. • Visual assessment including electroretinography (ERG) is recommended. • Chromosome testing. • Sleep study is important because of the frequency of apnea. • Imaging of the kidneys because of kidney dysplasia in some patients. • A large variety of genetic mutations have been found.

TIP • Surgical decompression of the posterior fossa should only be done in patients who have a cervical cord syrinx and progressive or intractable symptomatology. Intervention is not based on the degree of displacement of the tonsils.

Type II

• The majority have hydrocephalus and require a ventriculoperitoneal shunt. • In utero repair of the meningomyelocele reduces the incidence of hydrocephalus, but it is not without risks.

Dandy–Walker syndrome

• Shunting procedure to treat the accompanying hydrocephalus. • When the posterior fossa cyst clearly communicates with the ventricles, a cystoperitoneal shunt may be sufficient. It is not uncommon, however, for patients to have both a ventriculoperitoneal shunt and a shunt of the cyst. • Management of seizures. • Intellectual assessments.

Joubert’s syndrome

• Patients may require respiratory support. • Feeding difficulties related to poor oral motor coordination may require a gastrostomy tube. • Seizures require treatment but are usually not severe problems. • Vision, kidney, and liver function must be assessed regularly because of associated complications.

Prognosis Arnold–Chiari malformations Type I

Surgical decompression is not without complications including pseudomeningocele, CSF leaks, meningitis, and a cerebellar slump in which the enlargement of the foramen magnum is too

Developmental Diseases of the Nervous System generous. Some patients also appear to have an inflammatory reaction to certain types of patches used for the duraplasty to close the posterior fossa. Results of decompression vary in different series with 45–86% of patients with type I Chiari and syrinx showing objective signs of improvement.

Type II

See discussion of meningomyelocele.

Type III

This defect is associated encephalocele, apnea, respiratory insufficiency, dysphagia, and hypotonia with death within the first year of life.

Dandy–Walker syndrome

• Compatible with a fairly normal life span. • Seizures are usually not extremely difficult to treat. • Patients may require revisions of their ventricular and cyst shunts. • Rarely, patients die unexpectedly from uncal or tonsillar herniation.

Joubert’s syndrome

There is substantial variability in the severity of the condition. The vast majority of patients survive the neonatal period and show improvement in breathing, motor function, and feeding over time.

DEFECTS IN FOREBRAIN AND CEREBRAL DEVELOPMENT Definition

A large number of defects in the formation of the cerebral hemispheres have been identified. These defects are organized according to the developmental processes involved: 1. Disorders of prosencephalic or forebrain development, which are largely defects in cleavage: holoprosencephaly (HPE), agenesis of the corpus callosum, and septo-optic dysplasia (SOD). 2. Disorders of neuronal proliferation: primary microcephaly (MCPH). 3. Disorders of neuronal migration: periventricular heterotopia, lissencephaly 1, Aristaless-related homeobox (ARX) spectrum disorders, and subcortical band heterotopia. 4. Disorders of cortical organization: polymicrogyria (PMG) and schizencephaly.

221 Etiology and pathophysiology Holoprosencephaly

HPE is a defect in which there is impaired midline cleavage of the embryonic forebrain. Classically there is a failure to divide sagittally into cerebral hemispheres, transversely into telencephalon and diencephalon, and horizontally into olfactory tracts and bulbs. Less severe forms have been identified so that it is customary to further divide these defects into alobar, semilobar, lobar, and middle interhemispheric HPE. An identifiable genetic cause represents 15–20% of cases, both monogenetic and chromosomal. Multiple genes have been linked to HPE including sonic hedgehog, zinc finger of the cerebellum, TGIF, and others. Trisomy 13, trisomy 18, and triploidy have also been linked to HPE. Teratogens such as hyperglycemia (diabetes mellitus), alcohol, and retinoic acid are implicated in some cases.

Alobar holoprosencephaly

• Small single ventricle without an interhemispheric fissure (Figure 9.19). • Thalami are undivided. • Corpus callosum and the olfactory tracts and bulb are absent.

Semilobar holoprosencephaly • • • •

Rudimentary cerebral hemispheres are present (Figure 9.20). Interhemispheric fissure is incomplete. Corpus callosum is largely underdeveloped. Olfactory tracts and bulbs are either absent or hypoplastic.

Lobar holoprosencephaly • • • • •

Cerebral hemispheres are well formed. Interhemispheric fissure is incomplete. Corpus callosum is usually absent or incomplete. Thalami are not completely separated. Olfactory bulbs and tracts are absent or hypoplastic.

Middle interhemispheric

• This variant is rare. • The posterior frontal and parietal areas have midline continuity. • The anterior frontal lobes and occipital regions are separated.

DISORDERS OF PROSENCEPHALIC DEVELOPMENT Epidemiology

Disorders of prosencephalic or forebrain cleavage that survive to delivery are uncommon (1 in 10,000–15,000 live births), but the incidence is higher in spontaneous abortions where it may occur in 1 in 250. It can be a recessive, autosomal dominant, or sexlinked condition. The sex ratio in alobar HPE is 3:1, female:male. There is no sex predilection for the lobar form. The incidence of agenesis of the corpus callosum and hypoplasia of the corpus callosum is 1.8 per 10,000 live births, and of SOD is 1 in 10,000 live births.

FIGURE 9.19  Alobar holoprosencephaly. CT of the brain shows a single ventricle, absence of the corpus callosum, and smooth simplified cortex with fused thalami.

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There are two separate groups of SOD patients: one group exhibits a high incidence of cortical malformations, and the second group appears to be within the HPE spectrum. Mutation in the HESX gene has been implicated in some patients, but a genetic cause cannot be identified in most.

Clinical features Holoprosencephaly Alobar HPE

FIGURE 9.20  Semilobar holoprosencephaly. Axial T1-weighted MRI of the brain shows persistent fusion of the frontal lobes, with partial segmentation of the temporal and occipital lobes, and the posterior horns of the lateral ventricles.

Agenesis of the corpus callosum

Agenesis of the corpus callosum is often part of the HPE spectrum (Figure 9.21). The corpus callosum has four parts (from front to back): rostrum, genu, body, and splenium. Formation starts with the genu and then progresses front to rear. If development is incomplete, the posterior portion is absent. • Seen in a variety of chromosomal disorders and genetic syndromes. • Autosomal recessive as well as X-linked inheritance have been demonstrated. • In some cases, advanced maternal age may be a contributing variable.

Septo-optic dysplasia

A heterogeneous group of disorders with midline brain abnormalities: • Hypoplasia or absence of the septum pellucidum and corpus callosum. • Optic nerve hypoplasia. • Pituitary/hypothalamic dysfunction.

FIGURE 9.21  Agenesis of the corpus callosum. Sagittal T1-weighted MRI of the brain, with absence of the corpus callosum and partial visualization of posterior horn of the lateral ventricle.

There is a variable number of severe facial dysmorphic features including cyclopia, nasal proboscis, hypotelorism, single nostril nose, absence of olfactory tracts and bulbs, median cleft lip, hypognathia, single maxillary incisor, pituitary hypoplasia or even absence, and iris coloboma (Figure 9.22). Amentia is a feature, sometimes with response to sensory stimuli and social smiling. Other defects include meningomyelocele; Dandy–Walker malformation; and heart, skeletal, and GI defects.

Semilobar and lobar HPE and middle interhemispheric

These include facial dysmorphism: ocular hypo- or hypertelorism, flat nose, cleft lip, iris coloboma. Pituitary abnormalities including diabetes insipidus are commonly found.

Agenesis of the corpus callosum

• This is an extremely heterogeneous group, associated with at least 50 congenital syndromes (including Aicardi’s syndrome), chromosomal disorders, and metabolic diseases. 8 • High incidence of cardiac, musculoskeletal, genitourinary, and GI defects. • >50% have other malformations of the CNS. • Mental impairment and seizures are frequent.

Septo-optic dysplasia

Patients with SODs are a heterogeneous group. Visual defects, including nystagmus, diminished acuity, and color blindness are found in all patients, as well as micro-ophthalmia and coloboma

FIGURE 9.22  Autopsy photograph of a patient with alobar holoprosencephaly showing severe facial dysmorphisms including a small head, single nasal proboscis, and cyclopia.

Developmental Diseases of the Nervous System of the iris or retina. Pituitary abnormalities occur in 62%, including diabetes insipidus. Mental retardation, spastic quadriplegia, and seizures are also present.

Investigations • • • • •

MRI of the brain. Plain skeletal X-rays. Tests of electrolytes and endocrine and pituitary function. Echocardiogram and renal ultrasound. Patients with seizures require electroencephalography (EEG) to characterize their seizure type. • Chromosomal testing as well as specific gene testing.

Diagnosis

Diagnosis is made by MRI of the brain.

Treatment

Treatment depends on the associated defects. These patients require a coordinated multidisciplinary team to treat their various problems. Because of the association with pituitary defects, particularly diabetes insipidus, careful monitoring of serum electrolytes and fluid intake is essential. Appropriate nutritional support usually requires placement of a gastrostomy tube. Patients with seizures require seizure medicines. Patients with cleft lip and palate require repair if they survive beyond the first 6 months of life. Because the spectrum of severity can be quite wide, the decision to repair any cardiac defects depends on the individual patient.

Prognosis

The spectrum of severity is quite wide, but life expectancy in most of these patients is reduced. Alobar HPE is probably not compatible with life beyond infancy. Patients with milder defects may survive into childhood or beyond and deserve appropriate and careful support.

DISORDERS OF NEURONAL PROLIFERATION PRIMARY MICROCEPHALY Definition and epidemiology

Primary microcephaly (MCPH) is a congenital reduction in brain size (usually 4 or more standard deviations [SDs] below age and sex means), in the absence of other gross structural abnormalities both within and outside the brain. MCPH has now been described with different phenotypes. Both autosomal dominant and autosomal recessive forms have been described. The incidence varies in different ethnic groups from 1 in 10,000 in northern Pakistan to 1 in 2 million in Scotland.

Etiology and pathophysiology

MCPH appears to be a primary disorder of neurogenic mitosis in which there are reduced numbers of neurons. Eight genetic loci have been found and five of the genes identified. All of the MCPH proteins appear to be ubiquitous and localize to the centrosome for at least part of the cell cycle. Normal head measurements have been documented up to 20 weeks’ gestation. Head growth declines subsequently.

223 After birth, the head size is 4–12 SDs below the mean. Thereafter, the degree of MCPH remains unchanged. Pathology shows: • Simplification of the cortical gyral pattern and reduction in brain volume. • Slight reduction in white matter (WM) volume. • The architecture of the brain is normal, with no evidence of any migrational defect.

Clinical features

• Mental retardation but the degree of mental retardation is only mild to moderate. • Motor milestones are slightly delayed, and speech is significantly delayed, but most children learn to talk. • Height and weight are usually normal. • Seizures are reported in some patients. • No spasticity or cognitive decline is present.

Investigations

MRI of the brain to look at the structure, computed tomography (CT) scan of the brain to look for calcification, eye examination to rule out congenital infection, TORCH titers to rule out congenital infection.

TIPS • MCPH must be distinguished from other genetic and nongenetic causes of microcephaly such as congenital infection, fetal alcohol syndrome, fetal irradiation, cocaine exposure, and Rubinstein–Taybi syndrome. • The head size in MCPH is at least 4 SDs below the mean, but the brain otherwise appears to be normal. A head circumference less than 3 SDs below the mean, especially associated with reduced height or weight, is more likely to be due to nongenetic causes.

Treatment

These patients usually do not require specific treatment.

Prognosis

Patients with MCPH tend to be happy children with reasonable motor coordination. They can be taught daily living skills and may have some ability to read and write. Life expectancy is normal.

DISORDERS OF NEURONAL MIGRATION A number of defects in neuronal migration have been identified. A complete review is beyond the scope of this chapter; here, four defects will be discussed. One of these defects, subcortical band heterotopia, shares a genetic basis with lissencephaly 1.9

Definition Periventricular nodular heterotopia

Ectopic neurons occur, located along the wall of the lateral ventricles, often bilaterally (Figure 9.23). Heterotopias also may occur as a single lesion adjacent to the ventricle or in the superficial WM.

Lissencephaly 1

In classical lissencephaly or type 1 lissencephaly, the brain is nearly devoid of gyri and the cortical mantle is thickened

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224

FIGURE 9.23  Periventricular nodular heterotopia. T2-weighted axial MRI of the brain shows gray matter ependymal nodules along the ventricular surface (arrows). (pachygyria) (Figure 9.24). The brain therefore has a smooth surface due to the absence or near absence of gyri. Microscopically, the brain lacks the normal six-layered structure of the cortex. A variety of disorders are associated with this appearance.

ARX spectrum disorders

These disorders result in X-linked mental retardation in males, due to a defect in radial and tangential migration of gamma aminobutyric acid (GABA) ergic neurons and early cholinergic neurons.

Subcortical band heterotopia

Heterotopic neurons form a thick band of gray matter that may be circumferential or more limited to either the fontal or occipital poles (Figure 9.25). Heterotopic neurons are positioned midway between the outer molecular layer and the deep VZ.

FIGURE 9.25  Subcortical band heterotopia. Axial inversion recovery MRI of the brain showing a circumferential band of gray matter (arrows) between the cortex and the ventricular surface.

Epidemiology Periventricular nodular heterotopia

• Autosomal recessive and an X-linked dominant form are described. • X-linked form is lethal in males. • A number of syndromes are included (e.g. frontal, frontoparietal, perisylvian, parasagittal, and generalized heterotopia syndromes). • Genetic disorders are now described with heterotopias.

Lissencephaly 1

This is an autosomal dominant disorder, with three clinical phenotypes: • Miller–Dieker phenotype is due to a large deletion of the LISI gene and neighboring genes. • Isolated lissencephaly is due to a small deletion or mutation in the LISI gene. • X-linked with abnormal genitalia (XLAG) is due to a mutation in the ARX homeobox gene. Most LISI mutations are de novo, with a low risk of recurrence. However, some parents have a balanced translocation involving the LISI gene with a higher risk of recurrence. Patients with lissencephaly may also have a mutation in the DCX gene or in the TUBA1A gene. The DCX gene is located on the X chromosome; a mutation in one of the X chromosomes in females results in subcortical band heterotopia (discussed below), whereas males inheriting the DCX mutation have classical lissencephaly. TUBA1A mutations are autosomal dominant disorders. Three-quarters of the patients with classical lissencephaly have a mutation either in the LISI gene or the DCX gene.

FIGURE 9.24  Lissencephaly. Axial T1-weighted MRI of the brain showing a thickened cortical mantle with few gyri.

ARX spectrum disorders

These occur in as many as 7% of families with X-linked mental retardation. Female carriers may have some changes.

Developmental Diseases of the Nervous System Subcortical band heterotopia

Predominantly females with a mutation in the DCX gene located on the X chromosome (see discussion of Lissencephaly above).

Etiology and pathophysiology Periventricular nodular heterotopia

Females with the X-linked form appear to have a somatic mosaic phenotype due to random X chromosome inactivation. • Neurons that express the mutant X chromosome fail to migrate. • All X-linked and most sporadic cases have a mutation in the filamin 1 gene that encodes an actin-binding protein, which is essential for neuronal migration. • A second gene, ARFGEF2, has been shown to be defective in some patients. Pathology shows: • Rounded nodules of neurons that are often confluent are found along the walls of the lateral ventricles. • The number and size of nodules vary. • Cortex is otherwise normal in appearance.

Lissencephaly 1

The lissencephaly genes LISI, DCX, and TUBA1A encode proteins closely related to microtubules. A network of microtubules is critical to neuronal migration. Migrating neurons extend processes along a framework of radial glia. The centrosome and nucleus of the neurons are pulled along the process. Microtubules are essential to the movement of the centrosome and nucleus, thereby controlling neuronal migration. Pathology shows: • The cortex is smooth and gyri are either absent or severely reduced. • The cortical mantle is thickened. • Microscopically, there is a four-layered cortex. The fourth layer is a broad band of disorganized neurons, and the WM may contain neuronal heterotopia.

ARX spectrum disorders

A wide variety of phenotypes are seen; some patients have no visible malformations, while the most severely affected patients have lissencephaly, hydranencephaly, and agenesis of the corpus callosum. The ARX spectrum disorders involve a mutation, deletion, insertion, or duplication in the ARX gene that is involved in ventral telencephalic morphogenesis, migration of GABAergic neuron progenitors, and early cholinergic neurons. There is a polyalanine tract insertion. Severity increases with the length of the polyalanine tract insertion.

Subcortical band heterotopia

Mutation in the DCX gene (see discussion of Lissencephaly above). Pathology shows: • Bands of gray matter in the WM are present between the cortex and the lateral ventricles. • The cortex is fairly normal in appearance, except for rather shallow sulci.

225 Clinical features Periventricular nodular heterotopia

• The spectrum of severity is quite wide and to some degree correlates with the extent of the heterotopia. • Most patients have seizures, which often come to attention in adolescence. • Seizures vary from mild to severe and intractable. • Cognitive impairment can be mild. • No motor impairment is present.

Lissencephaly 1

Patients with the Miller–Dieker phenotype have a dysmorphic appearance that includes a prominent forehead, bitemporal hollowing, short nose, protuberant upper lip, and small jaw. Other associated anomalies are present, such as omphalocele and cardiac defects. Isolated lissencephaly patients are without dysmorphic features. All lissencephaly patients have profound mental retardation, motor impairment, and seizures. The seizures are usually severe and intractable, with onset in infancy.

ARX spectrum disorders

At least 10 different clinical phenotypes have been described. The cardinal feature is X-linked intellectual disability that is usually severe. Patients are usually divided into nonmalformation and malformation groups. Nonmalformation patients have intractable epilepsy (often starting as infantile spasms), dystonic movements, and dysarthria or failure to speak. Some patients show marked difficulty with use of their hands. Malformation patients have profound mental retardation, intractable epilepsy, and a variety of brain abnormalities including agenesis of the corpus callosum, lissencephaly, and even hydranencephaly. Patients with lissencephaly may also have ambiguous genitalia.

Subcortical band heterotopia

The clinical course can be similar to lissencephaly 1, but the severity can be mild in some patients. There are no dysmorphic features.

Investigations and diagnosis

• MRI of the brain is diagnostic. • EEG is useful in characterizing seizures. • Chromosomal and genetic studies to exclude other conditions associated with lissencephaly.

Treatment

Treatment is symptomatic. Patients with periventricular nodular heterotopia may only require treatment for seizures. Patients with subcortical band heterotopia may only require treatment of seizures, although some may need additional support. Patients with lissencephaly 1 are more severely affected and usually require: • Gastrostomy tubes and nutritional support. • Physical and occupational therapy. • Surgical treatment of seizures may be useful in patients with focal heterotopias.

Prognosis

Prognosis is defined by the severity of seizures. Patients with periventricular nodular heterotopia tend to have a milder course. Patients with lissencephaly, ARX spectrum, and subcortical band

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226 heterotopia have a more severe clinical course with intractable seizures and significant motor and cognitive impairment, which contribute to a reduced life expectancy.

DISORDERS OF CORTICAL ORGANIZATION The defects in this section are characterized by excessive migration of neurons, differentiating them from conditions such as periventricular nodular heterotopia, where some neurons fail to migrate from the VZ. Thus, the defect seems to be a failure to arrest normal neuronal migration.

Definition Polymicrogyria

Excessive numbers of small prominent convolutions are present, giving the brain a lumpy appearance. Two major varieties of PMG are described: layered (with a four-layered cortex), and nonlayered (often associated with heterotopias). More commonly, however, PMG is classified according to location. Seven patterns have been described: bilateral perisylvian PMG (BPP), unilateral perisylvian PMG (UPP), bilateral generalized PMG (BGP), bilateral frontal PMG (BFP), bilateral frontoparietal PMG (BFPP), bilateral parasagittal parieto-occipital PMG (BPPP), and PMG associated with nodular heterotopia (PNH-PMG).

Schizencephaly

Unilateral or bilateral clefts in the brain are present that extend to the ventricles. Two forms are described. Type 1 has small symmetrical clefts and the edges of the clefts are fused within a pial-ependymal seam that is continuous with the ependyma of the lateral ventricle. Type 2 has extensive clefts that extend from the ventricle to the surface of the brain and subarachnoid space, and the edges are not fused. The clefts in schizencephaly are lined with polymicrogyric cortex (Figure 9.26).

FIGURE 9.26  Schizencephaly. Axial T1-weighted MRI of the brain showing a cleft (red arrow) extending from the ventricle to the surface of the cortex. The cleft is lined with polymicrogyric cortex (yellow arrows).

FIGURE 9.27  Bilateral perisylvian polymicrogyria. T2-weighted axial MRI of brain showing deep sylvian fissures (red arrows) lined with polymicrogyric cortex (yellow arrows).

Epidemiology Polymicrogyria

• Seen in association with other brain malformations such as heterotopia. • Seven distinct syndromes are seen (two of the most common will be discussed). • PMG is one of the most common brain malformations accounting for roughly 20% of all cortical malformations.

Bilateral perisylvian polymicrogyria

Variable inheritance patterns, including autosomal recessive and dominant and X-linked dominant and recessive (Figures 9.27 and 9.28). BPP is associated with defects in a variety of genes including AKT3, CCND2, MTOR, PIK3CA, and PIK3R2. It is the most common of the PMG family.

Bilateral frontal polymicrogyria

BFP PMG is primarily a sporadic condition, although autosomal recessive inheritance is reported. It is rare, but the true incidence is unknown.

FIGURE 9.28  Bilateral perisylvian polymicrogyria. Sagittal T1-weighted MRI shows the sylvian fissure lined with polymicrogyric cortex (arrows).

Developmental Diseases of the Nervous System Schizencephaly

This is a rare condition with a prevalence of 1.54 per 100,000 individuals. Both genetic and nongenetic etiologies are postulated.

Etiology and pathophysiology Polymicrogyria

Genetic loci have been identified in a number of patients. PMG has been implicated in contiguous and single gene disorders. PMG is associated with a number of metabolic disorders. Also, toxins including hypoxia, congenital infection, and carbon monoxide poisoning have also been implicated. Excessive numbers of small convolutions with shallow and enlarged sulci are present. Cortical folding is irregular due to packing of the microgyri. Histologically, there are two types: layered, which shows a four-layered cortex with a layer of laminar necrosis, and nonlayered, in which the molecular layer is continuous and does not follow the profile of the convolutions, and the neurons have a radial distribution without a laminar organization. However, more commonly PMG is classified by location/ distribution as discussed above.

Schizencephaly

The causes of schizencephaly are heterogeneous. Both genetic and nongenetic causes are postulated. There are some cases associated with chromosomal aneuploidy, single gene defects, and distinct syndromes, so it is likely that there is more than one genetic cause. The EMX2 gene was initially implicated, but more recent studies do not support that. Currently, another gene, LHX2, a gene expressed in the forebrain, has been suggested, as well as the genes HESX1 and SOX2. Pathology shows a deep cleft, either unilateral or bilateral, extending the full thickness of the brain. The walls of the cleft are usually widely separated, and the clefts are commonly in the perisylvian area. The cortex lining the clefts is polymicrogyric.

TIPS • Schizencephaly must be distinguished from porencephaly. • In porencephaly, an ischemic injury results in destruction of tissue between the lateral ventricle and the surface of the brain resulting in an open channel, while in schizencephaly, there is a deep cleft that communicates with the lateral ventricle and is lined with the cortex; this lining is the key distinguishing feature. • The clinical features and prognosis of the two conditions are quite different, with schizencephaly having a much more severe outcome.

Clinical features Polymicrogyria

Clinical manifestations depend in part on the extent of the abnormality. Virtually all patients have seizures. Patients with BPP PMG typically have impairment of oral motor function and dysarthria. Most have mental retardation, and some have severe generalized motor dysfunction, but severity varies widely. Patients with bilateral frontal PMG have developmental delay and seizures.

Schizencephaly

• Microcephaly. • Intractable seizures. • Severe intellectual and motor impairment, cortical blindness.

227 Investigations and diagnosis

• Diagnosis is made on the basis of MRI of the brain. • EEG is useful in characterizing seizures. • Because PMG can be found in other conditions, those need to be excluded. • There are now PMG multigene panels that include most of the genes implicated in PMG.

Treatment

Treatment is symptomatic. Seizures are the main complication of these disorders and require treatment. Severely impaired children require gastrostomy and nutritional supplementation.

Prognosis

Prognosis is determined in part by the severity of the seizures and degree of motor impairment. It is variable in PMG. In schizencephaly, the impairments are invariably severe, and life span is shortened.

NEUROCUTANEOUS DISORDERS The neurocutaneous disorders present a very different spectrum of problems compared with the malformations of the nervous system. However, there are areas of overlap. Many malformations of the nervous system involve poor regulation of cell division and proliferation, which is also an essential problem in the neurocutaneous disorders. Moreover, several of the neurocutaneous disorders, particularly tuberous sclerosis, neurofibromatosis type 1 (NF-1), incontinentia pigmenti, hypomelanosis of Ito (HI), the linear sebaceous nevus syndrome, and Lhermitte–Duclos disease (LDD) are associated with brain lesions caused by abnormal neuronal migration or organization.

Activation of mTOR pathway

The neurocutaneous disorders are a heterogeneous group that, at first glance, has little in common other than involvement of both skin and brain. The association of skin and nervous system defects can be understood at least in part because both are derived from the embryonic ectoderm. However, as we develop a greater molecular understanding of these conditions, it is apparent that most of the neurocutaneous disorders involve activation of the signaling components, both upstream and downstream of the protein kinase mammalian target of rapamycin (mTOR) (Figure 9.29). Upstream of mTOR, the key signaling molecules are p21 Ras GTPase, Raf, Mek, Erk, the lipid kinase PI3K, the Akt kinase, TSC1/TSC2, and the GTPase Rheb. Downstream are the pathways for angiogenesis, protein translation, gene amplification, and cell cycling. Defects in these signaling molecules and pathways are the basis for tuberous sclerosis, NF-1, Proteus’ syndrome, Cowden’s syndrome (CS), LDD, Sturge–Weber (SW), and von Hippel–Lindau (VHL) disease.10

TIP • All of the neurocutaneous disorders are progressive, implying: individual complications may worsen over time; complications are age specific, with different complications occurring at different times. There is also a high degree of variability of complications.

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228 IRS1

Ras

P13K

Raf

PTEN

PDK1

MEK1/2

LKB1

AMPK

Akt

Erk1/2

Wnt

GSK3β

P P P TSC2 P

RSK1

TSC1

P

IKKβ

NF1

TNFα

Rheb PC1

mTOR HIF

p70S8K 4EBP-1

VHL

VEGF

Protein transcription Angiogenesis

p27 Cell cycle

FIGURE 9.29  The mammalian rapamycin target (mTOR) signaling pathway showing key signaling molecules upstream of mTOR including Ras, the lipid kinase PI3K, the Akt kinase, and the GTPase Rheb, which are all known to be deregulated in different human cancers. Mutations in the mTOR component genes, TSC1, TSC2, LKB1, PTEN, VHL, NF1, PKD1 (PC1), and IKK, result in the development of tuberous sclerosis, Peutz–Jeghers syndrome, Cowden’s syndrome, Bannayan–Riley–Ruvalcaba syndrome, Lhermitte–Duclos disease, Proteus’ syndrome, von Hippel–Lindau disease, neurofibromatosis type 1, polycystic kidney disease, and incontinentia pigmenti, respectively. Activation of the PI3K-Akt pathway and increased vascular endothelial growth factor (VEGF) receptors are implicated in neurofibromatosis 2. HIF, hypoxia-inducible factor; TNF, tumor necrosis factor.

NEUROFIBROMATOSIS TYPE 1 Definition and epidemiology

NF-1 is a common autosomal dominant disorder, presenting with hyperpigmented macules of the skin (café-au-lait spots). There is multisystem involvement including frequent learning problems, bony abnormalities, eye abnormalities (optic gliomas and iris Lisch’s nodules), and an increased risk of cancer. Tumors of the peripheral nerves (cutaneous or dermal neurofibromas) and tumors of nerve trunks and roots (plexiform neurofibromas) occur. The incidence of NF-1 is 1 in 2500 to 3000 live births. NF-1 is an autosomal dominant disorder that equally affects males and females. It is reported in all racial and ethnic groups, although it may occur less frequently in people of Middle Eastern descent. Manifestations of NF-1 are often apparent at birth and more apparent in the first several years of life. One-half of all cases are spontaneous mutations.

Etiology and pathogenesis

NF-1 is due to a defect in a gene on chromosome 17q that encodes the protein neurofibromin, a Ras guanosine triphosphate (GTP)ase activating protein (Ras GAP). Neurofibromin stimulates the hydrolysis of GTP bound to p21 Ras, converting

it to the inactive state. Active Ras stimulates cell growth and proliferation and is part of the mTOR signaling pathway. Neurofibromin expression is ubiquitous but is particularly prominent in the nervous system. NF-1 is a disorder of poorly regulated cell growth and proliferation, i.e. increased growth and proliferation, thought to be secondary to excessive stimulation of Ras.11 The cardinal pathologic feature is a neurofibroma, which is a tumor of the nerve consisting of a proliferation of the Schwann cells, fibroblasts, mast cells, blood vessels, and extracellular matrix with nerve fibers running through the tumor mass. Neurofibromas can occur along small nerve fibers, spinal roots, plexi, nerve trunks, and autonomic nerves. Dermal neurofibromas are well-circumscribed tumors in the skin. Plexiform neurofibromas are similar, but contain more extracellular matrix and sometimes appear in grape-like clusters distorting large nerves. Plexiform neurofibromas may be well circumscribed or highly invasive and infiltrative.

Clinical features

The clinical features are highly variable even within the same pedigree, and virtually any organ system can be affected. There are a large number of potential complications, but some are quite rare. The complications of NF-1 are age specific, which help

Developmental Diseases of the Nervous System

FIGURE 9.30  Café-au-lait spot (arrow) and several pedunculated dermal neurofibromas on the forearm of a patient with neurofibromatosis type 1.

greatly in assessing and counseling patients. The major complications/features are listed below.

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FIGURE 9.32  MRI of the proximal legs showing nodular clusters of plexiform neurofibromas along the length of both sciatic nerves, with a number of isolated intramuscular and cutaneous neurofibromas that are visualized by increased signal intensity.

Skin 

Brain 

FIGURE 9.31  Superficial plexiform neurofibroma. CT of the abdomen showing an area of increased signal on the left side of the patient’s flank in the subcutaneous fat with some thickening of the skin (red arrow). The plexiform neurofibroma has thin “fingers” that extend to the limit of the abdominal musculature (yellow arrows).

FIGURE 9.33  Plexiform neurofibroma. CT of the pelvis shows a large soft tissue mass in the patient’s right sciatic notch (red arrow) extending into the pelvis and displacing the rectum. The mass is a plexiform neurofibroma, which also extends to the bladder resulting in marked thickening of the bladder wall (yellow arrows).

• Café-au-lait spots are hyperpigmented macules that must be at least 0.5 cm in children and >1.5 cm in adults and are found in virtually all patients (Figure 9.30). • Freckling: small hyperpigmented macules in areas protected from the sun such as the groin or axilla. • Cutaneous or dermal neurofibromas: start as small, raised, soft papules, or sometimes as purplish depressible macules along small nerve fibers and can enlarge over time to become pedunculated or even pendular (Figure 9.30). Cutaneous neurofibromas occur in late teenage or adult years in virtually all patients, but the number varies tremendously in different patients. • Plexiform neurofibromas sometimes involve the skin, underlying muscle, and nerve and often involve large nerves or the sympathetic chains (Figures 9.31–9.33). They are congenital. Including very small ones, they are found in 50% of patients. Large plexiform neurofibromas occur in 200 repeats (full mutation) in males produce a more severe childhood disorder (fragile X syndrome). FXTAS primarily affects males, with some affected females. Prevalence: 1:250 women and 1:800 men have the premutation. Penetrance varies depending on age and sex: • Male premutation carriers are at highest risk: • Age 50–59: 17%. • Age 60–69: 38%.

X-chromosome

• Age 70–79: 47%. • Age ≥79: 75%. • The overall estimated prevalence is about 1:3000 males. • Female penetrance is not as well understood, but prevalence is estimated at 1:5200.

Clinical features

Symptoms may begin as young as early 50s, but can be delayed a decade or more. Major criteria include: • Intention tremor. • Progressive ataxia. Minor criteria include: • Parkinsonian symptoms. • Cognitive decline: • Short-term memory disorder. • Executive function deficits. • Personality changes with volatile mood: anger outbursts, inappropriate or impulsive actions. • Peripheral neuropathy: sensory or autonomic. • Females may have the same symptoms as males, but usually less severe. In addition, they may have: • Fibromyalgia. • Hypothyroidism. • Epilepsy. • Premature ovarian failure.

Diagnosis

MRI shows major and minor criteria:

Normal

Pre-mutation

Fragile X

• Major criteria: white matter lesions in the middle cerebellar peduncles and/or brainstem (Figures 10.2, 10.3). • Minor criteria: lesions in cerebral white matter or generalized atrophy.

CGG repeats

FMRP production

FMR1 gene

FMRP production No FMRP production

FIGURE 10.1  The FMR1 gene is located on the long (q) arm of the X-chromosome at q27.3. This gene contains a stretch of repeated CGG trinucleotides that vary in length. Repeat lengths of >200 cause abnormal DNA methylation of the FMR1 gene and gene silencing, causing fragile X syndrome in males but not FXTAS. Repeat lengths of 55–200 (premutations) do not lead to complete gene silencing and can cause FXTAS.

FIGURE 10.2  FXTAS imaging. Sagittal (Figure 10.2) and axial (Figure 10.3) MRI images show characteristic increased signal in the cerebellar peduncles and pons. The sagittal image also demonstrates increased signal in the corpus callosum, along with generalized cerebral atrophy.

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Both hemizygote males and heterozygote females can have neurological disease. Prevalence in hemizygotes (affected males) is 1:21,000 or, combined with heterozygote females, is 1:16,800. Age of onset and clinical manifestations can vary within the same family.

Clinical features

FIGURE 10.3  FXTAS imaging. Sagittal (Figure 10.2) and axial (Figure 10.3) MRI images show characteristic increased signal in the cerebellar peduncles and pons. The sagittal image also demonstrates increased signal in the corpus callosum, along with generalized cerebral atrophy. Diagnosis requires the presence of a premutation along with MRI and physical findings. • Definitive diagnosis requires the presence of the premutation and one major MRI and two major neurological signs. • Probable diagnosis requires the presence of the premutation and either one major MRI finding or two major neurological findings. • Possible diagnosis requires the premutation and one minor MRI finding and one major neurological finding. Mutations in the FMR1 gene can affect multiple generations in the same family in different ways. When a mother carrying the premutation allele passes it to her child, the allele may expand to a full mutation allele. This means that if a child is diagnosed with fragile X syndrome, their mother is either a premutation or full-mutation carrier and at risk for FXTAS. Furthermore, the child’s grandparents, aunts, uncles, siblings, and cousins are at risk for carrying the premutation and developing FXTAS or having children with fragile X syndrome. Testing of family members should be done in conjunction with a genetic counselor who will review testing options, the probability of having symptoms if the premutation is present, and risk of recurrence with additional pregnancies.

X-LINKED ADRENOLEUKODYSTROPHY Definition and etiology

X-linked adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with progressive CNS demyelination and/or adrenal failure due to accumulation of saturated, very-long-chain fatty acids (VLCFAs). ALD is caused by mutations in the ABCD1 gene (ATPbinding cassette, subfamily D [ALD], member 1) located on the long arm of the X chromosome. ABCD1 encodes part of a membrane transporter within peroxisomal membranes. Without this transporter, VLCFAs cannot be metabolized so they accumulate in brain and adrenal cells.

• Childhood cerebral form: 30% of patients, onset usually 4–8 years, and rapidly progressive. • Adrenomyeloneuropathy (AMN): 40–45% cases: • Onset mid-20s to middle age. • Slowly progressive spastic paraparesis without upper limb involvement. • Impaired vibration and position sense. • Urinary and sexual dysfunction. • Mild peripheral nerve involvement: slowing of sensory and motor conduction velocities. • Hypogonadism is common. • Mild cognitive decline. • Adrenal insufficiency can occur after onset of paraparesis. • Addison’s disease only: 10%: • Onset 2 years to adulthood, usually around age 7. • Most develop AMN by middle age. • Atypical presentations seen in 5–10% of affected males: • Headache, increased intracranial pressure, focal neurological defects – usually present prior to age 10, rarely in adults. • Adult-onset progressive dementia, behavior disturbance, and paralysis. • Progressive ataxia in child or adult. • Neurogenic bladder and bowel abnormalities or impotence without other neurological or endocrine disorders. • Some males hemizygous for the pathogenic variant will remain asymptomatic. • Females: about 20% of carriers develop milder symptoms after age 35, and about 20% of carrier females develop spastic paraparesis in middle age.

Diagnosis and investigations

ALD should be suspected in young or middle-aged adult males with progressive lower limb spasticity, sensory changes, bladder and bowel abnormalities or impotence, and in all males with primary adrenal failure. ALD should also be considered in middleaged and older females with progressive lower limb spasticity and sensory changes with or without bladder and bowel abnormalities. MRI of the brain usually shows a characteristic pattern of symmetric hyperintense T2 signal in the parieto-occipital region with contrast enhancement at the advancing margin (Figure 10.4). White matter changes progress from posterior to anterior, with all white matter eventually involved. MRI may be normal in females and mildly affected in males. Laboratory evaluation for elevated VLCFA is the preferred first diagnostic test, and it is positive in 100% of males and about 80% of females. The ABCD1 gene can be tested: • Sequencing is positive for 99% of males and 93% of females. • Duplication/deletion testing will diagnose 6% of females.

Treatment

Treatment is supportive. Patients should be monitored for, and treated for, adrenal insufficiency. Adrenocorticotropic hormone (ACTH) levels will rise. Other treatments such as Lorenzo’s oil have not been studied in adults.

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Disease frequency is unknown, but it is estimated at 3:1,000,000. Onset is early childhood until adulthood (75% prior to age 10, 25% late teens until the third decade).

Clinical features

Neurological disability with extrapyramidal symptoms is the key feature in PKAN. Psychiatric symptoms can be the initial presentation in adults but motor impairment is inevitable.

FIGURE 10.4  Adrenoleukodystrophy. T2W axial MRI showing diffuse bilateral increased signal, mainly in the parieto-occipital white matter. The more anterior white matter is also beginning to look affected.

PANTOTHENATE KINASE–ASSOCIATED NEURODEGENERATION Definition and etiology

Pantothenate kinase–associated neurodegeneration (PKAN) is one of a growing family of disorders of NBIA. PKAN is an autosomal recessive disorder caused by mutations in the PANK2 gene. PANK2 codes for pantothenate kinase 2, which participates in the synthesis of coenzyme A and in the phosphorylation of pantothenate (vitamin B5), N-pantothenoyl-cysteine, and pantetheine. Without pantothenate kinase 2, cysteine and cysteine-containing compounds collect in the basal ganglia, causing chelation of iron in the globus pallidus, and oxidative cell death. Males and females are equally affected.

• Extrapyramidal dysfunction: • Dystonia. • Rigidity. • Choreoathetosis. • Parkinsonian features and dysarthria can be prominent in late-onset PKAN. • Corticospinal dysfunction: • Spasticity. • Hyperreflexia. • Babinski’s sign. • Psychiatric symptoms: • Cognitive decline – similar to frontotemporal dementia. • Personality changes. • Impulsivity. • Emotional lability – violent outbursts. • Depression. • Psychosis. • Retinal degeneration or optic atrophy occur in two-thirds of cases. Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) is now considered part of the PKAN disease spectrum.

Diagnosis

Diagnosis is by MRI, which shows iron deposition in basal ganglia. Abnormalities are restricted to the globus pallidus and substantia nigra, producing the “eye of the tiger” abnormality on T2-weighted imaging (Figure 10.5). This eventually develops

        FIGURE 10.5  T2-weighted MRI showing iron deposition in the pallidus and substantia nigra in pantothenate kinase–associated neurodegeneration mutations (left). When the axial image is rotated, an “eye of the tiger” abnormality is seen (right). (Courtesy of the Children’s Hospital and Research Center Oakland.)

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in virtually all patients, but is not absolutely specific for PKAN. Hypointensity of the dentate nuclei in T2 sequencing is sometimes seen. PANK2 gene analysis should be performed when MRI findings are present.

Treatment

Survival with progressive disability is usually 10 years, but 30 years has been reported. No treatments to prevent disease progression are available. • L-dopa may be effective in early cases. • Spasticity can be modulated by baclofen, trihexyphenidyl, and intramuscular botulinum toxin. • Supplementation with pantothenate, coenzyme Q, and other antioxidants has been attempted, but it is not proven to be effective.

FIGURE 10.6  Kayser–Fleischer ring: a 1- to 3-mm-thick brown ring (but may be other colors) of sulfur–copper complexes at the corneal margin. Extrapyramidal symptoms have two major and often dissociated findings:

WILSON’S DISEASE WD (familial hepatolenticular degeneration) is an autosomal recessive disease that causes heavy copper deposition in liver, cornea, kidneys, and CNS. The gene is located on chromosome 13q14.3 and codes for a copper transporting P-type protein, ATP7B. Deficient function of ATP7B causes impaired copper excretion with tissue accumulation. Because ATP7B is also involved in copper assembly into ceruloplasmin, biochemical markers of WD are low serum ceruloplasmin and high serum and urine copper. Prevalence: 1:30,000 (30 per million) are affected; 1:100 individuals in the general population have one copy of the WD gene. Age of onset is 8 to >50 years, and males and females are equally affected.

Clinical features

WD may present with primarily liver or CNS findings.

Liver disease

Isolated liver findings are common in childhood, but may be subtle or overlooked. Hepatic cirrhosis precedes neurological dysfunction.

CNS findings

CNS findings are common in WD, and become increasingly common after age 12 years. Copper deposits in Descemet’s membrane of the cornea (Kayser–Fleischer rings) are highly specific for WD, present in most patients with CNS disease, and are detected by slit-lamp examination (Figure 10.6). Behavioral and cognitive changes are common and are the first manifestation in about 20% of cases. These changes often precede extrapyramidal symptoms. Patients show loss of emotional control, and difficulty in conforming to societal norms is usual. Intellectual decline is present but may be masked by bizarre behavior. WD may be misdiagnosed as schizophrenia or other psychiatric disorders, which delays treatment, worsening the outcome.

• Rigidity: Wilsonian form has faciolinguopharyngeal rigidity with facial masking, dysarthria, and dysphagia. Rigidity progresses and can involve the trunk and limbs. • Tremor (Westphal–Strumpell form) may initially be in one limb. As symptoms progress, the face becomes mask-like, and there may be a forced grin. Speech and swallowing become more difficult and may be lost. Parkinsonian symptoms worsen, and a gross and irregular tremor develops, which is worse with arms outstretched (rubral tremor). Dyskinesia or chorea may be prominent in some patients.

Diagnosis and investigations

Laboratory investigation should include: • Serum ceruloplasmin and free copper: false positives and false negatives have occurred, and cannot be relied on to diagnose or exclude disease. Low ceruloplasmin is a secondary marker of impaired copper transport in WD and can be observed in other conditions, such as Menkes’ disease. • A 24-hour urinary copper excretion is collected three separate times – provocative testing with D-penicillamine to increase excretion has also been used in children. • Slit-lamp examination for Kayser–Fleischer rings. • Liver biopsy for excessive copper is usually diagnostic. • Genetic testing for biallelic ATP7B pathogenic variants. Genetic testing is not always positive and should not be used to rule out WD. Most cases are caused by two mutations: • H1069Q is the mutation found in populations of European origin. It accounts for 35–45% of WD in a mixed European population. • R778L is the mutation found in Asian populations, accounting for approximately 57% of WD in a mixed Asian population. MRI findings include: • T1-weighted images show increased signal intensity in globus pallidus and midbrain. • T2-weighted images can show increased signal intensity in caudate and putamen. Some show high signal with central

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Dietary modification includes avoidance of food high in copper (meat, shellfish, chocolate, mushrooms, dried beans, and peas) and increasing consumption of food high in antioxidants. Antioxidant supplements such as vitamin E may be of use.

ACUTE INTERMITTENT PORPHYRIA Definition and etiology

FIGURE 10.7  Wilson’s disease. T2-weighted MRI image shows hyperintense signal in the bilateral thalami, and subtle hyperintense signal in the putamen. (Courtesy of Dr. Paramdeep Singh.) dark signal intensity. In some, the thalamus and globus pallidus are affected (Figure 10.7). • The “face of the panda” is sometimes seen on T2 imaging of the midbrain. Extensive hyperintensity of the midbrain with relative sparing of red nucleus and superior colliculus reminds some of a panda’s markings (Figure 10.8).

Treatment

Copper chelating agents that increase urinary excretion of copper are the first-line treatment for WD. Penicillamine was introduced in 1956 and remains the standard treatment, but other agents such as trientine are available.

Porphyrias are disorders caused by the deficiency of enzymes that participate in the synthesis of heme, which lead to the accumulation of intermediaries called porphyrins. Acute intermittent porphyria (AIP) is an autosomal dominant disorder with variable penetrance. Many patients remain asymptomatic throughout life. It is caused by a porphobilinogen deaminase deficiency; this enzyme catalyzes the conversion of porphobilinogen to hydroxymethylbilane. Without it, porphyrin precursors, porphobilinogen and delta-aminolevulinic acid, accumulate. Prevalence is 1–5:100,000, and it is higher in those with a Swedish background. Onset is at any age postpuberty and can occur in previously healthy adults exposed to a new medication. Females are more often symptomatic than males.

Clinical features

Patients have episodes of acute decompensation or attacks provoked by metabolic stress, fasting, or a large number of drugs (databases of porphyrinogenic and safe drugs are available online). Phenobarbital, other anticonvulsants, and estrogens are frequently involved, but a large number of common drugs may provoke an attack. Attacks consist of a triad of abdominal pain, psychiatric/CNS symptoms, and peripheral neuropathies. Symptom severity can vary from mild abdominal pain to significant neuropathy or psychiatric disease.

FIGURE 10.8  Wilson’s disease. Copper deposition leads to a characteristic MRI brainstem “panda” image. Red arrows point to the “face of the giant panda” seen in the midbrain. There is hyperintense signal surrounding normal red nuclei. The yellow arrows point to the “panda cub” in the pons. (Courtesy of Dr. David S Liebeskind.)

Hereditary and Metabolic Diseases of the Central Nervous System in Adults • Brain dysfunction varies in severity: • Depression and insomnia are common. • May be mistaken for bipolar disorder. • Restlessness, crying, confusion, violent behavior, hallucinations, and psychosis may occur. • Mental status changes, cortical blindness, seizures, or coma may occur. • CNS dysfunction and abdominal pain usually occur together. • Predominantly motor polyneuropathy: • Distal weakness of fingers and wrist extensors are common – wrist drop is classic. • Can be severe and generalized with involvement of respiratory musculature leading to respiratory failure. • May be confused with Guillain–Barré syndrome. • Sensory and autonomic dysfunction may occur. • Cranial nerves VII and X are vulnerable, and may cause dangerous dysphagia. • Abdominal pain is severe, continuous, and lasts several days.

Diagnosis and investigations

All patients with AIP will have increased urinary porphobilinogen during acute attacks. This can be demonstrated using a quantitative test on a random urine sample that is kept protected from light. The classic red–brown discoloration of urine is not always visible. MRI is usually normal.

Treatment

The treatment goal is to decrease heme synthesis and thus porphyrin precursors. Most patients should be admitted during attacks because of pain and risk of respiratory depression from peripheral neuropathy. • High doses of glucose can inhibit heme synthesis and be used for mild attacks. • Severe attacks can be treated with hematin at a dose of 4 mg/kg/day for 4 days. Folic acid

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• Pain should be treated with narcotics. • Seizures can be treated with either levetiracetam, gabapentin, or benzodiazepines. However, most classic antiepileptics provoke attacks. Besides reduction of triggers and avoidance of porphyrinogenic medications, chronic management includes kidney function testing and liver imaging in some patients due to the increased risk of renal insufficiency and hepatocellular carcinoma.

HOMOCYSTINURIAS AND DISORDERS OF COBALAMIN METABOLISM Introduction

This group of metabolic disorders can be thought of in terms of various combinations of three general pathogenic mechanisms and symptom sets (Figure 10.9). First, disorders with high homocysteine involve thromboembolic strokes, other arterial and venous thromboses, and neurocognitive deficits. Besides endothelial dysfunction, high homocysteine also can cause other physical findings such as ectopia lentis and marfanoid body habitus. Second, some disorders lead to deficiency of methyl donors (S-adenosylmethionine) needed for normal physiological processes in the CNS. These remethylation disorders impair the transfer of methyl groups from folate to homocysteine to make methionine. Typical neurological manifestations include demyelination of the cerebral white matter, subacute combined degeneration of the spinal cord, and encephalopathy. Third, some disorders of cobalamin (vitamin B12) metabolism impair the metabolism of methylmalonic acid, which can accumulate during illness or physiological stress and cause acute, direct neurotoxicity with encephalopathy or acute “metabolic strokes” of the basal ganglia. Individuals with adult-onset, subacute presentations are welldescribed. In addition, individuals diagnosed in childhood can Dietary protein

Methionine

Tetrahydrofolate (THF)

DMG

SAM

Betaine

SAH

MS + B12

5, 10-methylene THF MTHFR

5-methyl THF REMETHYLATION PATHWAY

Homocysteine CBS + B6

Serine

Cystathione TRANSULFURATION PATHWAY Cysteine

FIGURE 10.9  Metabolism pathways of homocysteine and methionine. CBS, cystathionine β-synthase; DMG, dimethyl glycine; MS, methionine synthase; MTHFR, methyl tetrahydrofolate reductase; SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; THF, tetrahydrofolate.

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274 present with acute symptoms in adulthood triggered by physiological stress or dietary intake. These disorders can be diagnosed and distinguished based on specific abnormal levels of blood amino acids and urine organic acids, and they can have marked treatment responses such as reversal of demyelination. Treatment strategies for these disorders include dietary treatments, vitamin cofactors for specific enzymes, and large doses of betaine, which directly provide the methyl group to homocysteine to make methionine without relying on folate.

Cystathionine β-synthase deficiency Definition and etiology

Cystathionine β-synthase deficiency (CBS) is the classic and most severe form of homocystinuria. CBS can be differentiated from other forms of homocystinuria by elevated methionine levels. Patients have symptoms related to elevated homocysteine. • Prevalence: 1:100,000. • Age of onset: wide variability from infancy to middle age.

Clinical features

Symptoms can be severe or mild. Up to one-third of patients present with a thromboembolic event in adult life. Signs and symptoms may include one or all of the following: • Developmental delay/intellectual disability: • Mean intelligence quotient (IQ) for B6 -responsive subtype: 79. • Mean IQ for B6 -unresponsive subtype: 57. • IQ ranges from severe disability to above average. • Ectopia lentis and/or severe myopia: lens dislocation typically occurs before age 10. • Skeletal abnormalities: • Marfanoid appearance (excessive height, long limbs). • Osteoporosis. • Scoliosis, high-arched palate, pes cavus, pectus excavatum, or pectus carinatum, can also occur. • Thromboembolism: • Deep venous thrombosis. • Stroke. • Myocardial infarction. • Psychiatric problems: • Personality disorders. • Anxiety. • Depression. • Psychotic episodes. • Dystonia. • Seizures. • Skin findings: • Malar flush. • Hypopigmentation. • Livedo reticularis.

Diagnosis and investigations

• Amino acid analysis: • Elevated plasma and urine homocysteine and methionine levels. • Decreased levels of cysteine. • Enzyme activity: cystathionine β-synthase activity may be assessed in cultured fibroblasts, amniotic fluid, and chorionic villi cells.

• Genetic testing: • CBS is the only gene linked to classic homocystinuria. • Two most common mutations are CBS I278T and G307S, and account for about one-half of cases in the United States. • Targeted mutation analysis: sequence analysis will detect about 95% of cases. • Pyridoxine (vitamin B6) challenge: should be performed on all patients. Baseline homocysteine levels are obtained, and then 100 mg B6 is given. A 30% reduction is considered positive; if no effect, escalating doses of B6 are given up to 500 mg.

Carriers

Carriers are usually symptom free, although there are concerns of increased thromboembolic events when under physiological stress. Homocysteine levels are usually normal. Diagnosis is usually by gene analysis.

Treatment

In pyridoxine-responsive individuals, lifelong supplementation is necessary. Patients should undertake a protein-restricted diet, and infants should be on a methionine-restricted diet. Betaine treatment promotes clearance of homocysteine by conversion to methionine. It is useful for B6 -unresponsive patients, or when dietary treatment is unsuccessful. B12 (intramuscular injections) and folate are also used.

Methylenetetrahydrofolate reductase deficiency Introduction

Disorders related to deficiency of methylenetetrahydrofolate reductase (MTHFR) need to be distinguished from polymorphisms incidentally found on genetic testing. MTHFR deficiency is an autosomal recessive disorder due to pathogenic variants in the MTHFR gene that severely reduce the enzyme activity. Patients with MTHFR deficiency have symptoms of both high homocysteine and deficiency of methyl donors, typically with childhood onset of significant intellectual disability, epilepsy, and other features of homocystinuria. Rare late-onset cases of MTHFR deficiency present with a demyelinating leukoencephalopathy characterized by spastic paraparesis, recurrent or subacute encephalopathy, psychosis, or epilepsy. In contrast, MTHFR polymorphisms are often found if the gene is sequenced and do not cause MTHFR deficiency. These include the MTHFR C677T polymorphism and the A1298C polymorphism, which often occur together. These are common, benign variants present in a large fraction of the population. For example, >25% of Hispanic individuals and 10–15% of North American Caucasian individuals are homozygous for the C677T polymorphism, and an even larger fraction is heterozygous. Individuals homozygous for these polymorphisms have slightly higher homocysteine and lower folate levels than individuals who are not. Because to this, MTHFR polymorphisms were previously thought to increase risk for a variety of conditions, such as cardiovascular thromboses and spina bifida. However, combined evidence from multiple large studies has since showed no clinically significant disease associations, and there is a specific practice guideline against testing for MTHFR polymorphisms (including testing as part of the thrombophilia workup) due to minimal clinical utility.9 Although MTHFR polymorphisms are still included on some pharmacogenetic testing panels, these results are not useful in directing clinical management.

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• Mental status changes: • Confusion. • Coma. • Polyneuropathy.

Infantile and early childhood form:

• First 3 months: • Hypotonia. • Lethargy or coma. • Brain atrophy with white matter changes. • 3 months–10 years: • Microcephaly. • Severe developmental delay. • Epilepsy. • White matter changes on brain MRI.

Diagnosis and investigations

Childhood and adult forms may have similar neurological complications. Some adults will have developmental issues and microcephaly, but many appear relatively asymptomatic until presentation. • Mixed upper motor neuron findings – hypo- or hypertonia. • Extrapyramidal findings: • Dystonia. • Chorea. • Abnormal eye movements. • Acute paraplegia – subacute combined degeneration of the cord. • Thromboembolism: • Cerebral sinus thrombosis. • Stroke. • Myocardial infarction. • Psychiatric problems are more common in adults: • Personality disorders. • Anxiety. • Depression. • Psychotic episodes.

• MRI: • Diffuse white matter changes. • Atrophy common. • Diagnosis is based on elevated urine and serum homocysteine: • Low methionine. • Low folate. • Gene sequencing of MTHFR for biallelic pathogenic variants.

Treatment

Betaine is the mainstay of treatment, and it is used to bypass folate in the remethylation cycle. Other treatments such as vitamin cofactors include: • • • • • •

Folate. Cobalamin. Carnitine. Pyridoxine. Methyltetrahydrofolate. Riboflavin.

Disorders of cobalamin (vitamin B12) metabolism Definition and etiology

Vitamin B12, also known as cobalamin, is a cofactor for two enzymes, methylmalonyl-CoA mutase and methionine synthase. Disorders of cobalamin metabolism may affect one or both enzymes (Figure 10.10).

MITOCHONDRION

MCM

Methylmalonil-CoA

Succinyl-CoA

Adenosylcobalamin Cobalamin LYSOSOME

CELL CYTOPLASM

Methylcobalamin Homocysteine

Methionine MS

FIGURE 10.10  Summarized diagram of the pathways utilizing cobalamin. MCM (methylmalonyl-CoA mutase) deficiency causes methylmalonic acidemia, and MS (methionine synthase) deficiency causes hyperhomocysteinemia and deficiency of methyl donors. Disorders affecting the early steps of cobalamin metabolism cause a combined MCM/MS deficiency with all three symptom sets.

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276 • Methylmalonyl-CoA mutase (MUT) enzyme dysfunction causes methylmalonic acidemia, which typically presents in childhood but can cause acute metabolic-intoxication encephalopathy in adults as described at the beginning of this chapter. • Methionine synthase (MTR) enzyme dysfunction is a remethylation disorder that causes homocystinuria and deficiency of methyl donors. • Cobalamin C deficiency (MMACHC, cblC) and other disorders of early cobalamin metabolism result in combined deficiency of both the above enzymes, with symptoms of both disorders. Patients with cobalamin C deficiency have normal vitamin B12 levels, but processing of cobalamin inside cells is impaired. Cobalamin normally needs to be released from lysosomes and chemically modified before it can be used by methylmalonyl-CoA mutase and methionine synthase. These patients have high homocysteine, deficiency of methyl donors, and methylmalonic acidemia. • Disorders in this group known to have adult onset are autosomal recessive. Males and females are equally affected. Disease onset is from infancy to middle age.

Clinical features Cobalamin C deficiency and other combined disorders of cobalamin metabolism

Cobalamin C deficiency has well-defined early- and late-onset presentations. The early-onset presentation usually involves onset in infancy of hypotonia, poor feeding, metabolic acidosis, seizures, progressive maculopathy, and intellectual disability. Some children develop bone marrow failure, and others develop hemolytic uremic syndrome due to microangiopathy from homocysteine. Adults may present with acute crisis, or a subacute to chronic cognitive decline. Acute presentations will involve confusion or mental status changes, often triggered by metabolic stressors and sometimes associated with megaloblastic anemia. Chronic presentations are insidious, with: • Early progressive cognitive decline or psychiatric symptoms. • Nonspecific white matter changes on MRI. • Subacute combined degeneration of the spinal cord with white matter abnormalities and sometimes cystic changes. Some patients may have megaloblastic anemia or microangiopathic renal syndrome, but this is not universal. Total plasma homocysteine should be checked in patients with unexplained subacute cognitive or psychiatric symptoms, and elevations should prompt further diagnostic evaluation.

Homocystinuria due to isolated methionine synthase dysfunction

This is less common, and has a wide variation in onset. Infancy is the most common presentation with severe failure to thrive and megaloblastic anemia. Hypotonia, seizures, and developmental delay or decline occur. Adult presentation varies widely: • Weakness. • Megaloblastic anemia. • Psychosis and mental status changes.

• Significant thrombophilia. • Hemolytic uremic syndrome. • Optic nerve atrophy.

Diagnosis and investigations

Diagnosis is based on initial laboratory tests, which include: • Urine organic acid analysis. • Plasma amino acid analysis. • Vitamin B12 level, to rule out an acquired deficiency; the B12 level is expected to be normal in these metabolic disorders. • Total and free carnitine and fractionated acyl carnitines.

Treatment

Treatment of acute encephalopathic attacks is as described earlier in the chapter including IV glucose and correction of metabolic acidosis. High-dose vitamin B12 is a specific and effective treatment that can reverse encephalopathy and white matter changes in late-onset cobalamin C deficiency. However, it needs to be given as high-dose (>1 mg/day) hydroxocobalamin; other forms such as cyanocobalamin are not effective. Other specific treatments include betaine. Protein restriction is not needed.

LAFORA’S BODY DISEASE Definition and etiology

Lafora’s body disease is an autosomal recessive disorder involving one of two genes: EPM2A or NHLRC1 (EPM2B). Mutations in these genes lead to inappropriate synthesis of polyglucosan (long-chain polymers of sugars) in neurons. Males and females are equally affected. It is rare in most populations, but several regions of Africa, Europe, the Middle East, and North America have higher frequencies. Onset is in mid-teens into early adulthood, but it can present as young as age 6 and as old as the third decade.

Clinical features

Early findings include: • Epilepsy: myoclonic epilepsy prevails, but most have a mixed pattern including absence, visual seizures, and tonic–clonic seizures (Table 10.7). It may be initially mistaken for juvenile myoclonic epilepsy. The epilepsy rapidly becomes intractable. • Migraine-like headaches. • Cognitive decline. • Depression and apathy. Late findings include: • • • • • •

Dysarthria and ataxia. Prominent visual hallucinations. Agitation. Increasing dementia leading to vegetative state. Intractable epilepsy. Nonepileptic myoclonus.

Diagnosis and investigations

• MRI is initially normal. MR spectroscopy shows reduced N-acetylaspartate (NAA)/creatine ratio in frontal and occipital cortex, basal ganglia, and cerebellum.

Hereditary and Metabolic Diseases of the Central Nervous System in Adults • Visual evoked potentials show abnormally high voltage. • Diagnosis: mutations are sometimes not detected, requiring skin biopsy to detect Lafora’s bodies.

TIP • A negative gene test does not rule out inclusion body diseases. If the clinical findings are highly suspicious, follow a negative gene test with a biopsy.

Treatment

No specific treatment exists. Supportive care, management of epilepsy, and myoclonus must be addressed. Most patients die within 10 years of diagnosis.

ADULT NEURONAL CEROID LIPOFUSCINOSES Definition and etiology

Adult neuronal ceroid lipofuscinoses (ANCL) (Kufs’ disease) is a progressive degenerative disease. It is usually an autosomal recessive disorder, but it may be dominant in some families. Inclusion bodies develop within the cytoplasm of white blood cells and neurons and can be seen with electron microscopy (EM). Ceroid lipofuscinoses can occur from infancy to adulthood. Phenotypes are described by age of onset. Genetics is complicated as although >10 genes have been identified, they are not specific to phenotype or always to inclusion body type. The five genes mostly associated with ANCL are CTSD, PPT, CLN3, CLN5, and CLN4. Males and females are equally affected. Disease onset is usually in the third decade, but it can be from the second to sixth decades.

Clinical features

There are two major clinical phenotypes: • Type A: progressive myoclonic epilepsy with associated: • Dementia. • Ataxia. • Late pyramidal and extrapyramidal signs. • Seizures are often uncontrollable. • Type B: behavior abnormalities and dementia, with associated: • Motor dysfunction. • Ataxia. • Extrapyramidal signs. • Bulbar (brainstem) signs. • Presenile form (over age 50) usually have type B symptoms.

Inclusion body subtypes include: • Granular osmophilic deposits (GRODs). Associated genes are PPT1, CTSD, and CLN8. Autosomal dominant ANCL usually has GROD and has not been linked to a specific gene. • Curvilinear profiles (CVs). Associated genes are CLN8, MFSD8 (major facilitator superfamily domain-8), CLN6, and TPP1. • Fingerprint profiles (FPs). Associated genes are CLN3, CLN5, CLN6, and MFSD8. • Mixed type inclusions (GROD, CV, FP).

Treatment

Treatment is symptomatic. Epilepsy can be worsened by carbamazepine and lamotrigine, and these drugs should be avoided. Usual survival is about 10 years from diagnosis.

LATE-ONSET GM2 GANGLIOSIDOSIS Definition and etiology

This is a group of autosomal recessive disorders caused by mutations in at least one of three genes: HEXA, HEXB, and GM2A. Deficiency in one gene product prevents catabolism of GM2 gangliosides and other molecules with terminal N-acetyl hexosamines, leading to accumulation of these sphingolipids inside lysosomes and eventual cell death (Figure 10.11). • Hexosaminidase A is a heterodimer composed of an α subunit and a β subunit. The α subunit is encoded by the HEXA gene, while the β subunit is encoded by the HEXB gene. • Hexosaminidase B is a homodimer composed of two β subunits. Tay–Sachs disease may be caused by either: • HEXA gene mutations which lead to a decrease activity of hexosaminidase A, or • GM2 activator gene mutation (GM2A); this encodes for the hexosaminidase A cofactor. Sandhoff’s disease is caused by HEXB gene mutations, which lead to decreased activity of both hexosaminidase A and hexosaminidase B.

Diagnosis and investigations

Adult diagnosis may require EM histology to identify inclusion bodies. White blood cells usually have characteristic inclusion bodies, so biopsies are not normally required. However, biopsies are taken of neuron dense tissues such as conjunctiva, skin, or rectal mucosa. Three different tissues should be negative to rule out inclusion body disease. If characteristic inclusion bodies are present, there are biochemical assays for PPT1, TPP1, and CTSD enzyme activity. Gene panel testing for progressive myoclonic epilepsy or storage disorders in general may also be considered based on the patient’s phenotype.

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FIGURE 10.11  Distension of nerve cells with glycolipids.

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278 Tay–Sachs disease Definition and etiology

Gene frequency depends on the population. For HEXA, the carrier rate is 1:25–30 in Ashkenazi Jews, 1 per 2500–3600 prior to carrier screening. The carrier rate for Louisiana Cajun, French Canadian, and Pennsylvania Dutch populations is 1:50. The carrier rate for most populations is 1:250–1:300. Prevalence is 1 per 309,000 live births. For GM2A, the gene frequency is unknown. Males and females are equally affected. Onset is from infancy to middle age.

Clinical features

Unlike the better known infantile and late adolescent variants, chronic GM2 gangliosidosis has variable onset and slow progression, with some surviving into their eighth decade. Most are HEXA compound heterozygotes with less than 10% enzyme activity. Up to 60% have psychiatric disturbances, which may precede neurological symptoms. These can be mild to severe. Up to 30% present with schizophrenia or atypical psychosis, with agitation, delusions, hallucinations, and paranoia. Recurrent depression is common. This should not be treated with classic antidepressants that deplete hexosaminidase A activity. Dementia is usually not prominent. Neurological symptoms include cerebellar tremor, pyramidal signs, and lower motor neuron findings: • Diffuse cerebellar atrophy is an early finding, even with minimal symptoms. • Lower motor neuron disease with early proximal and late distal weakness. • Sensory involvement is late or absent. • Dysarthria. • Oculomotor apraxia. • Dystonia or choreiform movements.

Diagnosis and investigations

Biochemical assay of HEXA activity is the preferred diagnostic test for the general population. Up to 50% have negative genetic testing. If biochemical assay is positive, then sequence analysis of the HEXA gene should be performed. Pseudodeficiency, which refers to genetic variants present in healthy individuals that have apparent decreased enzyme activity to the artificial substrate used in the biochemical assay but appropriate activity on the biologically relevant substrate, can also occur. DNA testing can differentiate pseudodeficiency from disease alleles. DNA analysis may be preferred in high-risk populations with known mutations; Ashkenazi Jews have 98% detection with either DNA analysis or biochemical assay.

Sandhoff’s disease: GM2 gangliosidosis type II Definition and etiology

Sandhoff’s disease results from HEXB mutation. Gene frequency depends on the population, estimated to be 1 in 300 non-Jewish and 1 in 500 Jewish persons; most recognized cases are not in Jewish persons. Males and females are equally affected. Onset is from infancy to middle age.

Clinical features

Unlike the better known infantile and juvenile forms, adult Sandhoff’s disease usually presents as motor neuron disease. Dementia, psychiatric symptoms, and extrapyramidal symptoms have been reported but appear rare.

LATE-ONSET METACHROMATIC LEUKODYSTROPHY Definition and etiology

Late-onset metachromatic leukodystrophy (MLD) is an autosomal recessive disease involving the lysosomal enzyme arylsulfatase A (ARSA), preventing degradation of sulfated glycolipids with a secondary buildup of metachromatic granules resulting in widespread demyelination. It is caused by a mutation in the ARSA gene. Disease frequency is 1:40,000, with males and females equally affected. Onset is early infancy to middle age, with 50–60% of patients with late infantile MLD, 20–30% of patients with juvenile MLD, and 15–20% of patients with adult MLD. Age at onset is similar in affected family members.

Clinical features

Adult MLD frequently begins with psychiatric symptoms or cognitive decline: • Decreased work or school performance. • Personality changes: • Drug or alcohol use. • Emotional lability. • Progressive memory loss. • Atypical psychosis. • Seizures. Motor abnormalities may appear later, but can be the presenting symptom, with ataxia, dystonia, and choreoathetosis. Peripheral neuropathy can be prominent but is not universal in adult MLD and cannot be used to exclude diagnosis. Neuropathy is, however, prominent in infantile MLD.

Diagnosis and investigations

• Elevated cerebrospinal fluid (CSF) protein is often present but not universally in adult MLD. It is prominent in infantile MLD. • MRI shows white matter changes: periventricular white matter with initial posterior involvement with gradual rostral to caudal progression; anterior lesions may occur in adult MLD, cerebral atrophy is expected in chronic cases. • ARSA enzyme deficiency is the preferred initial test. It occurs in 10% of normal controls, and ARSA enzyme pseudodeficiency can occur in otherwise healthy individuals with enzyme activity of 5–20% of normal. • ARSA gene testing confirmation is required to rule out pseudodeficiency, as there are specific alleles on genetic testing. ARSA gene testing may be negative in some affected individuals, so it should not be the first test.

Most patients survive for 5–10 years, but fulminate courses with short survival have been described.

LATE-ONSET KRABBE’S DISEASE Definition and etiology

This is an autosomal recessive disease caused by a mutation of the GALC gene which encodes for galactocerebrosidase (GALC). The deficiency of this lysosomal enzyme leads to the accumulation of several sphingolipids, including galactosylceramide and

Hereditary and Metabolic Diseases of the Central Nervous System in Adults psychosine, which result in oligodendrocyte death and demyelination. Disease frequency is 1:100,000, and 1:150 carriers. Males and females are equally affected. Onset is in infancy (90%) to the fifth decade (10% juvenile to adult).

Clinical features

Adult presentations vary widely even in the same family. For instance, some may maintain normal intellect and have primarily motor findings. Symptoms may include:

•

• Intellectual decline. • Progressive spasticity. • Peripheral neuropathy of motor and sensory nerves such as burning paresthesias, visual loss, and optic atrophy.

Diagnosis and investigations

MRI typically shows atrophy and abnormal signal in cerebral white matter, with demyelination in brainstem and cerebellum. At least one adult had abnormality restricted to the pyramidal tract and optic radiations. MR spectroscopy may show elevated myoinositolcontaining and choline-containing compounds, with decreased N-aspartylaspartate in affected white matter areas. Nerve conduction studies usually show motor neuropathy, but a few reported normal in adult-onset disease. CSF protein is usually elevated. GALC enzyme assay is the preferred first evaluation: • Usually less than 5% of normal. • Patients with 8–20% activity may be normal or symptomatic. GALC gene testing is available. Individual states within the United States have introduced newborn screening for GALC deficiency. The frequent occurrence of decreased GALC activity with no neurological symptoms has been documented. It is unclear if these children will later develop the disease, or if asymptomatic cases exist.

FABRY’S DISEASE Definition and etiology

Fabry’s disease is an X-linked lysosomal enzyme disorder of α-galactosidase, resulting in accumulation of glycosphingolipids with α-galactosyl moieties. The inability to process these glycosphingolipids results in their buildup in multiple organs. Most of the early, prominent symptoms are the result of accumulation in the blood vessels and the peripheral and central autonomic nervous system, although all tissues are affected. As the disease progresses, accumulation in kidneys and heart will lead to organ failure. Progressive arterial accumulations result in infarction. Fabry’s disease usually affects males (1:60,000), but many heterozygous females have disease symptoms including strokes. Furthermore, some heterozygous females have symptoms as severe as the classic male phenotype due to nonrandom X-inactivation, where the unaffected X-chromosome is inactivated in more than 50% of cells, leading to more pronounced deficiency of α-galactosidase. Onset is late childhood (usual) into middle age.

Clinical features Early symptoms

• Pain: • Attacks of severe lancinating or burning pain and paresthesias in fingers and toes (acroparesthesia). • Late childhood onset is common, but adult onset has been reported.

•

• •

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• Attacks last days to weeks. • Precipitated by physiological stress, such as fever, exercise, and dehydration. • Joint swelling and elevated erythrocyte sedimentation rate (ESR) are common, and may lead to misdiagnosis of rheumatologic disease. • Pain responds to anticonvulsants. Skin findings: • Typically are small, red, flat or slightly raised telangiectasias called angiokeratoma. • Usually around the umbilicus and thighs (bathingtrunk distribution). • Abnormal sweating, usually anhidrosis or hypohydrosis but sometimes hyperhidrosis. Eye findings: • Focal dilation of retinal arteries. • Corneal opacities – curved or straight lines radiating out from the center of the cornea (cornea verticillata), best seen with a slit lamp. Tinnitus and vertigo. High-frequency hearing loss, occasionally progresses rapidly to deafness.

Late symptoms

• Progressive renal involvement. • Unexplained proteinuria or microalbuminuria. • Increased blood urea nitrogen. • Sometimes polyuria. • Kidney failure. • Stroke: thromboembolic events leading to focal findings: • Usually occurs in young adult life. • Predilection for the posterior circulation with basilar ectasia, but any vessel may be involved. • Cardiac: • Valvulopathy (mitral valve insufficiency). • Cardiac arrhythmia. • Coronary artery disease. • Cardiomyopathy – may present in isolation in adults; left ventricular hypertrophy is common.

Mild cases presenting in adulthood may not have classic findings of acroparesthesia, pain, and angiokeratoma. Here, patients may have: • • • •

Peripheral neuropathy. Unexplained cardiomyopathy. Cerebrovascular events before age 40. Most will have corneal findings on slit-lamp examination.

Diagnosis and investigations

• α-Galactosidase activity: • Males have decreased activity. Both plasma and leukocytes should be tested. • Affected females have variable activity (undetectable up to normal range). • GLA gene sequencing and deletion/duplication analysis. • This can be the only way to establish the diagnosis in an affected female. • Biopsy will show linear deposits; seldom used as a primary diagnostic method, but can be used in unusual cases, such as in isolated cardiomyopathy.

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280 Treatment

• Enzyme replacement therapy is commercially available in North America and Europe, using IV treatments usually monthly for life. • Aspirin or other antiplatelet treatment for stroke prevention. • Pain attacks usually respond to anticonvulsants such as phenytoin, carbamazepine, and gabapentin.

Prior to enzyme replacement therapy, most affected males became increasingly debilitated from recurrent stroke and progressive heart and renal failure. Current survival is improved, but long-term outcome studies are lacking.

NIEMANN–PICK TYPE C Definition and etiology

NPC is an atypical autosomal recessive lysosomal storage disease caused by one of two genes: NPC1 (98% of families) or NPC2 (2% of families). The exact function of the NPC1 and NPC2 protein is unknown, but deficits cause accumulation of unesterified cholesterol in perinuclear vesicles. Males and females are equally affected. Disease frequency is at least 1:120,000, but it is most likely underestimated. There is a higher incidence in native Hispanic families in the American southwest and Acadians of Nova Scotia. Onset is infants to adults. Age of onset usually, but not always, is consistent within families. Infantile cases may have family members with late onset.

Clinical features

• Infantile: present at birth with splenomegaly, hepatic, and/ or pulmonary disease. • Late infantile: splenomegaly, hypotonia, progression to supernuclear palsy, developmental arrest, or regression. • Juvenile: clumsiness, progressing to ataxia, supranuclear gaze palsy, progressive intellectual regression, variable splenomegaly. • Adults: may present with either motor or psychiatric findings. Onset occurs from teens up to the sixth decade. Splenomegaly occurs in about 50%.

Psychiatric presentation occurs in about 30%. Neurological findings may be absent on presentation, but will develop later: • Psychosis or schizophrenia: • Can be acute or insidious. • Paranoid delusions. • Auditory or visual hallucinations. • Symptoms may fluctuate. • Major depression: • Social withdrawal. • Disturbed behavior. • Aggressiveness or agitation. Bipolar disorder, transient isolated visual hallucinations, or obsessive–compulsive disorder have been reported. Neurological symptoms vary. The most characteristic neurological finding is vertical supranuclear gaze palsy (VSGP), occurring in about 75%. Other findings may include: • Cerebellar ataxia. • Dysarthria.

• Dementia – mild to severe. • Movement disorders: • Dystonia. • Parkinsonism. • Chorea. • Progressive spasticity. • Epilepsy. • Cataplexy.

Diagnosis and investigations

• Neuro-ophthalmology evaluation is important; abnormal saccadic eye movements are usually the first neurological sign. VSGP occurs first, followed by lateral gaze. • Splenomegaly is present in about 50% of cases. • MRI is normal until late in disease. Late findings include: • Atrophy of cerebellar vermis. • Thinning of corpus callosum. • Mild generalized cortical atrophy.

Definitive diagnosis requires cultured fibroblasts. These accumulate unesterified cholesterol in lysosomes. Sequencing of NPC1 and NPC2 is available, but is not recommended for primary diagnosis. It is performed for prognosis and recurrence risk. The clinical course varies, with many patients surviving for 10 or more years.

Treatment

• Miglustat, an inhibitor of glycosphingolipids synthesis, has shown some benefit (stabilization or improvement) for the neurological manifestations of NPC, and it has been approved for this indication in some countries.

MITOCHONDRIAL DISORDERS Introduction

Mitochondrial disorders are a heterogeneous group of disorders whose primary deficit is failure of energy production due to alteration in mitochondrial function. Mitochondrial disorders can show any inheritance pattern, including maternal inheritance, autosomal recessive, autosomal dominant, or X-linked inheritance. This is because mitochondria contain their own DNA (mtDNA), which codes for some but not all components of the mitochondria. The other components of the mitochondria are produced from genes in the cell’s nuclear DNA (nDNA). Mitochondrial diseases due to mutations of nuclear DNA genes show typical autosomal or X-linked inheritance patterns and are not maternally inherited. On the other hand, mitochondrial diseases due to mutations of mtDNA show maternal inheritance, as well as wide variation in severity due to heteroplasmy. Maternal inheritance of mtDNA mitochondrial diseases occurs because essentially all mitochondria are inherited from the mother via the fertilized egg. However, the mother may be more mildly affected or even asymptomatic than the patient, even though she carries the same mtDNA mutation. This is because each mitochondrion has its own copy of mtDNA, and each cell contains hundreds of mitochondria. Therefore, any particular cell contains a mixture of normal and affected mitochondria, which is referred to as heteroplasmy. The overall ratio determines the severity of the phenotype, and it differs between each tissue within the body. This can lead to unexpected results on genetic testing because, for example, a patient with very severe neurological symptoms due to

Hereditary and Metabolic Diseases of the Central Nervous System in Adults a high ratio of mutant mitochondria in the brain may have blood genetic testing that only shows a few abnormal mitochondria in white blood cells.

TIP • Only mitochondrial disorders caused by mutations in mitochondrial DNA are maternally inherited. Many mitochondrial disorders, however, result from mutations in nuclear DNA and have autosomal dominant, autosomal recessive, or X-linked inheritance. There is no one identifying feature of mitochondrial disease. Patients may have one or more symptoms that can occur at any time in life. Mitochondrial disease should be suspected when a neurological presentation is atypical or may have more than one of the following findings: • • • • • • • • • • • • • • • •

Encephalopathy. Seizures. Early-onset or atypical late-onset dementia. Myoclonus. Movement disorders – dystonia, dyskinesias, chorea. Complicated migraine. Stroke or stroke-like events. Unexplained white matter changes (multiple sclerosis–like). Neuropathy. Cardiac conduction defects or cardiomyopathy. Hearing deficits. Disorders of extraocular muscles – ptosis, acquired strabismus, or ophthalmoplegia. Diabetes. Renal tubular disease. Visual loss (retinitis pigmentosa). Lactic acidosis.

MRI findings suggestive of mitochondrial disease include: • Symmetric basal ganglia or brainstem lesions. • Symmetric increased T2 intensity in white matter: • Generalized. • Primarily occipital or frontal. • Cerebral atrophy. • Cerebellar atrophy.

DISEASES OF MITOCHONDRIAL DNA Definition and etiology

There are multiple mitochondrial syndromes that have stereotypic presentations and clinical course. Specific mtDNA mutations are often associated with these syndromes, but it must be remembered that the same mutation may be associated with more than one syndrome. For instance, a mutation most commonly associated with neuropathy, ataxia, and retinitis pigmentosa (NARP) may be found in a patient with a primary myopathy or encephalopathy. Evaluation includes serum lactic acid, and, if negative, either MR spectroscopy or CSF analysis of lactate. Mutations may be identified in with blood cells, but a muscle biopsy is often needed to detect mutations.

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Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes • • • •

Onset at any age. Stroke-like events causing subacute focal brain dysfunction. Seizures and/or migraine headaches. Lactic acidosis: • Secondary hyperalaninemia. • Both may be normal between crisis.

MRI findings include diffusion-weighted imaging-positive lesions that are not hypointense on apparent diffusion coefficient. They do not follow vascular territory, and they have a predilection for the posterior circulation. Frequently seen clinical findings include retinitis pigmentosa, cerebellar ataxia, myopathy, cardiomyopathy, and diabetes.

Mitochondrial encephalopathy with ragged red fibers

• Myoclonus. • Epileptic seizures: myoclonic epilepsy, generalized seizures, or focal seizures. • Cerebellar ataxia. • Mitochondrial myopathy with ragged red fibers.

Frequently seen clinical findings include: • • • • • • • • •

Dementia. Optic neuropathy. Deafness. Corticospinal tract degeneration. Peripheral neuropathy. Myopathy. Proximal renal tubule dysfunction. Cardiomyopathy. Lactic academia with secondary hyperalaninemia.

Neurogenic weakness with ataxia and retinitis pigmentosa

MT-ATP6 is the only gene associated with NARP. Not all clinical cases have a detectable deletion. Clinical findings include: • • • •

Proximal muscle weakness. Sensory neuropathy. Ataxia. Retinal pigmentary degeneration.

Frequently associated clinical findings include: • Primary intellectual disability. • Dementia. • Epileptic seizures.

Leber’s hereditary optic neuropathy

• Subacute painless bilateral vision loss. • Males: females 4:1. • Median age of onset 24 years.

Frequently associated clinical findings include dystonia and cardiac pre-excitation syndromes.

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282 Subacute necrotizing encephalomyelopathy Definition and etiology

Subacute necrotizing encephalomyelopathy (Leigh’s syndrome) can be produced by nDNA and mtDNA mutations of genes encoding for enzymes involved in energy production, such as mitochondrial respiratory chain complexes I–V, and components of the pyruvate dehydrogenase complex. Leigh’s syndrome is therefore more than one disease with similar phenotypes. • Two-thirds of pediatric cases are nDNA mutations. • Most identified adult disease is secondary to mtDNA mutations, but a few cases have been linked to nDNA genes SURF1 and COQ. • An X-linked form has been described; this is caused by a mutation of the PDHA1 gene, which encodes for a component of the pyruvate dehydrogenase complex. Prevalence is probably 1:40,000, with males and females equally affected.

Clinical features

Key features are symmetric necrotizing lesions of the basal ganglia, thalamus and diencephalon, and brainstem, seen on MRI or autopsy. Cerebellum and spinal cord gray matter also may be involved, but cortex is seldom involved. Leigh’s syndrome may result in respiratory failure and death. Symptoms may fluctuate with apparent remissions and exacerbations, and include: • • • • • • • • • •

Ataxia. Movement disorders: dystonia, chorea. Nystagmus, ophthalmoparesis. Dysphagia. Peripheral neuropathy. Myopathy. Cardiomyopathy. Optic atrophy. Seizures. Slowly progressive dementia.

Treatment

Treatment is primarily symptomatic, with frequent monitoring of respiratory function, swallowing, and cardiac function. MELAS has been treated with IV arginine during acute strokes as well as prophylactic oral arginine and other supplements. Supplementation with a wide variety of vitamins and cofactors aimed at supporting the function of various mitochondrial enzymes has been tried. These include coenzyme Q, riboflavin, thiamine, niacin, folate, vitamin E, selenium, and lipoic acid. A high-fat diet may be effective with mutations in complex I.

Mitochondrial deletion syndromes Definition and etiology

These involve larger deletions of mtDNA. If inherited, they derive from the mother. Mitochondrial deletion syndromes

more often arise de novo and the mother and siblings are not affected. There are three overlapping phenotypes: Kearns–Sayre syndrome, Pearson’s syndrome, and progressive external ophthalmoplegia (PEO).

Kearns–Sayre syndrome

• Triad of symptoms: • Onset before age 20. • Pigmentary retinopathy. • PEO.

In addition, patients must have one of the following: • Cardiac conduction block. • CSF protein greater than 1 g/L (100 mg/dL). • Cerebellar ataxia. Patients may also have hearing loss, depression, dementia, weakness, or an endocrine deficiency such as diabetes mellitus, hypoparathyroidism, or growth hormone deficiency. Patients require frequent monitoring for cardiac and endocrine dysfunction.

Pearson’s syndrome

• Sideroblastic anemia. • Exocrine pancreas dysfunction. • Usually fatal in infancy.

Progressive external ophthalmoplegia • • • • •

Age at onset: childhood to middle age. Ptosis. Paralysis of extraocular muscles. Mild to severe proximal limb weakness. If there are more components of Kearns–Sayre syndrome, then it is referred to as PEO plus (PEO+). • Most have a normal life span. • Children may inherit from an affected mother.

Treatment

Treatment of mtDNA deletion syndromes is primarily supportive. Some Kearns–Sayre syndrome patients have low CSF folinic acid and require supplementation. Supplementation with coenzyme Q, L-carnitine, and B vitamins is common, as these are presumed to improve enzyme function.

REFERENCES



1. ACMG Board of Directors. Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics. Genet Med. 2015;17(6):505–507. 2. Ferreira CR, van Karnebeek CDM, Vockley J, Blau N. A proposed nosology of inborn errors of metabolism. Genet Med. 2019;21(1):102–106. 3. Saudubray JM, Mochel F, Lamari F, Garcia-Cazorla A. Proposal for a simplified classification of IMD based on a pathophysiological approach: a practical guide for clinicians. J Inherit Metab Dis. 2019;42(4):706–727.

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4. Lien J, Nyhan WL, Barshop BA. Fatal initial adultonset presentation of urea cycle defect. Arch Neurol. 2007;64(12):1777–1779. 5. Ketonen LM, Hiwatashi A, Sidhu R, Westesson P-L. Pediatric Brain and Spine. Berlin: Springer-Verlag; 2005. 6. Sedel F, Baumann N, Turpin JC, Lyon-Caen O, Saudubray JM, Cohen D. Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis. 2007;30(5):631–641.





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7. van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol. 2017; 134(3):351–382. 8. Van der Knaap MS, Valk J. Magnetic Resonance of Myelination and Myelin Disorders. Berlin: Springer-Verlag;2005. 9. Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153–156.

11

TRAUMA OF THE BRAIN AND SPINAL CORD

Fernando D. Goldenberg, Ali Mansour

Contents Introduction....................................................................................................................................................................................................................... 285 Head Injury......................................................................................................................................................................................................................... 286 Definition and etiology.............................................................................................................................................................................................. 286 Etiology and clinical features.................................................................................................................................................................................... 286 Diagnosis and investigations..................................................................................................................................................................................... 289 Management................................................................................................................................................................................................................ 290 Prehospital management..................................................................................................................................................................................... 290 Emergency department........................................................................................................................................................................................ 290 Intensive care unit................................................................................................................................................................................................. 290 Surgical decompression........................................................................................................................................................................................291 Concussion..........................................................................................................................................................................................................................292 Definition and etiology...............................................................................................................................................................................................292 Evaluation......................................................................................................................................................................................................................292 Spinal Cord Injury..............................................................................................................................................................................................................292 Definition and etiology...............................................................................................................................................................................................292 Pathophysiology......................................................................................................................................................................................................292 Clinical patterns......................................................................................................................................................................................................293 Complete spinal cord injury.......................................................................................................................................................................................293 Spinal shock.............................................................................................................................................................................................................293 Neurogenic shock...................................................................................................................................................................................................293 Incomplete spinal cord injury....................................................................................................................................................................................293 Clinical features........................................................................................................................................................................................................... 294 Diagnosis and investigations..................................................................................................................................................................................... 294 Imaging.................................................................................................................................................................................................................... 294 Treatment......................................................................................................................................................................................................................295 High-dose methylprednisolone.................................................................................................................................................................................295 Decompression and stabilization..............................................................................................................................................................................295 Closed reduction....................................................................................................................................................................................................295 Surgical treatment........................................................................................................................................................................................................295 Complications of spinal cord injury.........................................................................................................................................................................295 Syringomyelia..........................................................................................................................................................................................................295 Neuropathic arthropathy......................................................................................................................................................................................295 Spasticity..................................................................................................................................................................................................................295 Cardiovascular........................................................................................................................................................................................................295 Genitourinary and gastrointestinal....................................................................................................................................................................295 Neuropathic pain....................................................................................................................................................................................................295 Prognosis................................................................................................................................................................................................................. 296 References........................................................................................................................................................................................................................... 296

INTRODUCTION Traumatic brain injury (TBI) is a major public health concern, often dubbed as a “silent epidemic.”1 Of all other traumatic insults, TBI contributes the most to worldwide death and disability. Furthermore, the economic burden of TBI in the United States as estimated by lifetime cost, including medical and lost productivity, is around $60 billion annually. In 2014 alone, and only in the Unites States, a total of 2.87 million TBI-related emergency department (ED) visits, hospitalizations, and deaths (TBI-EDHDs) occurred. Of those, approximately 282,000 were hospitalized and 56,800 died accounting for 2.2% of

all deaths in the United States that year. The global annual incidence of all-cause, all-severity TBI is estimated at 939 cases per 100,000 people. This adds up to around 69 million people suffering from TBI annually. When considered by order of severity, the estimated incidence of mild TBI is 740 cases per 100,000 people annually. In comparison, the estimated incidence of severe TBI is 73 cases per 100,000 people annually.1,2 Rates of TBI vary by age, with the highest rates observed among older individuals who are over 75 years of age, children between the ages of 0 and 4 years, and young adults between 15 and 24 years of age. In the last few years, there has been a decrease in the ageadjusted rate of TBI-related deaths attributable to motor vehicle 285

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286 crashes and an increase in the ones related to falls and intentional self-harm. In the military setting, blasts are a leading cause of TBI.3 In recent decades, improvements in prehospital care, especially airway management, triage to a level 1 trauma center, prompt computed tomography (CT) imaging, removal of significant intracranial hemorrhagic collections, and avoidance of secondary insults (hypotension, hypoxemia) has reduced severe TBI mortality to about 30%. Guidelines for the management of severe TBI have been widely adopted in the United States and updated in 2016.4 Use of noninvasive and minimally invasive multimodality monitoring, such as transcranial Doppler (TCD), quantitative electroencephalography (qEEG), intracranial pressure (ICP) monitors, extracellular partial pressure of oxygen (PbO2) monitors, microdialysis catheters, fractional near-infrared spectroscopy (fNIRS), has gained stronger footing with trends toward developing patient-specific targets that aim at optimizing autoregulation, cerebral perfusion, and eventually outcomes.

HEAD INJURY Definition and etiology

Despite intensive treatment, some degree of disability or death occurs in the majority of patients with severe TBI, and physical and neuropsychologic disabilities are frequent in those with moderate or even mild injuries. Age is a major variable associated with outcome after TBI, with older individuals showing less favorable outcomes. Other factors, including, but not limited to, genetic differences, history of psychiatric disease, socioeconomic status, and history of substance abuse, are associated with variable outcomes.5,6 The Glasgow Coma Scale (GCS) is widely used to quantify the severity of injury (Table 11.1). Patients who open their eyes spontaneously, follow commands, and are fully oriented score all 15 points. Patients who do not open their eyes even to stimuli and cannot verbalize or move any extremities have the lowest score of 3. In cases of hemiparesis, the best motor response is the one scored. A comatose patient with a GCS score ≤8 is defined as severe TBI. Moderate TBI patients are usually lethargic and have a GCS of 9–12, and mild TBI patients have less alteration in consciousness and a GCS of 13–15. Extreme caution must be exercised in any patients with a GCS of 13, abnormal CT head,

and/or skull fracture given that their risk is similar to that of moderate TBI and should be considered as a high-risk mild TBI. Severe TBI carries an overall mortality of about 30%. Approximately 10–20% of moderate injuries will deteriorate into coma, and 10% will have serious morbidity or death. Additionally, the severe and moderate injuries yield large numbers of disabled survivors (20–30%). Most current studies measure longterm outcome at 6 months utilizing the Glasgow Outcome Scale Extended (GOS-E). However, reported outcomes are oftentimes confounded by limited follow-up and underreporting of complications and severity of injuries.7

Etiology and clinical features

TBI is a complex disease. The causes are broadly classified into penetrating and nonpenetrating mechanisms. A nonpenetrating or closed head injury, with or without skull fracture but intact dura, usually results from fall, motor vehicle crash, or assault with a blunt tool. Open injury is associated with dural penetration and is often related to gunshot (high-velocity projectile) or stab wound (low-velocity projectile). Less frequently, a blunt trauma can cause a compound depressed skull fracture with the depressed bone fragment piercing the dura into the parenchyma. Closed head injury can induce a variety of pathologies. Those include extra-axial pathologies like skull fracture, subdural hematoma (SDH), epidural hematoma (EDH), or subarachnoid hemorrhage, as well as intra-axial pathologies like brain contusion or hemorrhage, intraventricular hemorrhage, and diffuse axonal injury (DAI). SDH and EDH are often the result of mechanical injury of nearby vascular structures. EDH (Figure 11.1) frequently constitutes a surgical emergency. Radiologically, it is described as a lens-shaped extra-axial hematoma limited by suture lines, commonly resulting from an arterial bleed from a meningeal artery

TABLE 11.1  Glasgow Coma Scale Score Eye Opening

Score (1–4)

Spontaneous To voice To pain None Verbal response Oriented Confused, disoriented Inappropriate words Incomprehensible sounds None Best motor response Obeys Localizes Withdraws (flexion) Abnormal flexion posturing Extension posturing None Total

4 3 2 1 Score (1–5) 5 4 3 2 1 Score (1–6) 6 5 4 3 2 1 (3–15)

FIGURE 11.1  CT Head, axial projection: Acute right epidural hematoma (EDH) causing significant mass effect, horizontal midline shift and compression of the ipsilateral lateral ventricle.

Trauma of the Brain and Spinal Cord

FIGURE 11.2  CT head, axial projection: Left convexity acute on chronic Subdural Hematoma (SDH) causing significant mass effect, horizontal midline shift, left uncal herniation, compression of the ipsilateral ventricle and entrapment of the contralateral ventricle. (middle meningeal artery usually). A lucid interval after the trauma may be present; however, clinical deterioration can be rapid. The mortality of acute EDH continues to decrease in recent decades as outcome is largely related to triage and timely surgical management. Acute SDHs (Figures 11.2 and 11.3) are extra-axial blood collections that cross sutures lines and may lead to brain compression, and in some cases possible focal underlying cerebral ischemia. Because they are often the result of tearing of the bridging veins between the cerebral cortex and the dural sinuses,

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FIGURE 11.4  CT Head, axial projection showing basal right temporal and basal bifrontal cerebral contusions. conditions associated with brain atrophy (old age, alcoholism, and dementia) render those individuals more susceptible to SDH. Cerebral contusions (Figure 11.4) are typically hemorrhagic lesions that more commonly involve the basal and anterior portions of the frontal and temporal lobes. They occur when the brain hits against the rough surface of the inner table of the anterior and middle cranial fossa. The classic understanding is that the acceleration and deceleration of the brain within the cranial compartment result in a coup–contrecoup injury pattern, with the coup damage happening directly beneath the site of impact and the contrecoup on the opposite side. Contusions typically begin within the cortex and

FIGURE 11.3  A. CT Head. Coronal projection showing bilateral acute subdural hemorrhage (right larger than left). B. Brain MRI (Fluid attenuation inversion recovery [FLAIR] sequences) showing bilateral subdural hemorrhages (right larger than left) with mass effect and horizontal midline shift. C. Brain MRI (susceptibility weighted images [SWI]) showing hypointense lesions in the center of the midbrain (black arrow) that correspond to Duret hemorrhages secondary to transtentorial brain herniation.

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Hankey’s Clinical Neurology FIGURE 11.5  Brain MRI. A: Diffusion weighted images (DWI) showing hyperintense lesions bilaterally. B: Susceptibility weighted images (SWI) showing mixed hyper/hypointense lesions bilaterally in the same areas than the ones seen in DWI. These lesions represent DAI (diffuse axonal injury).

expand into the subcortical white matter with more severe injury. Pericontusional edema and ischemic changes lead to neuronal cell death in the afflicted areas, with eventual cavitation and reactive gliosis around the perimeter of the injury later on. “Blossoming” of a contusion refers to continued hemorrhagic progression or expansion of a seemingly subtle hemorrhage on initial evaluation. The mechanism of this hemorrhagic progression was classically attributed to coagulopathy. However, more recent literature argues that mechanosensitive endothelial cells are activated in the penumbra of the initial lesion. This penumbra does not experience the destructive forces occurring within the contusional core itself but causes endothelial mechanosensitive activation of transcription factors leading to endothelial necrosis and delayed hemorrhage.5

TIP • TBI can be closed or penetrating. Penetrating brain injuries are usually associated with more severe injury and worse outcomes. Posterior fossa skull fractures and hematomas result from impacts to the back of the head. These are particularly dangerous due to the proximity of the brainstem. DAI (Figure 11.5) consists of diffuse neuronal damage, microvascular changes, axonal transport perturbation, and axonal shearing/ disconnection from the neuronal body. DAI is a component of many

forms of severe TBI, occurs also as a consequence of acceleration and deceleration forces, and is a key determinant of morbidity. DAI was first described in the subcortical white matter, corpus callosum, and brainstem (grades I, II, and III, respectively). However, it is currently recognized that DAI can occur at numerous brain sites involving both gray and white matter. The pathophysiology of DAI was believed to be a result of direct axonal severing at the time of injury leading to retraction and expulsion of a ball of axoplasm. More recent studies have demonstrated that the injury starts with focal perturbation of axonal membranes leading to a chain of calcium-mediated events that impair axonal transport. This culminates in focal axonal swelling and disconnection, which lead to distal wallerian degeneration. DAI is a progressive process as opposed to an irreversible mechanism at the onset of injury. Research into finding neuroprotective agents that could reduce DAI are currently underway.5 Blast-related TBI is often observed in the war setting. “Blast injury” forces, as seen in proximity to a discharging explosive device, may result in concussion or prolonged unconsciousness even without skull penetration by fragments or shrapnel. Highintensity shock waves consisting of advancing wave fronts are believed to cause secondary complex interference patterns, which may result in diffuse physiologic or actual mechanical tissue disruption. This mechanism may also result in neuropsychologic deficits and posttraumatic stress disorders (PTSD). Penetrating brain injury (PBI) (Figure 11.6) is a subgroup of TBI associated with dural penetration. The most common cause of PBI in civilians is gun violence. Outcomes are oftentimes catastrophic. FIGURE 11.6  CT Head, axial projections. A is the bone window. B is the parenchymal window showing a gunshot wound to the head with significant bifrontal bony destruction and bifrontal brain contusions, as well as bilateral intraventricular hemorrhage (IVH).

Trauma of the Brain and Spinal Cord Admission GCS score seems to be the most important prognostic factor, although caution is advised as concomitant use of illicit drugs or sedatives may obscure the initial GCS assessment. More recently, scores such as the Social Phobia Inventory (SPIN) score have been validated for the prediction of mortality following gunshot wounds to the head (GSWH).8 Different mechanisms of injury occur in GSWH. The primary damage occurs through the “permanent cavity.” The bullet creates a path as it courses through the skin, bone, and eventually the brain parenchyma. This wound channel is approximately the same diameter as the bullet and is a function of bullet penetration and expansion. Bullets can also create “temporary cavities.” When a bullet hits soft tissue, the tissue acts more like a fluid than a solid as it gives way and absorbs the bullet’s energy creating an impact crater. As the bullet continues its path, it violently pushes the tissue ahead of it both directly and indirectly in such a way that the tissue is stretched beyond its elasticity and is cut and torn as it quickly tries to return to its original position. After the cavity expands to its maximum size, it starts to collapse under negative pressure. This results in a track of injury that is 10–20 times the size of the projectile.

Diagnosis and investigations

An adequate airway, usually by endotracheal intubation, must be promptly established in comatose or combative patients. This includes severe TBI (GCS 8 or less), possibly some moderate TBI (GCS 9–12), those with respiratory distress or hypoxemic, or sometimes patients with significant intracranial abnormalities on brain CT scan. Attention to airway, breathing, and circulatory stability (ABC) is the priority before adequate diagnosis and treatment can be carried out. While securing an airway, special attention must be given to the cervical spine. TBI and spinal cord injuries (SCIs) often occur together (16% of TBI patients), especially in patients with altered mental status or those with blunt injury above the clavicle.9

TIP • The ABCDE of trauma resuscitation: airway, breathing, circulation, disability, and exposure. It is fundamental to avoid, and correct, hypoxia (PaO2 < 60 mmHg, O2 sat < 90%), hypotension (systolic blood pressure [SBP] < 90 mmHg), hyperglycemia, and hyperthermia. Injury to visceral organs, or long bone fractures, may contribute to blood loss, hypovolemia, hypotension, and increased morbidity. In the traumatized patient, other diagnoses such as intoxication, anoxic insult, metabolic encephalopathy, postictal state, or status epilepticus may be present. Nonconvulsive status epilepticus may present with decreased level of consciousness. The diagnosis of this condition may require prolonged electroencephalographic monitoring. Following respiratory and circulatory stabilization, rapid neurologic assessment is performed including the GCS and pupillary examination. Verbal, and when necessary, physical (painful) stimulation must be applied and the responses recorded. Important findings include verbal responses, asymmetries in motor examination, decorticate (abnormal flexor) or decerebrate (abnormal extensor) responses, flaccid paralysis, deep tendon reflexes, and plantar responses. Sensory examination is only possible in awake and cooperative patients. Many times, it is not possible to examine the patient before neuromuscular blockage or sedation. In

289 such instances, consideration to reversal of paralytics and holding sedation must be individualized by carefully weighing the risk of precipitating intracranial hypertension and the benefits resulting from having a more accurate examination. Even in patients that have received sedatives and/or opiates, a limited neurologic examination should be obtained. In the absence of muscle relaxants, a motor response to painful stimulation can still be obtained, and if asymmetry is detected, a central nervous system lesion should be suspected. Abnormal motor responses like decorticate or decerebrate posturing are suggestive of supratentorial mass effect and probably intracranial hypertension and, therefore, constitute an emergency that needs to be rapidly addressed and treated. The pupillary size and reactivity to light should not be greatly influenced by the abovementioned medications (opiates may induce myosis, but the pupils should remain symmetric and reactive to light under normal conditions). Responses to corneal stimulation, gag and cough reflexes, and oculovestibular reflex (after ruling out external/middle ear trauma) should also be explored. Unilateral pupil enlargement (mid position 3–5 mm or dilated >5 mm) in an obtunded patient, with or without reaction to bright light is highly localizing and indicative of ipsilateral transtentorial and/or uncal herniation unless suggested otherwise by the patient’s history. Prophylactic temporary hyperventilation, blood pressure optimization, ensuring midline position of the neck, and administration of mannitol or hypertonic saline solutions should be considered in these situations. doll’s eye maneuver (oculocephalic reflex) should be avoided until cervical spine has been deemed stable. Cerebrospinal fluid (CSF) leaks in TBI increase the risk of central nervous system infection. However, the 2016 Brain Trauma Foundation guidelines do not call for empiric antibiotics.4 While antibiotic administration is controversial, a spinal drain may be considered for patients with a leak that persists after several days and have no intracranial mass-occupying lesions that could promote downward cerebral herniation. Tension pneumothorax is a feared complication in patients who suffer CSF leak. Overall, higher mortality rates are described in TBI patients presenting with CSF leak.9 Patients with a concussion or mild head injury who present for medical attention should at least receive plain skull X-rays, and any patient with a GCS score less than 15, prolonged unconsciousness (>1 minute), focal neurologic signs, headache, vomiting, skull fracture, or significant scalp swelling should receive a noninfused CT scan of the head. Further treatment will usually depend on the CT scan results. According to the New Orleans Criteria (NOC), patients with a GCS of 15 require a head CT if they have headache, vomiting, age >60 years, drug or alcohol intoxication, persistent anterograde amnesia, seizure, or visible trauma above the clavicle.10 Magnetic resonance imaging (MRI) brain scans are usually unnecessary and inconvenient in the earlier stages of TBI. In the subacute phase, characteristic MRI findings can often establish a suspected diagnosis of DAI. Blunt cerebrovascular injuries (BCVIs) happen after trauma and are often underdiagnosed. The Denver group11 has proposed screening guidelines. Patients presenting signs or symptoms suggestive of BCVI, including potential arterial hemorrhage from neck/nose/mouth, cervical bruit in patient 100 GPL units (anticardiolipin antibodies, lupus anticoagulant, anti-β2-glycoprotein) Coagulation disorders associated with malignancy Hyperhomocysteinemia Disseminated intravascular coagulation Disturbances of primary hemostasis: • • • • •

High vWF Low ADAMTS13 Disorders of fibrin formation and fibrinolysis High fibrinogen Impaired fibrinolysis: • Plasminogen activator inhibitor 4G/5G promoter polymorphism of the encoding gene • Increased thrombin-activatable fibrinolysis inhibitor Polycythemia rubra vera Thrombocytosis (platelets >800,000): • Primary thrombocytosis: • Essential thrombocythemia • Polycythemia vera • Idiopathic myelofibrosis • Chronic myeloid leukemia • Myelodysplasia • Acute leukemia • Secondary thrombocytosis: • Infection • Inflammation • Connective tissue disease • Iron deficiency • Blood loss (e.g. surgery) • Malignancy • Postsplenectomy • Hemolytic anemia Leukemia Sickle cell disease Abbreviations: ADAMTS13, A disintegrin and metalloprotease with thrombospondin motif; vWF, von Willebrand’s factor.

The thrombosis is more often venous (DVT and pulmonary embolism) than arterial and in any sized vessel. Stroke and TIA are the most common types of arterial thrombosis in APS, with APS accounting for about 10% of strokes in patients aged under 50 years. Other features are nonspecific and include recurrent miscarriage, migraine, memory loss, confusion, visual disturbances, abdominal pain, heart valve vegetations, a characteristic

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341

TABLE 12.33  Clinical Features of Antiphospholipid Syndrome Vascular Thrombosis • TIA, stroke, or multifocal encephalopathy (cognitive dysfunction, white matter lesions on imaging) due to arterial or venous thrombosis in any size of vessel before 50 years of age • Unexplained deep vein thrombosis or pulmonary embolism before 50 years of age • Recurrent thrombosis (without evidence of inflammation in the vessel wall) • Thrombosis at an unusual site Pregnancy Morbidity • Three or more unexplained consecutive spontaneous miscarriages before the 10th week of gestation, with maternal anatomical or hormonal abnormalities excluded and paternal and maternal chromosomal causes excluded • Recurrent spontaneous miscarriage/fetal loss due to intrauterine death after 10 weeks’ gestation with normal fetal morphology documented by ultrasound or by direct examination of the fetus • Severe intrauterine fetal growth retardation • Severe or early-onset pre-eclampsia • Pre-eclampsia with severe thrombocytopenia • Prematurity (one or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia or severe pre-eclampsia defined according to standard definitions, or recognized features of placental insufficiency) Heart Disease • Cardiac valve disease (e.g. valve thickening and nodules) • Coronary artery disease and myocardial infarction Skin • • • •

Livedo reticularis (Figure 12.108) Nonhealing ulceration of the ankles and skin necrosis Raynaud’s phenomenon Splinter hemorrhages

Renal • Glomerular disease • Thrombotic microangiopathy Hematological • Thrombocytopenia (usually mild, asymptomatic, persistent, unexplained) • Hemolytic anemia Autoimmune Disease • New diagnosis of systemic lupus erythematosis

rash (livedo reticularis) (Figure 12.108), thrombocytopenia, hemolytic anemia, circulating lupus anticoagulant, and falsepositive nonspecific serological tests for syphilis. APLAbs are not specific to APS, particularly if they are not present in high titers on repeated testing. They can be found in up to 12% of the general population, including normal individuals (prevalence increasing with age); SLE and other collagen vascular disorders; malignancy; lymphoma; paraproteinemias; human immunodeficiency virus (HIV) and other infections; patients with multiple vascular risk factors; on hemodialysis; and as a result of a variety of medications such as phenothiazines, hydralazine, phenytoin, valproate, procainamide, and quinidine.

FIGURE 12.108  Livedo reticularis in a patient with antiphospholipid antibody syndrome.

Cryptogenic (of unknown cause) ischemic strokes

Cryptogenic ischemic strokes are symptomatic cerebral infarcts for which no probable cause is identified after adequate standard diagnostic evaluation, including CT or MRA of the aortic arch, neck and brain arteries, echocardiography, and 24-hour Holter monitoring (see the section Investigation section below). Cryptogenic stroke is therefore a diagnosis of exclusion, after ruling out other causes. Cryptogenic strokes comprise about 20% of all ischemic strokes, depending on definitions, diagnostic technology, and perceived adequacy of investigation in excluding the >200 known causes of ischemic stroke.12 More specialized testing suggests that most cryptogenic strokes are thromboembolic in origin. The source of the relevant thrombus includes: • Veins via paradoxical embolism. • Hypercoagulable states. • Minor-risk or covert cardiac sources (e.g. paroxysmal AF, moderate dilated cardiomyopathy, congenital heart disease). • Occult nonocclusive but unstable atherosclerotic plaques in the aortic arch, cervical, or cerebral arteries. • Nonatherosclerotic arteriopathies (dissection, vasculitis).

Embolic stroke of undetermined source

The entity of embolic strokes of undetermined source (ESUS) has been proposed to describe a large subgroup (about 80–90%) of cryptogenic ischemic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of specific etiologies; ESUS are nonlacunar brain infarcts without substantial proximal arterial stenosis or major cardioembolic sources. When the concept of ESUS was originally proposed, it was thought that covert AF may frequently underlie ESUS and that anticoagulation may be beneficial for stroke prevention after ESUS. Subsequently, it has been shown that the characteristics of ESUS patients differ from those of stroke in patients with AF. On average, ESUS patients are younger, have lower baseline stroke severity, have lower burden of cardiovascular risk factors, and have lower mortality compared with patients with cardioembolic ischemic stroke. Moreover, they continue to have a high risk of recurrent stroke (about 5% per year) despite current antiplatelet or anticoagulant treatment regimens, and most of these recurrent strokes are also ESUS.17,18 The lack of success of anticoagulation

Hankey’s Clinical Neurology

342 in the NAVIGATE-ESUS and RESPECT-ESUS trials17,18 does not support the assumption that AF-related cardiogenic embolism underpins most cases of ESUS (although it is acknowledged that the follow-up in these trials was short and that, in the longer term, anticoagulation may be more effective than antiplatelet therapy in some ESUS patients). Nevertheless, ESUS patients who develop AF during follow-up tend to have recurrent ischemic strokes that are more disabling and fatal than other recurrent stroke types. Therefore, although covert AF may not underlie the vast majority of recurrent strokes after ESUS, the severity of the recurrent strokes that arise in the minority of patients who do develop AF underpins the rationale for an extensive search for AF in ESUS patients (e.g. in the NAVIGATE-ESUS trial, an increased HAVOC

score [hypertension, age ≥75 years, valvular heart disease, vascular disease, obesity with body mass index >30, congestive heart failure, and coronary artery disease], left atrial diameter >4.6 cm, and premature atrial contraction frequency predicted subsequent clinical AF). Hence, the quest continues to identify subgroups within the ESUS syndrome that are likely to benefit from an antiplatelet, anticoagulant, or combined antiplatelet with low-dose anticoagulant, preventive strategy.

Etiologic classification of ischemic stroke

Etiologic subtypes of ischemic stroke may be classified in several ways (Table 12.34), but most commonly according to the

TABLE 12.34  Classification of Etiologic Subtypes of Acute Ischemic Stroke Large Artery Disease

Small Artery Disease

CLINICAL

CLINICAL

• Embolic syndrome: cerebral cortical, brainstem or cerebellar symptoms (e.g. TACS, PACS, POCS) • Supported by other evidence of large artery disease; e.g. atherosclerosis: presence of vascular risk factors (hypertension, diabetes, smoking, hypercholesterolemia), family history of symptomatic atherosclerotic events, history of intermittent claudication, previous TIA in same vascular territory, myocardial infarction, carotid bruits, diminished peripheral pulses BRAIN IMAGING • Cerebral cortical or cerebellar lesions or brainstem/subcortical lesions >1.5 cm diameter on CT/MRI brain VASCULAR IMAGING • Visible plaque or dissection of appropriate intracranial or extracranial artery on duplex ultrasound or arteriography (CT, MRI, or digital subtraction) ECG, HOLTER MONITOR, AND CARDIAC IMAGING • Potential sources of embolism from the heart excluded Cardiac embolism CLINICAL

• Patient should have one of the traditional clinical lacunar syndromes and no evidence of cerebral cortical dysfunction • Supported by risk factors for, or clinical and laboratory features of, a small artery disease BRAIN IMAGING • Normal CT/MRI or relevant brainstem or subcortical hemispheric lesion 1.5 cm diameter on CT/MRI brain VASCULAR IMAGING • Potential sources of thrombosis or embolism in large arteries (e.g. atheroma, dissection, moyamoya disease) excluded ECG, HOLTER MONITOR, AND CARDIAC IMAGING • At least one cardiac source of embolism should be identified (from high-risk group for “probable” or medium-risk group for “possible” cardiac embolism)

• Cardiac sources of embolism excluded OTHER INVESTIGATIONS • Includes patients with nonatherosclerotic vasculopathies, hypercoagulable states, or hematological disorders Undetermined etiology • Patients with two or more potential causes of stroke • No etiology determined despite extensive evaluation • No etiology determined but cursory evaluation

Abbreviations: CT, computed tomography; ECG, electrocardiography; MRI, magnetic resonance imaging; PACS, partial anterior circulation syndrome; POCS, posterior circulation syndrome; TACS, total anterior circulation syndrome; TIA, transient ischemic attack.

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TABLE 12.35 Sites of Primary Intracerebral Hemorrhage (Irrespective of Age) • • • • • • •

Putamen or internal capsule (Figures 12.6–12.8) 30% Caudate nucleus 5% Entire basal ganglia region 5% Lobar (Figures 12.13, 12.32–35, 12.43) 30% Thalamus (Figure 12.48) 15% Cerebellum 10% Pons or midbrain 5%

TOAST classification, the ASCOD phenotyping system (A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other cause; D: dissection), and the causative classification system.

Intracerebral hemorrhage

ICH accounts for about 15% (5–40%) of all strokes, depending on geography and race.19 The incidence of ICH is higher in Asian and older populations, but is overall about 25 (2–130) per 100,000 person-years (Table 12.35). ICH is caused by rupture of an intracerebral artery (Figure 12.109). About 85% of spontaneous ICHs have no underlying macrovascular cause and are attributed to small-vessel (deep perforating) disease, mostly arteriolosclerosis, with or without CAA. Arteriovenous malformations are the most common cause of ICH in younger patients. The most common causes of ICH, according to the age of the patient and the location of the ICH are listed in Table 12.36.

FIGURE 12.109  Brain (coronal section) at autopsy, showing a large intracerebral hematoma that extended into the ventricular system and was fatal. Clinical clues to the cause of ICH are listed in Table 12.37. Predisposing factors include: • Anatomical factors: diseases or malformations of cerebral arteries. • Hemostatic factors: diseases of the blood clotting system. • Hemodynamic factors: excessively high systemic arterial BP. There may be a history of preceding physical activity such as heavy exertion, defecation, lifting, or sexual intercourse; administration of anticoagulant, antiplatelet or recreational drugs; ischemic stroke (hemorrhagic transformation of an infarct); or recent pregnancy (choriocarcinoma, intracranial venous thrombosis).

TABLE 12.36  Most Common Causes of Intracerebral Hemorrhage (in approximate rank order, coagulopathies and hemodynamic factors excluded, according to the patient’s age and the location of the hematoma) Location of Hematoma

Age 70 Years • • • • •

Small-vessel disease Tumor AVM or cavernoma Cerebral vein thrombosis Infective endocarditisb

• • • •

Amyloid angiopathy Small-vessel disease Saccular aneurysmc AVM or cavernoma

• Small-vessel disease • Amyloid angiopathy • Tumor

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TABLE 12.37  Clinical Clues to the Cause of Intracerebral Hemorrhage Arterial disease (anatomical factors) • Deep perforating vasculopathy or arteriosclerosis: • Most common cause in middle and older age • Hemorrhages often deep, in the putamen (40%), caudate nucleus (8%), thalamus (15%), cerebral hemispheres (lobar) (20%), cerebellum (8%), and brainstem (8%), in the distribution of deep perforating arteries • Associated lacunar infarcts and subcortical white matter lesions • Amyloid (congophilic) angiopathya: • Most common cause in old age • Lobar intracerebral hemorrhage (commonly with finger-like extensions) • Cortical–subcortical microbleeds, subarachnoid hemorrhage • Cortical superficial siderosis • Apolipoprotein E ε4 • May be associated with cognitive decline • Transient focal neurologic attacks. • Brain arteriovenous malformation: • Dural or brain; may extend to other brain compartments • Most common cause in young normotensive people • Seizures and headaches may antedate hemorrhage • Flow voids • Calcification • Cerebral cavernous malformations 7q21–q22, 7p13–p15, 3q25.2–q27 AD or sporadic • Small, homogenous intracerebral hemorrhage with no extension to other brain compartments • Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu disease) Endoglin and activin AD receptor-like kinase 1 genes • Dural arteriovenous fistula: • Subarachnoid or subdural extension • Abnormal dilated cortical vessels • Caroticocavernous fistula • Intracranial arterial saccular aneurysm: • Cause of 1 in 13 intracerebral hemorrhages (2 in 13 140/90 mm Hg Regular physical activity Psychosocial factors Diet risk score (T3 vs. T1) Waist-to-hip ratio (T3 vs. T1) Alcohol intake heavy or episodic Current smoking ApoB/ApoA1 ratio (T3 vs. T1) Cardiac causes Diabetes Composite PARa

Population-Attributable Risk (99% CI) 56% (52–61%) 35% (21–51%) 25% (18–33%) 24% (16–35%) 13% (6–25%) 10% (6–15%) 4% (0.9–13%) 1% (0–98%) 1% (0.6–3%) −7% (−11 to −3%) 87.1% (82.2–90.8%)

13,447 cases of acute first-ever stroke (within 5 days of symptom onset) compared with 13,472 controls with no history of stroke who were matched with cases for age and sex. a Composite patient-attributable risk (PAR) includes all 10 risk factors. Abbreviations:  BP, blood pressure; CI, confidence interval. Table adapted from O’Donnell MJ, et al.24

TABLE 12.44  Risk Factors for Subarachnoid Hemorrhage Risk Factors Cigarette smoking Systolic BP > 140 mm Hg Alcohol > 300 g/week Alcohol 100–299 g/week First-degree relative with SAH AD polycystic kidney disease

Relative Risk

(95% CI)

Prevalence (%)

PAR (%)

2.4 2.0 5.6 3.5 6.6 4.4

(1.8–3.4) (1.5–2.7) (1.9–16.7) (1.1–11.0) (2.0–21.0) (2.7–7.2)

28 12 6 5 2 0.1

29 19 19 11 11 0.3

Abbreviations: AD, autosomal dominant; BP, blood pressure; CI, confidence interval; PAR population-attributable risk; SAH, subarachnoid hemorrhage.

Stroke and Transient Ischemic Attacks of the Brain and Eye SAH have a positive family history for SAH. SAH occurs six to seven times more often in first-degree than in second-degree relatives of patients with SAH. Familial clustering does not necessarily imply a genetic predisposition to aneurysm formation, but because familial hypertension only partly explains the familial clustering of SAH, genetic factors related to aneurysm formation are likely to play a role. SAH is also associated with heritable disorders, such as autosomal dominant polycystic kidney disease, Ehlers–Danlos type IV, and NF-1, but these account for a small minority of patients with SAH.

Triggers

Stroke can be triggered by several activities (e.g. neck trauma and coitus) and risk factors (e.g. alcohol, amphetamines, infection, and air pollution, and perhaps psychosocial stress).

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INVESTIGATION The decision to investigate, and the choice of investigations, is primarily driven by the need to answer a specific clinical question relevant to the diagnosis or management of the patient. However, it is also based on the patient’s symptoms, age, pre- and poststroke condition, willingness to accept any risks, costs or inconvenience associated with the investigations, and the cost-effectiveness of the investigations.

STANDARD INVESTIGATION Patients with TIA or stroke in whom active management is being considered should undergo the following standard, investigations (Table 12.45).

TABLE 12.45  Standard Diagnostic Tests for Suspected TIA or Stroke Test Imaging Topography CT and/or MRI brain scan

Vascular imaging CT or MR angiography (CTA or MRA) of the aortic arch, neck, and head Or Duplex carotid and vertebral ultrasonography

Cerebral perfusion CT or MR perfusion

Chest Chest X-ray

Potential Indications and Findings Associated with TIA or Stroke

• Suspected TIA or stroke • Exclude nonvascular causes of focal neurologic symptoms • Distinguish ischemic and hemorrhagic stroke • Ascertain likely cause of the ischemic or hemorrhagic stroke from the topography (site, size, multiplicity, and timing of the lesion[s])

• The ASPECTS26 quantifies the extent of early ischemic changesa, which may help stratify risk of hemorrhagic transformation of fresh brain infarct associated with early thrombolysis, and long-term prognosis Identifies large-vessel atherosclerotic stenosis, occlusion or dissection, vascular malformation or aneurysm

Notes

Small deep infarcts plus white matter hyperintensities suggest intrinsic small-vessel disease. Infarcts in multiple territories suggest emboli from a proximal aortocardiac source; infarcts along the borders between brain artery territories suggest multiple emboli or systemic hypotension; infarcts of different ages in a single territory suggest emboli of arterial origin Lower ASPECTS scores are associated with an increased risk of intraparenchymal hemorrhage associated with thrombolysis and are predictive of a poor functional outcome

CTA has risks associated with radiation and contrast exposure. It may underestimate degree of arterial stenosis Contrast-enhanced (CE) MRA may overestimate degree of arterial stenosis Cervical magnetization transfer MRI, with fat suppression and axial fat-saturated T1 images, is most sensitive for dissection For patients with embolic carotid and vertebrobasilar Carotid ultrasound is a good screening technique for territory ischemic events and atherosclerotic imaging the carotid bifurcation and measuring blood stenosis/occlusion, dissection as possible causes of velocities, but it has limited ability to image the extracranial symptoms vasculature proximal or distal to the bifurcation To identify ischemic core and penumbra in acute ischemic stroke To help rule out stroke mimics such as epileptic seizure and migraine Cardiomegaly (large left atrium or ventricle); aortic dissection; hilar lymphadenopathy (sarcoid); pulmonary edema

Routinely recommended, but low yield

(Continued)

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358 TABLE 12.45  Standard Diagnostic Tests for Suspected TIA or Stroke (Continued) Test Blood Hematology Full blood count

Erythrocyte sedimentation rate and/or C-reactive protein Coagulation profile: INR, aPTT

Dilute thrombin time (Hemoclot test) Factor Xa activity

Biochemistry: Glucose, Hemoglobin A1C; Urea, electrolytes, Creatinine, eGFR Lipids including total, LDL and HDL cholesterol, apolipoprotein B and apolipoprotein A1, and lipoprotein (a) Cardiac Electrocardiography: 12-lead 24-hour Holter monitor or inpatient cardiac telemetry Echocardiography (transthoracic)

Echocardiography (transesophageal)

Urine Urinalysis a

Potential Indications and Findings Associated with TIA or Stroke

Anemia, disseminated intravascular coagulation, myeloproliferative disorders, sickle cell disease, thrombocytopenia, thrombocytosis, thrombotic thrombocytopenic purpura Inflammatory arteriopathies (temporal arteritis, etc.), and infective endocarditis Indicated if intracerebral or subarachnoid hemorrhage, taking anticoagulants, or planned treatment with thrombolysis Also may identify a hypercoagulable state such as lupus anticoagulant (prolonged aPTT) Indicated if taking direct thrombin inhibitor (e.g. dabigatran) and thrombolysis being considered Indicated if taking factor Xa inhibitor (e.g. apixaban, rivaroxaban, edoxaban) and thrombolysis being considered Hypoglycemia, hyperglycemia Diabetes, Hyponatraemia, hypernatremia Renal impairment Hyperlipidemia

Notes

Nonspecific but sensitive; raised in >60% of patients with infective endocarditis

Treatable causes of focal neurologic symptoms Risk factor for stroke Treatable causes of focal neurologic symptoms Risk factor for stroke, determines choice of oral anticoagulant Risk factor for stroke

Arrhythmias (e.g. atrial fibrillation/flutter), ischemia, myocardial infarction, left ventricular hypertrophy Cardiac arrhythmia Disorders of heart structure and function Indicated if embolic TIA or ischemic stroke, particularly if no other likely source, and if abnormal heart clinically, on ECG or on chest X-ray Findings include valve lesions, global or segmental left ventricular dysfunction, patent foramen ovale in young patients, spontaneous echo contrast, intracardiac tumors, and vegetations (endocarditis) Cryptogenic stroke in young patients, aortic atheromatous disease, infective endocarditis More sensitive than transthoracic echocardiography for cardiac sources of embolism, particularly in left atrium, interatrial septum, heart valves, and aortic arch Proteinuria, albuminuria, hematuria

Images anterior/ventral portion of the heart (e.g. left ventricle) better than posterior portion of the heart (left atrium and appendage, ascending aorta and arch); hence, used first in patients with coronary artery disease, congestive heart failure, or other ventricular disease evident from history or ECG

Transesophageal echocardiography is the best imaging modality for infective endocarditis, particularly if prosthetic material is present Specificity for detecting vegetations, abscesses, or other evidence of infective endocarditis can approach 100% Serial studies should be performed if the initial diagnosis of endocarditis remains in doubt Bacteremia in the elderly from urinary tract infections may produce neurologic findings

The Alberta Stroke Program Early CT Score (ASPECTS) is a nonlinear 10-point score that subtracts a point for each region of parenchymal hypoattenuation within the supratentorial compartment supplied by the anterior circulation and quantifies the extent of early ischemic changes.26

Abbreviations: aPTT, activated partial thromboplastin time; CT, computed tomography; ECG, electrocardiography; eGFR, estimated glomerular infiltration rate; HDL, highdensity lipoprotein; INR, international normalized ratio; LDL, low-density lipoprotein; MRI, magnetic resonance imaging; TIA, transient ischemic attack.

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  FIGURES 12.143, 12.144  CT brain scan, noncontrast, axial (Figure 12.143) and coronal (Figure 12.144) plane, showing a small cortical hemorrhage (high attenuation) in the posterior left frontal lobe, and periventricular low density due to chronic small-vessel ischemic change, in a patient with multiple microbleeds on MRI SWI scan and amyloid angiopathy.

TIP • The results of investigations may not be any more sensitive or specific than the clinical findings. Investigations contribute most to the diagnostic process when set in a proper clinical context and when they take the pretest probability of the disorder to be diagnosed into account.

Imaging Stroke topography CT or MRI brain scan

As stated above, the purpose of immediate imaging of the brain is to: • Exclude nonvascular causes of the suspected TIA or stroke such as subdural hemorrhage (Figures 12.17–12.20), venous hemorrhagic infarction (Figures 12.21–12.23, Table 12.11), or a brain tumor (Figures 12.24–12.26).

• Distinguish intracranial hemorrhage (Figures 12.143, 12.144) from cerebral infarction. The CT must be done within about 1 week of stroke onset otherwise the CT features of acute hemorrhage (high signal intensity [whiteness]) may resolve (in the same way that a bruise resolves under the skin) and all that remains are CT changes of low signal density (blackness) in the area of previous hemorrhage, which can be misinterpreted as previous infarction. • Ascertain the location, nature, and size of early ischemic changes in patients being considered for early thrombolysis, as some of these features may be associated with response to reperfusion therapy (research is ongoing). • Ascertain the likely cause of the ischemic or hemorrhagic stroke (from the site, size, shape, and distribution of the infarcts (Figures 12.145, 12.146) or hemorrhage[s]), and the appearance of the blood vessels (Figure 12.147).

    FIGURES 12.145, 12.146  Diffusion-weighted MRI brain (axial plane) showing multiple small areas of restricted diffusion in the right and left frontal and parietal lobes due to multifocal infarction in a patient with multiple septic emboli from the heart to multiple vascular territories of the brain in a patient with infective endocarditis.

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• In patients with SAH, the location of the subarachnoid ± intracerebral ± intraventricular blood on CT brain scan is a clue to the source of the hemorrhage (e.g. blood in the interhemispheric fissure suggests a ruptured aneurysm on the anterior communicating artery complex, and blood in the sylvian fissure suggests a ruptured aneurysm of the MCA).

Vascular imaging

TIP • The cerebral, cervical, and thoracic arteries are assessed by CT or MRA (which have similar sensitivity and specificity). If these are contraindicated or not available, the assessment is done by carotid duplex ultrasonography and transcranial Doppler (TCD) ultrasonography.

CT angiography of the head, neck, and thorax FIGURE 12.147  MRI brain scan, proton density image (axial plane) showing hypodense flow voids in the middle cerebral arteries and a left middle cerebral artery aneurysm (arrow).

CT angiography (CTA) is undertaken concurrently with noncontrast CT brain scan (above) ± CT perfusion (see below) as a part of a multimodal CT assessment in patients with acute stroke. It involves IV injection of iodinated radiocontrast agent to image, via a static acquisition, the lumen of the extracranial and intracranial blood vessels, including the aortic arch (Figures 12.148—12.152). A

   

   

FIGURES 12.148–12.150  CT angiogram of the cerebral, cervical, and thoracic arteries, posterior–anterior view, showing the aortic arch, extracranial and intracranial cerebral circulation.

    FIGURES 12.151, 12.152  CT angiogram, right common and internal carotid artery (Figure 12.151) and left common and internal carotid artery (Figure 12.152), showing extensive multifocal nonstenosing calcified atherosclerotic plaques in a heavy smoker.

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FIGURE 12.153  CTA of the left common and internal and external carotid arteries (sagittal plane) showing 60–70% stenosis of the origin of the left internal carotid artery. drawback to CTA is exposure to iodinated contrast and ionizing radiation; thus, patients with contrast allergies may be excluded from undergoing CTA. CTA is an effective means of identifying large, proximal vessel stenosis, and occlusions (Figures 12.153, 12.154), as possible targets for revascularization (mechanical thrombectomy and/or carotid stenting/endarterectomy), and the site, characteristics, and length of intracranial thrombosis. CTA also can be used to assess the extent of the Willisian and pial collateral blood supply which is an important determinant of the rate and degree at which ischemic brain tissue dies following cerebral artery occlusion. However, as standard single-phase acquisitions are timed to coincide with peak arterial enhancement, this is too early to accurately characterize collateral blood flow that arrives later. Single-phase CTA can therefore underestimate the extent of the collateral circulation. The assessment of collateral status is improved by multiphase CTA, which generates time-resolved images of the pial arteries. While monitoring the timing of the contrast bolus, the first scan is triggered in the late arterial phase and

FIGURE 12.154  CT angiogram showing the aortic arch, left common carotid artery, and left internal and external carotid arteries, with calcification (white) in terminal left common carotid artery, and calcification (white) and thrombus (black) causing very severe stenosis at the origin of the left internal carotid artery.

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FIGURE 12.155  CTA showing a large, white, contrast-enhancing central mass measuring 2.5 cm (1 inch) in diameter, which is compressing the upper brainstem anteriorly and the floor of the third ventricle inferiorly, consistent with an aneurysm of the tip of the basilar artery. subsequent scans are acquired, without additional contrast, in the mid- and late-venous phases. Collateral status is estimated by comparing backfilling pial arteries distal to the occlusion in the affected hemisphere with pial arteries in the unaffected hemisphere. Poor collateral status is associated with larger volumes of irreversibly injured brain (ischemic core) at the time of imaging, and with worse functional outcome after reperfusion therapy, independent of time since symptom onset, patient age, and vessel occlusion. In patients with SAH, multislice CTA with three-dimensional reconstruction should be performed immediately after the plain CT brain scan, as it identifies aneurysms greater than 3 mm in diameter with a sensitivity of about 96% (less for smaller aneurysms) (Figure 12.155).

Magnetic resonance angiography of the head and neck

Time-of-flight MRA uses signals from endogenous blood to provide flow-dependent visualization of the arterial lumen without the need for a contrast agent (Figure 12.30). Contrast-enhanced dynamic MRA (CE-MRA) allows time-resolved assessment of arterial occlusions, cerebral hemodynamics, and collateral circulation in the acute setting. MRA can be helpful for detecting atherothrombotic lesions in the neck and head (Figure 12.156), and other, less common

FIGURE 12.156  MRA (lateral view) showing a flow void, consistent with >70% diameter stenosis, of the origin of the left internal carotid artery.

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FIGURES 12.157–12.159  MRI brain, DWI, axial plane (Figure 12.157) showing an area of restricted diffusion, consistent with infarction, in the left superior cerebellum due to embolic occlusion of the left superior cerebellar artery. MRA, AP view (Figure 12.158), and CTA, lateral view (Figure 12.159) showing a filling defect in the left vertebral artery due to dissection.

causes of ischemic stroke or TIAs, such as arterial dissection (Figures 12.157–12.159), FMD, venous thrombosis, and some cases of vasculitis. CE-MRA may improve the detection of arterial dissections. For patients with suspected craniocervical arterial dissection of a carotid or vertebral artery, nonenhanced T1-weighted MRI in the axial plane, with fat-saturation techniques, frequently can depict a subacute hematoma within the wall of an artery, which is highly suggestive of a recent dissection (Figure 12.160). However, an acute intramural hematoma may not be well visualized on fat-saturated T1-weighted MRI until the blood is metabolized to methemoglobin, which may not occur until a few days after ictus. Intramural hemorrhage is almost pathognomonic of dissection and differentiates dissection from vasospasm in patients with subarachnoid hemorrhage.

FIGURE 12.160  Proton density-weighted axial MRI of the skull base showing the carotid canals. A ring of high signal (due to thrombus within the arterial wall) around the left internal carotid artery (arrow) is suggestive of dissection, though is not specific.

For patients with hemorrhagic stroke, MRA may be used to detect intracranial aneurysms and arteriovenous malformations, providing the patient is not restless or requiring mechanical ventilation (Figure 12.161). MRA cannot be used in patients with some pacemakers and metallic implants, and those with allergies to MR contrast agents, and its use is limited in patients with severe claustrophobia.

Duplex ultrasound of the carotid and vertebral arteries

Carotid and vertebral artery duplex studies consist of two elements: a B-mode evaluation that obtains an ultrasonographic image of the carotid artery and a Doppler mode evaluation that assesses the velocity and direction of blood flow within the artery. Doppler measures that have been correlated with angiographic stenosis include ICA peak systolic velocity (PSV) and end-diastolic velocity, as well as ratios of ICA PSV and common carotid artery PSV. The combination of a PSV > 230 cm/s and an end-diastolic velocity > 100 cm/s defines a stenosis of 70–99%. Other criteria for the diagnosis of a stenosis of 70–99% are an ICA PSV/common carotid artery PSV ratio > 4.0; and a combination of PSV > 210 cm/s, end-diastolic velocity > 70 cm/s, ICA PSV/common carotid artery PSV ratio > 3.0, and ICA

FIGURE 12.161  MRA (coronal plane) showing a left middle cerebral artery aneurysm (arrow).

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TABLE 12.46 Classification of ICA Stenosis by Doppler Velocity Criteria Velocity Criteria (cm/sec)

ICA Stenosis (%)

PSV 3.3 (Table 12.46). Figures 12.162—12.164 display an example of a stenosis in the proximal ICA, with resulting increased velocity. Advantages of carotid Doppler ultrasonography include safety, relatively low cost, portability, and reasonable ability to detect a hemodynamically significant stenosis. However, there are limitations. Doppler test results and diagnostic criteria are influenced by several factors, such as the equipment, the specific laboratory, and the technologist performing the test. In addition, factors such as contralateral occlusive disease have been associated with increased carotid volume flow that may result in an overestimation of the severity of stenosis. Carotid ultrasonography is less sensitive for dissection; it typically demonstrates very poor flow in the artery, giving a “to-and-fro” high-resistance signal. Occasionally, the line of the dissection and a double lumen can be imaged. Another limitation of carotid ultrasound is that it evaluates only relatively short segments of the common carotid, carotid bifurcation, and proximal ICA.

Penumbral imaging

The ischemic penumbra is electrically nonfunctioning but metabolically viable brain tissue that is salvageable with rapid restoration of CBF. Distal to an arterial occlusion, the penumbra is maintained by several factors, one of which, collateral blood flow (via leptomeningeal anastomoses and other pathways), varies markedly among patients.

FIGURE 12.162  Carotid ultrasound showing a B-mode image of the left ICA with an atherosclerotic plaque compromising the lumen by about 60–70%.

FIGURE 12.163  Color-flow carotid ultrasound of the image in Figure 12.162, showing arterial flow in the left ICA in red/yellow, and venous flow in the internal jugular vein in blue. Perfusion imaging by CT and MRI can estimate potentially salvageable ischemic penumbra and the irreversibly injured ischemic core with reasonable accuracy in individual patients when processed using validated blood flow parameter thresholds. The salvageable penumbra is estimated by the difference in measures of volume between the critically hypoperfused tissue (or territory of the occluded artery) and the ischemic core. Imaging evidence of a salvageable penumbra is now used as a tissue clock to aid selection of patients who may benefit from reperfusion therapy with thrombolysis beyond 4.5 hours (up to 9 hours)27,28 and endovascular thrombectomy beyond 6 hours (up to 24 hours)29,30 after stroke onset. 31

FIGURE 12.164  Color-flow carotid ultrasound of the image in Figure 12.162, showing an atherosclerotic plaque compromising the lumen by about 60–70%, arterial flow in the left ICA in red/yellow, and venous flow in the internal jugular vein in blue. Doppler ultrasound measured a peak systolic velocity of 181.8 cm/s and end-diastolic velocity of 53.7 cm/s.

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364 CT perfusion

The primary aim of CT perfusion imaging in acute ischemic stroke is to identify and distinguish areas of potentially salvageable tissue (ischemic penumbra) from likely infarcted and unsalvageable regions of brain tissue (the ischemic core), and thus inform patient selection for reperfusion therapies that aim to salvage the penumbra. Secondary aims of CT perfusion are to aid the diagnosis of acute ischemic stroke and help exclude stroke mimics (see Diagnosis section above), and aid assessment of prognosis. CT perfusion using modern CT scanners takes about 5 minutes to acquire the data and process it with automated software. During CT perfusion acquisition, the brain is scanned repeatedly during the IV infusion of iodinated contrast media. As the contrast flows through regions of the brain, the relative increase, peak, and subsequent decrease in radiodensity, is measured in Hounsfield’s units. Attenuation-time curves are derived for an arterial input function and a venous outflow function, and several measures of perfusion are calculated for each voxel. • The time to peak (TTP) is the time taken from the start of injection until the maximum peak of contrast enhancement (attenuation). • The time to maximum (Tmax) represents the time from the start of the scan until the maximum intensity of contrast material arrives at each voxel. • The time to drain (TTD) is the time taken to return from maximum enhancement (peak) to baseline (a defined low cutoff). • The cerebral blood flow (CBF) rate is the volume of blood flowing through a given volume of brain per unit time. It corresponds to the slope (maximum gradient) of the rising curve. • The cerebral blood volume (CBV) is the total volume of flowing blood in a given volume of brain, and it is represented by area underneath the curve. • The mean transit time (MTT) is the average time taken for contrast to flow through the region of the brain. Automated software can display each of these as a parametric map of the brain superimposed onto the CT scan maps with a color scale representing the values (Figures 12.165—12.169).

FIGURE 12.165  Plain CT brain (axial plane) showing hyperintensity, consistent with thrombus, of the M2 arteries in the left sylvian fissure and low density in left insular cortex, consistent with early infarction.

FIGURE 12.166  Plain CT brain scan (axial plane) showing low density in the left internal capsule, putamen, frontal and parietal lobes, and loss of the gray–white interface of the left frontal and parietal lobes consistent with early infarction. CT perfusion should be interpreted in conjunction with CTA because proximal arterial stenosis causing hemodynamic compromise can reduce the transit time, and may reduce CBF with preserved CBV. Ischemic core  The ischemic “core” (Figures 12.165–12.169), representing likely irreversibly damaged tissue, is characterized by: • • • • • •

TTP: markedly prolonged/delayed. MTT: markedly prolonged/delayed. CBF: markedly reduced, 3 seconds. • MTT or Tmax: prolonged/delayed, >6 seconds. • CBF: only moderately reduced.

1. Is there a focal area/region of ischemia/hypoperfusion (prolonged TTP and corresponding reduction in CBF) that conforms to a vascular territory and is relevant to the patient’s symptoms and signs? 2. What is the extent of the core (intense/severe reduction in CBF and reduced CBV) and the penumbra (reduced CBF but near-normal or increased CBV)? NB. Tmax or delay time is a more accurate measure of penumbral tissue than CBV.

TIP • CT perfusion helps identify which patients may benefit from IV thrombolysis (up to at least 9 hours) and thrombectomy (up to at least 24 hours), and perhaps beyond up to 36 or more hours.27–30

Other roles of CT perfusion  CT perfusion also can be helpful in making the diagnosis of acute ischemic stroke and excluding stroke mimics (see Diagnosis section above).

FIGURE 12.169  CT perfusion in the same patient as in Figures 12.165–12.168 showing in the left frontal and parietal lobes a prolonged time to peak (top right, red) and very low CBF (bottom left, blue) with a matching reduction in CBV (top middle, blue), consistent with a large ischemic core without penumbra.

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FIGURE 12.170  Noncontrast CT brain scan (axial plane) showing hyperdense right MCA.

FIGURE 12.173  Cerebral CT perfusion (axial plane) showing prolonged Tmax in the right MCA territory (blue).

FIGURE 12.171  Cerebral CT angiogram (axial plane) showing occlusion of right MCA (the internal carotid artery was also occluded).

FIGURE 12.174  CT perfusion (axial plane) showing low regional cerebral blood flow in the right MCA territory (blue).

FIGURE 12.172  Intra-arterial digital subtraction catheter cerebral angiogram showing a tapering occlusion of the origin of the extracranial right internal carotid artery due to arterial dissection.

FIGURE 12.175  CT perfusion (axial plane) showing reduced cerebral blood volume in the right striatocapsular region (caudate nucleus, anterior limb internal capsule, lentiform nucleus) (blue).

Stroke and Transient Ischemic Attacks of the Brain and Eye

FIGURE 12.176  Automated CT perfusion showing a small infarct core in the right striatocapsular region (red) and a large area of salvageable ischemic penumbra (blue) in the remainder of the right MCA territory.

FIGURE 12.177  Intra-arterial digital subtraction catheter cerebral angiogram showing restored perfusion in right MCA territory after endovascular thrombectomy and right internal carotid artery stent.

CT perfusion also can help define prognosis and response to reperfusion The volume of core infarction, as defined by CT perfusion, correlates reasonably well with clinical assessments of stroke severity (e.g. the NIHSS score), the volume of the DWI MRI lesion, complication rates of reperfusion therapy, the size of the infarct on MRI after 24 hours, and longer-term functional recovery. Although the estimated ischemic core volume is independently associated with functional recovery, it does not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improving functional outcome. 32 Combining ischemic core volume with age and expected imaging-to-reperfusion time (age, core, time) improves the assessment of prognosis and informs decisions regarding reperfusion therapy. The volume of ischemic penumbra, as defined by CT perfusion, if rescued by reperfusion, correlates with improvements in clinical assessments of stroke severity (e.g. NIHSS) and clinical outcome. Time is a modifier of the effect of reperfusion.

MR perfusion

MR perfusion imaging produces similar maps to CT perfusion. A bolus of gadolinium contrast agent is injected intravenously and tracked through the cerebral circulation. Images are processed to form maps of the time for contrast to arrive and the regional CBF. Arterial spin labeling perfusion imaging does not require contrast injection, but the delay in endogenous tracer arrival limits measurements of CBF within the territory affected by stroke. Like CT perfusion, perfusion MR estimates the volume of critically hypoperfused tissue (the penumbra and core combined) according to a time delay in tissue enhancement, after a bolus of IV contrast has been given, of a (time to maximum) threshold of more than 6 seconds. Mismatch volume (i.e. estimated penumbral volume) is also typically defined as critically hypoperfused tissue volume minus ischemic core volume. Mismatch ratio is defined as critically hypoperfused tissue volume divided by ischemic core volume. For diffusion MRI, ischemic core is typically defined as an ADC of 1.2, a mismatch volume greater than 10 mL, and an ischemic core volume less than 70 mL. The mismatch between a larger perfusion lesion on perfusion MR (or a severe clinical deficit) and a small diffusion lesion on DWI also may be used to select patients who may benefit from reperfusion therapies beyond traditional time windows (4.5 hours for thrombolysis, 6 hours for thrombectomy). Most thrombectomy-capable centers use CT perfusion rather than MRI for first-line imaging because CT perfusion is more widely available, faster to perform, and less prone to contraindications than MRI. Also, the clinical benefit of reperfusion therapies in patients with an unknown time of symptom onset who are selected for reperfusion on the basis of CT perfusion findings is similar to that in those who are selected on the basis of MRI findings.

Blood tests

FIGURE 12.178  MRI DWI (axial plane) 2 days after stroke onset showing residual right striatocapsular hemorrhagic infarction.

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There is no blood biomarker that can reliably diagnose acute ischemic or hemorrhagic stroke or TIA, or differentiate ischemic from hemorrhagic stroke. The aim of standard blood tests is to identify the cause of the stroke and aid assessment of risk and optimal therapies. Standard blood tests include red cell and platelet counts, measurement of the prothrombin time and partial thromboplastin time, renal function, glucose control (hemoglobin (Hb)A1c) and lipids (total cholesterol, LDL-C, HDL-cholesterol, apoB), and triglycerides

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368 Lead I

Lead aVR

Lead V1

Lead V4

Lead II

Lead aVL

Lead V2

Lead V4

Lead III

Lead aVF

Lead V3

Lead V6

Rhythm strip

FIGURE 12.179  Electrocardiograph showing atrial fibrillation. (Table 12.45). ApoB can be measured accurately and inexpensively, and more accurately measures atherogenic risk than does LDL-C or non–HDL-cholesterol.

Heart rhythm, structure, and function 12-Lead electrocardiography

All patients with suspected TIA or stroke should undergo 12-lead ECG, as it may reveal AF (Figure 12.179) or flutter; evidence of previous, recent, or ongoing myocardial ischemia (Figure 12.180); and evidence of left ventricular hypertrophy.

TIP • Cardiac arrhythmias are initially assessed by 12-lead ECG and inpatient cardiac telemetry or 24-hour Holter monitor.

Monitoring of the heart rate and rhythm

A systematic review of 50 observational studies of the yield of cardiac monitoring for diagnosing new AF after stroke or TIA in

Lead I

Lead aVR

Lead V1

Lead V4

Lead II

Lead aVL

Lead V2

Lead V4

Lead III

Lead aVF

Lead V3

Lead V6

Rhythm strip

a total of 11,658 patients reported that the overall proportion of patients diagnosed with AF after stroke was: • 7.7% (95% CI: 5.0–10.8) by admission ECG in the emergency room (phase 1). • 5.1% (3.8–6.5) by serial ECG in hospital, continuous inpatient ECG monitoring, continuous inpatient cardiac telemetry, and in-hospital Holter monitoring (phase 2). • 10.7% (5.6–17.2) by ambulatory Holter (phase 3). • 16.9% (13.0–21.2) by mobile cardiac outpatient telemetry, external loop recording, and implantable loop recording (phase 4). 33 The overall AF detection yield after all phases of sequential cardiac monitoring was 23.7% (95% CI: 17.2–31.0). 33

Chest X-ray

Chest X-ray may identify structural abnormalities of the heart such as an enlarged left atrium (Figure 12.181) or, in patients with

FIGURE 12.180 Electrocardiograph of a patient with a recent acute anteroseptal myocardial infarction, showing sinus tachycardia, and Q waves and ST segment elevation in leads V1–V3.

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FIGURE 12.181  Chest X-ray showing straightening of the left heart border due to left atrial enlargement in a patient with rheumatic mitral stenosis and a cardioembolic ischemic stroke.

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FIGURE 12.182  Chest X-ray (posteroanterior view) showing bilateral hilar lymphadenopathy in a patient with sarcoidosis.

suspected cerebral vasculitis, features of hilar lymphadenopathy (Figure 12.182) or pulmonary infiltration (Figure 12.183).

Transthoracic echocardiography

Transthoracic echocardiography (TTE) provides good views of the anterior/ventral aspects of the heart, such as the left ventricle (Figures 12.184, 12.185). TTE should be considered particularly for patients in whom a proximal source of embolism in the heart or aortic arch is suspected, such as those with a nonlacunar stroke syndrome (e.g. total anterior circulation infarct [TACI], partial anterior circulation infarct [PACI], or POCI, which are all commonly caused by embolic occlusion of a cerebral artery), an abnormal heart clinically, and abnormal ECG or chest X-ray, and a CT or MRI brain scan showing wedge-shaped cortical–subcortical cerebral infarction, particularly if there are multiple brain infarcts and in different arterial territories (Figures 12.145, 12.146). TTE also may

FIGURE 12.183  Chest X-ray (posteroanterior view) of a patient with granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, showing a loss of volume in the upper zones of the lungs bilaterally and coarse interstitial infiltrate with confluence and cavitation in the upper zones bilaterally.

4

2

3

1

FIGURES 12.184, 12.185  Transthoracic two-dimensional echocardiograph, apical four-chamber view (Figure 12.184), showing thrombus in the apex of the left ventricle (arrow). 1, left atrium; 2, left ventricle; 3, right atrium; 4, right ventricle. The arrow in Figure 12.185 is pointing at a thrombus in the apex of the left ventricle, in this higher magnification image of the left ventricle that is shown (section 2) in Figure 12.184. (Reproduced with permission from Hankey GJ, Warlow CP [1994]; Transient Ischemic Attacks of the Brain and Eye. WB Saunders, London.)

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4

2

4

2

3

1

3

1

    FIGURES 12.186, 12.187  Transthoracic two-dimensional echocardiograph, apical four-chamber view, using contrast (agitated Hemaccel) in a patient with a right-to-left shunt due to a PFO. Pre-Valsalva’s maneuver (Figure 12.186): after intravenous injection of agitated Hemaccel, contrast appears in the right atrium and right ventricle without passage across the PFO because left atrial pressure is slightly greater than right atrial pressure. Note: contrast does not traverse the pulmonary circulation to appear in the left atrium unless there is a right-to-left shunt, such as a pulmonary arteriovenous malformation; Valsalva’s maneuver (Figure 12.187): after intravenous injection of agitated Hemaccel and during Valsalva’s maneuver (which increases right atrial pressure) contrast appears in the right atrium and simultaneously moves into the right ventricle (across the tricuspid valve) and left atrium (through the PFO), where it is seen here crossing the mitral valve and entering the left ventricle (arrow). 1, left atrium; 2, left ventricle; 3, right atrium; 4, right ventricle. (Reproduced with permission from Hankey GJ, Warlow CP [1994]; Transient Ischemic Attacks of the Brain and Eye. WB Saunders, London.) identify a PFO (Figures 12.186, 12.187) or valve vegetations due to infective endocarditis (Figure 12.188). For patients with no history or signs of heart disease and a normal ECG, the yield of TTE in identifying an abnormality suggestive of a cardioembolic source is nevertheless quite low.

TIP

Transesophageal echocardiography

TEE provides better views of the posterior/dorsal aspects of the heart than TTE; it is more sensitive than TTE for detecting atheroma of the aortic arch, abnormalities of the interatrial septum (e.g. atrial septal aneurysm, PFO, atrial septal defect), atrial thrombi and spontaneous echo contrast (Figure 12.189), and valvular disease (Table 12.47).

• TTE evaluates the structure and function of the heart, imaging the ventricles more clearly than the atria and aorta. 1 3 2

4

1

2

FIGURE 12.188  Transthoracic two-dimensional echocardiograph (parasternal long axis view) showing vegetations (arrow) on the anterior leaflet of the mitral valve, which is situated behind the aortic valve. This image is taken during diastole when the mitral valve is open and the aortic valve closed. 1, left ventricle; 2, left atrium. (Reproduced with permission from Hankey GJ, Warlow CP [1994]; Transient Ischemic Attacks of the Brain and Eye. WB Saunders, London.)

FIGURE 12.189  Biplane transesophageal echocardiograph (longitudinal view) in a patient with atrial fibrillation showing left atrial appendage, an enlarged left atrium, and spontaneous echo contrast. In the absence of regular atrial contractions and the presence of a dilated left atrium, blood flow in the left atrium is slower than normal and is seen on the real-time echocardiography study to be swirling around slowly in the left atrium; slowly flowing or static blood has increased echogenicity and is called spontaneous echo contrast (as opposed to echo contrast that is introduced into the circulation such as agitated Hemaccel). 1, left atrium; 2, left ventricle; 3, mitral valve; 4, left atrial appendage. (Reproduced with permission from Hankey GJ, Warlow CP [1994]; Transient Ischemic Attacks of the Brain and Eye. WB Saunders, London.)

Stroke and Transient Ischemic Attacks of the Brain and Eye TABLE 12.47  Transthoracic versus Transesophageal Echo‑ cardiography for Detecting Potential Cardiac Sources of Embolism Transthoracic echocardiography • Left ventricular thrombus • Left ventricular dyskinesis • Mitral stenosis • Mitral annulus calcification • Aortic stenosis Transesophageal echocardiography

a

b

The use of contrast increases the detection of right-to-left shunts. TEE is indicated if TTE is negative, and there is still a suspected embolic source in the heart, such as in the: • • • •

a

• • • • • • • • • • •

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Left atrial thrombusa Left atrial appendage thrombusa Spontaneous echo contrast Intracardiac tumors Atrial septal defectb Atrial septal aneurysm Patent foramen ovaleb Mitral and aortic valve vegetations Prosthetic heart valve malfunction Aortic arch atherothrombosis/dissection Mitral leaflet prolapsed

The detection of an intracardiac thrombus may be a false positive (not all thrombi embolize) and the failure to detect an intracardiac thrombus may be a false negative, either because it is too small to be detected or it has all embolized already. A less invasive alternative is to inject air bubbles or other echocontrast material intravenously and, if there is a patent foramen ovale, it can be detected by TCD sonography of the middle cerebral artery, particularly with a provocative Valsalva’s maneuver. There is considerable variation in the methods, and this influences the diagnostic sensitivity and specificity. It is also uncertain what size of shunt is “clinically relevant,” and some bubbles may pass to the brain through pulmonary rather than cardiac shunts.

Venous system (i.e. via a right-to-left shunt, such as a PFO). Interatrial septum (e.g. atrial septal aneurysm). Left atrium or LAA. Aortic arch.

TEE identifies potentially salient abnormalities in about 50–75% of young patients with otherwise cryptogenic stroke, including PFO, atrial septal aneurysm, endocarditis, aortic atherosclerosis, regional myocardial wall dysfunction, dilated left atrium, and atrial appendage thrombus.

TIP • TEE images the atria and aortic arch better than TTE. Hence, TEE is preferred in patients with embolic (i.e. nonlacunar) infarcts who have no evidence of ventricular disease on TTE or an unrevealing TTE result.

ADVANCED INVESTIGATION After assessing the patient’s medical history, physical examination, and standard investigations, further investigation may be required to address questions that have arisen from the initial assessment and suggest a particular nonvascular cause of the neurologic symptoms, a particular cause of the TIA or stroke, or a particular response to therapy or prognosis. Table 12.48 presents various scenarios when additional testing may be considered.

TABLE 12.48  Advanced (Optional) Diagnostic Tests for Suspected TIA or Stroke Test

Potential Indications and Findings Associated with TIA or Stroke

Cerebrospinal fluid Spectrophotometry

Subarachnoid hemorrhage

Cell count, protein, glucose, culture, HSV Primary CNS or secondary vasculitis (e.g. Immune markers (oligoclonal infective), herpes encephalitis bands, IgG, aquaporin 4, and Demyelination (e.g. multiple sclerosis), MOG antibodies) autoimmune encephalitis Imaging TCD Ongoing emboli detection, intracranial stenoses, right-to-left shunting

Intra-arterial cerebral angiography (intra-arterial DSA)

Primary CNS and other medium- and large-vessel vasculitis, nonatherosclerotic arteriopathies (e.g. moyamoya syndrome); arteriovenous malformations; aneurysms

Notes Wait 6–12 hours after symptom onset if subarachnoid hemorrhage is suspected

TCD is useful for monitoring the development of vasospasm in large vessels at the base of the brain and for determining major occlusive disease in those arteries, although CTA, MRA, and DSA are more accurate for occlusive/stenotic lesions TCD is also useful for monitoring blood flow velocities in large brain vessels in patients with sickle cell disease TCD may detect some cases of PFO that are not detected on TTE or TEE Intra-arterial DSA remains the optimal technique for imaging the cerebral vasculature, particularly when making decisions about invasive therapies In addition to providing information about a specific vascular lesion, DSA can provide valuable information about collateral flow, perfusion status, and other occult vascular lesions that may affect patient management; however, DSA is associated with a risk, albeit small (40 IgG or IgM phospholipid units [1 unit is 1 pg of antibody], or >99th percentile) of IgG or IgM anticardiolipin antibody • Anti-β2-glycoprotein I antibody in serum or plasma on two or more occasions, at least 12 weeks apart, measured by standardized ELISA Abnormally low concentrations in the acute phase, or in anticoagulated patients, should be confirmed 6 weeks later or when oral anticoagulants are stopped

Risk factor for venous thrombosis, acute coronary syndrome, and stroke

Risk factors for cerebral, pelvic, and leg vein thromboses

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TABLE 12.48  Advanced (Optional) Diagnostic Tests for Suspected TIA or Stroke (Continued) Test

Potential Indications and Findings Associated with TIA or Stroke

Notes

Serum titers for syphilis, Borrelia, Infective arteritis; specific infections herpes zoster virus, hepatitis B and C virus, and HIV infection Blood cultures Infective endocarditis

Pregnancy test (blood or urine)

Serum and urine drug toxicology concentrations

Cardiac enzyme levels (troponin) Serum ammonia level Thyroid function tests Vitamin B12 level

Electroencephalograph Ophthalmologic examination

Skin pathergy test Skin biopsy Muscle biopsy Temporal artery biopsy Brain and meningeal biopsy

Prevalent infections and workup may vary according to region

Positive blood cultures for Staphylococcus. aureus, Streptococcus, or Enterococcus species, or other serology and cardiac imaging (echocardiography) are the mainstays of definitive diagnosis Stroke risk is greatest in the third trimester or immediately postpartum

Human chorionic gonadotropin Pregnancy changes levels of many clotting factors Suspected toxic encephalopathy; suspected infective endocarditis due to IV drug use; suspected toxic cause of stroke (e.g. amphetamines, cocaine, alcohol); therapeutic levels of prescribed drugs (phenytoin, etc.) and toxic levels of drugs of abuse Myocardial ischemia Recent or ongoing myocardial infarction is a risk factor for cardioembolism Hepatic encephalopathy Atrial fibrillation; cognitive impairment; hypothyroidism/hyperthyroidism Cognitive impairment; deficiency produces neurologic symptoms (paresthesias, ataxia, confusion) Unilateral slow-wave activity; nonconvulsive status epilepticus Arteriopathies: genetic, inflammatory, infectious, retinocerebral Retinopathies: hypertensive, diabetic, ischemic, hemorrhagic, Roth’s spots Subarachnoid hemorrhage (subhyaloid hemorrhages) Behçet’s disease CADASIL MELAS Giant cell arteritis Primary CNS vasculitis

Abbreviations: ANCA, antineutrophil cytoplasmic antibody; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS, central nervous system; CT, computed tomography; DSA, digital subtraction angiography; dsDNA, double-stranded deoxyribonucleic acid; ELISA, enzymelinked immunosorbent assay; ENA, extractable nuclear antigen; HIV, human immunodeficiency virus; HSV, herpes simplex virus; Ig, immunoglobulin; IV, intravenous; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MOG, myelin oligodendrocyte glycoprotein; MRA, magnetic resonance angiography; PFO, patent foramen ovale; TCD, transcranial Doppler ultrasonography; TIA, transient ischemic attack; TTE transthoracic echocardiography (or TEE, transesophageal echocardiography)

Cerebrospinal fluid

CSF examination may be required initially for the diagnosis of SAH when suspected clinically and brain imaging is inconclusive (see Lumbar puncture and cerebrospinal fluid examination for the diagnosis of SAH above). CSF examination also may aid in the diagnosis of vasculitis and its causes, such as bacterial meningitis

Vascular imaging Transcranial Doppler ultrasonography

TCD ultrasonography uses 2–4 MHz to insonate cerebral vessels, typically through several bony windows in the skull. This

technique can detect intracranial flow velocities, the direction of flow, vessel occlusion, the presence of emboli, and vascular reactivity. The arteries best evaluated are those at the base of the brain (MCA, anterior cerebral artery, carotid siphon, vertebral artery, and basilar artery) and the ophthalmic artery. The primary applications of TCD are to detect and quantify intracranial vessel stenosis, occlusion, collateral flow, and cerebral vasospasm (particularly after SAH). More extended TCD monitoring, over 30–60 minutes, can detect microemboli covertly traveling to the brain from proximal venous (via a rightto-left shunt), cardiac, aortic, or more distal arterial sources.

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     FIGURES 12.190, 12.191  Intra-arterial DSA lateral view (Figure 12.190) and AP view (Figure 12.191) showing a parasagittal arteriovenous malformation. TCD with the use of agitated saline contrast material is as sensitive as TEE for the detection of a right-to-left shunt across a PFO and may detect some cases of PFO that are not detected on TEE. As stated below, TEE is preferred to TCD because it also screens for aortic and cardiac causes of ischemic stroke.

Catheter contrast angiography

Intra-arterial, catheter contrast cerebral angiography demonstrates medium and small arteries that are not seen well with other techniques. It is particularly useful for characterizing small- and medium-vessel arteriopathies that may include dissection (e.g. of the superior cerebellar artery), vasculitis, RCVS, moyamoya, small aneurysm, and AVMs (Figures 12.190, 12.191). It also can help determine collateral flow patterns. Angiography of a carotid or vertebral dissection shows a smoothly stenosed artery with a double lumen or intimal flap, or a smooth tapering occlusion (Figure 12.192). The “string sign” is due to hematoma in the wall of the artery compressing the normal lumen to a “fine thread.” Sometimes, the artery is completely occluded, but the occlusive stump often has a tapered shape, suggestive of dissection. Other angiographic findings include intraluminal clot, intimal flaps, pseudoaneurysm formation (usually at the base of the skull), and evidence of distal emboli obstructing smaller intracranial arteries. Angiography of vasculitis may show areas of alternate narrowing and dilation of intracranial arterial branches (“beading”) (Figures 12.193—12.195), or areas of extracranial arterial occlusion (e.g. Takayasu’s arteritis). These findings are nonspecific, however (Table 12.49). In primary angiitis of the brain, the small intracranial arteries and arterioles are involved, whereas in vasculitis complicating meningitis, tumors, or other causes, the major basal intracranial arteries may be involved. However, the angiogram may be normal even in biopsy-proven vasculitis, particularly if the affected vessels are 55 years with a recent cryptogenic stroke or TIA, noninvasive ambulatory ECG monitoring for 30 days significantly improved the detection of AF more than fivefold compared with the standard practice of 24-hour ECG monitoring (16.1% vs. 3.2%, absolute difference 12.9%, 95% CI: 8.0–17.6%). 34 Noninvasive ambulatory ECG monitoring for 30 days also nearly doubled the rate of anticoagulant treatment at 90 days after randomization compared with the short-duration 24-hour ECG monitoring (18.6% vs. 11.1%, absolute difference 7.5%, 95% CI: 1.6–13.3). 34 In the CRYSTAL AF study of 441 patients >40 years of age with recent cryptogenic stroke (24 hours prior to ECG monitoring, longterm monitoring with an insertable cardiac monitor (ICM) was more effective than conventional follow-up (control) for detecting AF at 6 months (8.9% ICM vs. 1.4% control; hazard ratio [HR]: 6.4; 95% CI: 1.9–21.7; p < 0.001). 35 The frequency of detection of paroxysmal AF was 12% at 1 year and 30% at 3 years. Clinical features associated with a higher yield of AF after prolonged monitoring include a higher HAVOC (hypertension, age, valvular heart disease, peripheral vascular disease, obesity, congestive heart failure, and coronary artery disease) score or CHA 2DS2-VASc score, features of embolic ischemic stroke on brain imaging (e.g. infarcts involving the cortex and multiple vascular territories), frequency of premature atrial contractions, P-wave dispersion on ECG, left atrial cardiopathy (left atrial dilatation), LAA size and single-­lobe morphologic features, and elevated N-terminal pro–brain natriuretic peptide (NT-proBNP) serum concentrations.

TIP • AF might be newly detected in nearly a quarter of patients with stroke or TIA by sequentially combining cardiac monitoring methods. Hence, it is recommended that for patients with acute ischemic stroke or TIA and no apparent cause, prolonged rhythm monitoring (≈30 days) for AF is reasonable within 6 months of the event. The therapeutic implications of detecting paroxysmal AF in these circumstances remain uncertain, however.

Blood tests for hypercoagulable states (thrombophilia) Venous hypercoagulable state

Inherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency) are well-established predisposing factors for venous thromboembolism (VTE). In patients with an ESUS who have a right-to-left shunt (e.g. PFO), testing for a venous hypercoagulable state (as well as for the presence of occult deep venous thrombi by means of ultrasound of the pelvis and legs) may provide supporting evidence that the PFO is the cause of the embolic ischemic stroke. Tests include activated protein C resistance (factor V Leiden if abnormal), protein C, protein S, antithrombin III, prothrombin gene mutation, factor VIII level, fibrinogen, APLAbs (anticardiolipin antibodies, dilute Russell viper venom test [DRVVT] [lupus anticoagulant], β 2-glycoprotein 1 antibodies), and fasting homocysteine.

Arterial hypercoagulable state

A recent systematic review reported that, compared with controls, patients with arterial ischemic stroke were significantly more likely to have factor V Leiden (odds ratio [OR]: 1.25; 95% CI: 1.08–1.44; I2 = 0%), prothrombin G20210A mutation (OR: 1.48; 95% CI: 1.22–1.80; I2 = 0%), protein C deficiency (OR: 2.13; 95% CI: 1.16–3.90; I2 = 0%), and protein S deficiency (OR: 2.26; 95% CI: 1.34–3.80; I2 = 8.8%).36 Potential mechanisms by which thrombophilias could contribute to arterial ischemic stroke include the following: (1) ischemic stroke may arise in the setting of DVT and subsequent paradoxical embolism via a PFO, and (2) unbalanced thrombin activation associated with inherited thrombophilia may contribute to formation and progression of atherosclerotic lesions by means of platelet activation, endothelial and vascular smooth muscle cell dysregulation, recruitment of monocytes and macrophages, in situ arterial thrombosis, and nonbacterial thrombotic endocarditis.

Specialized investigations Genetic testing

Blood tests for DNA analysis include testing for mtDNA mutations (MELAS), the Notch 3 mutation (19p13) (CADASIL), α-GAL (Xq22) mutation (FD), the apolipoprotein E gene (APOE ε [19q13]), and amyloid precursor protein (APP [21q21]).

Vasculitis

Further blood tests for vasculitis include complement levels, antiDNA antibodies, and anti-RNP antibodies.

Heart rhythm and structure

Cardiac CT or MRI may provide complementary information to echocardiography about etiologically relevant structural cardiac disease.

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Causes of death

Death within a few hours of stroke onset is usually due to the direct effects of ICH, SAH, or brainstem infarction. Death occurring within the first week after stroke also may be caused by brain herniation secondary to massive cerebral hemisphere infarction; ischemic cerebral edema is maximal about days 2–3 (but can occur into the second week). Later, the complications of immobility (e.g. pneumonia and VTE) and recurrent vascular events of the brain and heart are the common causes of death.

Intracerebral hemorrhage

After ICH, nearly 25% of patients deteriorate during transport to the hospital and another 25% deteriorate in the emergency department. Risk factors for early deterioration include prior use of antiplatelet agents, short time (37.5°C, associated IVH, and midline shift of at least 2 mm. Independent predictors of ICH growth are similar and include: FIGURE 12.200  Finger clubbing in a patient with metastatic carcinoma of the lung and a hypercoagulable state.

Blood

Blood tests for FD include alpha-galactosidase A. Males with classic FD essentially have no alpha-galactosidase A enzyme ( 180 mm Hg) were excluded from the trials of thrombolysis. The risks of symptomatic ICH, particularly hemorrhagic transformation of the infarct, appear larger according to several prognostic factors, such as a high SEDAN score (blood Sugar, Early infarct signs, [hyper] Dense cerebral artery sign, Age, and NIHSS score). Leukoaraiosis also is associated with an increased risk of symptomatic ICH, but thrombolysis has a net clinical benefit in these patients and should not be withheld on the basis of this finding alone. Time from stroke onset is not a major determinant of the risk of fatal ICH with ALT. Concomitant antithrombotic drugs (e.g. aspirin) are to be avoided for the first 24 hours after ALT to limit hemorrhagic transformation of any infarcted brain. Dose  Using a lower dose of ALT (0.6 mg/kg) in predominantly Asian patients reduces the incidence of symptomatic ICH versus standard-dose ALT treatment but does improve functional outcome at 90 days. Imaging  Estimates of the benefits of ALT shown in Table 12.52 may be conservative because most of the clinical trials of thrombolysis recruited patients on the basis of a clinical diagnosis of stroke supported by a noncontrast CT brain scan that excluded ICH. Hence, stroke mimics and stroke patients without occlusion of the symptomatic/relevant artery were included. A subgroup analysis from the IST-3 trial suggests a greater benefit of thrombolysis in patients with relevant arterial occlusion (including small distal occlusions) and little effect in the absence of vessel occlusion.44 Nevertheless, patients with occlusion of a small perforating artery causing a lacunar ischemic stroke also seem to benefit from thrombolysis. More recent trials of thrombolysis have studied extended time windows beyond 4.5 hours and used advanced brain imaging (MRI or CT perfusion) to select patients for inclusion. In the WAKE-UP trial of 503 patients with acute ischemic stroke and an unknown time of symptom onset who had MRI findings of an

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TABLE 12.52  Effect of Treatments or Care Strategies for Ischemic Stroke, Hemorrhagic Stroke, and All Stroke on Functional Outcome Proportion of Patients with Reported Functional Outcome Treatment (Rx)

Rx (%)

Control (%)

Ischemic stroke Thrombolysis with alteplase43 Good recovery (mRS 0–1) 0–4.5 hours after stroke 34.4 27.6 0–3 hours 32.9 23.1 3–4.5 hours 35.3 30.1 4.5–9 hours (and penumbra) 36.0 29.1 Intracranial hemorrhage (ICH) Symptomatic ICH within 7 days 6.8 1.3 Fatal ICH within 7 days 2.7 0.4 Endovascular thrombectomy Second-generation devices Good recovery (mRS:0–1) 26.9 12.9 Independent (mRS: 0–2) 46.0 26.5 Aspirin Independent (mRS 0–2) 55.0 53.8 Death or dependence (mRS 3–6) 45.0 46.2 Hemicraniectomy 29.8 71.2 Death (mRS = 6) Severe disability/death (mRS 5,6) 41.7 84.0 Major disability/death (mRS 4–6) 73.5 87.1 Major/severe disability (mRS 4–5) 62.3 55.3 Intracerebral hemorrhage Intensive BP lowering to target systolic BP 105 mm Hg, and administer antihypertensive drugs as needed to maintain BP at or below those levels. • Obtain a follow-up CT brain scan at 24 hours before starting antiplatelet therapy.

Management of elevated blood pressure complicating alteplase treatment

If BP is elevated on two readings 10 minutes apart (i.e. SBP >185 mm Hg, or diastolic BP >110 mm Hg), consider treatment with glyceryl trinitrate (GTN) infusion administered via separate IV line, as per local hospital protocol. For GTN infusion, 50 mg/100 mL, start at 3 mL/h (1.5 mg/h or 25 μg/min) and titrate until BP 185 mm Hg or diastolic blood pressure >110 mm Hg • Anticoagulation with a direct oral anticoagulant (thrombin or factor Xa inhibitor), heparin or full treatment dose of LMWH within the previous 48 hours (24 hours for LMWH) unless proof of normal coagulation status (normal dilute thrombin time or dabigatran 180/110 mm Hg, consider admission to the intensive care unit for treatment with IV sodium nitroprusside.

Management of intracranial hemorrhage complicating alteplase treatment Suspect intracranial hemorrhage if: • • • •

Acute neurologic deterioration. New headache. Nausea or vomiting. Acute increase in BP out of proportion to the baseline measures.

If intracranial hemorrhage is suspected: • Discontinue ALT administration. • Organize urgent noncontrast CT brain. • Bloods: full blood count (FBC), activated partial thromboplastin time (aPTT), INR, fibrinogen, and type and crossmatch. • Call hematology to provisionally request cryoprecipitate and platelets. If hemorrhage is observed: • Administer cryoprecipitate (includes factor VIII): 1 unit/10 kg body weight (e.g. 10 units infused over 10–30 minutes; onset in 1 hour, peaks in 12 hours). Give additional dose if fibrinogen level is 33% of the MCA

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territory or ASPECTS 50% of the affected vascular area in about 70% of patients). The achieved grade of reperfusion after endovascular thrombectomy is critical. Guidelines recommend modified thrombolysis in cerebral infarction (mTICI) grades of 2b or 3 for endovascular thrombectomy, with mTICI 2b referring to 50–99% reperfusion and mTICI 3 referring to 100% reperfusion. However, as mTICI 2b is broad, the expanded seven-point TICI (eTICI) classification has been introduced as: • eTICI 0 = 0% reperfusion = mTICI 0. • eTICI 1 = minimal flow past the occlusion but no perfusion = mTICI 1. • eTICI 2a = 1–49% = mTICI 2a. • eTICI 2b50 = 50–66% = mTICI 2b. • eTICI 2b67 = 67–89% = mTICI 2b. • eTICI 2c = 90–99% = mTICI 2c. • eTICI 3 = complete reperfusion = mTICI 3. Subsequent trials, the DAWN (DWI or Computerized Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention) and DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trials have demonstrated that the substantial efficacy (and also procedural success rates and safety outcomes) of endovascular thrombectomy within 6 hours of stroke onset also is consistent among patients up to 24 hours after symptom onset if the patient have evidence of salvageable penumbra as identified by perfusion imaging (Figures 12.201—12.205). 29,30 The DAWN trial identified patients with salvageable brain tissue by the presence of mismatch between a clinical deficit that was disproportionately severe (as measured by the NIHSS score) compared with the volume of infarcted brain (as measured by MRI DWI or perfusion CT imaging). 30 The mismatch criteria were defined according to the patient’s age ( 40%). Loss is widespread (hippocampus, entorhinal cortex, association areas of neocortex, and nucleus basalis of Meynert [the substantia innominata] and locus ceruleus) and predominantly involves cholinergic, noradrenergic, and dopaminergic neurons. There is loss of neuronal synapses, assessed using antibodies to synaptic proteins such as synaptophysin. The degree of synaptic loss best correlates with the severity of dementia.

Chemical pathology

A cholinergic deficit is found secondary to degeneration of subcortical neurons (e.g. in the basal nucleus of Meynert), which project to the cortex and hippocampus. Alterations in some neurotrophic factors, especially brain-derived nerve growth factor (BDNF) and nerve growth factor (NGF), important protective chemicals for the survival of cholinergic cells, are thought to contribute to this degeneration.

FIGURE 16.4  Amyloid in the walls of small blood vessels near senile plaques (amyloid or congophilic angiopathy).

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FIGURE 16.8  Microscopic section of brain, showing granulovacuolar degeneration of neurons in the pyramidal layer of the hippocampus.

Acetylcholinesterase inhibitors

FIGURES 16.5–16.7  Microscopic sections of brain, showing neurofibrillary tangles as thick, fiber-like strands of silver-staining material, often in the form of loops, coils, or tangled masses in the nerve cell cytoplasm. Diminution of monoaminergic neurons and noradrenergic, gamma aminobutyric acid (GABA)ergic, and serotonergic functions occurs in affected neocortex, along with decreased neuropeptide transmitters, including substance P, somatostatin, and cholecystokinin.

Treatment

At present, treatment is primarily symptomatic and not curative. The two classes of medications in use currently are described below, and may slow the rate of disease symptom progression, but they do not specifically modify the underlying disease. Targeting Aβ has been the principal focus of investigational therapies, particularly using monoclonal antibodies against this peptide, 8 with minimal success. Antibodies against tau are now being tested as a possible therapy.

Acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are used as symptomatic treatment of cognitive and behavioral manifestations in AD. Donepezil has been approved for all stages of AD, and rivastigmine has been approved for Parkinson-related dementia as well.9,10 These drugs inhibit acetylcholinesterase and act to decrease acetylcholine breakdown in the synapse. They do not affect the underlying pathophysiologic disease process. Efficacy is generally similar among all of these agents, which amounts to approximately 6–12 months’ delay in the course of the disease after 30 weeks’ treatment in about twothirds of the patients with mild to moderate AD. The main goal of these medications is to delay some end-points associated with AD, including the need for outside care or placement in a nursing home or other facility. Donepezil is a reversible, noncompetitive inhibitor of acetylcholinesterase approved in the United States and United Kingdom in 1997. The drug is started at a dose of 5 mg once daily for the first 4–6 weeks and is generally administered at night to avoid potential side effects. If tolerated, the dose can then be increased to 10 mg once daily. Nausea may occur in up to 19%, and diarrhea may occur in up to 15% of users. These effects are generally transient, occurring on initiation or uptitration of the drug. If they do not subside, a rest from the medication or a reduction in dose for 1–2 weeks may be necessary. Subsequent increase is often without recurrence of side effects. Other symptoms may include headache, fatigue, insomnia, dizziness, muscle cramps (8%), agitation, hallucinations, unpleasant dreams, and urinary urgency. The drug can be administered in the morning in patients who develop insomnia or vivid dreams. It should be used with caution in patients with supraventricular conduction abnormalities, bradycardia, peptic ulcers, and obstructive airway disease. Rivastigmine is a pseudo-irreversible acetyl-butyrylcholinesterase inhibitor selective for the central nervous system (CNS) with regional selectivity for the cortex and hippocampus.11 Dosage is initially 1.5 mg orally twice daily for a minimum of 2 weeks, at which point the dose can be increased by 1.5 mg twice daily every 2 weeks if tolerated. The patient should be maintained on the highest dose tolerated, up to a maximum of 6 mg twice daily. Adverse effects include nausea, vomiting, diarrhea, headaches, and dizziness with 6–12 mg/day. These are usually transient and minimized by gradual titration and administration

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540 with food. To offset gastrointestinal side effects, this drug is also available in patch form with daily application. A 4.6 mg/24 hours patch is used to initiate therapy, and after 4–6 weeks, a 9.5 mg/24 hours patch is applied daily. Galantamine reversibly and competitively inhibits acetylcholinesterase and enhances the response of nicotinic receptors to acetylcholine.12 Galantamine is available in 4 mg and 8 mg, with a liquid preparation (4 mg/mL), which is useful for titration. The dose can be titrated from 4 mg twice daily to 8 mg twice daily over 4 weeks according to tolerance and benefit, but patients with hepatic impairment should be started with 4 mg daily. Galantamine is contraindicated in patients with severe renal impairment, but no dose adjustment is required for mild to moderate renal impairment (creatinine clearance rate > 9 mL/min). Most adverse effects occur in the first 4 weeks, including nausea, vomiting, diarrhea, anorexia, and agitation. A long-acting form of galantamine is also available and can be given once a day.

Memantine

Memantine is an ‘open channel’ antagonist of the N-methyl-daspartate (NMDA) receptors, and prevents excess glutamate from binding them.13 It is approved for use in the treatment of moderate to severe AD, and is typically used in conjunction with the acetylcholinesterase inhibitors (following dosage stabilization). The immediate release formulation can be initiated at 5 mg daily and titrated up by 5 mg daily per week to a target dose of 20 mg daily. Doses over 5 mg should be divided for twice-daily dosing. Patients with severe renal failure should not exceed 5 mg twice daily. The extended release formulation can be initiated at 7 mg daily and increased by 7 mg daily per week to a target dose of 28 mg daily. Patients with severe renal failure should not exceed 14 mg daily. Both formulations are typically well tolerated, though potential adverse effects include headache (6%), dizziness (7%), diarrhea (5%), constipation (5%), delusions, and hallucinations.

Symptomatic treatment

Depression can coexist with AD, and should be treated appropriately (i.e. supportive counseling and, if necessary, antidepressant drug therapy). Selective serotonin reuptake inhibitors (SSRIs) are the preferred choice because of their relatively short half-lives and minimal anticholinergic, adrenergic, and histaminic adverse effects, whereas tricyclic antidepressants may aggravate AD based on their anticholinergic effect. Behavioral manifestations are often difficult to treat. Some behaviors improve with initiation of an acetylcholinesterase inhibitor. Acute worsening of chronic behavioral issues may relate to an underlying medical condition and, as such, physical symptoms or iatrogenic factors should be sought out and corrected. Infection of either the bladder or lungs, for example, can cause a marked change in behavior in patients with AD. Overmedication, or the lack of administration of prescribed medications, might also produce new behavioral symptoms. Pharmacologic treatment of behavioral symptoms should be reserved for drug-responsive symptoms that are causing at least moderate distress to the patient primarily. Hallucinations that are tolerable to the patient do not necessarily need to be treated. Newer antipsychotic agents such as risperidone, olanzapine, and quetiapine have very few anticholinergic or extrapyramidal side effects and appear to be at least as effective as conventional neuroleptics for those symptoms that might be treatable by neuroleptics. However, these drugs do carry a black box warning, as

they have been associated with a higher risk of sudden death and/ or stroke in elderly patients with dementia. In general, medication use should be minimized so as to avoid polypharmacy and adverse side effects. Caregiver education and counseling should be considered first in dealing with difficult behaviors expressed by the patient. Often, with education by a social worker or nurse experienced in AD, caregivers and family members can learn how to diffuse situations that precipitate aggressive or agitated behaviors.

TIP • The best management of the behavioral manifestations of AD involves behavior management and training of the caregiver. A negative reaction to the patient’s behavior escalates problematic behaviors. A calming, supportive, and reassuring voice that is nonconfrontational works best.

Prevention

There is insufficient evidence to support the use of antioxidants, anti-inflammatory agents, monoamine oxidase B inhibitors, folic acid, antihypertensive drugs, cholesterol-lowering agents, or estrogen replacement therapy for AD risk reduction. An emerging field promotes healthy lifestyle for prevention of AD, including diet, physical exercise, and ‘brain exercise’. Laboratory rodents that are genetically engineered to develop AD had a significant delay in the onset of disease when their cage was enriched with apparatus to increase their activities, in addition to physical activity. Clinical studies have also suggested daily exercise in the form of a brisk walk for 30 minutes or other aerobic exercise might enhance cognitive abilities and reduce the risk for AD. Appropriate levels of sleep of 7–9 hours at night, a diet rich in fish, fruits, and vegetables, as in the Mediterranean-style diet, have been found to promote good brain health. Omega-3 fatty acids in the diet are heart healthy and appear to be beneficial for brain health as well, and are currently promoted as a way to reduce the risk for developing cognitive impairment in AD although evidence for this is conflicting. It is unclear whether challenging the brain with puzzles, such as crossword puzzles, Sudoku, word jumbles, word searches, or a variety of other brain exercises that are promoted commercially, are beneficial.

Prognosis

Upon initial presentation and diagnosis of AD, cognitive deficits may be relatively circumscribed and related primarily to memory decline, along with minor features in other cognitive domains. However, as the disease progresses, the impairment becomes more generalized to involve all cognitive domains. The average survival after diagnosis ranges from 2 to 20 years, with the actual duration dependent primarily on the severity of disease at the time of diagnosis and the age of the individual, but most patients will have a disease duration between 3 and 10 years.

FRONTOTEMPORAL DEMENTIA Definition and epidemiology

The frontotemporal dementias are a group of neurodegenerative disorders characterized pathologically by anterior frontal and/or temporal lobe degeneration, and clinically by progressive decline in behavior and/or language that begins at a relatively young age.

Degenerative Diseases of the Nervous System Microscopically, there is neuronal loss, astrocytic gliosis, and sometimes intraneuronal inclusions of tau, ubiquitin, and/or TAR DNA binding protein (TDP-43). Currently, FTD is classified into the following subtypes: • Behavioral variant of FTD (bvFTD). • Primary progressive aphasia (PPA): • Semantic variant (svPPA). • Nonfluent/agrammatic variant (nfvPPA or PPA-G). • Logopenic variant (lvPPA or PPA-L) (although mentioned here, this variant is most often associated with AD pathology). • FTD associated with motor neuron disease or amyotrophic lateral sclerosis (FTD-MND or FTD-ALS). • Corticobasal disease (CBD), also clinically classified as corticobasal syndrome (CBS). • PSP. CBD and PSP are discussed in greater detail in later sections of this chapter. FTDs are estimated to account for up to 10–20% of all cases of dementias, and they may be the most common type of dementia affecting patients under the age of 60.14 • Prevalence is unclear. • Mean age of onset is approximately 58 years; however, the disorder has been observed in patients as young as 21 and as old as 80 years. • Females and males are equally affected according to most case series, though some do cite a higher proportion of males.

Etiology and pathophysiology

Up to 25% of FTD cases appear to have an autosomal dominant inheritance pattern; however, 20–40% show instead a polygenic familial inheritance pattern. Mutations in the following genes are associated with familial FTDs:15–19 • • • •

MAPτ on chromosome 17q21–22, encoding tau protein. GRN on chromosome 17q21.32, encoding progranulin. C9orf72 on the short arm of chromosome 9, noncoding. VCP, CHMP2B, TBK1, FUS, and TARDBP (less commonly).

Mutations in MAPt alter the ratio of tau aggregates and increase neurotoxic tau aggregation. Carriers typically exhibit bvFTD, with or without parkinsonism. Mutations within GRN result in truncated progranulin mRNA, which undergoes nonsensemediated decay. The progranulin protein has been identified as a growth factor for development, neuroinflammatory response, autophagy, lysosomal function, and wound repair.20 GRN mutation carriers may exhibit bvFTD, nfvPPA, or CBS. A hexanucleotide repeat expansion (GGGGCC) greater than the normal length of 30 (up to hundreds) of C9orf72 is linked to bvFTD, ALS, and FTD-ALS. Potential mechanisms involve protein haploinsufficiency, repeat RNA foci, and abnormal dipeptide repeat proteins.21 Carriers most often exhibit bvFTD with or without MND.

Clinical features

• Gradual onset, frequently beginning in the mid-50s–60s. • Initial clinical manifestations include changes in personality and behavior or language, followed by global cognitive decline. • May or may not involve motor symptoms.

541 Behavioral variant FTD

Progressive deterioration in the ability to control or adjust behavior to different social situations. • • • • • • • • • • • •

Apathy. Lack of empathy. Emotional withdrawal. Poor hygiene. Lack of insight. Disinhibition (approaching strangers, using offensive language or making offensive remarks, etc.). Hyperactivity (pacing, wandering, outbursts of frustration, or aggression). Hypersexuality. Impulsivity. Hyperorality and dietary changes (excessive eating, consumption of inedible objects, etc.). Stereotyped and/or repetitive behaviors. Deficits in executive function with relative sparing of episodic memory and visuospatial functions.

Nonfluent variant PPA

Deficits in expressive language function: • • • • • • • • •

Halting, effortful speech. Difficulty with articulation or speech apraxia. Paraphasias. Agrammatism (poor sentence structure, omission of connecting words, misordered words). Impaired comprehension of complex sentences. Spared single-word comprehension. Spared object knowledge. Eventual decline in reading and writing. May exhibit swallowing difficulties later in disease.

Semantic variant PPA

Difficulty generating or recalling familiar words followed by progressive loss of assigned meaning: • • • • • • • • •

Impaired confrontational naming. Impaired single-word comprehension. Impaired object knowledge. Circumlocution. Surface dyslexia. Dysgraphia. Prosopagnosia. Relative sparing of repetition and fluency. Behavioral symptoms may emerge with disease progression.

Logopenic variant PPA

Language impairment specifically affecting naming and syntax. Speech is nonfluent, slowed, hesitant, with frequent pauses, but grammatically correct. • • • • •

Impaired confrontational naming. Impaired repetition of complex sentences. Phonologic errors. Lack of descriptive detail. Relative sparing of single-word repetition, single-word comprehension, object knowledge, and grammar.

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542 FTD-MND or FTD-ALS

Can experience behavior and language symptoms associated with the other FTD syndromes. Motor symptoms arise from motor neuron dysfunction similar to those seen in ALS and may include: • Muscle weakness affecting the arms, legs, face, tongue, or neck. • Clumsiness, tripping, or falling due to weak or stiff legs. • Shortness of breath. • Muscle atrophy, fasciculations, muscle cramps. • Dysphagia. • Dysarthria. • Spasticity. • Hyperreflexia. • Pseudobulbar affect (uncontrollable outbursts of laughing or crying).

Corticobasal degeneration

• May present with cognitive changes. • Frontal lobe features are evident.22 . • Alien limb syndrome (patient does not recognize the actions of their limb and cannot control its movement). • Apraxia. • Acalculia. • Visuospatial impairment. • Motor symptoms (bradykinesia, rigidity, tremor, limb dystonia, all more prominent unilaterally). • Language symptoms (hesitant and halting speech in some patients).

Progressive supranuclear palsy23

• Difficulty coordinating eye movements (the most distinguishing and earliest symptom, manifested as difficulty with voluntary vertical gaze, especially downward gaze). • Impaired balance and stability. • Slowness and stiffness of movement. • Upright or hyperextended posture, in contrast to flexed posture of PD. • Dysphagia. • Dysarthria.

 

• Alterations in mood and behavior. • Behavioral symptoms (similar to bvFTD, but usually milder and develop late in the disease course).

Differential diagnosis • • • • • • • • • • • •

AD. DLB. Vascular dementia. Alcoholic dementia. Slow-growing mass lesion. HD. CJD. Gerstmann–Sträussler–Scheinker (GSS) disease. Depression. Mania. Schizophrenia. obsessive-compulsive disorder (OCD).

Investigations

• Laboratory evaluation: includes testing to rule out other metabolic and infectious causes of encephalopathy: TSH, vitamin B12, HIV, RPR, complete blood count, complete metabolic panel, as usual for dementia work-up. • Paraneoplastic panel may be warranted in some individuals to rule out an autoimmune process related to an occult malignancy. • MoCA examination. • Frontal assessment battery: six tasks that assess frontal lobe performance, and may be helpful as a screening tool and used to distinguish between early FTD and early AD. • Full neuropsychological battery: for detailed documentation of frontal and temporal lobe dysfunction. • MRI brain: bilateral or asymmetric atrophy of the cortex and white matter of the frontal and/or temporal lobes (bvFTD), or temporal lobes in isolation (svPPA), perisylvian area (nfvPPA), and paracentral gyrus (FTD-ALS), may be observed. Enlarged ventricles secondary to cortical and subcortical atrophy may be seen. These signs are not always evident on initial scans and vary considerably among the different FTD subtypes24 (Figures 16.9–16.11). Coronal section through the hippocampus may best visualize temporal atrophy, while sagittal or axial images demonstrate frontal atrophy.

 

FIGURES 16.9–16.11  Brain imaging in FTD. (Figure 16.9) Midsagittal brain MRI of FTD, showing prominent atrophy of frontal lobe. While a useful diagnostic marker, this finding may be subtle or absent in the early presentation of disease; (Figure 16.11) a case of nfvPPA, demonstrating focal left perisylvian and temporal lobe atrophy. (Figure 16.10) Positron emission tomography (PET) of FTD case displays frontotemporal hypometabolism following radiolabeled fluorodeoxyglucose injection.

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• Dynamic/functional neuroimaging: PET imaging may show decreased metabolic activity (uptake of fluorodeoxyglucose) in affected areas of frontal and temporal regions, in contrast to the temporoparietal hypometabolism seen in AD (Figure 16.10). • Electroencephalography (EEG): normal or nonspecific slowing. • Electromyography (EMG): FTD-ALS may show findings similar to those seen in ALS. • Genetic testing: available for the mutations known to cause familial FTD syndromes, should be approached and offered on a case-by-case basis.

TIP • The neuropsychologic assessment should be focused on distinguishing frontal lobe features (language, executive function, and attentional tasks) relative to visuospatial abilities, a parietal function.

Diagnosis

The International Behavioral Variant FTD Consortium (FTDC) developed revised guidelines for the diagnosis of bvFTD in 2011.25 To meet criteria, patients must demonstrate progressive deterioration of behavior and/or cognition. Their symptoms must not be accounted for by other medical, psychiatric, or nondegenerative neurologic conditions. They are categorized as possible, probable, and definite bvFTD: Possible bvFTD: three of the following must be present: • • • •

Early behavioral disinhibition. Early apathy or inertia. Early loss of sympathy or empathy. Early perseverative, stereotyped, compulsive, or ritualistic behavior. • Hyperorality and dietary changes. • Executive/generation deficits with relative sparing of memory and visuospatial functions. Probable bvFTD: all of the following must be present: • Criteria for possible bvFTD. • Significant functional decline. • Supportive imaging results (frontal and/or anterior temporal atrophy on CT or MRI, hypometabolism on PET, or hypoperfusion on SPECT). • Absence of biomarkers strongly indicative of AD or other neurodegenerative processes. For a diagnosis of bvFTD with definite frontotemporal lobar degeneration (FTLD) pathology, the following must be present: • Criteria for possible or probable bvFTD. • Evidence of FTD-related pathology (biopsy or postmortem) and/or a known pathogenic mutation. An international expert panel established consensus criteria for the diagnosis of PPA in 2011 as well.26 To meet criteria, patients must demonstrate aphasia as the earliest and most prominent symptom, and language difficulty must be the principal cause of

FIGURE 16.12  Gross brain atrophy in frontal and temporal lobes seen in FTD. impairment in ADLs. They are classified into nonfluent, semantic, and logopenic variants based on combinations of clinical, imaging, pathologic, and genetic findings. Again, symptoms must not be accounted for by other medical, psychiatric, or nondegenerative neurologic conditions. Prominent initial behavioral disturbance is exclusionary, as are prominent initial deficits in episodic memory, visual memory, and visuoperceptual function.

Pathology

FTLD denotes the gross pathologic changes seen in FTD clinical syndromes. Macroscopic changes are variable between FTD subtypes, and may include decreased brain weight and frontotemporal atrophy that is most severe in the mesial and temporal areas (Figure 16.12). In the subtype FTD-ALS, atrophy of the motor strip has been noted on gross examination. Atrophy less frequently affects the hippocampus and parietal lobes. There is a thinned cortical ribbon of affected gyri, with some evidence of left perisylvian atrophy in those with nfvPPA. Enlarged ventricles and thickened overlying pia–arachnoid are present. Microscopic elements are also subtype-dependent, but the following pathologies may be seen:23 • Varying degrees of neuronal loss and astrocytosis in the frontal and temporal lobes, most marked in the first three cortical layers with characteristic superficial spongy change in the second layer of the cortex. • Neuronal loss in the basal ganglia and substantia nigra. • Loss of myelinated fibers in the affected subcortical white matter. • Astrocytic gliosis of the cortex and subcortical white matter tracts. • NFTs composed of tau protein found in both neuronal and glial cells (Figure 16.13). • Pick cells: swollen (ballooned or chromatolytic-appearing) neurons found randomly scattered throughout the cortex (Figure 16.14). • Pick bodies: argyrophilic intracytoplasmic inclusions found most frequently in the mesial temporal lobes. They are both tau and ubiquitin positive (Figures 16.15, 16.16). • Intranuclear inclusions containing ubiquitin and TDP-43. • Fused in sarcoma (FUS): abnormal intracellular FUS inclusions. The majority of FTLD cases (> 90%) are FTLD-tau or FTLD-TDP, with intracellular aggregates of tau and TDP-43, respectively.

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TDP-43

Ubiquitin

       

  FIGURES 16.13–16.16  Histopathologies associated with FTDs. (Figure 16.13) Immunohistochemical staining of TDP-43 and ubiquitin containing neurons; (Figure 16.14) H&E stained section of temporal neocortex showing cortical neurons with expanded, abnormally pale, pink cytoplasm that corresponds to abnormal aggregation of neurofilament and causes the morphologic appearance of ballooned neurons that are also referred to in the case of Pick’s disease; (Figure 16.15) H&E stained section of the dentate granular neurons in the hippocampal formation showing discrete, rounded pink inclusions in the cytoplasm of several cells (Pick’s bodies); (Figure 16.16) Immunohistochemical staining of the same area for tau highlights the presence of abundant rounded cytoplasmic inclusions (Pick’s bodies). (Courtesy of Peter Pytel, University of Chicago.)

FTLD-tau is associated with mutations in MAPT. FTLD-TDP is associated with mutations in GRN, TARDBP, C9orf72, and VCP. The remaining cases are typically FTD-FUS, with intracellular FUS inclusions. Regarding clinicopathologic correlations, most cases of nfvFTD have FTLD-tau pathology, while most cases of FTDALS and svPPA have FTLD-TDP pathology.27 The behavioral variant of FTD might have tau, TDP-43, or FUS pathology.27 Notably, lvPPA cases typically have underlying Alzheimer’s pathology, but with greater left hemispheric distribution of NFTs than is seen in AD.

Treatment

No specific treatment is available to reverse or slow the progression of FTD. Caregiver education regarding the nature of the disease is key to management. Family members should be counseled on how to manage behavioral improprieties, impulsivity, etc. Support groups for family members should

be offered as a mechanism to learn behavioral management techniques. Early speech therapy and assistive devices may be useful in patients with predominant language difficulties. Symptomatic treatment: • Neither cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) nor memantine have been shown to provide clinical benefit for FTD. • SSRIs (i.e. sertraline, paroxetine, and citalopram) may benefit patients with apathy, depression, social withdrawal, disinhibition, and/or impulsivity • Trazadone can be used to treat irritability, agitation, and/or aggression. Atypical antipsychotics (i.e. quetiapine) should be considered a last resort due to potential adverse effects and increased mortality. • Benzodiazepines are not recommended due to negative cognitive effects and potential paradoxical agitation.

Degenerative Diseases of the Nervous System • Parkinsonian features including bradykinesia/akinesia, rigidity, tremor, and limb dystonia may benefit from: • L-dopa: start with carbidopa/levodopa 25/100 mg three times a day and titrate upward slowly. Benefit may not be significant, and patients should be monitored for hallucinations and worsening behavior. • Other dopaminergics, such as ropinirole, pergolide, or pramipexole at low doses. Clinical trials for potentially disease-modifying drugs are underway. Experimental therapies include anti-tau antibodies, tau aggregation inhibitors, microtubule stabilizers, and agents that target FTD mutations.28

Prognosis

The rate of progression is variable with some patients progressing to dementia over a course of more than 10–15 years, and others within a few years. Many patients eventually display akinetic mutism in the final stages. Loss of language function to the point of muteness is uncharacteristic of AD and a distinguishing feature of FTD. Patients with isolated PPA may show isolated language impairment, without global development of dementia in as many as 50% of affected individuals. In those with concomitant MND, the time to death tends to be shorter, secondary to the more common sequelae of swallowing difficulty and aspiration pneumonia. Long-term prognosis for all cases is poor.

DEMENTIA WITH LEWY BODIES Definition and epidemiology

DLB was first reported in 1961. It is chiefly characterized clinically by visual hallucinations and/or delusions, parkinsonism, fluctuating confusion and alertness, and progressive dementia. Microscopically, it is characterized by Lewy bodies, which are also found in up to 40% of AD cases. However, DLB is considered a separate entity from AD. It is not uncommon, and is currently recognized as one of the most common causes of neurodegenerative dementia. • Accounts for approximately 20% of all dementia cases. • Onset is in the elderly, between ages 60 and 90. • Males and females are equally affected.

Etiology and pathophysiology

The incidence of DLB in monozygotic twins is discordant, indicating that environmental and/or epigenetic factors play a role in disease pathogenesis. However, risk factors for DLB have not been clearly identified to date. Most cases are sporadic and late onset, though familial cases have been reported. The heritable component of DLB has been estimated to be approximately 36% based on one genomewide association study.29 Mutations in genes linked to other neurodegenerative disease have also been implicated in DLB, including: • • • • • • •

SNCA: encoding alpha-synuclein protein. ApoE: encoding apolipoprotein E. APP: encoding amyloid precursor protein. PSEN-1/PSEN-2: encoding presenilin. MAPT: encoding microtubule-associated protein tau. GBA: encoding glucocerebrosidase. CNTN1: encoding contactin 1 (J).

DLB is complex and poorly understood. The features of disease are multifactorial. Motor symptoms likely result from the loss of

545 dopamine-containing neurons within the substantia nigra, the key feature associated with PD. Cognitive dysfunction may be related to the loss of cholinergic neurons within the nucleus basalis of Meynert, as is typically present in AD. The presence of Lewy bodies in cortical layers V and VI likely impairs informational processing from neocortex to subcortical structures. Hallucinations may relate to early impairment in the parietal and occipital association cortices, which may also account for the predominance of visuospatial dysfunction in these patients compared with AD. The extreme fluctuations in alertness have not been explained.

Clinical features

The clinical presentation includes any combination of the following: • Cognitive decline: cognitive impairment is present, affecting memory, language, visuospatial ability, praxis, and reasoning skills (e.g. early prominent attention deficits, disproportionate difficulties with problem solving, and visual–spatial–perceptual function). Cognitive impairment is persistent and progressive, but characterized by pronounced fluctuation, varying between lucid intervals and episodic confusion. Memory may be relatively spared in early stages compared to AD. • Hallucinations: usually persistent, well-formed, visual hallucinations, may be accompanied by secondary paranoid delusions. Auditory hallucinations may occur. • Fluctuating alertness: typically, delirium-like, with recurrent falls and/or transient clouding or loss of consciousness. Episodes may last from a few minutes to several days. • Extrapyramidal syndrome: mild akinetic–rigid parkinsonism occurs in some patients at presentation, but more often occurs later or after treatment with neuroleptic drugs. Overall, rest tremor is less common, and axial features (postural instability, gait difficulty, and facial immobility) are more common. Unusually, severe parkinsonism or sedation occurs after administration of standard doses of neuroleptic agents (patients are ‘exquisitely’ sensitive to neuroleptic agents). • Dysautonomia: urinary incontinence (may precede, but more commonly follows the onset of cognitive decline), orthostatic hypotension, constipation. • Sleep disorders: excessive daytime sleepiness, rapid eye movement (REM) sleep behavioral disorder may be present.

TIP • In contrast to the hallucinations of AD, hallucinations of DLB are described as ‘benign’, often consisting of children or animals. Patients often recognize that these are hallucinations, rather than believing they are real.

Differential diagnosis Cognitive decline

• AD: behavioral/psychiatric symptoms and urinary incontinence tend to occur later in the AD disease course. Marked fluctuations in alertness are not typically present. Aphasia, apraxia, and visuospatial abnormalities are more common. NFTs and senile neuritic plaques are present. • PD: PD dementia (PDD), when present, tends to occur several years after the established PD diagnosis. Lewy bodies

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• • • • •

are predominantly subcortical in location (substantia nigra, locus ceruleus, substantia innominata, and dorsal motor nucleus of the vagus nerve), in contrast to DLB, where immunocytochemically similar Lewy bodies are more widespread and found in the neocortex as well as brainstem neurons. VaD: evidence of strokes on clinical examination and/or brain imaging. PSP: vertical gaze palsy present. NPH: gait dysfunction and urinary incontinence followed by dementia. CJD: rapidly progressive cognitive decline and myoclonus. Delirium: due to drug toxicity (particularly anticholinergics or catecholaminergics) or intercurrent illness.

Repeated falls, syncope, and transient loss of consciousness • Transient ischemic attacks. • Cardiogenic: • Orthostatic hypotension. • Paroxysmal arrhythmia. • Seizures.

Delusions and hallucinations

• Complex partial seizures. • Delusional disorder (late paraphrenia).

Investigations

• Reversible encephalopathy laboratories: as described in AD work-up above. • Neuropsychological testing: nonamnestic, early in disease course, with more apparent impairments in attention, executive function, and visuospatial function. • CT head/MRI brain scan: normal or generalized cortical atrophy, may be more prominent in parietal/occipital lobe and frontal lobe. • Dopamine transporter imaging: may be able to distinguish DLB from AD, but not DLB from PD or multiple system atrophy (MSA). • Other ancillary testing (PET, SPECT, EEG, and MRI): see below.

• REM sleep behavior disorder. Supportive clinical features include: • • • • • • • • • •

Severe neuroleptic sensitivity (occurs in only ∼50%). Postural instability. Repeated falls. Syncope or unexplained, transient loss of consciousness. Severe autonomic dysfunction. Hypersomnia. Hyposmia. Nonvisual hallucinations. Delusions. Apathy, depression, anxiety.

Indicative biomarkers include: • SPECT/PET with low dopamine transporter uptake in basal ganglia. • Myocardial scintigraphy with low 123Iodine-MIBG uptake. • Polysomnography demonstrating REM sleep without atonia. Supportive biomarkers include: • CT/MRI with relatively preserved medial temporal lobe structures. • SPECT/PET with generalized low uptake, more prominent in the occipital regions. (Figure 16.17) • EEG demonstrating prominent slow-wave activity with periodic fluctuations in the pre-alpha/theta range. A diagnosis of DLB is less likely in the presence of: • Evidence of any physical illness or other brain disorder sufficient to account for the clinical picture, including cerebrovascular disease.

Diagnosis

Definite diagnosis is pathologic/postmortem. According to revised DLB consortium diagnostic criteria,30 progressive cognitive decline of sufficient magnitude to interfere with normal social function, occupational function, or daily activities is required for the clinical diagnosis of probable and possible DLB. Deficits on tests of attention, executive function, and visuospatial ability may occur in the early stages, and prominently so. Significant memory impairment may not occur in the early stages but is typically evident with progression. Probable DLB can be diagnosed based on the presence of two or more core clinical features, or one core clinical feature with positive biomarkers. Possible DLB can be diagnosed based on the presence of either one core clinical feature or biomarker positivity. Core DLB clinical features include: • Fluctuating cognition with pronounced variations in attention and alertness. • Recurrent visual hallucinations that are typically well formed and detailed. • Spontaneous motor features of parkinsonism (e.g. bradykinesia, rest tremor, or rigidity).

FIGURE 16.17  FDG-PET of a patient with dementia with Lewy bodies. Typical pattern of posterior cortical hypometabolism that also involves occipital cortex, but spares the posterior cingulate gyrus (arrowhead), also known as the ‘cingulate island sign’.

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• Parkinsonism as the sole core clinical feature, occurring in the setting of severe dementia. The complex overlap between AD, DLB, and PD is illustrated in Figure 16.18.

TIP • PD, MSA, and DLB are all related to deposition of alphasynuclein in the brain and are therefore sometimes called ‘synucleinopathies’. The symptoms of these disorders have significant overlap, and they are often hard to differentiate from one another clinically.

Pathology

Microscopically, Lewy body dementia (LBD) is characterized by the presence of Lewy bodies in the neocortex (temporal > frontal = parietal), limbic cortex (cingulate, entorhinal, amygdala), subcortical nuclei, and brainstem (as opposed to more prominent nigrostriatal and brainstem Lewy bodies associated with PD). Lewy bodies are intracytoplasmic, spherical, eosinophilic neuronal inclusions composed of abnormally ubiquitinated neurofilament proteins (Figures 16.19–16.24). Immunohistochemical staining for alpha-synuclein, ubiquitin,

PD Lewy bodies in nigra, locus

AD Plaques and tangles

LBV Lewy bodies in cortex, brainstem; plaques, fewer tangles

PDD

DLB Lewy bodies in cortex, brainstem; changes

FIGURE 16.18  Relationship of DLB to Alzheimer’s disease and Parkinson’s disease. AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; LBV, Lewy body variant of AD; PD, Parkinson’s disease; PDD, Parkinson’s disease with dementia. (Adapted from Weisman 2007, with permission.) and nuclear envelope protein p62 (which colocalizes with ubiquitinated proteins) aids in detecting and quantifying Lewy bodies and Lewy neurites.

 

 

 

 

FIGURES 16.19–16.24  (Figures 16.19, 16.20) Multiple Lewy bodies in the same neuron of the substantia nigra (arrows); (Figures 16.21, 16.22) cortical Lewy bodies in the anterior cingulate cortex (arrows); (Figure 16.23) Lewy bodies and Lewy neurites in the dorsal motor nucleus of the vagus nerve; (Figure 16.24) numerous Lewy neurites in the CA 2–3 field of the hippocampus. (Figures 16.19, 16.21) Hematoxylin–eosin staining; (Figure 16.20, Figures 16.22–16.24) anti–alpha-synuclein immunostaining. (Reproduced from Kovari 2009, with permission.)

548 Additional pathologic findings may include the following: • Lewy body–related neurites: found by means of ubiquitin staining in the hippocampus (CA2–3 region), amygdala, nucleus basalis of Meynert, dorsal vagal nucleus, and other brainstem nuclei. They are a neurofilament abnormality in which the proteins are present as a diffuse aggregate that does not contain crystallin. • Plaques (all morphologic types). Senile neuritic plaques, often in similar numbers to those found in AD, and Aβ deposition are common. • Neocortical NFTs are few or absent. • Regional neuronal loss occurs, particularly in brainstem (substantia nigra and locus ceruleus) and nucleus basalis of Meynert. • Microvacuolation (spongiform change) and synapse loss. • Neurochemical abnormalities and neurotransmitter deficits.

Treatment

Caregiver education and behavioral modification should be considered first. Pharmacologic therapy is challenging due to the combination of parkinsonism and neuropsychiatric features, as improvement of one symptom is often achieved at the expense of the other. Cholinesterase inhibitors may be effective for cognitive, neuropsychiatric, and motor symptoms. Rivastigmine has been shown to improve attention and hallucinations, delusions, and anxiety. 31 Donepezil has been shown to improve cognition as well. 32 Patients initiating cholinesterase inhibitors should be monitored for GI distress, weight loss, and other adverse effects. Drugs with anticholinergic properties should be avoided. Memantine has also been tried in the treatment of DLB, however, data are conflicting. Antipsychotic drugs, often used as the first choice for psychiatric symptoms and behavioral disturbances in dementia, should be avoided. DLB patients may develop a sensitivity reaction to these, resulting in exacerbation of motor and mental disability. If antipsychotic therapy is required, atypical agents (quetiapine and clozapine) with fewer extrapyramidal side effects are preferred. There are no systematic studies for treatment of depression in DLB, but SSRIs or serotonin–norepinephrine reuptake inhibitors (SNRIs) can be tried. Regarding motor symptoms, physical therapy and mobility aids may be beneficial. Levodopa may be cautiously and slowly introduced if motor features interfere with function, though this may worsen neuropsychiatric features. For REM sleep behavior disorder, melatonin, clonazepam, and cautious use of quetiapine are recommended. In all other scenarios, benzodiazepines should be avoided.

Prognosis

Progressive deterioration occurs over 5–8 years, with worsening parkinsonism, cognitive decline, and psychiatric symptoms.

VASCULAR DEMENTIA Definition and epidemiology

VaD is an acquired syndrome of cognitive impairment characterized by the abrupt onset and often stepwise progression of deficits of memory and other cognitive functions, sufficient to interfere with the person’s usual social activities, and related to

Hankey’s Clinical Neurology vascular disease of the brain. VaD can occur independently, but more often coexists with AD pathology, the coexistence termed as ‘mixed dementia’. • Incidence: 2.5 per 1000 nondemented individuals per year. • Prevalence: in the Western world, the prevalence is ∼1.5%, but slightly higher in Japan, at slightly more than 2%. The prevalence rises steeply with age. VaD accounts for up to 40% of dementia cases, and is the second most common cause of dementia after AD. Please note, however, that estimates of the prevalence of VaD may be unreliable because of different diagnostic and pathologic criteria used in different studies, and the co-occurrence of AD in many. 33 • Onset is in the elderly. • Males are affected more than females.

Etiology and pathophysiology

Cerebral infarction, atherosclerosis, arteriosclerosis, and cerebral amyloid angiopathy are highly prevalent in aging populations, and are known independent risk factors for cognitive impairment and dementia. 34 However, it is important to recognize that cerebrovascular disease – particularly in patients with cognitive decline – does not typically occur in isolation. Rather, it frequently co-occurs with AD. Molecular mechanisms linking the two disease processes have been described. For example, some studies suggest that vascular changes impair clearance of Aβ, accelerating AD progression. Further research is needed in order to better understand this relationship, whether it is additive or synergistic, and its role in VaD pathophysiology. The vascular aspect of VaD and mixed dementias relate to diseases of both cerebral and cardiac vasculature. The site of brain tissue loss is a more important determinant of cognitive function than the volume of tissue lost.

Single strategically placed infarcts or hemorrhages

A single infarct or hemorrhage, if located in a strategically important brain region, such as the circuits involving the dorsolateral frontal convexity, caudate nucleus, globus pallidus, and thalamus, can produce a vascular-related dementia. Examples include: • Angular gyrus lesions: located within the inferior parietal lobule. Classically result in ‘Gerstmann’s syndrome’, with acalculia, agraphia, right–left confusion, and finger agnosia. An acute onset of this syndrome, resulting from embolic occlusion of the angular branch of the inferior division of the middle cerebral artery, may be accompanied by fluent aphasia due to involvement of Wernicke’s area. • Thalamic lesions: particularly those involving the dominant dorsomedial thalamus, present with memory loss, slowness, apathy, ocular palsies, and drowsiness. They result from occlusion of the paramedian thalamic (thalamoperforate) branches of the posterior cerebral artery. • Caudate nucleus and globus pallidus lesions: typically occur by thrombotic or embolic occlusion of the penetrating lateral lenticulostriate branches of the middle cerebral artery. • Hippocampal lesions: typically occur by embolic occlusion of the cortical branches of the posterior cerebral artery, or diffuse cerebral ischemia. • Basal forebrain and dorsolateral prefrontal cortex lesions.

Degenerative Diseases of the Nervous System Multiple infarcts or hemorrhages

Cortical–subcortical infarcts or hemorrhages may cause a ‘cortical’ type dementia with signs of amnesia, aphasia, apraxia, and agnosia. These infarcts are commonly the result of thromboembolism from the heart or a large artery (aortic arch, carotid, and vertebrobasilar) to the anterior, middle, or posterior cerebral arteries or their branches. They can also be caused by large-vessel disease causing hypoperfusion and infarcts in the borderzones between major arterial territories, as well as small-vessel diseases such as microatheroma/lipohyalinosis and vasculitis. Multiple cortical hemorrhages are most commonly due to amyloid angiopathy but can also be seen with vasculitis, bleeding diatheses, metastases, hemorrhagic infarction, and trauma. Small, deep lacunar infarcts may cause a subcortical dementia characterized by psychomotor slowing, poor concentration, indecision, and mental apathy. Other features besides cognitive impairment include hemiparesis, small stepping gait (i.e. marche å petits pas), dysarthria, and dysphagia. Typical patients are elderly, ex- or current smokers, with hypertension and/or diabetes. Rarely, they may be a result of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (i.e. CADASIL), a hereditary disease linked to the NOTCH3 gene on chromosome 19.

Diffuse white matter infarction

Also described as subcortical arteriosclerotic leukoencephalopathy, or Binswanger’s disease. This appears as diffuse or multifocal, often periventricular, areas of demyelination, axonal loss, and reactive gliosis in the white matter, likely due to anoxia from arteriosclerotic changes (hyalinization, fibrosis, and thickening) in the long penetrating end arteries and arterioles of the periventricular white matter. White matter lesions are found in about 80% of patients with VaD, but also in about 15% of patients with early-onset AD, and as much as 75% of patients with late-onset AD. They are associated with hypertension and, in some studies, with heart disease and diabetes. They are thought to cause dementia by disrupting the pathways between the cortical and subcortical areas. 35 Diffuse laminar necrosis (global cerebral ischemia) can also occur. Vascular pathophysiology includes: • Hypoxic–ischemic lesions: • Large artery atherosclerosis. • Small-vessel hyaline wall thickening (arteriosclerosis), microatheroma, and lipohyalinosis. • Embolism from the heart. • Nonatheromatous angiopathies. • Granular degeneration of the media of small arteries (CADASIL). • Cerebral vasculitis. • Neoplastic angioendotheliomatosis (malignant lymphoma of blood vessels). • Mural dissections. • Dural arteriovenous malformation. • Hematologic disease (thrombophilia). • Hemorrhagic lesions: • Subdural hematoma. • Subarachnoid hemorrhage: anterior communicating artery aneurysm. • Intracerebral hemorrhage: amyloid angiopathy; hypertensive small-vessel disease.

549 Risk factors for vascular dementia

• Advanced age. • Past history of stroke (symptomatic stroke increases the risk of dementia more than ninefold) or myocardial infarction (one-third of patients).

Other putative risk factors include: • • • • • • • • • • • •

Hypertension (60% of patients). Smoking (35%). Diabetes (20%). Hyperlipidemia (20%). Obesity. Peripheral arterial disease. Coronary artery disease. Atrial fibrillation. Chronic kidney disease. Alcohol abuse. Family history (CADASIL). Brain white matter lesions.

Clinical assessment History

• Presenting symptoms: more commonly, sudden onset and stepwise course of cognitive decline with a history of transient ischemic attacks, strokes, or both. Epileptic seizures occur in 10% of patients. Incontinence of urine and stool is not uncommon. • Past history of vascular risk factors: hypertension, diabetes, heart disease, or smoking. • Family history: CADASIL.

Neurologic examination

• Focal neurologic deficits such as pyramidal tract signs (hemiparesis, extensor plantar response, pseudobulbar palsy), extrapyramidal signs, hemisensory loss, hemianopsia, and dysarthria. • Gait abnormality: start and turn hesitation, shuffling, reduced arm swing. • Grasp reflexes. • Hypertension and hypertensive retinopathy. • Signs of a potential source of thromboembolism such as atrial fibrillation, valvular heart disease, heart failure, and carotid artery disease.

Neuropsychologic examination

• Concentration and executive function: poor learning strategies, impaired word-list generation, emotional blunting and lability, poor insight and judgment. • Memory: impaired learning of verbal and visual information, reduced recall following a delay, but relatively spared recognition memory (i.e. ability to pick correct items from a previously presented list). • Verbal output: dysarthria, reduced grammatical complexity of spontaneous speech. • Depression: present in 25% of patients; depressive symptoms in 60%. • Anxiety: common. • Delusions: may be present in up to one-half of patients. • Personality alterations: apathetic, listless, lifeless, quiet, and labile.

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550 Differential diagnosis

All conditions listed in ‘Differential diagnosis’ of AD.

Investigations CT or MR imaging of the brain

To exclude other causes of dementia (e.g. frontal tumor, hydrocephalus) and identify one or more vascular lesions. These studies are important, as the diagnosis of VaD requires a significant burden of cerebrovascular disease to account for the cognitive disturbance present in patients. CT brain scan often reveals more or less symmetric periventricular and subcortical hypodensity in the cerebral white matter, with or without ventricular dilation and focal hypodensities thought to be due to ‘small-vessel’ ischemia and infarction. MRI demonstrates high signal areas of infarction on T2-weighted, or fluid-attenuated inversion recovery (FLAIR) imaging (Figures 16.25, 16.26). These radiological appearances (leukoaraiosis [leuko = white, ariosis = rarefaction]) are rather nonspecific and can be found in apparently normal elderly people. However, they are more commonly associated with gradual overall cognitive decline, unsteadiness of gait, and recurrent ischemic (particularly lacunar, occasionally hemorrhagic) strokes. These changes are more frequent in patients with hypertension, other vascular risk factors, atherosclerosis, and cerebral atrophy. Additional features may include multiple infarcts in the basal ganglia and pons, or cortical infarcts.

TIP • A key to the diagnosis of VaD is the temporal correlation of the strokes (and/or brain imaging findings consistent with vascular insults) and the dementia. In addition, the degree of white matter disease must be ‘sufficient to account for the dementia’. This can be difficult, and pairing the neuropsychologic test results (especially the prominence of retrieval deficits) with the imaging findings is often necessary.

FIGURE 16.26  T2-weighted MRI at the level of the lateral ventricles in a 75-year-old woman with cognitive impairment due to multi-infarct dementia. Note the atrophy and multiple hyperintense areas in the periventricular white matter.

Blood tests

As described in the section on AD. With suspicion for VaD, consider addition of the following: • • • • • • • • •

Lipid panel. Hemoglobin A1c. Antinuclear antibodies. Serum protein electrophoresis. Coagulation studies (younger patients). Antiphospholipid antibodies. Proteins C and S. Antithrombin III. Factor V Leiden mutation.

Other tests

• Electrocardiography (ECG). • Echocardiography: if prosthetic heart valves, rheumatic valvular heart disease, or suspected left atrial myxoma. • Doppler ultrasonography of the carotid arteries. • SPECT: asymmetric patchy areas of reduced cerebral blood flow. • Genetic testing (to assess for NOTCH3 mutations) and skin biopsy (to assess for granular osmiophilic material on electron microscopy) in cases suspicious for CADASIL.

Diagnosis

FIGURE 16.25  T2-weighted MRI in a 78-year-old woman with possible vascular dementia. Note the cerebral atrophy and the diffuse hyperintense areas adjacent to the frontal and posterior horns of the lateral ventricles, representing subcortical ischemic leukoencephalopathy.

The clinical and laboratory assessments are used to establish the diagnosis of VaD, the cause of the cerebrovascular disease, and other factors that may be contributing to the cognitive compromise. The diagnosis of VaD is based on a decline in cognitive function that has a clear temporal correlation with a history of strokes. However, the association between dementia and cerebrovascular disease may not be causal; it may be merely contributory or even coincidental. Various diagnostic criteria exist to aid the diagnosis but many have not been validated.36 The National Institute for Neurological Disorders and Stroke-Association Internationale pour la Recherché et l’Enseignement en Neurosciences (NINDS-AIREN) criteria37 for VaD are most widely used. According to these criteria:

Degenerative Diseases of the Nervous System Possible VaD: • Dementia with focal neurologic signs but without neuroimaging confirmation of definite cerebrovascular disease. • Dementia with focal neurologic signs but without a clear temporal relationship between dementia and stroke. • Dementia with focal neurologic signs but with a subtle onset and variable course of cognitive deficits. Probable VaD: • Evidence of dementia. • Focal neurologic signs consistent with stroke. • Neuroimaging evidence of extensive vascular lesions that are sufficient to account for the cognitive impairment. • Relationship between the dementia and the cerebrovascular disease established by abrupt deterioration, a fluctuating course, or stepwise progression of the cognitive deficit. Definite VaD: • Clinical criteria for probable VaD. • Autopsy demonstration of appropriate ischemic brain injury and no other cause of dementia.

Treatment

There are no FDA-approved therapies for VaD at this time. The acetylcholinesterase inhibitors commonly used to treat AD, including donepezil, rivastigmine, and galantamine have been studied for use in VaD and do appear to improve cognition modestly. They have shown no consistent benefit on measures of global change or ADLs, however. The NMDA receptor antagonist, memantine, has also been tried. Results were similar, with cognitive improvement but unchanged functionality. Nonpharmacologic therapies including cognitive therapy for cognitive impairment; physiotherapy for motor dysfunction, spasticity, and gait instability; and speech therapy for dysarthria, aphasia, and dysphagia, can be utilized. Management should focus on prevention of further cerebrovascular injury. Patients with cognitive impairment, and particularly those with clinical and/or radiographic evidence of cerebrovascular disease, should be screened for vascular risk factors including hypertension, hyperlipidemia, diabetes, atrial fibrillation, obstructive sleep apnea, and smoking. Treatment should be consistent with up-to-date guidelines for primary and secondary stroke prevention, including antiplatelet therapy and anticoagulation, as indicated. Interestingly, and despite the increase in average life expectancy, recent estimates suggest that the age-specific incidence of dementia is declining – in parallel with improvements in cardiovascular health. 38 Blood pressure control, specifically, has led to a major decline in stroke risk, and it has been suggested that the improved control of vascular risk factors has translated into a decreased risk of dementia. Evidence also suggests, as noted earlier, that lifestyle modifications, including Mediterranean diet, aerobic exercise at least three times weekly, and adequate sleep (∼8 hours per night) is associated with preserved cognition in the elderly.

Prognosis

Characteristically, a progressive stepwise course of cognitive decline is described, though it can be slowly progressive. The 50% survival is 6.7 years (cf. 8.1 years for AD). Causes of death include heart disease and recurrent stroke.

551

PRION DISEASES Definition and epidemiology

Prion diseases are fatal neurodegenerative disorders characterized by the CNS accumulation of a misfolded isoform of a membranebound glycoprotein, the prion protein (PrP), which acquires the property of transmissibility. These diseases were formerly known as transmissible spongiform encephalopathies (TSEs). • Incidence: ∼1–1.5 cases per million per year (sporadic), 1 per 10 million per year (familial). • Age: median age of onset: 67 years; rare cases younger than 30 (especially variant CJD), and older than 80 years. • Gender: M = F.

Etiology and pathophysiology Sporadic • • • •

85–90% of cases. Occurs spontaneously. No exogenous source of prions identified. Randomly distributed incidence.

Inherited

• ∼10% of cases. • Autosomal dominant pattern of inheritance. • Caused by missense, nonsense, or insertional mutations within the PRNP gene located on the short arm of chromosome 20. • Includes genetic CJD, Gerstmann–Straussler–Scheinker disease, and fatal familial insomnia. • Codon 200Lys and 178Asn mutations are associated with neuropathologic changes essentially indistinguishable from sporadic CJD.

Acquired

• < 0.1% of cases. • Result from iatrogenic transmission via exposure to prioncontaminated food (bovine spongiform encephalopathy [BSE], i.e. mad cow disease). • Over 450 cases reported, 39 with the vast majority in recipients of human pituitary growth hormone or human dura mater grafts. • Can also result from prion-containing human gonadotrophin, corneal transplant, and inadequately sterilized neurosurgical instruments and depth electrodes.

Prion disease is transmissible to experimental animals following inoculation or dietary exposure. The long incubation period led to the initial concept that a slow virus was the etiology of these diseases.

Prion hypothesis

• The transmissible agent is a proteinaceous infectious particle, i.e. prion.40 • A prion consists principally or entirely of a partially protease-resistant, misfolded isoform of a normal host-encoded cellular glycoprotein, PrP. • The nonpathogenic, or cellular form of PrP, designated PrPC, is a normal constituent of the surface of the neuronal cell. • In disease, PrPC is converted into a disease-related isoform41 known as PrPSc or PrPres.

Hankey’s Clinical Neurology

552 • PrPSc conformational change can occur spontaneously, be promoted by the presence of a mutation of PRNP, or be induced by exposure to prions. • Clinical heterogeneity in prion disease (see below) appears to reflect differences in PrPSc structural isoforms, and these may be modified by the host genotype, especially with regard to a common polymorphism at codon 129 (e.g. for sporadic CJD, two major protease-resistant subtypes exist – Type 1 and Type 2 – that carry different clinical features and are more commonly associated with 129MM and 129VV, respectively).

Genetic susceptibility to acquired iatrogenic and sporadic CJD

The general population has a common silent protein polymorphism at codon 129 of the PRNP gene, where either a methionine (Met) or valine (Val) may be encoded. About 40% of the Caucasian population are homozygous for the more frequent Met alleles, 50% are heterozygotes, and 10% are homozygous for the Val allele. Homozygosity at codon 129 appears to confer susceptibility to iatrogenic and sporadic disease: • More than 80% of patients with sporadic CJD are homozygous for either allele.42 • Nearly all primary cases of variant CJD (see below) are 129Met homozygotes. • Most patients with iatrogenic CJD (treatment with cadaveric pituitary-derived human growth hormone [hGH]) are homozygous, mainly for Val. • Heterozygosity for codon 129 of the PRNP gene appears to be protective.

Risk factors

• Family history and/or the presence of a mutation in the PRNP gene. Inheritance is autosomal dominant (50% risk of acquiring defective gene if one of the parents carries a mutation). • Exposure to bovine-derived prions. • Exposure to known iatrogenic sources of prions.

Genetic counseling coupled with prenatal genetic screening is possible, but the apparent incomplete penetrance of some of the inherited prion diseases increases the uncertainty of predicting the future for an asymptomatic individual. hGH is now manufactured using recombinant DNA technology, thereby eliminating the need for human sources. Dura mater as a source has been identified. The safety of the blood supply, especially within countries where vCJD has been reported, has been under scrutiny due to vCJD transmission attributed to blood product transfusion.

Clinical features

Variable (particularly with familial cases, and even within the same pedigree), and may include: • Insidious onset. • Early behavioral abnormalities (initial symptom in about 10% of cases). • Personality change, withdrawal, apathy, depression, and sleep disturbance. • Agitation, fear, and paranoia. • Rapidly progressive and profound dementia: forgetfulness, confusion, visual distortions, and hallucinations may occur.

• Myoclonus, usually stimulus-sensitive (> 80% of patients with CJD). • Motor abnormalities: • Cerebellar ataxia. • Extrapyramidal signs: tremor, rigidity, bradykinesia, dystonic posturing, choreoathetosis. • Pyramidal signs: weakness, spasticity, hyperreflexia, and Babinski’s signs. • Generalized seizures.

Clinical variants (the spectrum) CJD

• Heidenhain’s variant: cortical blindness due to early pathologic involvement of the occipital cortex. • Brownell–Oppenheimer variant: early and prominent ataxia.

Variant CJD

• Young age of onset, typically in teens and younger adults. • Early behavioral/psychiatric disturbance (anxiety, depression, apathy), and sensory disturbance followed by progressive ataxia, pyramidal and extrapyramidal signs, and progressive cognitive impairment. • Clinical course is more protracted, with average duration of 13 months compared with a mean of 6 months in other types. • Absence of typical EEG changes of CJD, although the EEG is abnormal. • High-signal changes in the pulvinar of the thalamus on diffusion-weighted (DWI) and proton-weighted MRI imaging of the brain. • Specific neuropathologic profile includes ‘florid plaques’, identified as a central region of dense core PrP plaques resembling those seen in kuru, but surrounded by a zone of spongiform change. • Typically characterized by homozygosity for Met at codon 129 of the PRNP gene, though one case with Met–Val heterozygosity has been identified.43 • Associated with a specific pattern of protease-resistant PrPSc on Western blot analysis. The biochemical signature is distinct from other types of CJD and matches that of animals experimentally infected with BSE, supporting the link between vCJD and BSE. • Linked causally to BSE, vCJD results from consumption of bovine tissues contaminated with BSE prions.44

Fatal insomnia (genetic and sporadic)

• Sleep disturbance is often the presenting feature. • The classic phenotype includes initial onset of insomnia resistant to sleep medications and progressive in nature, followed by autonomic disturbances (blood pressure and heart rate fluctuations, lacrimation, etc.), ataxia, and dementia. • Familial fatal insomnia (FFI) and sporadic FI (sFI) have remarkably similar phenotypes, although the autonomic features may be less common in sFI.45 • The genetic mutation linked to FFI is an aspartate (D) change to asparagine (N) at codon 178, but only when allelic with Met coding at 129. If coding is 129Val on the D178N mutation, the presentation is more typical of familial CJD (fCJD).

GSS

• Ataxia is the presenting symptom in most cases (gait ataxia, dysarthria, ocular dysmetria, or appendicular ataxia), followed by pyramidal and/or extrapyramidal features, and dementia in the later stages.

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553

• Variability is great; some patients present with isolated cognitive decline, without prominent ataxia (telencephalic presentation), spastic paraparesis, or with behavioral changes that suggest FTD.

Variably protease-sensitive prionopathy

• Clinical features are similar to CJD, although aphasia and behavioral features seem more common. • Distinguished primarily by the relatively lower protease resistance of PrP.

Differential diagnosis • • • • • • • • • • • •

AD with myoclonus. Spinocerebellar ataxias. Whipple’s disease. Paraneoplastic syndrome. Nonconvulsive status epilepticus. Metabolic/toxic encephalopathy (e.g. drugs). Bilateral subdural hematomas. CNS vasculitis. SSPE. Infiltrating corpus callosum glioma. HD. Psychiatric illness (anxiety, depression).

Investigations See Table 16.2.

Brain CT or MRI

• Scans are normal (45% of cases) or show cerebral atrophy (30% of cases) at presentation. • DWI MRI commonly reveals high-signal changes in the basal ganglia or cortical ribboning in cases of CJD (Figures 16.27, 16.28). • Proton density or DWI MRI images show hyperintensity of thalamus (especially pulvinar) in cases of vCJD (Figure 16.29). • Fluorodeoxyglucose PET shows reduction in thalamic metabolic activity in cases of FI.45,46

FIGURES 16.27, 16.28  Diffusion-weighted MRIs from two patients with sCJD, revealing the two major patterns of restricted diffusion. Hyperintensities of the caudate (red arrows) and putamen (yellow arrows) may be observed in isolation (Figure 16.27), or in combination with cortical ribbon hyperintensities (Figure 16.28).

TABLE 16.2 Investigation Findings in Creutzfeldt–Jakob Disease Disease

Typical EEG

Sporadic CJD

+ (65%)

Familial CJD

±

Iatrogenic CJD • CNS route ± • Peripheral route New variant – (100%)

14-3-3 High Signal on +ve CSFa MRI Brain

Other

+ (50–90%) + ( > 90%) (basal ganglia and/ or cortical ribbon) PRNP gene ± ± analysis ?

± (50%) ± (50%)

?

± + (> 70%) (posterior Tonsil biopsy thalamus)

Percentage of cases with a positive investigation, where known, is in parentheses. a Total CSF tau protein has similar, if not slightly better, results. RT-QuIC > 90% of sCJD, but not fully studied in other subtypes.

FIGURE 16.29  Proton-weighted imaging of the brain demonstrates pulvinar hyperintensity in a patient with vCJD.

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554

FIGURE 16.30  Electroencephalograph showing periodic triphasic wave complexes that are rather simple in contour and recurring every 0.7–0.8 seconds, against a slow polymorphous background, in a patient with rapidly progressive dementia and myoclonus due to CJD. Occasionally, the periodic discharges begin unilaterally and may resemble periodic lateralized epileptiform discharges.

EEG

• Early: nonspecific disorganization and generalized slowwave activity. • Later (within 12 weeks of onset of symptoms): • Slow background rhythm. • Periodic sharp wave complexes (PSWCs) (Figure 16.30): – Bisynchronous, and most commonly anterior and central (but may be lateralized and localized, i.e. with occipital preponderance in Heidenhain’s variant). – Duration: 100–600 ms; repetitive, occurring every 0.5–2.0 seconds. – Amplitude up to 300 mV; may be monophasic, biphasic, triphasic, or multiphasic. – May be associated with myoclonic jerks; may be activated by startle. – Present in > 65% of cases, particularly sporadic CJD, rarely in iatrogenic CJD, and generally not present in fCJD, vCJD, GSS, FFI, or sFI. • Evolution from intermittent to persistent PSWCs may be detected by serial EEGs (Figures 16.31, 16.32): – Nonspecific; also occur in several encephalopathies, epilepsy, and postictal states, or during barbiturate overdose and deep anesthesia.

CSF

• Normal or slightly elevated protein. • Immunoassay for the 14-3-3 protein, a nonspecific marker of CNS neuronal injury or death, is used. A positive test is highly sensitive (90%) although specificity has varied widely from study to study, ranging from 30% to 90%, perhaps dependent on the pretest likelihood that the patient has CJD.47 This test has also been reported to be elevated in CNS herpes, acute strokes, multiple sclerosis, and other inflammatory conditions. • More recently, the in vitro amplification technology real-time quaking-induced conversion (RT-QuIC) was

developed for the detection of PrPSc. This method measures very low levels of PrPSc in CSF samples by acting as a seed that converts recombinant PrP to new PrPSc that can be measured by spectrophotometric detection in the reaction test tube.48 The sensitivity of CSF RT-QuIC for a diagnosis of sCJD is comparable with that of CSF 14-3-3. The specificity of CSF RT-QuIC is superior, at 99.5% in a recent systematic review.49 This test can also be performed on olfactory epithelium from nasal brushing. • Neuron-specific enolase (NSE) concentrations may be increased early (> 35 ng/mL; sensitivity 80%, specificity 92%) and when myoclonus and periodic sharp complexes appear, and return to normal in the late stage. Raised NSE in CSF is also reported in brain trauma, tumor, and acute stroke including subarachnoid hemorrhage. The enzyme is localized in neurons and neuroendocrine cells and is synthesized completely in the CNS. • Tau (nonphosphorylated) levels may be elevated to extremely high levels (> 1250 pg/mL).49

TIP • CSF 14-3-3 and/or tau are most likely to be elevated in prion disease that runs a rapidly progressive course.

Molecular genetic analysis

The prion protein gene (PRNP) blood test is a genetic test for mutations that cause familial prion disease, using DNA analysis from blood or brain. The PRNP gene is sequenced for the presence of pathogenic mutations, and the polymorphic risk factor found at codon 129. It is important to perform, even if no family history is apparent, as mutations are occasionally detected in apparently sporadic cases as a result of incomplete penetrance, nonpaternity, adoption, or because the gene-carrying parent died from another cause at a young age, prior to their manifestation of prion disease.

Degenerative Diseases of the Nervous System Fp1–F7 F7–T3 T3–T5 T5–O1 Fp1–F3 F3–C3 C3–P3 P3–O1 Fz–Cz Cz–Pz Fp2–F4 F4–C4 C4–P4 P4–O2 Fp2–F8 F8–T4 T4–T6 T6–O2

Fp1–F7 F7–T3 T3–T5 T5–O1 Fp1–F3 F3–C3 C3–P3 P3–O1 Fz–Cz Cz–Pz Fp2–F4 F4–C4 C4–P4 P4–O2 Fp2–F8 F8–T4 T4–T6 T6–O2

Fp1–F7 F7–T3 T3–T5 T5–O1 Fp1–F3 F3–C3 C3–P3 P3–O1 Fz–Cz Cz–Pz Fp2–F4 F4–C4 C4–P4 P4–O2 Fp2–F8 F8–T4 T4–T6 T6–O2

555

1s

50µV

1 s 50µV

1 s 50µV

FIGURES 16.31–16.33  Serial electroencephalographs, every 3 days, from a patient with CJD, showing the progressive evolution of periodic triphasic wave complexes (arrows) and the background rhythm.

Hankey’s Clinical Neurology

556 Several mutations occurring throughout the entire length of the PRNP gene have been identified. Point mutations that result in single amino acid substitutions are most common. Of these, the two most frequently detected include an asparagine (N) substitution for aspartate (D) at codon 178 (D178N) and a lysine (K) substitution for glutamate (E) at codon 200 (E200K). In addition, four nonsense mutations produce a truncated PrP and insertions of one to nine multiples of an eight or nine amino acid repeat segment, known as the octarepeat region, result in expression of a longer PrP.

Tonsil biopsy

Western blot analysis of tonsil material obtained by biopsy of tonsil or lingual tonsillar remnants under local anesthetic can provide the antemortem detection of protease-resistant PrP in the lymphoreticular system of patients with vCJD, but not with other forms of prion disease.

Brain biopsy

Biopsy is mainly indicated to diagnose a suspected treatable cause of the clinical state, such as CNS vasculitis or SSPE. It is rarely indicated to diagnose prion disease because: • It may miss the diagnosis, as prion immunostaining may be patchy. • The elaborate preparation and decontamination of the operating suite is often prohibitive. • The availability of the RT-QuIC test has essentially obviated the need for biopsy.

Diagnosis

The most recent diagnostic criteria from the Center for Disease Control and Prevention criteria are as follows:50

Sporadic CJD Definite:

• Neuropathologically and/or immunohistochemically confirmed, and/or Western blot confirmed proteinase-resistant PrP, and/or scrapie-associated fibrils present. Probable: • Neuropsychiatric disorder plus positive RT-QuIC in CSF or other tissues OR rapidly progressive dementia with at least two of the following clinical features: • Myoclonus. • Visual or cerebellar disturbance. • Pyramidal/extrapyramidal dysfunction. • Akinetic mutism. • At least one of the following: • Typical EEG findings (periodic sharp wave complexes). • CSF 14-3-3 positivity in patients with disease duration < 2 years. • Typical MRI findings (high signal in caudate/putamen on MRI or at least two cortical regions on DWI or FLAIR). • No indication of alternative diagnosis in routine investigations.

Possible: • • • • •

Progressive dementia. At least two of the clinical features listed above Absence of any typical EEG, CSF, and imaging findings. Duration < 2 years. No indication of alternative diagnosis in routine investigations.

Iatrogenic CJD

• Progressive cerebellar syndrome in a human pituitary hormone recipient OR sporadic CJD with a recognized exposure risk (e.g. dura mater transplant).

Familial CJD

• Definite or probable CJD plus definite or probable CJD in a first-degree relative and/or neuropsychiatric disorder plus disease-specific PRNP mutation.

vCJD

Definite: • Neuropathologic features including: • Numerous widespread kuru-type amyloid plaques surrounded by vacuoles in both the cerebellum and cerebrum. • Spongiform change and extensive prion protein deposition throughout the cerebrum and cerebellum on immunohistochemistry. Suspected: • Current age or age at death < 55 years. • Psychiatric symptoms at illness onset and/or persistent painful sensory symptoms (frank pain and/or dysesthesia). • Dementia, and development ≥ 4 months after illness onset of at least two of the following five neurologic signs: – Poor coordination. – Myoclonus. – Chorea. – Hyperreflexia. – Visual signs. • Note: if persistent painful sensory symptoms exist, ≥ 4 months delay in the development of the neurologic signs is not required. • A normal or an abnormal EEG, but not the diagnostic EEG changes often seen in classic CJD. • Duration of illness over 6 months. • Routine investigations of the patient do not suggest an alternative, non-CJD, diagnosis. • No history of receipt of cadaveric human pituitary growth hormone or a dura mater graft. • No history of CJD in a first-degree relative or prion protein gene mutation.

Pathology

The demonstration of protease-resistant PrP in brain is the neuropathologic diagnostic marker of prion disease. Specific banding patterns of the protease-resistant PrPSc (by Western blot analysis) correspond to the major prion disease subtypes of CJD, GSS, FI,

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557

FIGURE 16.34  Western blots of the four major prion subtypes. The banding pattern represents the major fractions of the proteaseresistant pathogenic prion protein (in essence, the prion). These differences support the notion that the phenotype of each disease is determined by the respective conformational subtype of the prion. Left to right; CJD, FI, vCJD, GSS. and vCJD (Figure 16.34). Proteinase-resistant PrPSc can also be assessed by immunohistochemistry on brain sections, using antibodies against PrP. Molecular genetic analyses of the PRNP gene can be used to confirm a mutation. Macroscopically, the brain is atrophic. Microscopically, CJD consists of a triad of: • Neuronal loss. • Reactive astrocytic proliferation and gliosis. • Spongiform degeneration (spongiform change): vacuolation of the neuropil, particularly in deeper laminae of the gray matter of the frontal and temporal lobes, but also the gray matter of the striatum, thalamus, tegmentum of the upper brainstem, and cerebellar cortex (Figures 16.35, 16.36). Ultrastructurally, spongiform degeneration appears as intraneuronal, complex, clear vacuoles whose membranous septa look curled in profile. Kuru plaques may also be present: eosinophilic, round, compact extracellular depositions of PrP; these are pathognomonic of a prion disease but are found in roughly 10% of sporadic cases. GSS shows mild spongiform degeneration, prominent extracellular amyloid deposits composed of PrP, most prominent within the cerebellum, but also common in frontal and temporal cortex. FI shows neuronal loss and gliosis typically present within thalamic nuclei, especially anterior and dorsomedial nuclei, in addition to inferior olivary nucleus. There is minimal spongiform degeneration and no amyloid plaque deposits are present.

FIGURE 16.36  Glial fibrillary acidic protein antibody demonstrates the proliferation and hypertrophy of glial cells that commonly occur in prion disease.

Treatment

At present, no effective curative therapy is available, and treatment is therefore symptomatic. Patients should be nursed similarly to others with infectious disease, using disposable supplies when possible. Antiepileptic drugs may be required for seizures, intermittent or indwelling bladder catheters for urinary incontinence, and appropriate posturing and regular turning to prevent bedsores.

Prognosis

About 90% of CJD patients display a rapidly progressive decline to akinetic mutism and death over 2–12 months. About 10% have a protracted clinical course (these usually begin with ataxia rather than dementia). GSS has a significantly more protracted course, lasting over several years, resulting in severe disability from ataxia, whereas FI has a similar, if not slightly more prolonged course, to CJD.

NORMAL PRESSURE HYDROCEPHALUS Definition and epidemiology FIGURE 16.35  Neuronal vacuolation, also known as spongiform degeneration, is the key histopathologic feature of CJD.

Normal pressure hydrocephalus (NPH) is a clinical syndrome characterized by abnormal gait, urinary incontinence, and cognitive impairment. A frequently missed, or late diagnosed condition, NPH is a potentially reversible cause of dementia. First

Hankey’s Clinical Neurology

558 described by Hakim in 1965, NPH was described as hydrocephalus without evidence of papilledema and with normal CSF opening pressure on lumbar puncture. • Incidence: 5.5 per 100,000. • Prevalence: ∼5% of all dementia cases. Up to 14% in the elderly population living within a care facility. • Age: predominately seen in the elderly population and incidence as well as prevalence tend to increase with age. • Gender: M = F.

Etiology and pathophysiology

NPH tends to be idiopathic in up to 50% of patients. NPH has been attributed to decreased resorption of CSF at the level of the arachnoid villi, leading to a transient high-pressure hydrocephalus with ventricular enlargement and subsequent normalization of CSF pressure. It has also been suggested that chronic periventricular ischemia may lead to increased compliance and gradual enlargement of the ventricular wall. Alternatively, because of the high rate of comorbid neurodegenerative disease, it has been suggested that pathologies such as AD may play a role in ventricular enlargement.51 Secondary causes may include head injury, subarachnoid hemorrhage, meningitis, CNS tumor, and previously compensated congenital hydrocephalus. Symptoms of NPH are due to distortion of the corona radiata caused by distention of the lateral ventricles, with ensuing white matter edema and impaired blood flow. Abnormal gait and incontinence are due to distortion of the periventricular white matter which includes sacral motor fibers that innervate the legs and bladder. Abnormal gait may also be due to compression of brainstem structures related to gait. Dementia is due to distortion of the periventricular limbic system.

Clinical features

• Progressive disorder. • Gait disorder: the most prominent symptom, apraxia of gait characterized as a wide-based, bradykinetic, magnetic, and/or shuffling gait. Patients may experience difficulty or arrest in initiation of ambulation as well as multiple falls. • Urinary incontinence: 95% have been found to have detrusor overactivity leading to urinary frequency, urgency, or frank incontinence, often with lack of concern. • Apathy may be present. • Dementia, usually of the subcortical type and includes: • Memory impairment – primarily retrieval, rather than encoding deficits (patients do better than AD patients on recognition memory tasks). • Bradyphrenia – slowness of thought processing. • Decreased attention. • Executive dysfunction.

Differential diagnosis

• AD (many patients are noted to have AD pathology at the time of shunt surgery). • PD. • DLB. • Multiple system atrophy. • FTD (particularly PSP). • Cortical basal degeneration. • Dementia with motor neuron disease. • Chronic alcoholism. • Multi-infarct dementia. • Confusional state and acute memory disorders.

• • • • •

Marchiafava–Bignami disease. Paraneoplastic encephalomyelitis. Carcinomatous meningitis. Uremic encephalopathy. Wilson’s disease.

Investigations

• Laboratory evaluation: includes testing to rule out other metabolic and infectious causes of dementia, as described in the AD work-up. • Imaging studies: both CT and MRI can be used, though MRI is superior. Findings include ventricular enlargement out of proportion to sulcal atrophy and may show periventricular hyperintensity due to transependymal flow of CSF. There may also be a prominent flow void in the cerebral aqueduct and third ventricle (known as the ‘jet sign’), thinning and elevation of the corpus callosum on sagittal images, and narrow CSF space at the high convexities as compared to the sylvian fissure size. In order to rule out the possibility that the imaging findings may be secondary to hydrocephalus ex vacuo, at least one of the following must be present: • • • •

Temporal horn enlargement. Periventricular signal changes. Periventricular edema. Aqueductal/fourth ventricle flow void.

• Cisternography: involves injection of a radiolabeled isotope into the lumbar cistern and visualizing its distribution. Nonappearance of the isotope over the brain convexities at 72 hours is suggestive of NPH. • Lumbar puncture: in idiopathic NPH, CSF cell count and glucose will be normal, and protein normal to mildly elevated. Opening pressure is also expected to be normal, though some may have transiently elevated CSF pressures. Symptomatic improvement (especially gait) with large volume (∼40–50 ml) drainage is supportive of a diagnosis of NPH. This is typically performed in the outpatient setting, with pre- and postprocedural cognitive evaluation and documentation of speed, stride length, and steps per turn. Accounts of subjective improvement in the days that follow are also valuable. • Lumbar drain trial: an alternative method in which a temporary catheter is placed in the lumbar spine, and CSF is drained continuously at 5–10 cc/h. This is typically performed in the hospital setting, where patients are monitored for up to 1 week. It is often used to identify candidates for shunting; however, its predictive value has been questioned.

Treatment

Levodopa has been used to rule out the possibility that the clinical picture is due to PD, as NPH may produce extrapyramidal features. Symptoms related to NPH do not respond to dopamine agonists. CSF shunting is currently the mainstay of treatment. Those with a clear improvement in mental status and/or gait following high-volume tap or lumbar drain trial may have a favorable response to shunt surgery. Potential complications from shunt surgery are numerous, and include low-pressure headache, subdural hematoma, other intracranial hemorrhage related to catheter placement, CNS infection, and shunt malfunction.

Degenerative Diseases of the Nervous System

TIP • Placement of a shunt should be performed before dementia progresses to a significant level, as its cognitive benefit declines with disease progression.

REFERENCES Dementia

1. Rajan KB, Weuve J, Barnes LL, Wilson RS, Evans DA (2019). Prevalence and incidence of clinically diagnosed Alzheimer’s disease dementia from 1994 to 2012 in a population study. Alzheimers Dement 15(1):1–7. 2. Craddock N, Lendon C (1998). New susceptibility gene for Alzheimer’s disease on chromosome 12. Lancet 352:1720–1721. 3. Kunkle BW, Grenier-Boley B, Sims R, et al. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet 51:414–430. 4. Harris SA, Harris EA (2015). Herpes simplex virus type 1 and other pathogens are key causative factors in sporadic Alzheimer’s disease. J. Alzheimers Dis 9:319–353. 5. Tsoi KK, Chan JY, Hirai HW, Wong SY, Kwok TC (2015). Cognitive tests to detect dementia: a systematic review and meta-analysis. JAMA Intern Med 175(9):1450. 6. Petersen RC (2011). Clinical practice. Mild cognitive impairment. N Engl J Med 364(23):2227–2234. 7. Okonkwo OC, Alosco ML, Griffith HR, et al.; Alzheimer’s Disease Neuroimag-ing Initiative (2010). Cerebrospinal fluid abnormalities and rate of decline in everyday function across the dementia spectrum: normal aging, mild cognitive impairment, and Alzheimer disease. Arch Neurol 67(6):688–696. 8. Schenk D, Basi GS, Pangalos MN (2012). Treatment strategies targeting amyloid β-protein. Cold Spring Harb Perspect Med 2(9):a006387. 9. Flicker L (1999). Acetylcholinesterase inhibitors for Alzheimer’s disease. BMJ 318:615–616. 10. Mayeux R, Sano M (1999). Treatment of Alzheimer’s disease. N Engl J Med 341:1670–1679. 11. Rösler M, Anand R, Gcm-Sam A, et al. (1999). Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomized controlled trial. BMJ 318:633–640. 12. Wilcock GK, Lilienfeld S, Gaens E. Galantamine International-1 Study Group (2000). Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease. Multicentre randomised controlled trial. BMJ 321:1445–1449. 13. Farimond LE, Roberts E, McShane R (2012). Memantine and cholinesterase inhibitor combination therapy for Alzheimer’s disease: a systematic review. BMJ Open 2(3):e000917. 14. Rabinovici GD, Miller BL (2010). Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs 24(5):375–398.

559 Prognosis

Overall prognosis is poor as the clinical course is progressive. Between 21% and 90% of NPH patients may show marked improvement after shunt surgery. Because of the risk of serious complications, however, patients considered for shunt placement must be chosen carefully.

15. Gass J, Cannon A, Mackenzie IR, et al. (2006). Mutations in progranulin are a major cause of ubiquitin-positive fronto-temporal lobar degeneration. Hum Mol Genet 15(20):2988–3001. 16. Hutton M (2000). ‘Missing’ tau mutation identified. Ann Neurol 46:417–418. 17. Neumann M, Sampathu DM, Kwong LK, et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133. 18. Renton AE, Majounie E, Waite A, et al. (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2):257–268. 19. Wilhelmsen KC (1997). Frontotemporal dementia is on the MAPt. Ann Neurol 41:139–140. 20. Kao AW, McKay A, Singh PP, Brunet A, Huang EJ (2017). Progranulin, lysosomal regulation and neurodegenerative disease. Nat Rev Neurosci 18:325–333. 21. Gendron TF, Belzil VV, Zhang YJ, Petrucelli L (2014). Mechanisms of toxicity in C9FTLD/ALS. Acta Neuropathol 127:359–376. 22. Mathuranath PS, Xuereb JH, Bak T, Hodges J (2000). Corticobasal ganglionic degeneration and/or frontotemporal dementia? A report of two overlap cases and review of the literature. J Neurol Neurosurg Psychiatry 68:304–312. 23. Cairns NJ, Bigio EH, Mackenzie IR, et al.; Consortium for Frontotemporal Lobar Degeneration (2007). Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the consortium for frontotemporal lobar degeneration. Acta Neuropathol 114(1):5–22. 24. Gordon E, Rohrer JD, Fox NC (2016). Advances in neuroimaging in frontotemporal dementia. J Neurochem 138:193–210. 25. Rascovsky K, Hodges JR, Knopman D, et al. (2011). Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134:2456. 26. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. (2011) Classification of primary progressive aphasia and its variants. Neurology 76:1006. 27. Elahi FM, Miller BL (2017). A clinicopathological approach to the diagnosis of dementia. Nat Rev Neurol 13(8):457–476. 28. Tsai RM, Boxer AL (2016). Therapy and clinical trials in frontotemporal dementia: past, present, and future. J Neurochem 138:211. 29. Guerreiro R, Ross OA, Kun-Rodrigues C, Hernandez DG, Orme T, Eicher JD, et al. (2018). Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 17:64–74. 30. McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. (2017). Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology 89:88–100.

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560 31. McKeith I, Del Ser T, Spano PF, et al. (2000). Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 356:2031–2036. 32. Mori E, Ikeda M, Kosaka K (2012). Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol 72:41–52. 33. Amar K, Wilcock G (1996). Vascular dementia. BMJ 312:227–231. 34. Snyder HM, Corriveau RA, Craft S, et al. (2015). Vascular contributions to cognitive impairment and dementia including Alzheimer’s disease. Alzheimers Dement 11:710–717. 35. de Groot JC, de Leeuw FE, Oudkerk M, et al. (2000). Cerebral white matter lesions and cognitive function: the Rotterdam scan study. Ann Neurol 47:145–151. 36. Chui HC, Mack W, Jackson JE, et al. (2000). Clinical criteria for the diagnosis of vascular dementia: a multicenter study of comparability and interrater reliability. Arch Neurol 57:191–196. 37. Roman GC, Tatemichi TK, Erkinjuntti T, et al. (1993). Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43:250–260. 38. Satizabal CL, Beiser AS, Chouraki V, Chêne G, Dufouil C, Seshadri S (2016). Incidence of dementia over three decades in the Framingham heart study. N Engl J Med 374:523–532. 39. Ironside JW, Ritchie DL, Head MW (2017). Prion diseases. Handb Clin Neurol 145:393–403. 40. Prusiner SB (1982). Novel proteinaceous infectious particles cause scrapie. Science 216:136–144. 41. Bueler H, Aguzzi A, Sailer A, et al. (1993). Mice devoid of PrP are resistant to scrapie. Cell 73:1339–1347. 42. Palmer MS, Dryden AJ, Hughes JT, Collinge J (1991). Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 352:340–342. 43. Mok T, Jaunmuktane Z, Joiner S, et al. (2017). Variant Creutzfeldt-Jakob disease in a patient with heterozygosity at PRNP codon 129. N Engl J Med 376:292–294. 44. Will RG, Ironside JW, Zeidler M, et al. (1996). A new variant of CreutzfeldtJakob disease in the UK. Lancet 347:921–925. 45. Mastrianni JA, Nixon R, Layzer R, et al. (1999). Prion protein conformation in a patient with sporadic fatal insomnia. N Engl J Med 340(21):1630–1638. 46. Perani D, Cortelli P, Lucignani G, et al. (1993). [18 F]DG PET in fatal familial insomnia: the functional effects of thalamic lesions. Neurology 43:2565–2569. 47. Geschwind MD, Martindale J, Miller D, et al. (2003). Challenging the clinical utility of the 14–3–3 protein for the diagnosis of sporadic Creutzfeldt-Jakob disease. Arch Neurol 60:813–816. 48. Atarashi R, Sano K, Satoh K, Nishida N (2011). Real-time quaking-induced conversion: a highly sensitive assay for prion detection. Prion 5(3):150–153. 49. Behaeghe O, Mangelschots E, De Vil B, et al. (2018). A systematic review comparing the diagnostic value of 14-3-3 protein in the cerebrospinal fluid, RT-QuIC and RT-QuIC on nasal brushing in sporadic Creutzfeldt–Jakob disease. Acta Neurol Belg 118(3):395–403. 50. Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases, Division of High-Consequence Pathogens and Pathology (2018). CDC’s Diagnostic Criteria for Creutzfeldt-Jakob

Disease (CJD), 2018. Retrieved from https://www.cdc.gov/ prions/cjd/diagnostic-criteria.html. 51. Espay AJ, Da Prat GA, Dwivedi AK, et al. (2017). Deconstructing normal pressure hydrocephalus: ventriculomegaly as early sign of neurodegeneration .Ann Neurol 82(4):503–513.

Further reading

Dementia Alzheimer’s disease Bigio EH (2008). Update on recent molecular and genetic advances in frontotemporal lobar degeneration. J Neuropathol Exp Neurol 67(7):635–648. Caycedo AM, Miller B, Kramer J, Rascovsky K (2009). Early features in frontotemporal dementia. Curr Alzheimer Res 6(4): 337–340. Dubinsky RM, Stem AC, Lyons K (2000). Practice parameter: risk of driving and Alzheimer’s disease (an evidence-based review). Neurology 54:2205–2211. Golbe LI (2000). Progressive supranuclear palsy in the molecular age. Lancet 356:870–871. Heneka MT, Carson MJ, Khoury JE, et al. (2015). Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4): 388–405. Kepp KP (2017). Ten challenges of the amyloid hypothesis of Alzheimer’s disease. J Alzheimers Dis 55:447–457. Mathuranath PS, Nestor PJ, Berrios GE, et al. (2000). A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 55:1613–1620. Pasquier F, Delacourte A (1998). Non-Alzheimer degenerative dementias. Curr Opin Neurol 11:417–427. Pickering-Brown S, Baker M, Yen S-H, et al. (2000). Pick’s disease is associated with mutations in the tau gene. Ann Neurol 48:859–867. Poorkaj P, Bird TD, Wijsman E, et al. (1998). Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–825. (Erratum, Ann Neurol 1998;44:428.) Richards SS, Hendrie HC (1999). Diagnosis, management, and treatment of Alzheimer disease. Arch Intern Med 159:789–798. Schrag A, Ben-Shlomo Y, Quinn NP (1999). Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 354:1771–1775. Snowden JS (1999). Neuropsychological evaluation and the diagnosis and differential diagnosis of dementia. Rev Clin Gerontol 9:65–72. Terry RD (2000). Where in the brain does Alzheimer’s disease begin? Ann Neurol 47:421. Dementia with Lewy bodies Galasko D (1999). A clinical approach to dementia with Lewy bodies. Neurologist 5:247–257. Weisman D, McKeith I (2007). Dementia with Lewy bodies. Semin Neurol 27(1):42–47. Vascular dementia Bousser MG, Tournier-Lasserve E (2001). Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: from stroke to vessel wall physiology. J Neurol Neurosurg Psychiatry 70:285–287. Chui HC (2006). Vascular cognitive impairment: today and tomorrow. Alzheimers Dement 2(3):185–194.

Degenerative Diseases of the Nervous System Dichgans M, Mayer M, Uttner I, et al. (1998). The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 44:731–739. Garde E, Mortensen EL, Krabbe K, et al. (2000). Relation between age-related decline in intelligence and cerebral white-matter hyperintensities in healthy octogenarians: a longitudinal study. Lancet 356:628–634. Hebert R, Lindsay J, Verreault R, et al. (2000). Vascular dementia. Incidence and risk factors in the Canadian Study of Health and Aging. Stroke 31:1487–1493. Jagust WJ, Zheng L, Harvey DJ, et al. (2008). Neuropathological basis of magnetic resonance images in aging and dementia. Ann Neurol 63(1):72–80. Pohjasvaara T, Mäntylä R, Ylikoski R, et al. (2000). Comparison of different clinical criteria (DSM-III, ADDTC, ICD-10, NINDS-AIREN, DSM-IV) for the diagnosis of vascular dementia. Stroke 31:2952–2957. Reed BR, Eberling JL, Mungas D, et al. (2000). Memory failure has different mechanisms in subcortical stroke and Alzheimer’s disease. Ann Neurol 48:275–284. van Gijn J (1998). Leukoaraiosis and vascular dementia. Neurology 51(Suppl 3):S3–S8. Iadecola C. (2013). The pathobiology of vascular dementia. Neuron 80(4):844–866. Prion diseases Brown K, Mastrianni JA (2010). The prion diseases. J Geriatr Psychiatry Neurol 23(4):277–298. Brown P, Preece M, Brandel JP, et al. (2000). Iatrogenic CreutzfeldtJakob disease at the millennium. Neurology 55:1075–1081. Gambetti P, Cali I, Notari S, Kong Q, Zou WQ, Surewicz WK (2011). Molecular biology and pathology of prion strains in sporadic human prion diseases. Acta Neuropathol 121(1):79–90. Hewitt PE, Llewelyn CA, Mackenzie J, Will RG (2006). CreutzfeldtJakob disease and blood transfusion: results of the UK

PARKINSON’S DISEASE AND PARKINSONIAN DISORDERS Brandon R. Barton, Roshi Patel

INTRODUCTION The term parkinsonism refers to a motor syndrome with any combination of the following cardinal features: • Bradykinesia/hypokinesia: slowness with decrement and degradation of repetitive movements (‘fatiguing’). • Rigidity. • Tremor: usually at rest. • Loss of postural reflexes not attributable to other deficits. In addition to the above cardinal features, the following motor signs are frequently associated with parkinsonism: • Gait abnormalities: freezing, festinating, short/shuffling steps, slower speed. • Flexed posture of limbs, neck, and trunk.

561 Transfusion Medicine Epidemiological Review study. Vox Sang 91:221–230. Hsiao K, Baker HF, Crow TJ, et al. (1989). Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature 338:342–345. Monari L, Chen SG, Brown P, et al. (1994) Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism. Proc Natl Acad Sci USA 91:2839–2842. Parchi P, Castellani R, Capellari S, et al. (1996). Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol 39:767–778. Peden AH, Head MW, Ritchie DL, et al. (2004). Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364:527–529. Saa P, Castilla J, Soto C (2006). Presymptomatic detection of prions in blood. Science 313:92–94. Sanchez-Juan P, Green A, Ladogana A, et al. (2006). CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease 67(4):637–643. Telling GC, Scott M, Hsiao KK, et al. (1994). Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proc Natl Acad Sci USA 91:9936–9940. Willison HJ, Gale AN, McLaughlin JE (1991). Creutzfeldt-Jakob disease following cadaveric dura mater graft. J Neurol Neurosurg Psychiatry 54:940. Normal pressure hydrocephalus Halperin JJ, Kurlan R, Schwalb JM, et al. (2015). Practice guideline: idiopathic normal pressure hydrocephalus: response to shunting and predictors of response: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 85:2063–2071.

• Masked facial features (hypomimia), decreased blink rate. • Progressively smaller handwriting (micrographia). • Softer speech (hypophonia). While the most common cause of parkinsonism encountered by the clinician is Parkinson’s disease, a large number of other disorders may cause parkinsonism; these other disorders often associated with other neurologic or systemic signs and symptoms not typically seen in Parkinson’s disease. Causes of parkinsonism may be grouped into the following four categories: • Primary (idiopathic) parkinsonism: Parkinson’s disease, sporadic or familial. • Multisystem degenerations (‘parkinsonism plus’ or atypical parkinsonism). • Heredodegenerative parkinsonism. • Secondary (symptomatic, acquired) parkinsonism. Figure 16.37 outlines a basic categorization algorithm for the most common causes of parkinsonism, which are further explored in the following sections. Neurodegenerative parkinsonian disorders may also be subdivided by the predominant types of proteins found on pathologic examinations of brain tissue, with the most common

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Heredodegenerative parkinsonian disorders

PARKINSONISM

Secondary

Neurodegenerative

Idiopathic Parkinson’s disease

Atypical parkinsonian disorders

Familial

Familial

MATP, progranulin, C9orf72 mutations, and others

Sporadic

Sporadic

Dementia with Lewy bodies (DLB)

Progressive supranuclear palsy (PSP)

Corticobasal degeneration (CBD)

Multiple system atrophy (MSA)

FIGURE 16.37  Classification of parkinsonian disorders. disorders related to either deposition of tau (‘tauopathies’) or alphasynuclein (‘synucleinopathies’) protein (Table 16.3).

PRIMARY (IDIOPATHIC) PARKINSONISM: PARKINSON’S DISEASE

TIP

Definition and epidemiology1,2

• Parkinsonian signs are not specific to Parkinson’s disease; a patient presenting with parkinsonism should be carefully evaluated. Secondary or atypical causes of parkinsonism are usually differentiated from Parkinson’s disease by the history and examination.

TABLE 16.3 Classification of Neurodegenerative Parkinsonian Disorders by Predominant Protein Synucleinopathies

Tauopathies

Parkinson’s disease Multiple system atrophy Dementia with Lewy bodies/ diffuse Lewy body disease Primary autonomic failure

Corticobasal degeneration Progressive supranuclear palsy Frontotemporal dementia Pantothenate kinase–associated neurodegeneration Postencephalitic parkinsonism Parkinsonism–dementia complex of Guam Chronic traumatic encephalopathy (CTE) MAPT mutation (familial frontotemporal dementia and parkinsonism linked to chromosome 17)

Parkinson’s disease is a slowly progressive, age-related, degenerative disorder of the CNS, with motor features characterized clinically by tremor, bradykinesia, rigidity, and disturbed postural reflexes (parkinsonism), as well as nonmotor features including neuropsychiatric, sleep, autonomic, and sensory disturbances. PD is classically characterized pathologically by loss of dopaminergic cells in the pars compacta of the substantia nigra with typical neuronal inclusions known as Lewy bodies, although it has proven to be clinically, pathologically, and etiologically diverse. The disease was named in honor of James Parkinson who in 1817 wrote a classic monograph entitled ‘An Essay on the Shaking Palsy’. • Incidence: 16–19 per 100,000 per year. Incidence increases progressively with advancing age, affecting 1–2% over age 65 and up to 4–5% over 85. Incidence may decrease in ninth decade. • Lifetime risk of developing PD is 2% for males and 1.3% for women. • The number of individuals affected with PD is expected to double (from 4.1–4.6 million to 8.7–9.3 million) by the year 2030, based on projections from data published in the most populous nations. • Prevalence increases steeply with age: 50–59 years: 17.4 in 100,000; 70–79 years: 93.1 per 100,000.

Degenerative Diseases of the Nervous System • Median age of onset 60 years; however, onset < 45 years of age in about 10% of patients. • Gender: M > F with a 3:2 ratio; male predominance most reported in elderly, Western epidemiologic studies.

Etiology and pathophysiology1,3

PD is a mostly sporadic disease which is likely multifactorial and heterogeneous in etiology. PD occurs due to a complex interaction among genetic, environmental, and other individual factors. PD is not one condition with a single cause for all patients, but is rather a downstream clinical syndrome resulting from different types of insults to the substantia nigra (e.g. hereditary, toxic, infectious, age-related). Despite continued expansion of scientific understanding, the cause of dopaminergic cell death in PD is not fully understood and probably heterogeneous and multifactorial, related to a probable self-propagating series of reactions including: • • • • • •

Oxidative stress, reactive oxygen species production. Mitochondrial dysfunction. Excitotoxicity. A rise in intracellular free calcium. Protein aggregation. Inflammation.

Heredity/genetic susceptibility4

Up to 10% of patients with PD have a positive family history of a similar disease. Autosomal dominant, recessive, and X-linked inheritances are known. Many monogenetic forms of PD (labeled PARK1–23 and others) have been characterized, which are inherited in mendelian fashion, and susceptibility loci (e.g. glucocerebrosidase gene, GBA) have also been identified. There is variable and sometimes incomplete penetrance of these genes, therefore one can think of gene mutations associated with PD as genetic risk factors (Table 16.4). Notable genes include: • Alpha-synuclein gene mutations (PARK1, PARK4): Rare and occurring mostly in families from Italy, Spain, and Germany. Two types of mutations include point mutation (PARK1) and duplication or triplication (PARK4) of the SNCA gene. • Parkin gene mutations (PARK2): second most common cause of genetic parkinsonism with autosomal recessive inheritance. The parkin gene product, parkin protein, is a ubiquitin protein ligase (E3), a component of the ubiquitin system, which is an important adenosine triphosphate (ATP)-dependent protein degradation machine, and a component of Lewy bodies. Most patients do not have Lewy body pathology. • Ubiquitin carboxy-terminal hydrolase and ligase (PARK5): a deubiquitinating enzyme. • PINK1 (PARK6): mitochondrial serine/threonine kinase. • DJ-1 (PARK7): altered antioxidant protection. • LRRK2 (PARK8): a kinase encoding the protein dardarin. Responsible for a significant portion of familial (4%) and sporadic (1%) PD, with autosomal dominant inheritance, making it as common as MSA and PSP. Patients tend to have a more benign course with lower incidence of dementia but more limb dystonia and psychiatric symptoms. • GBA mutation: approximately 7–15% of PD patients carry GBA mutation; and rates are higher among Ashkenazi Jewish population. This risk gene is associated with earlier age of onset and higher incidence of dementia.

563 TABLE 16.4  Risk and Protective Factors for PD Factors associated with increased PD risk: • Advanced age (highest risk factor for PD) • Male gender • Pesticide exposure has consistently found to be associated with increased PD risk, e.g. paraquat, rotenone, organochlorine, organophosphates • Agent orange (used by US military in Vietnam) • Solvent exposure, e.g. trichloroethylene • Head injury • Obesity • Personality traits and behaviors: low novelty seeking (may represent early disease feature) • Possible associations with manganese exposure among welders, other pollutants, and postmenopausal hormone levels Factors associated with reduced PD risk: • • • • •

Cigarette smoking Caffeine intake Elevated uric acid Midlife moderate to vigorous physical activity Possible associations with NSAID and statin use, oral contraceptives, and “Mediterranean diet”

Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; PD, Parkinson’s disease.

• Prevalence of PD in first-degree relatives is 1.3–2.1%, which is about double of what is expected. • The lifetime risk of PD in first-degree relatives of sporadic cases is as high as 17%. • For the vast majority of patients (98% or more) who have no family history, there may be no genetic contribution, or several genes may be responsible.

Environmental toxins5

• N-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP), a synthetic opiate derivative, causes a form of parkinsonism that strongly resembles PD both clinically and in response to levodopa, altering mitochondrial function. • Epidemics of von Economo’s encephalitis (encephalitis lethargica) swept Europe in the early 1920s with some patients developing progressive parkinsonism, not identical to PD. Postencephalitic parkinsonism is now very rare. • ‘Dual-hit theory’: a neurotrophic (perhaps viral) pathogen enters the brain via both nasal routes (with anterograde progression into the temporal lobe) and gastric routes, secondary to swallowing nasal secretions in saliva and retrograde transport to the medulla through the enteric plexus and preganglionic vagal nerve fibers. • Prion hypothesis: alpha-synuclein misfolding triggers protein aggregation in interconnected neuronal groups.

Classic pathophysiologic model of basal ganglia

The dopamine pathway in the basal ganglia participates in a complex circuit of both excitatory and inhibitory pathways that are part of a loop connecting the cortex to the thalamus via the basal ganglia and back to the frontal cortex, and serves to modulate the motor system (Figure 16.38). The pathophysiologic hallmark of

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564 Normal

Putamen

GPe

Parkinson’s disease

Cerebral cortex

Thalamus

SNc

STN

Thalamus

Putamen

GPe

GPi

Cerebral cortex

SNc

STN

GPi

SNr

SNr

PPN

PPN

Inhibitory pathway Excitatory pathway

Overactivated pathway Underactivated pathway

FIGURE 16.38  Classical schematic representation of basal ganglia circuitry, illustrating the direct and indirect pathways connecting the striatum and globus pallidus, and the modulatory effects of dopaminergic neurons on each of these systems. In PD, the loss of input from the SNc leads to a net increased inhibitory output to the thalamus. GPe, external globus pallidus; Gpi, internal globus pallidus; PPN, pedunculopontine nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticularis; STN, subthalamic nucleus. parkinsonism is hyperactivity in the subthalamic nucleus (STN) and internal globus pallidus (GPi). Despite lack of correlation with animal models of the disease, the classic basal ganglia model proposes that loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) results in dopamine deficiency in the nigrostriatal pathway, which subsequently reduces the normal inhibition of the nigrostriatal pathway on GABA–enkephalin neurons in the putamen. This increases the activity in the GABA/enkephalinergic putaminal neurons that project to, and inhibit, the globus pallidus externus (GPe). The GPe, which sends GABAergic inhibitory projections to the STN and the GPi, is now inhibited, and so the inhibitory tone of GPi on the STN and GPi is reduced. The STN, which exerts a powerful excitatory drive on to the GPi and substantia nigra reticulata (SNr), now increases its activity well above normal to excite the GPi/SNr. The GPi and SNr are the major output nuclei of the basal ganglia, and finally project, via inhibitory GABAergic pathways, to the ventrolateral thalamus (VL) on their route to the premotor cortices. The increased inhibitory GABAergic outflow from neurons in the GPi/SNr leads to increased inhibition of thalamocortical projection neurons and decreased activation of the precentral motor fields, resulting in bradykinesia. Excessive tonic discharges are not the only physiologic abnormality of the basal ganglia in PD; phasic oscillations in neuronal firing appear to be responsible for tremor. Traditionally, it was thought that changes in the firing rate of individual neurons within basal ganglia and thalamocortical circuitry lead to motor dysfunction. This was referred to as the ‘rate’ model of PD pathophysiology. More recently, this model has been challenged. The so-called ‘firing pattern’ model posits that oscillatory and synchronized firing of the basal ganglia may relay information, i.e. that changes in firing patterns and synchrony of basal ganglia neurons lead to circuit dysfunction. This may explain the efficacy of deep brain stimulation; its mechanism of action is not well understood, but it is hypothesized that stimulation to target

nuclei (typically GPi or STN) may lead to disruption of abnormal firing patterns, as opposed to causing a purely inhibitory or excitatory effect.6,7

Clinical features1,3 Motor features Insidious onset of:

• Tremor*: at rest, 4–6 Hz, rhythmic, involves hand (‘pill-rolling’ due to thumb involvement is typical) ± leg, voice, jaw. • Bradykinesia: diminished rate and range of movements (e.g. impassive face [hypomimia]; Figure 16.39), reduced rate of finger tapping, rapid alternating movements, toe tapping, and arm swing). Typically, a decrementing pattern is seen with progressively slower movements upon more repetition. • Rigidity: increased resistance (‘lead-pipe’ rigidity), to passive movement of the wrist and elbow joints during passive

FIGURE 16.39  Typical masked facial features of Parkinson’s disease.

Degenerative Diseases of the Nervous System

• •

• • •

•

•

movement through their whole range of movement; with or without a superimposed jerky ‘cogwheel’ character due to a superimposed tremor that rhythmically interrupts tone. Postural instability: impaired equilibrium reactions/righting reflexes: slow to correct balance and tendency to fall backward (retropulsion) or accelerate forward (festination). Gait disturbance: • Stooped posture with arms flexed, narrow stance base (Figure 16.40), reduced or absent swinging of one arm initially, followed by shortening of stride length (shuffling steps), difficulty initiating gait, stiffening of the trunk so that when the patient turns, the whole body moves in one mass (en bloc), stooped posture, festination, and freezing. • The gait has a narrow base, irrespective of the severity of the disease. Asymmetry*: onset is usually unilateral, eventually becoming bilateral after a few years. A good response* to levodopa therapy (70–100%). Several features of PD may be considered secondary to the core main features: infrequent blinking, facial immobility, soft voice, saccadic ocular pursuit, hypometric ocular saccades, drooling, micrographia, flexed body posture at the trunk, neck, elbows, and knees; joint and muscle pain (e.g. frozen shoulder, and possibly bursitis) are likely a result of muscle rigidity and bradykinesia. Treatment-induced dyskinesias*: writhing, swinging movements of the limbs and trunks typically occur in patients with advanced disease and prominent motor fluctuations and are caused by excess levodopa, but may also occur with dopamine agonists. Dystonic dyskinesia (sustained twisting movements) may be painful and necessitate reduction of levodopa dosage. The deep tendon reflexes remain preserved, and the plantar responses are flexor.

(*Best predictors of PD.)

FIGURE 16.40  Illustration of the slightly anxious, frozen face, and characteristic flexed posture of a Parkinson’s disease patient.

565 TABLE

16.5  Spectrum of Parkinson’s Disease

Nonmotor

Symptoms

in

Neuropsychiatric Depression, apathy, anxiety, anhedonia; dementia; impulse control disorders; psychosis: hallucinations, delusions Autonomic Bladder dysfunction; orthostatic hypotension, supine hypertension; hyperhidrosis; dysphagia/sialorrhea; constipation, nausea, vomiting, delayed gastric emptying; sexual dysfunction Sleep Insomnia, poor sleep efficiency, excessive daytime sleepiness, sleep fragmentation; primary sleep disorders (restless leg syndrome, periodic limb movement disorder, obstructive sleep apnea); REM behavioral disorder; vivid dreams Sensory Pain, paresthesias; olfactory dysfunction, ageusia; visual symptoms: diplopia, blurring Other Fatigue; weight loss/gain; seborrhea; respiratory complaints; sialorrhea Abbreviation: REM, rapid eye movement.

Nonmotor features8

Almost all patients experience a combination of the many possible nonmotor symptoms (Table 16.5): • May occur early, even before motor features9, and contribute to reduced quality of life, in many cases outweighing disability from motor symptoms. • More highly prevalent and disabling as disease course advances. • Result from multifocal pathologic lesions in extranigral pathways (e.g. brain, spine, ganglion, visceral organs) and nondopaminergic neurotransmitter systems. • Pain and sensory phenomena are common. Deep cramping sensations in the limbs may be a primary symptom or related to levodopa medication. Superficial burning dysesthesia also may occur. • REM behavior disorder (RBD) is associated with increased risk of developing synucleinopathy. • Anxiety and depression (40%). • Cognitive impairment: common, even in early PD (up to onethird), mainly subcortical features: bradyphrenia, decreased attention, executive dysfunction, memory deficits, visuospatial dysfunction, apathy, decreased verbal fluency. • Dementia: • Occurs in 22–48% of cases, accounting for 3–4% of dementia in general population. Increased relative risk of dementia 1.7–5.9 with PD; 10% of PD population may develop dementia per year. • Must be distinguished from depression, physical slowness, and adverse effects of drug treatment. • Cognitive impairment is one of the strongest predictors of nursing home placement in PD. • Psychosis and hallucinations: often secondary to antiparkinsonian medications. • Autonomic dysfunction: due to central and peripheral involvement of autonomic regulatory neurons: • Orthostatic hypotension and/or supine hypertension. • Urinary dysfunction: urinary urgency, frequency, nocturia, delayed emptying, difficulty initiating, recurrent infections. Usually related to detrusor or sphincter

Hankey’s Clinical Neurology

566 muscle hyperactivity, less frequently to hypoactive detrusor; paradoxical cocontraction of urinary sphincter. • Erectile dysfunction. • Thermoregulatory dysfunction: excessive sweating; may be related to ‘on’ state (with peak-dose dyskinesias) or ‘off’ state.

TIP • Nonmotor symptoms of PD are present in nearly all patients, and should not be neglected in evaluation and treatment of the disorder. Often these symptoms contribute more disability to the patient than the motor symptoms, particularly as the disease progresses.

Clinical Subtypes10

Subtypes of PD have emerged based on distinct clinic features. They include: • Tremor-dominant: in which tremor is an early and prominent feature. This is often misdiagnosed as essential tremor, and there may be a pathological link between the two disorders. There is a related entity called ‘benign tremulous parkinsonism’ in patients who have prominent rest tremor in the absence of other nontremor signs and gait disorder, and lack of progression. • Postural instability with gait difficulty (PIGD): in which patients demonstrate early gait abnormalities; and there is prominent bradykinesia and rigidity (sometimes referred to as ‘akinetic rigid subtype’). • Young-onset PD (age < 50). • Late-onset PD (age > 50).

Differential diagnosis Tremor

• Benign essential tremor (BET): upper limb tremor which is worse with posture and action (on attempted writing, the tremor is exacerbated and the script becomes enlarged and irregular, whereas in PD, the tremor usually abates and the writing becomes smaller as the script progresses across the page [micrographia]), positive family history, tremor response to alcohol, later developing head/voice tremor. However, a subset of PD patients has action tremor without rest tremor. BET patients lack significant parkinsonism. • Dystonic tremor: associated with dystonic hand posturing, decreased arm swing, or sometimes cogwheel rigidity at the wrist. May resemble parkinsonian tremor, but typically more irregular with a ‘null point’ or position where the tremor stops. • Cerebellar tremor: slower frequency 1–2 Hz and associated with ataxia.

Parkinsonism

• Multisystem degenerations (‘parkinsonism plus’ or atypical parkinsonism) (see later section). • Heredodegenerative parkinsonism (see later section). • Secondary parkinsonism (see later section). • Progressive pallidal atrophy. • Parkinsonism–dementia–ALS complex of Guam (PDACG), or Lytico–Bodig. • X-linked dystonia–parkinsonism. • Rapid-onset dystonia–parkinsonism. • Pallidopyramidal disease.

Neuropsychiatric features

As either an alternative primary or concurrent diagnosis to PD: • • • • •

AD. Vascular dementia (VaD). Dementia with Lewy bodies (DLB). Brain injury: alcohol, head trauma. Other causes: • NPH. • Intracranial mass lesion: frontal or temporal lobe tumor, chronic subdural hematoma. • Metabolic/toxic: chronic drug intoxication (e.g. alcohol, barbiturates, sedatives), chronic hepatic encephalopathy. • Endocrine: hypothyroidism, Cushing’s syndrome. • Autoimmune: SLE. • Nutritional: vitamin B12 deficiency; Wernicke– Korsakoff syndrome. • Infection: syphilis (general paresis of the insane), HIV. • FTD. • HD. • PSP. • Prion disease. • Pseudodementia: related to depression. • Age-related cognitive impairment in ‘normal’ (not diagnosed with a specific neurologic disease) aged persons. • Multiple causes (i.e. combinations of the above).

Investigations11

In general, Parkinson’s disease diagnosis can be made by history and clinical examination. Investigations are indicated if parkinsonism is atypical for idiopathic PD to rule out other etiologies (see below). • Serum copper and ceruloplasmin, 24-hour urine copper, slit-lamp examination; in younger patients, to exclude Wilson’s disease. • CT brain scan: to exclude hydrocephalus, cerebral infarction, or hemorrhage, and a structural lesion such as an arteriovenous malformation (AVM) or tumor (usually convexity meningioma causing contralateral hemiparkinsonism). Usually shows nonspecific generalized atrophy of the brain. • MRI brain scan: • May show generalized atrophy. • More prominent iron deposition (dark signal on T2-­ weighted imaging) in the substantia nigra may be noted. • Some narrowing of part of the substantia nigra has been demonstrated in some cases but both this and the previous feature are very nonspecific and hard to spot. • A combination of putamenal hypointensity and brainstem atrophy is a consistent finding in Parkinson’s plus syndromes and excludes PD. • Functional imaging: • Positron emission tomography (PET): limited availability/cost precludes use as screening or diagnostic tool. – 18F-dopa-PET is a form of metabolic imaging which may indirectly provide a quantitative assessment of presynaptic nigrostriatal dopaminergic function, with early PD patients showing reduced metabolism in the dorsal striatum, though this finding is not entirely specific to PD. – 18F-fluorodeoxyglucose-PET may provide an assessment of regional metabolic rates of glucose, which in addition to 18F-dopa-PET may help distinguish PD from other atypical parkinsonian disorders.

Degenerative Diseases of the Nervous System

• • •

•

• Dopamine transporter imaging (FP-CIT-SPECT DaTSCAN): – Sensitive method to detect presynaptic dopamine neuronal dysfunction, assisting in differentiation between PD and other conditions, such as dystonia, essential tremor, or secondary etiologies. – Does not distinguish between PD and other forms of atypical degenerative parkinsonism. – More widely available as a clinical diagnostic test, although the cost of the test prohibits widespread use, particularly since clinical examination and history remain the gold standard for the diagnosis of PD. – Best applied in cases where diagnosis is unclear, examination is equivocal, or if results would change treatment and prognosis, most helpful in distinguishing BET from PD (Figures 16.41, 16.42). Transcranial ultrasound of the substantia nigra: shows midbrain hyperechogenicity in 90% of PD patients, but is not specific, also seen in depression and normal individuals. Reduced update on myocardial scintigraphy (MIGB) is seen in PD. This reflects peripheral postsynaptic noradrenergic depletion, likely reflecting dysautonomia seen in PD. Acute drug challenges: apomorphine test, levodopa challenge; no longer considered reliable as a sensitive means of diagnosing PD, since not all PD patients have acute responses to medication, particularly early in the disease course. Bloodwork to exclude secondary causes, as indicated: complete blood count, peripheral blood smear, thyroid function tests, VDRL/RPR/TPHA, vitamin B12, antinuclear antibodies, HIV, serology.

567 Early clinical features raising doubts about the diagnosis of idiopathic PD

• Atypical levodopa-induced dyskinesias (e.g. torticollis, antecollis, sustained dystonic spasm of facial musculature). • Onset before the age of 40 years. • Strictly unilateral disease. • Symmetric disease.

Diagnosis11

A clinical diagnosis can be made with confidence when: • There are two of the four cardinal clinical features of parkinsonism. One must be bradykinesia, in addition to one of the following: tremor (present in 70%), rigidity, and disturbed postural reflexes. Keep in mind that early impairment of postural reflexes may be a sign of an atypical cause of parkinsonism. • There is no detectable alternative cause for the parkinsonism. • The patient significantly responds to levodopa. • The course is slowly progressive. • Premotor/nonmotor symptoms are present (e.g. anosmia, REM behavior disorder, constipation). Keep in mind that early severe autonomic dysfunction may suggest atypical parkinsonism. However, the clinical diagnosis may be incorrect in up to 25% of patients, particularly early on in the clinical course. Clues to an alternative diagnosis are the presence of additional nonparkinsonian features, absence of progression, absence of nonmotor symptoms, and a partial or absent response to dopaminergic drugs.

TIP • The diagnosis of PD is a clinical one, based on the presence of typical symptoms and the absence of atypical features. However, since PD is a heterogeneous disorder, and the spectrum of findings in any single patient can vary significantly, often the diagnosis may be unclear in the beginning. Progression of atypical features over time and response to antiparkinsonian medications usually improve the certainty of diagnosis.

FIGURES 16.41, 16.42  FP-CIT-SPECT (DaTSCAN) differentiation of parkinsonian and tremor disorders. A normal test (Figure 16.41) shows the comma-shaped caudate and putamen; this pattern is seen in healthy individuals or patients with other causes of tremor or parkinsonism not involving degeneration of the presynaptic dopaminergic neurons. (Figure 16.42) This abnormal image shows a reduction in the left more than in the right putamen. The scan asymmetry typically corresponds to the asymmetry of parkinsonism in an affected patient. (Courtesy of Donald D. Grosset, Southern General Hospital, Glasgow.)

568 • Early, more prominent: • Dysphagia. • Severe autonomic failure (orthostatic hypotension, incontinence, erectile dysfunction). • Speech abnormalities: dysarthria, palilalia, laryngeal stridor. • Postural instability and falls. • Cognitive signs: dementia, hallucinations, psychosis, pseudobulbar affect, apraxia. • Dystonia: disproportionate antecollis. • Absence of: • Rest tremor. • Levodopa-induced dyskinesias after several years or despite high levodopa dose. • Typical nonmotor symptoms as the disease progresses. • Clinical signs outside the spectrum of PD: • Oculomotor (e.g. restricted eye movements due to supranuclear gaze palsy). • Cerebellar features (nystagmus, dysarthria, widebased gait, ataxia). • Pyramidal tract signs (hyperreflexia, weakness, Babinski’s sign). • Nondrug-induced myoclonus. • Inspiratory stridor. • Peripheral neuropathy. • Poor or limited response to adequate doses of levodopa. • Family history of a movement disorder. • Rapid or stepwise progression.

Hankey’s Clinical Neurology

FIGURE 16.44  Axial section through the midbrain of a patient with Parkinson’s disease, showing lack of pigmentation in the substantia nigra due to loss of melanin-containing pigmented dopaminergic neurons.

Pathology

• Loss (> 50%) of melanin-containing, pigmented, dopaminergic neurons in the substantia nigra; preferentially affects the ventrolateral substantia nigra pars compacta which projects to the posterior putamen, with less involvement of the medial tegmental pigmented neurons that project to the caudate nucleus (Figures 16.43–16.46). • Braak’s hypothesis of early PD pathology progression (Figure 16.47):12 • Stages 1 and 2 (medulla/pontine tegmentum): pathologic process of PD initially affects dorsal motor nucleus of the vagal and glossopharyngeal nerves, anterior olfactory nucleus, and locus ceruleus. • Stages 3 and 4 (lower and upper brainstem): thereafter, the disease process ascends in the brainstem, affecting the

FIGURE 16.43  Axial section through the midbrain of a normal patient showing normal pigmentation of the substantia nigra.

FIGURE 16.45  Section of the substantia nigra of a normal patient at low magnification power showing normal melanincontaining, pigmented, dopaminergic neurons.

FIGURE 16.46  Section of the substantia nigra of a patient with Parkinson’s disease, showing a reduced number of normal melanin-containing, pigmented, dopaminergic neurons.

Degenerative Diseases of the Nervous System substantia nigra and mesocortex (transentorhinal region and CA2-plexus). • Stages 5 and 6 (neocortical areas): more severe brain involvement, with neocortical involvement of prefrontal and high-order sensory association areas. While the Braak hypothesis has had a profound effect on current models of PD, it is criticized for its lack of explaining other

569 synuclein-related diseases (e.g. DBLD), lack of predictive validity, limitation to CNS structures, the observation of ‘silent’ stages 4–6 pathology in some subjects at autopsy, and the absence of this pattern in at least 15% of PD patients. • Presence of eosinophilic intracellular cytoplasmic inclusions, known as Lewy bodies (which contain phosphorylated neurofilaments, ubiquitin, phospholipids, and many other

a

b Sites dm

co

sn

mc

hc

fc

1

PD stages

2 3 4 5 6

FIGURE 16.47  Progression of PD-related intraneuronal pathology. (a) The pathologic process targets specific subcortical and cortical induction sites. Lesions initially occur in the dorsal IX/X motor nucleus and frequently in the anterior olfactory nucleus. Thereafter, less susceptible brain structures gradually become involved (arrows). The brainstem pathology takes an upward course with cortical involvement following. (b) Simplified diagram showing the topographic expansion of the lesions (from left to right: dm to fc) and, simultaneously, the growing severity of the overall pathology (from top to bottom: stages 1–6). With the addition of further predilection sites, the pathology in the previously involved regions increases. Co, ceruleus–subceruleus complex; dm, dorsal motor nucleus of the glossopharyngeal and vagal nerves; fc, first-order sensory association areas, premotor areas, as well as primary sensory and motor fields; hc, high-order sensory association areas and prefrontal fields; mc, anteromedial temporal mesocortex; sn, substantia nigra. (Adapted from Braak 2003, with permission.)

Hankey’s Clinical Neurology

570 Treatment13

FIGURE 16.48  Microscopic sections of the substantia nigra at high magnification power showing normal melanin-containing, pigmented, dopaminergic neurons in a normal patient. cytoskeletal components), in the brainstem and other parts of the brain (Figures 16.48– 16.50). Of note, not all genetically determined Parkinson syndromes include Lewy bodies. • Dopamine deficiency (> 80%) in the nigrostriatal pathway and relative hyperactivity of striatal (putamen and caudate nucleus) cholinergic activity. Clinical features do not emerge until 40–50% of nigral neurons and 60–80% striatal dopamine are lost.

The great majority of patients are adequately managed in the outpatient setting. Patients should be encouraged to keep as physically active as possible, with most evidence suggesting that exercise and physical activity may have at least short-term benefit in reducing the severity of many PD symptoms and reduce the need for more medication. Nonmotor symptoms of PD are often overlooked. Be aware of and treat concurrent symptoms such as pain (e.g. with tricyclic antidepressants), anxiety (e.g. with benzodiazepines), depression (with antidepressants or electroconvulsive therapy [ECT]), autonomic symptoms, sleep disturbances, and cognitive or sensory features. The decision when to start symptomatic treatment is an individual decision for each patient based on personal needs and disability from PD symptoms. There is no conclusive evidence to suggest that early medical treatment of PD affects the progression of the disease, although some experts advocate that early treatment may reduce potentially harmful compensatory mechanisms related to untreated disease. Treatment-related adverse effects such as motor fluctuations and dyskinesias may be caused partly by the duration and total dose of drug treatment, particularly with levodopa, so keeping the drugs to minimally needed doses is usually the goal. However, delaying definitive treatment of disability due to fear of drug side effects is unjustified, particularly in light of increasingly better options for treating drug side effects. Compelling indications for starting symptomatic treatment are when employment is in jeopardy or when falling becomes a risk. Commence medical therapy (dopamine replacement) at the lowest required dose and proceed with dose increases slowly in order to minimize risk of adverse effects such as nausea, dizziness, or confusion, particularly in the elderly (Table 16.6). An hour-by-hour diary of the presence and severity of parkinsonian symptoms and dyskinesias can be helpful in guiding medication schedules for more advanced patients.

Medical therapies Levodopa14

Levodopa is a naturally occurring amino acid, most of which is metabolized by catechol-O-methyltransferase (COMT) to form an inactive metabolite, and some of which is decarboxylated by an aromatic amino acid decarboxylase to form dopamine (Figure 16.51). It is still the gold standard drug for PD, after 30 years of use, for TABLE 16.6 Commonly Used Dopaminergic Drugs in Parkinson’s Disease and Dose Ranges

FIGURES 16.49, 16.50  Microscopic sections of the substantia nigra at high magnification power showing reduction in the number of normal melanin-containing, pigmented, dopaminergic neurons and the presence of eosinophilic, intracellular, cytoplasmic inclusions (Lewy bodies) in the neurons (arrow).

Drug

Initial Dose

Effective Daily Dose

Amantadine Carbidopa/levodopa

100 mg daily 12.5–25/50–100 mg bid–tid 0.125 mg tid 0.25 mg tid 2 mg daily 2–6 mg (individual titration) 200 mg tid (give with carbidopa/levodopa) 5 mg daily 0.5 mg daily

200–400 mg daily 37.5/150–500/2000 mg daily 1.5–4.5 mg daily 8–24 mg daily 6–8 mg daily 2–6 mg for sudden ‘off ’

Pramipexole Ropinirole Rotigotine Apomorphine subcutaneous Entacapone Selegiline Rasagiline

Up to 1600 mg daily 5 mg bid 1.0 mg daily

Degenerative Diseases of the Nervous System

571

Levodopa DDC

COMT 3-OMD

Dopamine

Blood–brain barrier

Levodopa COMT

DDC

3-OMD

Dopamine COMT

MAO DOPAC

3-MT

MAO

HVA

COMT

FIGURE 16.51  Metabolism of levodopa. Dopamine itself is unsuitable as a treatment for PD, as it cannot cross the blood–brain barrier, but its immediate precursor, levodopa, is metabolized to dopamine by the enzymes catechol-O-methyltransferase (COMT) and dopa decarboxylase (DDC). Orally administered levodopa is converted into dopamine in the GI tract, leaving less available for transport into the CNS, while its generation within the peripheral circulation has adverse effects. 3-MT, 3-methoxytyramine; 3-OMD: 3-O-methyldopa; DOPAC, 3, 4-dihydroxyphenylacetic acid; HVA, homovanillic acid; MAO, monoamine oxidase. improving the cardinal features of the illness. Currently, many formulations exist on the market (Table 16.7). Levodopa is usually combined with a peripheral decarboxylase inhibitor (carbidopa [Sinemet] or benserazide [Madopar]) that does not cross the blood–brain barrier. This combination minimizes production of dopamine in the systemic (peripheral) circulation and helps prevent adverse effects such as nausea and vomiting. Early in the disease, low-dose levodopa (i.e. 100 mg, in combination with 25 mg of decarboxylase inhibitor, taken three to four TABLE 16.7  Formulations of Levodopa Drug Name Carbidopa/levodopa (Sinemet) Carbidopa/levodopa CR (Sinemet CR) Benserazide/levodopa Carbidopa/levodopa ODT (Parcopa, orally disintegrating) Carbidopa/levodopa/entacapone (Stalevo)

Dosing (mg) 10/100, 25/100, 25/250 25/100, 50/200 12.5/50, 25/100, 50/200 10/100, 25/100, 25/250 12.5/50/200, 18.75/75/200, 25/100/200, 31.25/125/200, 37.5/150/200, 50/200/200 23.75/95, 36.25/145, 61.25/245

Carbidopa/levodopa extended-release capsules (Rytary, strength is ∼1.5× normal levodopa) Levodopa inhalation powder (Inbrija) 42 mg per use Carbidopa/levodopa enteral suspension 2000 mg levodopa, administered (Duopa) based on infusion rate

times daily) controls most patients’ symptoms very well (referred to as the ‘honeymoon period’ of a few years): • If not effective but tolerated, the dose can be increased slowly to an effective dose (that improves function), which is commonly about 500–600 mg/day, and which does not cause adverse effects such as confusion, nausea, or dyskinesias. • Failure to evoke substantial benefit should lead to a reevaluation of the diagnosis. Trial of levodopa up to 900 mg daily is usually considered an adequate dose to evaluate for benefit. • In the early stages of PD, the response to levodopa is sustained, despite the relatively short half-life of levodopa (about 90 minutes). Patients are often able to miss doses without any deterioration in clinical response. • It may take as long as 30 days to achieve maximal benefit at a given dose, an adequate duration therapeutic trial is important. As the disease progresses, with continued loss of dopaminergic neurons in the substantia nigra, the duration of benefit following a single dose of levodopa diminishes, eventually mirroring the drug’s plasma concentration curve. This phenomenon is known as ‘end of dose failure’ or ‘wearing off’ and is characterized by increasing bradykinesia and tremor in the hour or two before the next dose of levodopa is due. These predictable motor fluctuations are best managed by aiming for relatively constant levels of levodopa by reducing the time interval between each dose

Hankey’s Clinical Neurology

572 and prescribing more frequent and sometimes smaller doses of levodopa. Subsequently, the patient may develop unpredictable motor fluctuations that are independent of plasma levodopa concentration and are attributed to postsynaptic changes in the dopamine receptors and second messengers: • Recurrent swings between dyskinetic adverse effects of levodopa (‘on’) and severe bradykinesia (‘off’) may occur, as may sudden episodes of ‘freezing’. • Individual levodopa doses may fail to provide any benefit at all, known as ‘no-on’ phenomenon. The addition of a dopamine agonist or an enzyme inhibitor (see below) may be helpful. • Controlled-release levodopa for patients with motor fluctuations may cause a reduction in end of dose dystonia, and may be particularly helpful for overnight or early morning dystonia or breakthrough symptoms. The older controlledrelease levodopa has less bioavailability and may be difficult to titrate in more advanced patients. The newer extendedrelease levodopa has a significantly extended half-life (4 hours, vs. 90 minutes for immediate-release levodopa). • Increasing the dose of levodopa runs the risk of causing adverse effects which include nausea, postural hypotension, neuropsychiatric problems (mental confusion and hallucinations), impulsive and compulsive behaviors, and involuntary movements of the mouth, tongue, and limbs (peak-dose dyskinesia).

Anticholinergics

Anticholinergics primarily have a role in young patients with early PD and prominent or refractory resting (alternating) tremor, although benefit may be modest. Available drugs include benztropine and trihexyphenidyl. Adverse effects include dry mouth, mental confusion, hallucinations, blurred vision, and difficulty initiating micturition with urinary retention. Anticholinergics are contraindicated in glaucoma, and should be avoided, or used with caution, in the elderly because of the high incidence of confusion and only modest antiparkinsonian benefit. Acute withdrawal of anticholinergics may be associated with dramatic worsening of parkinsonism, so the drugs should be discontinued gradually.

Amantadine

Amantadine is approved as an antiviral agent and has unclear but likely multifactorial mechanisms of action including: • Anticholinergic (antimuscarinic) effects. • Weak dopamine agonist activity: releases dopamine from body stores. • Glutamate receptor antagonist effect. Amantadine may have a mild and temporary antiparkinsonian effect in early stages of the disease and may reduce levodopainduced dyskinesias in patients with motor fluctuations. Doses should begin with 100-mg capsule in the morning and, if necessary, another added at midday, with a maximal dose of 300–400 mg daily. A lower dose should be used in renal impairment, as its elimination depends on renal clearance. A once-daily dose is now available (68.5 and 137 mg). Adverse effects include skin mottling (livedo reticularis) in one-half of patients, inflamed, swollen legs (erythromelalgia), hallucinations, and anticholinergic effects.

Dopamine receptor agonists

These are synthetic agents that act directly on dopamine receptors, and can be used as a sole treatment agent or in conjunction with other antiparkinsonian drugs. Possible advantages over levodopa include: • Do not require biologic conversion to an active agent and therefore are not dependent on the presence of residual dopaminergic neurons or a pool of decarboxylase enzyme. • Long half-life which helps to smooth out motor fluctuations and reduce ‘on–off’ phenomena. • Less likely to cause dyskinesias. • Lack of competition for absorption into the brain. • Potential to stimulate selectively a subset of dopamine receptors. • Fewer long-term adverse motor effects (motor fluctuations, dyskinesias). • Can help alleviate comorbid restless leg syndrome. Disadvantages over levodopa: • Less potent and therefore less antiparkinsonian effect. • More likely to cause confusion, hallucinations, peripheral edema, or autonomic symptoms than levodopa, particularly in the elderly. • Associated with development of impulse control disorders 17% or more of patients on this class of drugs, e.g. inability to resist excessive involvement in normally pleasurable activities such as gambling, eating, sex, shopping, or other hobbies, potentially resulting in devastating personal and social consequences. • Sudden withdrawal can be associated with dopamine agonist withdrawal syndrome (DAWS). Ergot-derived dopamine agonists  These are now less commonly used in clinical practice, as they may have more severe side effects such as valvular heart disease, vasospasm, pulmonary edema, and (rarely) pleuropulmonary or retroperitoneal fibrosis. Monitoring requires yearly echocardiograms and chest X-ray before starting treatment. • • • •

Bromocriptine. Pergolide. Lisuride. Cabergoline.

Nonergot dopamine agonists  • Pramipexole: • Dose: up to 3–4.5 mg/day, divided bid or tid. • A once-daily extended-release formulation is available. • For patients with early untreated PD, monotherapy improves motor scores by 20–30% compared with placebo. • For patients with motor fluctuations, pramipexole increases motor and ADL scores by 20–25%, and reduces ‘off’ time by about 30% compared with placebo; and increases motor scores by 12% and ADL scores by 4% compared to bromocriptine. • Ropinirole: • Dose: up to 24 mg/day, divided bid or tid. • A once-daily extended-release formulation is available. • For patients with early untreated PD, monotherapy increases motor scores by 24% compared with placebo,

Degenerative Diseases of the Nervous System and controls symptoms in about 30% of patients. After 5 years’ monotherapy, patients have fewer dyskinesias than if taking levodopa. • For patients with motor fluctuations, ropinirole reduces ‘off’ time by 20%, and enables the levodopa dose to be reduced by about 30%. • Rotigotine: • Dose 2–8 mg daily. • Designed as a daily transdermal patch with slow release. • Apomorphine: • A combined D1 and D2 dopamine receptor agonist. • Used in patients with motor fluctuations for rapid relief from sudden ‘off’ periods. • Given by subcutaneous injection intermittently. • Available in some countries as a continuous-infusion subcutaneous pump. • The only other dopaminergic drug with equivalent potency to levodopa. • Fast onset: benefit occurs within 5–15 minutes, lasting 40–90 minutes. • Adverse effects similar to those from levodopa can occur, with the addition of yawning, drowsiness, and local skin reactions or abscesses at injection sites. • Requires careful initial titration, usually in a monitored setting, to avoid significant side effects; oral domperidone, ondansetron, or trimethobenzamide are often given before each dose to prevent nausea. Patient should be started with low dose and titrated up under observation and monitoring of vital signs including blood pressure.

Catechol-O-methyltransferase inhibition

COMT inhibition increases availability of levodopa for transport across the blood–brain barrier by reducing levodopa metabolism, thus extending the duration of action of each levodopa dose by about 30–50 minutes, irrespective of whether a standard or slowrelease form of levodopa is used. It is indicated for PD with motor fluctuations, not for early untreated PD, and must be used in conjunction with levodopa and a peripheral decarboxylase inhibitor. Adverse effects include an increase in dyskinesias and other dopaminergic adverse effects, which may require a reduction in levodopa dose; diarrhea (usually in 4–12 weeks); orange/brown discoloration of urine, saliva, or sweat. • Entacapone: extends levodopa half-life by acting as a peripheral COMT inhibitor. • Tolcapone: extends levodopa half-life more than entacapone by acting as a central and peripheral COMT inhibitor, but is associated with the potentially serious side effect of hepatic failure, requiring monitoring of liver enzymes, which limits its wide clinical application.

Monoamine oxidase type B inhibitors

These drugs selectively and irreversibly inhibit monoamine oxidase type B (MAO-B), one of the enzymes that catabolizes dopamine in the brain, thereby retarding the breakdown of dopamine and increasing its duration of action. They have mild symptomatic benefit as monotherapy in early PD. There is argument as to whether they protect dopaminergic neurons and slow the progression of PD, but this has never been conclusively shown in human trials. The presumed mechanism is that oxygen-free radical

573 formation generated by the MAO-B oxidation of dopamine is reduced, and the activation of exogenous neurotoxins is prevented. MAO-B inhibitors should be used with caution in conjunction with antidepressants, due to theoretical risk of serotonin syndrome. When taken with levodopa, MAO-B inhibitors can slightly improve the duration of the levodopa effect and can smooth out early wearing off, but can also provoke or worsen dyskinesias and psychiatric adverse effects. • Selegiline HCl: • Metabolized to desmethyldeprenyl, methylamphetamine, and amphetamine; these metabolites may have a theoretical effect on fatigue. • 5-mg tablets, taken in the morning and, if necessary, at midday to a maximum of 10 mg daily. Avoid evening doses as this may cause insomnia. • Adverse effects include nausea, insomnia, musculoskeletal injuries, nonthreatening cardiac arrhythmias, and elevations in liver enzyme levels. • Controversy exists as to whether it may be associated with excess mortality. • Zydis selegiline: wafer formulation that dissolves in the mouth, bypassing hepatic first-pass metabolism. • Rasagiline: • Once-daily MAO-B inhibitor, up to 1 mg daily. • Free of amphetamine metabolites. • Initial US Food and Drug Administration (FDA) warning of avoiding high tyramine foods (red wine, aged cheeses, aged meats) was removed after further safety monitoring.

TIP • Levodopa still remains the gold standard pharmacologic treatment for PD. Patient disease characteristics (both motor and nonmotor symptoms), medical comorbidities, general health, and concomitant medications should be reviewed before determining an individual patient’s antiparkinsonian medication regimen.

Complications of medical therapy and treatment strategies Motor fluctuations15

See Table 16.8. After about 5 years of treatment, 30–80% of patients develop motor fluctuations. Motor fluctuations consist of variations in response to a single dose of levodopa, i.e. swings between parkinsonism and dyskinesias, with a variety of manifestations. This is due to shortening of the striatal half-life of levodopa, resulting in a shortened response from each dose of levodopa and a narrower therapeutic window (Figure 16.52). Patients oscillate between periods in which they respond to the drug (‘on’ periods) and periods in which they do not (‘off’ periods). This is related to a reduction in the PD brain’s capacity to store dopamine, due to progressive reduction in the number of nerve terminals capable of storing dopamine and a reduced capacity to buffer fluctuations in the plasma levodopa concentration. Concurrently, there is an increasing dependency on exogenously administered levodopa to provide dopamine for stimulation of striatal receptors. Accordingly, factors that interfere with levodopa absorption, such as dietary protein or alterations in gastrointestinal transit time, can lead to ‘off’ episodes.

Hankey’s Clinical Neurology

574 TABLE 16.8 Medical Management of Motor Fluctuations and Dyskinesias Motor Fluctuations WEARING OFF, END-OF-DOSE DETERIORATION Take levodopa 30 minutes before meals Smaller, more frequent doses of levodopa Add dopamine agonist Add COMT inhibitor Add MAO-B inhibitor Switch to enteral levodopa or extendedrelease capsule

DELAYED ‘ON’ RESPONSE Take levodopa apart from meals (at least 30 minutes) Low-protein diet Antacids, gastric prokinetic agents Take levodopa apart from meals (at least 30 minutes) Low-protein diet Antacids, gastric prokinetic agents SUDDEN ‘OFF’ PERIODS Liquid levodopa Subcutaneous apomorphine Low-protein diet Levodopa inhalation powder ‘ON–OFF’ PHENOMENA (‘yo-yo-ing’) Higher, less frequent doses of levodopa Add dopamine agonist Apomorphine infusion Switch to enteral levodopa or extended-release capsule

Dyskinesias

Dyskinesi a thresho ld

PEAK-DOSE DYSKINESIA Reduce total levodopa dose Add dopamine agonist to maintain motor response

Efficacy EARLY MORNING DYSTONIA Slow-release levodopa at night Long-acting dopamine agonist at night Antispasmodic (e.g. baclofen) Slow-release levodopa at night Long-acting dopamine agonist at night Antispasmodic (e.g. baclofen) END-OF-DOSE DYSTONIA Slow-release levodopa Long-acting dopamine agonist ‘OFF’ PERIOD DYSTONIA Liquid levodopa Subcutaneous apomorphine Levodopa inhalation powder DIPHASIC DYSKINESIAS (beginning and end of dose) Higher, less frequent doses of levodopa

Abbreviations: COMT, catechol-O-methyltransferase; MAO, monoamine oxidase.

Some evidence suggests that nonphysiologic, pulsatile stimulation of dopamine receptors physiologically induces the development of motor fluctuations and dyskinesias. Other mechanisms may include changes in neurotransmitters, cellular signaling pathways, or dopamine receptor expression. Motor fluctuations can be controlled in the early stages by: • Strategies that enhance levodopa absorption in the brain (e.g. reschedule protein intake, low-protein diet [to avoid competition of neutral amino acids with L-dopa absorption and entry into the brain]). • Manipulation of the levodopa dose or use of the sustainedrelease formulations of levodopa. • Inhibiting levodopa catabolism (COMT or MAO-B inhibitors) and prolonging plasma half-life of levodopa. • Adding dopamine agonists to treatment regime. • Switching to enteral levodopa infusion (Duopa) or extended-release capsule (Rytary).

ld

thresho

Early disease

Mid-disease

Late disease

FIGURE 16.52  The therapeutic window of Parkinson’s disease narrows with progression of the disease, paralleling the progressively shorter striatal half-life of levodopa. In addition, peak-dose dyskinesias may develop, with threshold to the development of dyskinesias lowering over time. In advanced stages of the disease, fluctuations are difficult to treat and patients frequently cycle between ‘on’ periods complicated by dyskinesia and ‘off’ periods in which they are frozen and akinetic. Liquid levodopa or surgical approaches should be considered for such patients.

Dyskinesias

Dyskinesias are abnormal involuntary movements occurring as a complication of dopaminergic therapy. The cause is unclear, but may be related to: • Upregulation of dopamine receptors. • Postsynaptic changes associated with both PD and exposure to levodopa. • Influences of glutamatergic projections and other transmitter systems including serotonergic, alpha-2 adrenergic, histaminergic, and cannabinoid pathways. Dyskinesias tend to develop earlier and more severely in younger PD patients. They are usually choreiform (dance-like), and also may be dystonic (sustained and often painful muscle contractions) or myoclonic (sudden jerks) in character. While milder dyskinesias are typically not disabling, severe dyskinesias may be more disabling than the parkinsonism itself. Dyskinesias may be monophasic, occurring at the time of maximal clinical improvement (peak-dose dyskinesias), or biphasic, occurring at the time of disappearance and reappearance of parkinsonian symptoms (onset- and end-of-dose dyskinesias). Monophasic dyskinesias can be reduced by decreasing and spreading the daily doses of antiparkinsonian medication, but this may preclude a satisfactory antiparkinsonian response and lead to the emergence of motor fluctuations in the form of endof-dose akinesia and ‘on–off’ phenomena. Diphasic dyskinesias can be alleviated by increasing the daily dose of antiparkinsonian medication to maintain constant high plasma levels of medication (e.g. levodopa), but this may produce chaotic dyskinesias and severe psychiatric disorders. The only antidyskinetic agent with evidence-based efficacy is amantadine. Various agents such as anticholinergics,

Degenerative Diseases of the Nervous System benzodiazepines, serotonin antagonists (e.g. fluoxetine), betablockers, low-dose clozapine (50 mg) (a dibenzodiazepine derivative that blocks D1, D2, and D4 dopamine receptors), levetiracetam, and riluzole (an inhibitor of glutamatergic transmission in the CNS) have been tried for antidyskinetic effects but are not commonly used or recommended in clinical practice. Surgical treatment of PD with advanced motor fluctuations may allow reductions in dyskinesias by allowing reduction in required medication doses and by modulating the abnormal circuitry predisposing to dyskinesias.

Nonmotor symptoms

Neuropsychiatric symptoms16  These include confusion, hallucinations, delusions, and psychosis. They are more frequent in older patients and more common with longer disease duration. Hallucinations may occur in up to one-third of patients on chronic dopaminergic treatment, usually comprising visual images of people or animals. Neuropsychiatric symptoms may be induced by all antiparkinsonian drugs, but more commonly with anticholinergics or dopamine agonists. In patients with dementia, it may be difficult to control parkinsonism without adversely affecting mental function. Symptoms can be minimized or treated by: • Eliminating unnecessary psychoactive or sedative medications. • Ruling out other medical and neurologic causes of altered mental status (i.e. infections, strokes, mass lesions, medications). • Withdrawing anticholinergics, dopamine agonists, amantadine, and MAO-B inhibitors as tolerated, restricting antiparkinsonian therapy to levodopa monotherapy. • Using the lowest dose of antiparkinsonian medication that will provide a satisfactory motor response. While many antipsychotics are labeled as atypical, only two have more consistently been demonstrated not to worsen parkinsonism significantly: • Clozapine: given in smaller doses than needed for psychosis (starting at 12.5 mg daily and seldom increasing above 100 mg daily), may help to control the psychotic features and permit higher doses of levodopa–carbidopa to be used. Disadvantages are that weekly blood counts are required because of the risk of agranulocytosis, and it also causes sedation, hypotension, or rarely myocarditis. • Quetiapine: while appearing clinically efficacious, three randomized, controlled trials do not support its efficacy over placebo. Regardless, it is commonly used as first-line therapy in low doses (12.5–150 mg daily), preferably at night as it may also cause sedation and therefore improve any coexistent insomnia. Note that long-term use of atypical antipsychotics in elderly patients are associated with sudden risk of cardiac death. • Pimavanserin: selective serotonin 5-HT2A inverse agonist is approved for treatment of PD psychosis (34 mg daily, or 10 mg daily if taking CYP3A4 inhibitor). It was efficacious in treating psychosis over a 6-week study period. Side effect includes QT prolongation, edema, and fatigue. • Acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) were developed as symptomatic treatment of cognition and behavior in mild to moderate

575 dementia of Alzheimer’s type, but have been extended to use in PD dementia. They inhibit acetylcholinesterase and thus decrease acetylcholine breakdown in the synaptic cleft. All have broadly similar efficacy, although only rivastigmine has been demonstrated to show improvement in a randomized, controlled trial. • Memantine: Two randomized, double-blind trials suggest that memantine (an NMDA receptor antagonist) may lead to global improvement of cognitive function or at least in some cognitive subdomains, such as speed on attention tasks. Nonpharmacologic therapies (e.g. transcranial magnetic stimulation, cognitive rehabilitation) are under investigation. Mood disorders: PD patients may have coexisting depression (20– 40% prevalence) and anxiety (5–40% prevalence). These may be an inherent component of parkinsonism (given degeneration of noradrenergic, serotonergic, and cholinergic nuclei and disruption of neocortical, limbic, and frontal pathways) or a reaction to having a chronic progressive neurodegenerative disorder. In depression, treatment for PD should be the first consideration and may itself improve the depression. Tricyclic antidepressants (amitriptyline, nortriptyline, and imipramine) have anticholinergic properties that may improve PD features in the early stages but may aggravate mental function in patients with more advanced disease. SSRIs (fluoxetine, paroxetine, citalopram, or sertraline) are probably preferable. While earlier reports suggest that this class of drugs may worsen parkinsonism, they do not appear to do so on average, and may even improve symptoms. Other non-SSRI agents used in practice but not studied specifically in PD include venlafaxine, mirtazapine, duloxetine, and bupropion. Class IV studies suggest that ECT may be effective. In anxiety, there are no clinical trials to support PD-specific therapies. Nonpharmacologic therapies include psychotherapy, relaxation therapy, and biofeedback, while pharmacologic therapies include benzodiazepines, SSRIs, buspirone, and adjusting PD medication if symptoms are ‘off’ related. Cognitive behavioral therapy may be useful for both depression and anxiety. Impulse control disorders: Prevention, education, and screening for abnormal behaviors by physician and families are important. Behaviors usually resolve/improve with dopamine agonist dose reduction or discontinuing agonist treatment entirely, with increase in levodopa to counter any motor decline. Dysautonomia  • Nausea: may be a side effect of dopaminergic medications: • Start treatment slowly with low doses of levodopa/ dopamine agonists, i.e. one-half of a tablet of the smallest dose, and increase by one-half of a tablet every third day. Initial tolerance may be poor, but may improve with slow titration. • Take the medication 30 minutes after food. • If nausea persists, options include: – Supplemental carbidopa 25-mg tablets with each dose. – Administering the peripherally acting antiemetic drug domperidone 10 mg, taken 30 minutes before each dose of antiparkinsonian medication (i.e. with food, followed by antiparkinsonian drug 30 minutes later). – Avoid other dopamine receptor–blocking antiemetics such as metoclopramide and prochlorperazine, which may worsen parkinsonism.

Hankey’s Clinical Neurology

576 • Constipation: standard measures such as dietary modifications with high fiber, increase fluid intake, laxative medications (Colace, senna, bisacodyl, magnesium sulfate, polyethylene glycol), suppositories, enemas. • Sialorrhea: anticholinergic drugs, botulinum toxin. • Urinary dysfunction: • Urodynamic testing, urologic evaluation. • Standard agents for neurogenic bladder dysfunction (no validation in PD population), such as the anticholinergics oxybutynin and tolterodine; cholinergic side effects are possible (orthostatic hypotension, cognitive dysfunction, urinary retention). • Muscarinic agonists (bethanechol). • Intermittent self-catheterization or indwelling catheter. • Pelvic floor physical therapy. • Botulinum toxin. • Orthostatic hypotension: • Minimize dose of non-levodopa antiparkinsonian drugs (particularly dopamine agonists, selegiline). • Take antiparkinsonian drugs after meals. • Increase fluid consumption. • Adequate salt intake. • Elastic support/compression stockings (typically poorly tolerated). • Small frequent meals to minimize postprandial hypotension. • Head-up tilt of the bed at night. • Conditioning exercises. • Medications: – Volume expanders: fludrocortisone. – Vasoconstrictors: midodrine (peripherally acting alpha-1 agonist); droxidopa (norepinephrine prodrug) may also be associated with reduced falls. – Other: caffeine, pseudoephedrine, indomethacin, domperidone, desmopressin (DDAVP), subcutaneous octreotide (inhibits release of vasodilator peptides). • Hyperhydrosis: adjustment of PD medications, propranolol. Sleep disorders  • Obstructive sleep apnea (OSA): detection by sleep study, positive-pressure ventilation, weight loss. • REM behavioral disorder: clonazepam, melatonin. • Excessive daytime sleepiness: eliminate sedating medications, minimize dopaminergic medications, identify and treat underling sleep disorders, consider stimulants such as modafinil, methylphenidate, or caffeine (no clear evidence, may worsen tremor or neuropsychiatric symptoms). Impotence  • Impotence may be treated with sildenafil, tadalafil, yohimbine, intracavernosal injections of papaverine, prostaglandin E, or implantation of a penile prosthesis.

TIP • Both motor and nonmotor side effects can occur at any point during treatment with antiparkinsonian medications, and should be screened for regularly during followup visits.

Surgical therapies

Surgical treatments for PD are now standard treatment options after the development of models of basal ganglia circuitry, refinements of stereotactic surgery (due to better stereotactic frames, imaging by high-resolution brain CT and MRI, and intraoperative electrophysiologic microelectrode assessment), and continued long-term evidence of overall safe and effective outcomes with positive impact on quality of life in select patients. The main surgical targets are the internal (medial or posteroventral) globus pallidus and the subthalamic nucleus. The most common surgical strategy is reversible, unilateral or bilateral, high-frequency deep brain stimulation (DBS) via stimulating electrodes, while lesional surgery has become less favorable due to its irreversible effects, usual limitation to a unilateral procedure, and higher incidence of side effects.

Deep brain stimulation17

High-frequency DBS (about 150 cycles per second) functionally inhibits neuronal activity in specific brain targets without the need to make a lesion. By connecting an implanted stimulating electrode to a subcutaneous pacemaker, target sites can be continuously stimulated by adjustable parameters. Proper patient selection is critical, with the ideal patient showing the following characteristics: • Diagnosis of idiopathic PD. • Significant clinical improvement or motor symptoms with levodopa therapy. • Presence of motor fluctuations and dyskinesia that are not fully managed by medications; or, medication refractory tremor. • Absence of significant dementia, psychosis, or depression. • Age under 75 and general good medical health, although select healthy older patients may benefit. • Appropriate understanding of risks and outcomes of surgery. • Supportive caregivers and family. Chronic bilateral stimulation of the subthalamic nucleus may dramatically improve all cardinal features of PD, reduce medication requirements, with generally controllable adverse effects such as ballism. DBL was first used in PD patients in 1993, and is currently the preferred surgical treatment for PD. Mechanism of action is unclear and likely complex, but stimulation appears to mimic the effects of an ablative lesion. Studies show significant postoperative reduction of off-state UPRDRS scores (by ∼50%) and dyskinesias (by ∼69%), and reduction of antiparkinsonian medications (by ∼56%). Quality of life is improved in comparison to medical management alone. Speech, gait, and cognitive symptoms may be less improved than other cardinal features, and in some cases can worsen postoperatively. Stimulation of the GPi may also improve the cardinal features of PD, and is effective for treating severe dyskinesias. Stimulation of ventralis intermediate nucleus of the thalamus may effectively and safely suppresses tremor in > 80% of patients, but has no effect on the other cardinal symptoms of PD. The advantages of DBS over thermolytic lesioning are that it is reversible and causes minimal or no damage to the brain. However, it requires two surgical procedures (one for targeting and another for definitive electrode internalization), the life of the battery is limited to a few years, and it does not combat continued progression of underlying disease.

Degenerative Diseases of the Nervous System Complications of DBS may include hardware or electroderelated difficulties, side effects of stimulation (dysarthria, visual symptoms, paresthesias, dyskinesias), cognitive deficits (particularly decreased word fluency), apathy, mood or psychiatric disorders (depression, mania), tissue infection, weight gain, or stroke. Newer DBS targets include the pedunculopontine nucleus, median parafascicular complex of the thalamus, or caudal zona incerta. With regard to timing of DBS, traditionally it was delayed until late stages of the disease, e.g. 14–15 years after diagnosis, when motor fluctuations were severe. One study showed that bilateral STN DBS within 3 years of onset of motor fluctuations (with average disease duration 7.5 years among subjects) lead to improved quality of life compared to medical management during 2-year follow-up.18 However, decision to pursue ‘early’ DBS should be considered with caution since medical management can often suffice in many cases without carrying risks associated with the surgery. Additionally, there is limited knowledge on patient progression and long-term outcomes of early DBS patients.19

Lesional surgery

• Pallidotomy: • Lesions in the posteroventral portion of the GPi presumably reduce the inhibitory output from the medial globus pallidus and thereby improve many of the ‘off’ period symptoms of PD (tremor, rigidity, and bradykinesia on the side contralateral to the surgery and some elements of gait). Lesions may also reduce levodopainduced dyskinesias by up to 75%. • However, they do not improve the patient’s level of function when ‘on’ except for elimination of peak-dose levodopa-induced dyskinesias. Midline symptoms, such as postural instability and abnormal gait, also improve less. Any improvements are immediate and sustained for at least 6 months. • Complications include homonymous hemianopia (up to 14%), facial paresis (up to 51%), and hemiparesis (up to 4%). • Subthalamotomy: lesions may improve motor signs but at present carry an unacceptable risk of inducing hemiballismus or causing midbrain hemorrhage due to its high vascularity. • Thalamotomy: • Effective predominantly for medically intractable tremor. • A thermally induced lesion of the ventrointermediate nucleus of the thalamus improves contralateral tremor in about 90% of patients. • Recurrence of tremor occurs in about 5–10% of cases, usually within the first 3 months. • Lesioning the ventralis oralis anterior/posterior (rostral to the ventrointermediate nucleus) may improve rigidity of the contralateral limbs. • Risks of this procedure are intracerebral hemorrhage and lesioning of structures adjacent to the target site. Mortality varies from 0.4% to 6%. • Unilateral MRI-guided focused ultrasound thalamotomy is a recently emerging treatment. While more established for treatment of essential tremor, this technique is under investigation for use in Parkinson’s disease, with potential targets including thalamus and subthalamic nucleus. This would have an advantage of being less surgically invasive compared to DBS, however, as a lesionbased technique, it would be irreversible, and currently, it is only approved for unilateral treatment.20

577 Dopaminergic transplantation strategies

While strategies based on the notion that dopaminergic cells transplanted to the striatum may compensate for degenerating nigral neurons have been pursued, none has yet been demonstrated as effective in double-blind trials. Transplantation of fetal porcine nigral cells, fetal nigral cells, and retinal pigmented epithelial cells has not demonstrated significant benefit over placebo, with some patients experiencing disabling forms of dyskinesias (‘off-medication dyskinesias’), some requiring treatment with DBS surgery, likely related to nonphysiologic dopaminergic stimulation. Additionally, autopsy examination of implanted dopamine neurons has been noted to contain Lewy bodies, suggesting that the PD pathologic process may overwhelm transplanted cells.21 Stem cell transplantation, growth factor infusion, and gene therapies are currently in investigational stages.

Prognosis

Symptoms progress slowly over several years. About one-half of patients experience significant complications of therapy after 5 years. Unless there is an intercurrent cause of death, patients may eventually succumb to secondary complications of the disease, with pneumonia as the most common. The average duration of the disease from diagnosis to death is about 15 years, with a wide range of deviation depending on individual factors, with a mortality ratio of 2:1. The longest prospective study in PD (Sydney Multicenter study)22 showed: • Nonmotor features predominate after 15 years of disease in the one-third of surviving cohort: cognitive decline (83%), falls (81%), daytime sleepiness (79%), depression (50%), incontinence (41%) in survivors after 20 years. • Mean duration from diagnosis to death was 9.1 years. • Prognostic factors include: • Gait disturbance or postural instability at presentation (PIGD phenotype) are associated with more severe disease including faster rate of progression and higher incidence of dementia. • Tremor-dominant parkinsonism tends to have a more favorable course with slower progression. • Onset of PD after the age of 60 years is associated with a greater likelihood of developing dementia, while younger patients have a greater risk of developing adverse effects associated with using levodopa long term (i.e. dyskinesias, motor fluctuations).

MULTISYSTEM DEGENERATIONS (‘PARKINSONISM PLUS’ OR ATYPICAL PARKINSONISM) MULTIPLE SYSTEM ATROPHY Definition and epidemiology

Multiple system atrophy (MSA) is a sporadic, adult-onset, progressive, neurodegenerative disease of unknown etiology, characterized by autonomic dysfunction combined with parkinsonism and/or ataxia. While clinically protean, different manifestations of the disease are unified by common cellular pathology featuring glial cytoplasmic inclusions.

Hankey’s Clinical Neurology

578 The term MSA was coined in 1969 by Graham and Oppenheimer. They reported a patient who developed autonomic failure followed by cerebellar and pyramidal signs, dying at age 62 years only 4 months after disease onset. Autopsy revealed cell loss and gliosis (without Lewy bodies) in the substantia nigra, striatum, olives, pons, cerebellum, and intermediolateral cell columns of the spinal cord. The term was proposed as shorthand to cover many cases described under different titles that overlapped with each other, including: • Sporadic olivopontocerebellar atrophy (OPCA): cerebellar signs, dysautonomia, later development of parkinsonism, pyramidal signs. • Shy–Drager syndrome (SDS), described in 1960 by Shy and Drager: progressive, primary orthostatic hypotension due to autonomic failure owing to loss of cells in the intermediolateral column of the spinal cord, and neurologic signs of extrapyramidal, pyramidal, and cerebellar dysfunction. Autopsy showed cell loss and gliosis in the striatum, substantia nigra, cerebellum, pons, olives, and intermediolateral cell columns. • Striatonigral degeneration (SND), described in 1964 by Adams et al.: with parkinsonism, brisk reflexes, autonomic failure, late cerebellar signs. Autopsy showed evidence of striatal neuronal loss, demyelination, and gliosis, principally in the putamen and substantia nigra, and also in the olives and the cerebellum (and the pons in one case). Incidental nigral Lewy bodies were found in one patient. MSA is now considered a well-defined clinicopathologic entity with protean manifestations, rather than three different diseases with several clinical features in common. • Prevalence: 1.9–4.9 per 100,000. • Age: mean age of onset: 60 years (range 34–83 years). • A predominantly parkinsonian phenotype (MSA-P) accounts for 80% of patients in Western countries, although Japanese series report a higher cerebellar phenotype (MSA-C) predominance. • Gender: M = F. • Risk factors: unclear. Rare familial cases have been reported, although spinocerebellar ataxia may present with MSA-like features and may be hard to differentiate. Variants in the alpha-synuclein gene (SNCA) appear to convey risk of developing MSA, particularly the MSA-C subtype.

Plus one of the following: • Predominantly cerebellar signs: dysarthria, gait ataxia, oculomotor dysfunction (termed MSA-C). • Predominantly parkinsonism, with poor, mild, or transient response to levodopa therapy (termed MSA-P). The following signs may be present and are considered ‘red flags’ of supportive features for the diagnosis of MSA: • Pyramidal signs: brisk reflexes, Babinski’s sign, spastic quadriparesis (about 50% of patients). • Stridor, inspiratory sighs, dysphonia, new or increased snoring. • Rapidly progressive parkinsonism. • Dysphagia within 5 years of motor onset. • Orofacial dystonia.26 • Disproportionate antecollis (Figure 16.53). • Camptocormia (severe anterior spine flexion) and/or Pisa syndrome (severe lateral spine flexion). • Contractures of hands/feet. • Pathologic laughter or crying (pseudobulbar affect). • Myoclonic, jerky action, and postural tremor. • The following features are not supportive of MSA and may suggest an alternative diagnosis: • Classic pill-rolling rest tremor (more common with PD). • Clinically significant neuropathy. • Family history of ataxia or parkinsonism (as MSA is sporadic). • Dementia or hallucinations not induced by drugs. • White matter lesions on brain MRI. • Onset after age 75.

Differential diagnosis Parkinsonism

• Idiopathic PD: • Most MSA patients are initially diagnosed as having idiopathic PD, and one-third retain this erroneous diagnosis until they die.

Etiology and pathophysiology

Complex and not well understood. It is thought to be a sporadic disease, likely involving complex interactions between genetic predisposition and environmental factors.

Clinical features23

Clinical diagnosis has been revised in 2008 by a group of experts via a consensus conference.24 Any combination of symptoms and signs of documented autonomic dysfunction, which, like PD, may predate the motor features:25 • Orthostatic hypotension. • Impotence. • Urinary incontinence.

FIGURE 16.53  A patient with multiple system atrophy–parkinsonism displaying early presentation of severe, disproportionate antecollis before the insidious development of dysautonomia and parkinsonism. Dystonic symptoms were helped mildly by botulinum toxin injections, but total dose and therapeutic effect were limited by risk of dysphagia related to anterior neck injections.

Degenerative Diseases of the Nervous System • A small subset of PD patients may present with earlier dysautonomia, making the early distinction between the two diseases difficult. • Between 4% and 22% (mean 8%) of brains in parkinsonian brain banks are found to have MSA. • Unlike MSA, idiopathic PD will not give rise to pyramidal or cerebellar signs. • PD and MSA may be distinguished by nuclear imaging tests: – 123I-MIBG cardiac scans: MSA involves preganglionic/central sympathetic degeneration (showing normal or only mildly reduced MIBG uptake), as opposed to the loss of integrity of postganglionic noradrenergic neurons in PD (showing reduced MIBG uptake). – PET scans show more widespread hypometabolism, including the putamen, brainstem, and cerebellum in MSA compared to PD. • DLB can also cause parkinsonism with autonomic failure, but not pyramidal or cerebellar signs. • PSP: autonomic features are rare, although urinary incontinence may develop with pathologic involvement of the spinal cord. • CBD: autonomic features are rare, more asymmetric, signs of cortical involvement in addition to extrapyramidal features. • Other heredodegenerative or secondary parkinsonism disorders (see later sections): manganese intoxication symptoms and imaging may overlap with MSA.

Autonomic failure

• Primary: pure autonomic failure (PAF) (isolated) is a syndrome that has several causes. It may be due to the rare dopamine-beta-hydroxylase deficiency or may persist in isolated form and be revealed at autopsy to be related to the pathology of DLBD or MSA. So, with the passage of time, an initial syndrome of pure autonomic failure may mature into clinical idiopathic PD, DLBD, or MSA. Helpful distinguishing tests are plasma norepinephrine concentrations in the supine resting position (normal in MSA, low in PAF), and plasma arginine vasopressin in upright tilt (very little increase in patients with MSA for the degree of hypotension, marked rise in patients with PAF for the same degree of hypotension). • Secondary: • Addison’s disease. • Amyloidosis. • Diabetes. • Drugs.

579 • NPH. • Cervical spondylitic myelopathy. • Amyotrophic lateral sclerosis.

Investigations CT brain scan

CT is used to exclude some of the differential diagnoses and to identify atrophy of the cerebellum and brainstem, particularly the pons, inferior olives, vermis, and cerebellar peduncles; however, MRI has a much higher resolution for these structures.

MRI brain

Several MRI findings may be detected in MSA, with varying degrees of sensitivity and specificity, including putaminal atrophy or hypointensity, a hyperintense rim bordering the putamen, or focal atrophy of the brain, particularly the pons, inferior olives, vermis, dentate nuclei, and cerebellar peduncles.27 The ‘hot cross bun’ sign (Figure 16.54) in the pontine basis accompanies this atrophy and is a sign of selective loss of transverse pontocerebellar fibers and neurons in the pontine raphe, with sparing of the pontine tegmentum and corticospinal tracts. • Abnormally low signal intensity may be noted in the putamen compared with the globus pallidus on T2-weighted images due to the excess iron deposition. • Linear signal changes along the outer/lateral margin of the dorsolateral putamen, manifesting as slit-like hyperintensities (on T2-weighted and proton density sequences and hypodensities on T1-weighted sequences): a useful MRI feature to help differentiate between PD and MSA predominantly affecting the extrapyramidal system. • Regional apparent diffusion coefficient (rADC) in the middle cerebellar peduncle and rostral pons may be a sensitive and specific sign in MSA.

Cerebellar ataxia

• Inherited spinocerebellar ataxia (SCA). • Multiple sclerosis. • Posterior fossa/diencephalic arteriovenous malformation/ tumor. • Drug toxicity. • Fragile X-associated tremor ataxia syndrome (FXTAS).

Pyramidal signs

• Parasagittal meningioma. • Multi-infarct state.

FIGURE 16.54  Axial T2-weighted image from a patient with multiple system atrophy of the cerebellar type (MSA-C), demonstrating the ‘hot cross bun’ sign (arrow).

Hankey’s Clinical Neurology

580 PET •

F-fluorodeoxyglucose PET: decreased glucose metabolism is found in cerebellum, thalamus, putamen, and cortex (i.e. forebrain glucose metabolic defects as well as cerebellar). • 11C-diprenorphine: decreased putamenal uptake. • 18F-fluorodopa: decreased putamenal uptake (as in all parkinsonian syndromes). 18

Transcranial ultrasonography

• Hyperechogenicity of the lentiform nucleus combined with normal echogenicity of the substantia nigra can differentiate MSA-P from PD.

Cardiovascular autonomic function tests

• Plasma norepinephrine concentrations are normal, and there is lack of vasopressin rise during head-up tilt, differentiating MSA from pure autonomic failure. • 123I MIBG cardiac scintigraphy could be helpful to differentiate PD from MSA, demonstrating that there is a myocardial postganglionic sympathetic dysfunction in PD with autonomic failure but not in MSA, which causes presynaptic dysfunction. • Tilt table test shows orthostatic hypotension with blunted heart rate increase on tilting, and decreased heart rate variability

Gastrointestinal testing

• Sphincter electromyogram: at least 80% of MSA patients may have signs of neuronal degeneration in Onuf’s nucleus with spontaneous activity and increased polyphasia. Anal sphincter EMG test may help to distinguish MSA from early PD, pure autonomic failure, or cerebellar ataxias, in the absence of other causes for sphincter denervation. • Videofluoroscopic swallow test: silent aspiration. • Colonic transit time measurement and rectal manometry: loss of anal-sphincter relaxation, decreased anal tone.

Urologic testing

• Vesicle detrusor overactivity, absence of detrusor–sphincter coordination, and bladder atony. • Large postvoid residual urine volumes (> 100 mL).

in blood pressure within three minutes of standing by at least 30 mmHg systolic or 15 mmHg diastolic and either poorly levodopa-responsive parkinsonism, or a cerebellar syndrome. • Possible MSA: at least one feature suggesting autonomic dysfunction (urinary urgency, erectile dysfunction, frequent or incomplete bladder emptying, orthostatic blood pressure drop that does not meet the probable criteria) and either poorly levodoparesponsive parkinsonism, or a cerebellar syndrome.

Pathology28

Cell loss and gliosis of varying degrees and proportions occur without Lewy bodies (unless incidental), in the striatum (particularly the putamen), substantia nigra, locus ceruleus, inferior olives, pontine nuclei, cerebellar Purkinje’s cells, intermediolateral cell columns, and Onuf ’s nucleus of the spinal cord; other, more widespread, pathologic changes may also be present. Five cellular features are present: • Glial cytoplasmic inclusions (GCIs) containing alphasynuclein filaments in oligodendroglia: the most characteristic cellular pathology (Figure 16.55).29 • Widely distributed, more common in white matter than gray matter, more common in motor fibers than sensory fibers, and may be flame- or sickle-shaped. • Ultrastructurally, they are randomly arranged tubules or filaments, of diameter 20–40 nm, and associated with granular material. • They are present in the brains of all cases of MSA (i.e. 100% sensitivity) but not all brains containing GCIs are from patients with MSA (i.e. < 100% specificity). • They are also found in CBD, PSP, SCA1, and chromosome 17–linked dementia. • Neuronal cytoplasmic inclusions. • Neuronal nuclear inclusions.

Respiratory testing

• Sleep laryngoscopy: nocturnal stridor, subclinical paralysis of vocal cord abductors. • Polysomnography: sleep apnea.

Thermoregulatory testing

• Sweat test: failure of whole-body sweating, differentiating MSA-P from PD. • Quantitative sudomotor axon reflex test: normal findings, differentiating MSA-P (abnormal) from PD.

Diagnosis

According to the second consensus statement on the diagnosis of MSA, the following categories of diagnostic certainty have been outlined: • Definite MSA: pathologically confirmed on autopsy. • Probable MSA: autonomic failure: urinary incontinence with erectile dysfunction in males, or orthostatic decrease

FIGURE 16.55  Alpha-synuclein immunostaining reveals glial cytoplasmic inclusions in subcortical white matter, often seen in MSA (hyperpigmented inclusions staining positive for alphasynuclein). (Jensflorian/Wikimedia Commons.)

Degenerative Diseases of the Nervous System • Glial nuclear inclusions. • Neuropil threads.

Treatment23

• Parkinsonism: dopaminergic agents: similar strategies to PD with the following caveats: • The response to levodopa is usually transient, poor, waning, or absent, due to striatal pathology; however, efficacy has been documented in up to 40% for up to a few years of therapy. Up to 1000 mg of levodopa daily may be tried if necessary and tolerated. In contrast, in idiopathic PD, the substantia nigra degenerates, but the striatum is normal, which is the reason that dopamine replacement therapy is so effective. The minimal responsiveness (or lack of) to levodopa is therefore a clinical clue to the diagnosis of MSA. • Levodopa may induce dyskinesias (predominantly dystonic) of the head and neck in 50% of MSA-P patients. • Dopamine agonists or other agents such as MAO inhibitors and amantadine are second- and third-line therapies due to side effect profiles and decreased efficacy. • Dysautonomia: similar to PD, as features of dysautonomia are otherwise indistinguishable between the two diseases. Briefly:30 • Neurogenic bladder: antimuscarinics for overactive bladder, botulinum toxin injections in detrusor muscle, desmopressin for nocturia, intermittent self-catheterization for urinary retention, pharmacologic therapies for urinary retention (cholinergics, alpha-1 antagonists). • Sildenafil for erectile dysfunction in men, though this may worsen hypotension. • Orthostatic hypotension: increase water and salt intake, raising head of bed during sleep, compression stockings/abdominal binders. Medications include midodrine, droxidopa, fludrocortisone. Exacerbation of supine hypertension is a frequent side effect. • Ataxia: no known effective treatments, some trials suggest possible benefit from riluzole and varenicline, but these drugs are difficult to obtain and require monitoring. • Palliative therapies: • Continuous positive airway pressure (CPAP) for prominent stridor; tracheostomy rarely needed and may fatally exacerbate sleep-disordered breathing. 31 • Botulinum toxin for drooling, dystonia, or contractures. • Percutaneous endoscopic gastrostomy (PEG) for severe dysphagia. • Physical, occupational, and speech therapies.

Prognosis

MSA has a more aggressive course than idiopathic PD, and in most cases significantly shortens life, with median survival about 6–9 years (range 0.5–15 years). 32 Poor prognostic factors include: • Older age of onset. • Female sex. • Early-onset autonomic failure or respiratory symptoms (stridor, respiratory insufficiency). • Earlier development of disability milestones (falls, dysphagia, dysarthria, and so on).

581 DEMENTIA WITH LEWY BODIES Definition and epidemiology

A dementia and motor syndrome associated with the widespread presence of Lewy bodies, characterized clinically by fluctuating visual hallucinations and delusions, parkinsonism (muscle rigidity and bradykinesia), progressive dementia, and a poor tolerance of neuroleptic drugs. Please see the Dementia section of this chapter for the full summary of DLB.

PROGRESSIVE SUPRANUCLEAR PALSY Definition and epidemiology33

PSP is a multisystem neurodegenerative disease of the basal ganglia and brainstem, originally known as the Steele–Richardson– Olszewski syndrome, which presents with a disturbance of balance, impaired downward gaze, subcortical FLD, and levodopa-unresponsive parkinsonism, first described in 1963 by Steele and colleagues. Patients suffer from progressive dysphagia and dysarthria. Death typically occurs from complications of immobility, aspiration, or falls. • • • •

Second most common form of parkinsonism after PD. Estimated prevalence: 6.4 per 100,000. Age of onset: 40–60 years of age, mean onset 60–65. Gender: M = F.

Etiology and pathophysiology

Complex and poorly understood, PSP is considered a sporadic disorder, but a few cases show autosomal dominant inheritance, and recent studies suggest some genetic influences. A genetically determined alteration in the microtubule-binding protein т (tau) may be a risk factor for neuronal degeneration (MAPT H1 haplotype), and may account for an increase in 4-repeat tau, which is found in both PSP and CBD as the predominant component of tau inclusions.

Clinical features34

Typical findings include: • Insidious onset of a progressive, symmetric (but may be asymmetric) parkinsonian syndrome, unresponsive to levodopa, characterized by: • Staring, nonblinking, wide-eyed (lid retracted) facies, described as worried or surprised, with suggestion of the term ‘procerus sign’ to describe the often-seen characteristic forehead wrinkling. • Axial (neck and trunk) dystonia and rigidity and symmetric bradykinesia. • Retrocollis or dystonic arm. • Unsteady gait (wide-based, shuffling, the patient moves ‘en bloc’). • Postural instability. • Sudden falls. • Supranuclear ophthalmoparesis, initially involving vertical (particularly downgaze) and subsequently horizontal eye movements. The disproportionate hypometria of vertical compared with horizontal saccades produces a curved course of oblique saccades. In some patients in whom full vertical excursions are present, vertical saccades can only be accomplished by moving the eyes in a lateral arc instead of strictly vertically, in the midline. The slowing of vertical saccades probably reflects impaired function of burst

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• • • • • • • • • • •

neurons in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). As a consequence of the downgaze paresis, patients have difficulty reading and walking downstairs. Mild subcortical dementia, characterized by slowness of central processing time. Pseudobulbar palsy. Dysarthria (spastic: voice has a strained, harsh quality). Dysphagia. Spasticity of lower and (less so) upper limbs, with hyperreflexia and extensor plantar responses. Bladder and bowel dysfunction in end-stage disease. Frontal lobe signs (bradyphrenia, perseveration, primitive reflexes: forced grasping, pout and palmomental reflex; imitation and utilization behavior). Stuttering speech, torticollis, and blepharospasm may occur. Segmental dystonia or myoclonus may occur. Nocturnal disturbances: prolonged latency of sleep onset, prolonged wakefulness, frequent early morning awakenings, and reduced total sleep time. No family history.

Atypical findings that do not exclude the diagnosis, but are less common, include: • • • • • • • •

Appendicular (limb) more than axial rigidity. Narrow-based gait. Mild rest tremor. Upper limb apraxia. Upper limb ataxia. Myoclonus. Chorea. Respiratory disturbance.

Absence of: • Unilateral presentation or pronounced asymmetry. • Early and prominent dysautonomia, particularly postural hypotension. • Prominent polyneuropathy. • Pronounced rest tremor. • Discriminative (‘cortical’) sensory loss. • Alien limb sign.

Atypical presentations of PSP

• PSP-parkinsonism (PSP-P): recent clinicopathological studies indicate that as many as 32% of patients with a retrospective pathologic diagnosis of PSP may have not shown the typical features of the classically described syndrome during life, instead mimic a more aggressive form of Parkinson’s disease, including features of asymmetric onset, tremor, and a moderate initial response to levodopa. This clinical manifestation of PSP has been termed ‘PSP-P’ (as opposed to the originally described ‘Richardson’s syndrome’). The PSP-P phenotype has a slightly more benign clinical course and may have a different pattern of tau isoform deposition.35 • Pure akinesia with gait freezing (PAGF): • Longer disease duration. • Highly predictive of PSP pathology. • Features of gait disturbance (freezing, start hesitation) and freezing of writing and speech, with late, if any, dementia or eye movement abnormalities and no evidence of significant cerebrovascular disease.

Differential diagnosis

This is broad, given the more detailed clinicopathologic reports of patients with PSP pathology (Figure 16.56).

Postencephalitic parkinsonism pathology Parkinson dementia complex of Guam pathology

Progressive supranuclear palsy– parkinsonism Pure akinesia with gait freezing

Progressive non-fluent aphasia Corticobasal degeneration pathology

Corticobasal syndrome

Richardson’s syndrome Progressive supranuclear palsy pathology

bvFTD FTDP-17 pathology PiD pathology

Predominant pathological distribution Cortical

Brainstem

FIGURE 16.56  Distribution of tau pathology in clinical and pathological nosological syndromes of progressive supranuclear palsy. Dashed boxes, clinical syndromes; solid boxes, pathologically defined diseases; PiD, Pick’s disease; FTDP-17, frontotemporal dementia with parkinsonism-17; bvFTD, behavioral variant of frontotemporal dementia. (Adapted from Williams 2009, with permission.)

Degenerative Diseases of the Nervous System Supranuclear vertical gaze paresis36

• Normal aging (typically affects upgaze more prominently). • Idiopathic PD, distinguished from PSP by: • More commonly asymmetric onset. • Less immobile facies without lid retraction. • Blink rate not so reduced until advanced disease. • Absence of supranuclear ophthalmoparesis, particularly downgaze. • Absence of early pronounced gait imbalance. • Absence of signs of pseudobulbar palsy (such as harsh, strained voice quality of spastic dysarthria) until late, if at all. • More appendicular than axial rigidity and bradykinesia. • Tremor is usually present; PSP tremor may occur in 5–10% of cases but is either absent, not pronounced, or of low amplitude. • Responsiveness to levodopa. • DLB. • Hydrocephalus. • FTD with parkinsonism linked to chromosome 17. • Prion diseases (CJD, familial progressive subcortical gliosis). • Infectious disease: Whipple’s disease, brucellosis, neurosyphilis: • Whipple’s disease:37 multisystem disorder caused by infection with Tropheryma whippeli, typically associated with weight loss, diarrhea, fevers, polyarthritis, and lymphadenopathy, but rarely manifesting in the CNS alone. • Main neurologic signs: supranuclear ophthalmoplegia, dementia, parkinsonism, myoclonus; oculomasticatory myorhythmia is considered pathognomonic, but is rare. • Detected by CSF PCR for T. whippeli or tissue (bowel, brain) biopsy. • Rare treatable cause of a parkinsonian syndrome. • Niemann–Pick disease type C. • Cerebrovascular disease (‘vascular PSP’ or ‘multi-infarct PSP’). • Compressive midbrain syndromes (Parinaud’s syndrome), e.g. pinealoma, glioma. • CBD. • Multiple sclerosis. • Syndrome resembling PSP after surgical repair of ascending aorta dissection or aneurysm. • Paraneoplastic: cases associated with bronchial carcinoma and B-cell lymphoma.

Other akinetic-rigid syndromes with parkinsonian features • • • • • • • •

• •

Idiopathic PD. MSA. CBD. Pallidal, pallidoluysian, and pallidoluysonigral degenerations; dentato-rubro-pallido-luysian atrophy. Neurodegeneration with brain iron accumulation diseases (NBIA). HD. Wilson’s disease. Cerebrovascular disease: • Top of the basilar syndrome causing midbrain and diencephalic infarction. • Multiple infarcts in brainstem and basal ganglia. Prion diseases. Progressive subcortical gliosis.

583 Subcortical dementia • DLBD. • AD. • VaD.

Investigations

Cranial CT scan may show enlargement of the third ventricle and interpeduncular cistern due to atrophy of the midbrain; however, MRI is more sensitive imaging for brainstem pathology. CT is performed to exclude structural lesions, hydrocephalus, and multiinfarct states, which may produce clinical findings similar to PSP. MRI brain38 can show various signs of brainstem atrophy such as reduction in size of part of the substantia nigra (as in PD). Reduced diameter of the midbrain on sagittal imaging has been termed the ‘hummingbird sign’ (Figure 16.57). A high signal in the periaqueductal gray matter is present, and signal hypointensity within the putamen (as in other parkinsonian syndromes) is seen.

Diagnosis39

Diagnostic criteria were recently revised to improve sensitivity and specificity of diagnosis, particularly in early disease course, and to capture the various clinical subtypes of PSP including PSP-RS (Richardson’s syndrome), PSP-PGF (progressive gait freezing), PSP-P (predominant parkinsonism), PSP-F (predominant frontal presentation), and PSP-OM (predominant ocular motor dysfunction). Core clinical features are rated based on severity as follows: • Ocular motor dysfunction: • O1 = vertical supranuclear gaze palsy. • O2 = slow velocity of vertical saccades. • O3 = square wave jerks or ‘eyelid opening apraxia’. • Postural instability: • P1 = repeated unprovoked falls within 3 years. • P2 = tendency to fall on pull test within 3 years. • P3 = more than 2 steps backward on pull test within 3 years. • Akinesia: • A1 = progressive gait freezing within 3 years. • A2 = parkinsonism, akinetic rigid, predominantly axial, and levodopa resistant. • A3 = parkinsonism with tremor and/or asymmetric and/or levodopa responsive. • Cognitive dysfunction: • C1 = speech/language disorder i.e. nonfluent/agrammatic variant of primary progressive aphasia or progressive apraxia of speech. • C2 = frontal cognitive/behavioral presentation. • C3 = corticobasal syndrome. Supportive features: • • • • • •

CC1 = levodopa resistance. CC2 = hypokinetic, spastic dysarthria. CC3 = dysphagia. CC4 =Photophobia IF1 = predominant midbrain atrophy or hypometabolism. IF2 = postsynaptic striatal dopaminergic degeneration.

Based on these features, diagnostic certainty is obtained by combinations of clinical features and supportive clues: • Definite PSP: • Neuropathological diagnosis.

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• Predominant multisegment upper and lower motor neuron signs, suggestive of motor neuron disease. • Sudden-onset or step-wise rapid progression, in conjunction with laboratory or imaging findings, suggestive of vascular etiology, autoimmune encephalitis, metabolic encephalopathies, or prion disease. • History of encephalitis. • Prominent appendicular ataxia. • Identifiable cause of postural instability (e.g. sensory deficit, vestibular dysfunction). • Severe leukoencephalopathy on imaging. • Relevant structural abnormalities (e.g. NPH, brainstem or basal ganglia infarction, hypoxic–ischemic injury, tumor, or malformation).

Pathology40

Gross pathology includes:

FIGURE 16.57  A helpful radiographic sign for the diagnosis of progressive supranuclear palsy (PSP), best seen on midsagittal MRI images, is the ‘hummingbird’ sign. Here, the shape of the midbrain tegmentum represents the bird’s head, and the pons the bird’s body. Recognition of this sign should strongly raise suspicion for the diagnosis of PSP. • Probable PSP (highly specific, but not sensitive for PSP): • (O1 or O2) + (P1 or P2) = probable PSP-RS. • (O1 or O2) + A1 = probable PSP-PGF. • (O1 or O2) + (A2 or A3) = probable PSP-P. • (O1 or O2) + C2 = probable PSP-F. • Possible PSP (more sensitive, but less specific for PSP): • O1 = possible PSP-OM. • O2 + P3 = possible PSP-RS. • A1 = possible PSP-PFG. • (O1 or O2) + C3 = possible PSP-CBS. • Suggestive of PSP: • O2 or O3 = suggestive of PSP-OM. • P1 or P2 = suggestive of PSP with predominant postural instability. • O3 + (P2 or P3) = suggestive of PSP-RS. • (A2 or A3) + (O3, P1, P2, C1, C2, CC1, CC2, CC3, or CC4) = suggestive of PSP-P. • C1 = suggestive of PSP with predominant speech/language disorder. • C2 + (O3 or P3) = suggestive of PSP-F. • C3 = suggestive of PSP-CBS.

• Atrophy of frontal, parasagittal, or paracentral lobes. • Atrophy of the brainstem occurs causing dilation of the third ventricle and cerebral aqueduct, thinning of the midbrain tegmentum (midbrain diameter < 17 mm [< 0.7 in]), and dilation of the fourth ventricle (Figure 16.58). • Decreased pigment in the substantia nigra and locus ceruleus. Microscopic changes include: • Neurofibrillary pathology (the cellular hallmark of the disease), with globose and flame-shaped NFT deposition in the striatum, globus pallidus, basal nucleus, subthalamic nucleus, substantia nigra, oculomotor nuclei, raphe nuclei, locus ceruleus, pontine nucleus, tegmental gray matter, and inferior olive. Both PSP and the related tau-deposition disease have similar but distinct patterns of tau deposition (Figures 16.59–16.61).

Mandatory inclusion criteria: • Sporadic occurrence. • Age 40 or older at onset of first PSP-related symptoms. • Gradual progression. Mandatory exclusion criteria: • Predominant impairment of episodic memory, suggestive of AD. • Predominant autonomic failure, suggestive of MSA. • Predominant visual hallucinations or fluctuations in alertness, suggestive of dementia with Lewy bodies.

FIGURE 16.58  Gross pathology: axial section through the midbrain of a patient with progressive supranuclear palsy, showing midbrain atrophy with dilation of the cerebral aqueduct due to loss of neurons and gliosis in the periaqueductal gray matter, the superior colliculus, substantia nigra, subthalamic nucleus of Luys, red nucleus, and to some extent in the oculomotor nucleus.

Degenerative Diseases of the Nervous System

585 • Neuronal loss and gliosis in substantia nigra, periaqueductal gray matter, superior colliculus, subthalamic nucleus of Luys, red nucleus, pallidum, dentate nucleus, pretectal and vestibular nuclei, and to some extent in the oculomotor nucleus. • Surviving neurons in these areas contain NFTs. • The cerebral and cerebellar cortices are usually spared. • Sparse-to-many neuropil threads in basal ganglia, internal capsule, thalamic fasciculus. • Grumose degeneration of cerebellar dentate nucleus. • Pick’s body–like tau inclusions in dentate fascia. • Tufted astrocytes in glia, coiled bodies. Neuronal degeneration is associated with deposition of hyperphosphorylated tau protein as NFTs. Tau NFTs appear on light microscopy most commonly as globose tangles and on electron microscopy as straight filaments with a diameter of 15–18 nm.

Treatment

Treatment is symptomatic.

FIGURES 16.59–16.61  Tau immunohistochemistry in a patient with pathologically confirmed progressive supranuclear palsy (PSP) demonstrates (Figure 16.59) neuropil threads (black arrows) in the substantia nigra, midbrain, and medullary tegmentum, locus ceruleus, inferior olivary nuclei, thalamus, and subthalamic nucleus; glial fibrillary tangles (red arrows); (Figure 16.60) tufted astrocytes; (Figure 16.61) globose neurofibrillary tangles in the midbrain tegmentum. Similar tau pathology may be found in corticobasal degeneration (CBD) but with a different distribution in the brain, including more numerous neuropil threads in the cortex, cerebral white matter, internal capsule, striatum, thalamic fasciculus, cerebral peduncle, and pons; this different distribution, as well as other features such as numerous ballooned neurons (not pictured) pathologically differentiate PSP from CBD.

• Parkinsonism: • Dopaminergic drugs: – In order of effectiveness and lower risk–benefit ratio: levodopa, dopamine agonists (bromocriptine > pergolide > lisuride in older literature) may reduce the symptoms in some cases but a sustained response is rare. – Amantadine may cause temporary improvement in a small subset of patients. – Higher doses of levodopa may be needed for clinical response (up to 1 g daily). – Levodopa-induced dyskinesias are rare, but dystonia may occur (dysarthria, apraxia of eyelid closure). • Case reports of improvement in some patients with zolpidem, anticholinergics, idazoxan, tricyclic antidepressants, L-threo-3,4-dihydroxy-phenylserine (L-DOPS), methysergide. • Visual disturbances: • Artificial tears (for decreased blink rate). • Prisms, talking books. • Palliative therapies: • Speech and swallowing assessment and management (dietary changes, gastrostomy tube). • Physical and occupational therapy. • Patient and family support: lay associations, supportive psychotherapy. • Other: • Drooling: botulinum toxin, anticholinergics. • Depression/anxiety/emotional incontinence: antidepressants, anxiolytics, dextromethorphan/quinidine. • Dystonia (fisted hand, neck extension): botulinum toxin. • Apraxia of eyelid opening: botulinum toxin.

Prognosis

PSP has a progressive clinical course leading to immobility and anarthria. Pneumonia is the most common immediate cause of death. Average disease duration is 5.6 (range 2–17) years. Predictors of a shorter survival time include onset of falls during the first year, early dysphagia, and incontinence.

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TIP • PSP, CBD, and most forms of FTD dementia are related to deposition of tau protein in the brain and are therefore sometimes called ‘tauopathies’. The symptoms of these disorders have significant overlap, and they are often hard to differentiate from one another clinically.

CORTICOBASAL DEGENERATION Definition and epidemiology

CBD is a rare, sporadic, progressive extrapyramidal degenerative disease of unknown etiology, characterized by co-occurrence of cortical and basal ganglia signs and symptoms. CBD was first described in 1967 by Rebeiz. True prevalence rates are difficult to estimate given the continued refinement of the pathologic and clinical manifestations of the disease. It is probably less common than PSP.

Etiology and pathophysiology Complex and poorly characterized.

Clinical features41

Clinical presentation of CBD varies widely, making the disease one of the most misdiagnosed neurodegenerative disorders. Patients may present with either dementia or primarily motor features with relatively preserved intellect until late in the disease. Symptoms may include: • An asymmetric akinetic-rigid syndrome with dystonic posturing of the hand, with the wrist flexed and the thumb flexed across the palm (Figures 16.62, 16.63). This may spread to the ipsilateral foot followed by the contralateral limbs.42 The hand often becomes functionally useless due to a severe apraxia rather than to any weakness. • Tremor: attempted movement of an affected limb may evoke episodes of fine myoclonus in the forearm flexor muscles that can be misinterpreted as an action tremor. • Gait disorder/postural instability: with parkinsonian, apraxic, dystonic, or spastic features. • Choreoathetosis. • Focal stimulus-sensitive myoclonus and action tremor. • Cortical sensory loss. • Some overlap with PSP, including supranuclear gaze palsy. • Corticospinal tract signs: Babinski’s signs, spasticity. • Pseudobulbar palsy. • Cortical sensory loss, altered visuospatial function. • Behavioral manifestations: frontal lobe–type behavior and language disturbances. • Dysarthria is a relatively late sign.

Differential diagnosis43,44

Clinicopathologic correlations have demonstrated poor clinical diagnostic accuracy in CBD, with a positive predictive value of 33.3%. This poor diagnostic accuracy has led some authors to reserve CBD as a pathologic diagnosis, designating the clinic presentation of mixed cortical and basal ganglia signs as ‘corticobasal syndrome’ (CBS).45 Approximately 55% of CBS cases have CBD. Many other alternate pathologies can present with the same clinical features, including:46 • DLBD. • AD.

FIGURES 16.62, 16.63  Illustration of a painful, dystonic arm (Figure 16.62) and hand (Figure 16.63) in a patient with clinically diagnosed corticobasal syndrome. Note the deformities of the fingers, wrist flexion, and thumb flexion into the palm. Painful spasms were partially relieved by botulinum toxin therapy.

• • • •

PSP. Prion disease (CJD). FTD. Pick’s disease.

Conversely, CBD pathology may clinically mimic clinical presentation of other pathologies including: • PSP: significant clinical overlap between clinical features of PSP and CBD is recognized. • FTD. • Primary progressive aphasia. • Progressive speech and oral apraxia. • Posterior cortical atrophy (early and prominent visuospatial/visuoperceptive deficits). • AD. Other conditions that could cause CBS include: • • • • •

Paraneoplastic disorders. Intracerebral mass lesion. Multi-infarct state. Prion disease. Other heredodegenerative and secondary forms of parkinsonism (see later section).

Degenerative Diseases of the Nervous System Investigations

MRI may be normal or nonspecific, or may demonstrate asymmetric atrophy in posterior frontal and parietal regions contralateral to the most affected side (Figures 16.64, 16.65); atrophy of the cerebral peduncle; FLAIR sequences show hyperintensity in the subcortical white matter. PET/SPECT show focal/asymmetric hypoperfusion on functional imaging, maximal in the frontoparietal cortex.

Diagnosis

Definitive diagnosis is established at autopsy. Research criteria have been proposed for corticobasal degeneration based on its varying phenotypes and complex clinicopathologic correlations.47 Diagnostic criteria for probable sporadic CBD includes: • Insidious onset and progressive development over the course of at least 1 year. • Age of onset over 50 years. • Negative family history and negative genetic mutation affecting tau (e.g. MAPT). • Clinical phenotype: • Asymmetric presentation of two of (a) limb rigidity or akinesia, (b) limb dystonia, (c) limb myoclonus plus two of (d) orobuccal or limb apraxia, (e) cortical sensory deficit, (f) alien limb phenomena (more than simple levitation).

587 • OR one feature (a–f) above plus one of the following: – Frontal behavioral–spatial syndrome: two of (a) executive dysfunction, (b) behavioral or personality changes, (c) visuospatial deficit. – Nonfluent/agrammatic variant of primary progressive aphasia: effortful, agrammatic speech plus at least one of: (a) impaired grammar/sentence comprehension with relatively preserved single word comprehension, or (b) groping, disoriented speech production (apraxia of speech).

Pathology48

Gross pathology includes: • Lobar neocortical atrophy: asymmetric, paracentral, or frontoparietal, most severe in pre- and postcentral regions. • Mild atrophy of midbrain tegmentum and enlargement of aqueduct. Microscopic pathology shows: • Numerous, large pale (achromatic) ballooned neurons in the basal ganglia and the motor and premotor cortex (layers III, V, and VI). These are intensely neurofilament protein positive (NFP+). These are not specific for CBD, but are found less prominently in PSP, Pick’s disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and AD. • Neuropil threads: numerous and widespread threadlike processes in gray and white matter in the cortex, cerebral white matter, internal capsule, striatum, thalamic fasciculus, cerebral peduncle, and pons (Figures 16.59–16.61). • Globose NFTs in the substantia nigra, locus ceruleus, and raphe nuclei. • Pick’s body–like tau inclusions in the cortex (layers II and III). • Astrocytic plaques in focal atrophic cortices. • Coiled bodies in oligodendrocytes (tau-positive fibers coiled around nucleus). • Corticospinal tract degeneration. Molecular pathology is as for PSP.

Treatment49

Symptomatic therapy only, as there is no cure or neuroprotective agent. Given the wide variation in presentation, treatment is highly individualized. Severe and widespread pathology typically prohibits any consistently effective or prolonged response to a single treatment method. The following treatments may be considered based on predominant symptoms, with the caveat that pharmacologic therapy is largely ineffective in the management of the disease:

FIGURES 16.64, 16.65  Axial (Figure 16.64) and sagittal (Figure 16.65) images from patients with clinically diagnosed corticobasal syndrome, with T1-weighted MRI imaging of the brain showing asymmetric parietofrontal atrophy.

• Parkinsonism: • Dopaminergic agents; relative reported effectiveness in a review of pooled data: levodopa > amantadine > selegiline > dopamine agonists. • Anticholinergics. • Myoclonus/tremor: benzodiazepines (most notably clonazepam), anticonvulsants, propranolol. • Dystonia: botulinum toxin, anticholinergics, baclofen, benzodiazepines.

588 • Other: • Eyelid movement disorders: botulinum toxin. • Behavioral abnormalities: antidepressants, anxiolytics, neuroleptics. • Palliative therapies: physical, occupational, speech therapies. Apraxia usually compromises benefit.

Prognosis

Prognosis is poor, given the lack of effective treatments and diffuse nature of the disease. Mean survival of 7 years after symptom onset. Death is typically due to secondary complications of generalized immobility.

FRONTOTEMPORAL DEMENTIA Definition

Frontotemporal dementia is a term used to describe patients with one of three major clinical syndromes: frontal variant FTD (dementia of frontal type), semantic dementia (progressive fluent aphasia), and progressive nonfluent aphasia. FTD causes progressive focal atrophy of the frontal and/or temporal lobes, leading to behavioral and personality changes, cognitive impairment, and various motor symptoms including parkinsonism. Please see the Dementia section of this chapter for the full summary of FTD.

HEREDODEGENERATIVE AND SECONDARY PARKINSONISM Definition and epidemiology

Parkinsonism not related primarily to a multifocal neurodegenerative process or occurring as a variable, secondary or minor feature of another nervous system disease. It is associated with a diverse number of underlying metabolic, traumatic, vascular, pharmacologic, structural, neurodegenerative, autoimmune, or toxic causes. Epidemiology varies widely by subtype, but is generally not well characterized.

Etiology and pathophysiology

Any disease process affecting the nuclei of the basal ganglia and their cortical–subcortical connections may cause parkinsonism, with features determined by combination and degree of involvement of different neuroanatomical structures.

Hankey’s Clinical Neurology • NBIA:50 a heterogeneous group of genetic disorders characterized by brain iron accumulation and neuronal death. Subtypes may be recognized by pattern of iron deposition on T2* and fast spin echo MRI sequences: • PKAN: – Rare, sometimes familial, condition of progressive rigidity, bradykinesia, dystonia, dysarthria, and dementia in childhood, or occasionally adulthood. – Epileptic seizures, chorea, cerebellar ataxia, muscle atrophy, and retinitis pigmentosa may also occur. – Iron-containing pigment deposited in the substantia nigra and globus pallidus (‘eye of the tiger sign’) can be imaged by MRI (Figure 16.66). • Neuroferritinopathy: more prominent chorea and dystonia; MRI demonstrates more involvement of dentate nuclei, globus pallidus, and putamen, along with confluent areas of hyperintensity. • Aceruloplasminemia: occurs with ataxia, dystonia, and chorea, as well as retinal degeneration and diabetes mellitus; MRI demonstrates low intensity in the striatum, thalamus, and dentate nucleus. • Infantile neuroaxonal dystrophy. • Neuroacanthocytosis. • Familial progressive subcortical gliosis. • Hereditary hemochromatosis (controversial). • Dentato-rubral-pallido-luysian atrophy (DRPLA). • HD: particularly with early onset (Westphal’s variant), characterized by: • Onset in childhood and adolescence. • Usually associated with paternally inherited mutations with large numbers of trinucleotide repeats. • Rigidity develops in the trunk and proximal limb muscles and spreads to involve all muscle groups. • More parkinsonian features and minimal chorea. • Progressive dementia, mask-like facies, and bilateral increased reflexes and extensor plantar responses. • Seizures. • Death within a few years of onset. • Spinocerebellar ataxia (particularly types 2, 3, and 17).

Clinical features

In general, motor signs in secondary causes of parkinsonism more commonly have the following features: • • • •

Rare occurrence of rest tremor. More symmetric motor findings. Earlier postural instability with falls. Signs of other systemic diseases, other concomitant movement disorders, or other neurologic deficits out of the realm of typical idiopathic PD, as reviewed below in the individual pathologic processes. • Pathology varies according to the underlying disorder.

Differential diagnosis Heredodegenerative parkinsonism

• Inherited: • Dopamine-responsive parkinsonism/dystonia: DYT5: levodopa-responsive dystonia-parkinsonism (typically manifests in childhood).

FIGURE 16.66  T2-weighted MRI imaging demonstrates the ‘eye of the tiger’ sign in pantothenate kinase–associated neurodegeneration, with low signal intensity in the globus pallidus circumscribing a central region of high signal intensity.

Degenerative Diseases of the Nervous System • FXTAS:51 • Core features of action tremor and ataxia, frequently associated with parkinsonism, executive function deficits/dementia, neuropathy, and dysautonomia. • Caused by moderate expansions of the FMR1 gene. • MRI demonstrates middle cerebellar peduncle (MCP) sign: increased T2 signal in the middle cerebellar peduncles. • Though recently discovered, may be one of the most common single-gene disorders causing a neurodegenerative syndrome in males. Key to diagnosis in history is obtaining a history of children or grandchildren with mental retardation, autism, or learning disorders or female relatives with premature menopause or early infertility. • Wilson’s disease (hepatocerebral degeneration):52 • Caused by autosomal recessive mutation in ATP7B gene, which encodes copper-transporter molecule; more than 500 mutations have been identified. Pathogenic mutation results in impaired copper excretion, and leads abnormal copper accumulation in brain, liver, eyes, and other organs. There is high phenotypic variability. • Onset of symptoms typically in second or third decade, but late-onset (> 70 years of age) cases have also been documented. • Neurologic manifestations may include dystonia, parkinsonism, tremor (typically described as ‘wingbeating’ or ‘flapping’ tremor), dysarthria, and cognitive impairment. Psychological symptoms typically include disinhibition, irritability, personality changes, anxiety/ depression, and, less commonly, psychosis. • Diagnostic clues include chronic liver disease of unknown etiology, positive family history, Kayser– Fleischer rings on ophthalmologic examination, low serum ceruloplasmin level, and elevated 24-hour urine copper level. • MRI abnormalities are often seen, though the wellknown ‘face of the giant panda’ sign (describing appearance of midbrain when red nucleus and substantia nigra are surrounded by high T2 signal) is present < 20% of the time. It is more common to see signal changes in the basal ganglia and pons. • Ceroid lipofuscinosis. • Gaucher’s disease: mutations in the GBA gene (encoding beta-glucocerebrosidase) found to be a common risk factor for PD, even in absence of other signs of the disease. • GM1 gangliosidosis. • Chediak–Higashi disease. • Perry’s syndrome: parkinsonism, depression, weight loss, and central hypoventilation.

Secondary parkinsonism53,54

• Drug-induced parkinsonism (Table 16.9):52 special note on dopamine receptor antagonists: • History of exposure may not be offered and should be sought out. • Parkinsonism typically improves after withdrawal, but may take months. Sometimes abrupt withdrawal can result in a withdrawal-emergent syndrome.

589 TABLE 16.9  Drugs Causing Secondary Parkinsonism Neuroleptic Drugs Typical Atypical Antiemetic agents Dopamine storage/transport inhibitors (dopamine depletors) Immunosuppressants/ chemotherapeutic agents Antiepileptics Other

Haloperidol, pimozide, chlorpromazine, fluphenazine Ziprasidone, olanzapine, risperidol, aripiprazole Metoclopramide, prochlorperazine, promethazine Reserpine, tetrabenazine, deutetrabenazine, valbenazine Cyclosporin, busulfan, vincristine, adriamycin Sodium valproate, phenytoin Methyldopa, amiodarone, calcium channel blockers (cinnarizine, flunarizine), alpha-methyldopa, chloroquine, domperidone

• Toxins (Table 16.10). • Cerebrovascular disease/vascular parkinsonism (VP)/vascular ‘pseudoparkinsonism’:55 • Controversial diagnosis with no universally used diagnostic criteria, but estimated to account for 3–12% of all cases of parkinsonism. • Many patients with true PD have incidental or concurrent cerebrovascular disease, and some patients with VP have some response to levodopa. • Attributed to ischemic or hemorrhagic strokes (usually multiple) in the subcortical white matter, striatum, or substantia nigra. • Most commonly described lesions: bilateral multiple basal ganglia lacunes or ‘Binswanger’s type’ confluent white matter lesions (Figure 16.67). • Heterogeneous syndrome with several possible clinical features: – By history: sudden onset, stepwise progression, history of strokes, early gait disturbance with postural instability, vascular risk factors, minimal or no benefit from levodopa, later age at onset, early involvement of lower extremities. – On examination: pyramidal signs, clasp-knife spasticity as opposed to parkinsonian-like cogwheeling rigidity, flexor spasms, concurrent dementia, pseudobulbar palsy, incontinence, TABLE 16.10  Toxic Exposures Associated with Parkinsonism • • • • • • • • • • • • • •

Aliphatic hydrocarbons Carbon disulfide Carbon monoxide Cyanide Kava (Piper methysticum) Manganese poisoning Mercury Methanol Methcathinone (ephedrine) abuse Methyl bromide N-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) Organophosphates Rauwolfia serpentina Street drugs (heroin, toluene, ecstasy)

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• • •

FIGURE 16.67  Axial FLAIR MRI brain images from a patient with clinically diagnosed vascular parkinsonism, showing confluent white matter subcortical hyperintensities with a frontal predominance and multiple subcortical lacunar infarcts. absence of rest tremor, lack of true akinesia (i.e. decrement or fatiguing with rapid movements). As opposed to the narrow-based gait of PD, there is predominantly a ‘lower body parkinsonism’, including standing more erect in a ‘stiff’ military posture, with the shoulders back, arms extended, with a wide stance base, and a short shuffling stepping pattern, often with frequent freezing and gait initiation failure. • May also appear similar to NPH or mimic atypical parkinsonian syndromes such as PSP or CBD (Table 16.11). • Functional imaging studies have not consistently differentiated VP from PD. • Autoimmune:56 • Poststreptococcal, associated with antibasal ganglia antibodies. • SLE. TABLE

16.11  Clinical Features Parkinsonian Disorders Feature

Motor symmetry Axial rigidity Limb dystonia Pyramidal signs Apraxia Postural instability Vertical supranuclear gaze palsy Frontal behavior Dysautonomia Levodopa response early in course Levodopa response late in course Asymmetric cortical atrophy on MRI

PSP

Differentiating PD

+++ + +++ ++ + + + − + − +++ ++ +++ + +++ + − + + +++ − ++ − −

• • •

• Nonvasculitic autoimmune inf lammatory meningoencephalitis. • Antiphospholipid antibody syndrome. Paraneoplastic: rare. Trauma: recurrent head trauma (dementia pugilistica/ pugilistic encephalopathy). Metabolic: • Calcifications:57 Fahr’s disease or other disturbances of calcium metabolism (hypo- and hyperparathyroidism, pseudohypoparathyroidism). • Mitochondrial disease: – Leigh’s disease (subacute necrotizing encephalopathy). – Mitochondrial cytopathies with striatal necrosis. Thyroid disease: hypothyroidism-related slowness. Central pontine or extrapontine myelinolysis Liver disease: Non-Wilsonian hepatocerebral degeneration (Figures 16.68, 16.69);58 often associated with bilateral, symmetric bilateral basal ganglia hyperintensities on T1-weighted imaging, presumed secondary to manganese deposition.

Major

MSA-P CBD MIP +++ ++ + ++ − ++ ++ + ++ + + −

− ++ +++ +++ +++ + ++ ++ − − − ++

+/− − +/− ++ + ++ + + − − − +/−

Abbreviations: CBD, corticobasal degeneration; MIP, multi-infarct parkinsonism; MRI, magnetic resonance imaging; MSA-P, multiple system atrophy of the parkinsonian type; PD, Parkinson’s disease; −, absent or rare; +, occasional, mild, or late; + +, usual, moderate; + + +, usual, severe, or early. (Adapted from Golbe 2007, with permission.)

FIGURES 16.68, 16.69  Tl-weighted MRI of the brain in a patient with chronic cirrhosis and tremor-predominant parkinsonism (with tremor limiting the resolution of many images). Bilateral, symmetric hyperintensities of the globus pallidus are seen on sagittal (Figure 16.68) and axial (Figure 16.69) images.

Degenerative Diseases of the Nervous System • Infection:59 • Primary infection invading basal ganglia structures (i.e. toxoplasmosis, viral encephalitis). • Postencephalitic parkinsonism; now rare, mainly reported as encephalitis lethargica followed a worldwide flu epidemic in 1918. • HIV infection/AIDS. • Prion disease (CJD, GSS). • Whipple’s disease. • SSPE. • West Nile virus.60 • Hemiparkinsonism/hemiatrophy: • Younger age, associated with early-onset dystonia, slow progression, and poor levodopa response, often with a history of perinatal asphyxia. • Contralateral cortical hemiatrophy on MRI. • Tumor involving the basal ganglia and cortical–subcortical connections. • NPH, noncommunicating hydrocephalus: • Greater involvement of the legs than arms (‘lower-half parkinsonism’). • Early dementia. • Urinary incontinence. • Psychogenic:61 • Parkinsonism, outside tremor, is a rare manifestation of a psychogenic movement disorder. • Clinical features: – Sudden onset. – Precipitating factor(s) such as traumatic events. – Tremor at rest and with action. – No cogwheeling. – No fatiguing (decrementing amplitude of movements). – Distractibility/entrainment of motor features. – Other psychogenic examination findings (giveaway weakness, patterns of false sensory loss, excessive fatigue and effort). • Depression: common.

TIP • As there are many causes of parkinsonism, some of which are treatable, every patient presenting with signs and symptoms of parkinsonism should have a thorough history and examination, with ancillary testing as indicated for the conditions listed in this chapter.

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48. Kouri, N., Whitwell, J. L., Josephs, K. A., Rademakers, R. & Dickson, D. W. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 7, 263–272 (2011). 49. Kompoliti, K. et al. Clinical presentation and pharmacological therapy in corticobasal degeneration. Arch Neurol 55, 957–961 (1998). 50. Schneider, S. A. & Bhatia, K. P. Syndromes of neurodegeneration with brain iron accumulation. Semin Pediatr Neurol 19, 57–66 (2012). 51. Berry-Kravis, E. et al. Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord 22, 2018–2030, quiz 2140 (2007). 52. Bandmann, O., Weiss, K. H. & Kaler, S. G. Wilson’s disease and other neurological copper disorders. Lancet Neurol 14, 103–113 (2015). 53. Barton, B., Zauber, S. E. & Goetz, C. G. Movement disorders caused by medical disease. Semin Neurol 29, 97–110 (2009). 54. Netravathi, M., Pal, P. K. & Indira Devi, B. A clinical profile of 103 patients with secondary movement disorders: correlation of etiology with phenomenology. Eur J Neurol 19, 226–233 (2012). 55. Vizcarra, J. A., Lang, A. E., Sethi, K. D. & Espay, A. J. Vascular parkinsonism: deconstructing a syndrome. Mov Disord 30, 886–894 (2015). 56. Baizabal-Carvallo, J. F. & Jankovic, J. Movement disorders in autoimmune diseases. Mov Disord 27, 935–946 (2012). 57. Saleem, S. et al. Fahr’s syndrome: literature review of current evidence. Orphanet J Rare Dis 8, (2013). 58. Burkhard, P. R., Delavelle, J., Du Pasquier, R. & Spahr, L. Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration. Arch Neurol 60, 521–528 (2003). 59. Alarcón, F. & Giménez-Roldán, S. Systemic diseases that cause movement disorders. Parkinsonism Relat Disor 11, 1–18 (2005). 60. Sejvar, J. J. et al. Neurologic manifestations and outcome of West Nile virus infection. JAMA 290, 511–515 (2003). 61. Thenganatt, M. A. & Jankovic, J. Psychogenic (functional) parkinsonism. Handb Clin Neurol 139, 259–262 (2016).

Further reading

Parkinson’s disease and parkinsonian disorders Parkinson’s disease Ascherio, A. & Schwarzschild, M. A. The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 15, 1257–1272 (2016). Blandini, F. et al. Glucocerebrosidase mutations and synucleinopathies: toward a model of precision medicine. Mov Disord 34, 9–21 (2019). Borghammer, P. How does parkinson’s disease begin? Perspectives on neuroanatomical pathways, prions, and histology. Mov Disord 33, 48–57 (2018). Braak, H., Del Tredici-Braak, K. & Gasser, T. Special issue “Parkinson’s disease”. Cell Tissue Res 373, 1–7 (2018). Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24, 197–211 (2003). Breen, D. P., Halliday, G. M. & Lang, A. E. Gut–brain axis and the spread of α-synuclein pathology: vagal highway or dead end? Mov Disord 34, 307–316 (2019). Caproni, S. & Colosimo, C. Diagnosis and differential diagnosis of Parkinson disease. Clin Geriatr Med 36, 13–24 (2020).

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Chen, Z., Li, G. & Liu, J. Autonomic dysfunction in Parkinson’s disease: implications for pathophysiology, diagnosis, and treatment. Neurobiol Dis 134, 104700 (2019). Coughlin, D. G., Hurtig, H. I. & Irwin, D. J. Pathological Influences on clinical heterogeneity in Lewy body diseases. Mov Disord (2019). Dutta, S. K. et al. Parkinson’s disease: the emerging role of gut dysbiosis, antibiotics, probiotics, and fecal microbiota transplantation. J Neurogastroenterol Motil 25, 363–376 (2019). Espay, A. J. et al. Levodopa-induced dyskinesia in Parkinson disease: current and evolving concepts. Ann Neurol 84, 797– 811 (2018). Fahn S. & Jankovic, J. Principles and Practice of Movement Disorders. (Elsevier Inc., 2007). Foguem, C. & Manckoundia, P. Lewy Body disease: clinical and pathological “overlap syndrome” between synucleinopathies (Parkinson disease) and tauopathies (Alzheimer disease). Curr Neurol Neurosci Rep 18, 24 (2018). Lang, A. E. & Espay, A. J. Disease modification in Parkinson’s disease: current approaches, challenges, and future considerations. Mov Disord 33, 660–677 (2018). Lizarraga, K. J., Fox, S. H., Strafella, A. P. & Lang, A. E. Hallucinations, delusions and impulse control disorders in Parkinson disease. Clin Geriatr Med 36, 105–118 (2020). Marsili, L. et al. Dystonia in atypical parkinsonian disorders. Parkinsonism Relat Disord 66, 25–33 (2019). Moore, H., Shpiner, D. S. & Luca, C. C. Management of motor features in advanced Parkinson disease. Clin Geriatr Med 36, 43–52 (2020). Okun, M. S. Deep-brain stimulation for Parkinson’s disease. N Engl J Med 367, 1529–1538 (2012). Payne, K., Walls, B. & Wojcieszek, J. Approach to assessment of Parkinson disease with emphasis on genetic testing. Med Clin North Am 103, 1055–1075 (2019). Pfeiffer, R. F. Non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 22, S119–S122 (2016). Postuma, R. B. & Berg, D. Prodromal Parkinson’s disease: the decade past, the decade to come. Mov Disord 34, 665–675 (2019). Postuma, R. B. et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 30, 1591–1601 (2015). Saeed, U. et al. Imaging biomarkers in Parkinson’s disease and Parkinsonian syndromes: current and emerging concepts. Transl Neurodegener 6, 8 (2017). Seppi, K. et al. Update on treatments for nonmotor symptoms of Parkinson’s disease—an evidence-based medicine review. Mov Disord 34, 180–198 (2019). Simonet, C., Tolosa, E., Camara, A. & Valldeoriola, F. Emergencies and critical issues in Parkinson’s disease. Pract Neurol 20, 15–25 (2020). Vizcarra, J. A., Lang, A. E., Sethi, K. D. & Espay, A. J. Vascular Parkinsonism: deconstructing a syndrome. Mov Disord 30, 886–894 (2015). Weintraub, D., David, A. S., Evans, A. H., Grant, J. E. & Stacy, M. Clinical spectrum of impulse control disorders in Parkinson’s disease. Mov Disord 30, 121–127 (2015). Zesiewicz, T. A. Parkinson disease. Continuum (Minneap Minn) 25, 896–918 (2019).

Batla, A. et al. Young-onset multiple system atrophy: clinical and pathological features. Mov Disord 33, 1099–1107 (2018). Ben-Shlomo, Y., Wenning, G. K., Tison, F. & Quinn, N. P. Survival of patients with pathologically proven multiple system atrophy: a meta-analysis. Neurology 48, 384–393 (1997). Cortelli, P. et al. Stridor in multiple system atrophy: consensus statement on diagnosis, prognosis, and treatment. Neurology 93, 630–639 (2019). Fanciulli, A. & Wenning, G. K. Multiple-system atrophy. N Engl J Med 372, 249–263 (2015). Gilman, S. et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71, 670–676 (2008). Jellinger, K. A. Neuropathology of multiple system atrophy: new thoughts about pathogenesis. Mov Disord 29, 1720–1741 (2014). Kan, A. E. Striatonigral degeneration. Pathology 10, 45–52 (1978). Meissner, W. G. et al. Multiple system atrophy: recent developments and future perspectives. Mov Disord 34, 1629–1642 (2019). Palma, J. A. & Kaufmann, H. Orthostatic hypotension in Parkinson disease. Clin Geriatr Med 36, 53–67 (2020). Rafanelli, M., Walsh, K., Hamdan, M. H. & Buyan-Dent, L. Autonomic dysfunction: diagnosis and management. Handb Clin Neurol 167, 123–137 (2019). Savica, R. et al. Survival and causes of death among people with clinically diagnosed synucleinopathies with parkinsonism: a population-based study. JAMA Neurol 74, 839–846 (2017).

Multiple system atrophy Abbott, S. M. & Videnovic, A. Sleep disorders in atypical Parkinsonism. Mov Disord Clin Pract 1, 89–96 (2014).

Corticobasal degeneration Ali, F. & Josephs, K. A. Corticobasal degeneration: key emerging issues. J Neurol 265, 439–445 (2018).

Progressive supranuclear palsy Ali, F. et al. Sensitivity and specificity of diagnostic criteria for progressive supranuclear palsy. Mov Disord 34, 1144–1153 (2019). Boxer, A. L. et al. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol 16, 552–563 (2017). Höglinger, G. U. et al. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord 32, 853–864 (2017). Peterson, K. A., Patterson, K. & Rowe, J. B. Language impairment in progressive supranuclear palsy and corticobasal syndrome. J Neurol (2019). Phokaewvarangkul, O. & Bhidayasiri, R. How to spot ocular abnormalities in progressive supranuclear palsy? A practical review. Transl Neurodegener 8, 20 (2019). Sakurai, K. et al. Beyond the midbrain atrophy: wide spectrum of structural MRI finding in cases of pathologically proven progressive supranuclear palsy. Neuroradiology 59, 431–443 (2017). Shoeibi, A., Olfati, N. & Litvan, I. Frontrunner in translation: progressive supranuclear palsy. Front Neurol 10, (2019). Stamelou, M., Giagkou, N. & Höglinger, G. U. One decade ago, one decade ahead in progressive supranuclear palsy. Mov Disord 34, 1284–1293 (2019). Stang, C. D. et al. Progressive supranuclear palsy and corticobasal syndrome: a population-based study. J Parkinsons Dis 10, 179–184 (2020).

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594 Burrell, J. R., Hodges, J. R. & Rowe, J. B. Cognition in corticobasal syndrome and progressive supranuclear palsy: a review. Mov Disord 29, 684–693 (2014). Di Stasio, F. et al. Corticobasal syndrome: neuroimaging and neurophysiological advances. Eur J Neurol 26, 701 (2019). Lamb, R., Rohrer, J. D., Lees, A. J. & Morris, H. R. Progressive supranuclear palsy and corticobasal degeneration: pathophysiology and treatment options. Curr Treat Options Neurol 18, 42 (2016). Heredodegenerative and secondary parkinsonism Baizabal-Carvallo, J. F. & Jankovic, J. Autoimmune and paraneoplastic movement disorders: an update. J Neurol Sci 385, 175–184 (2018). Bandmann, O., Weiss, K. H. & Kaler, S. G. Wilson’s disease and other neurological copper disorders. Lancet Neurol 14, 103– 113 (2015).

HEREDITARY ATAXIAS Vikram G. Shakkottai, Sharan Srinivasan

INTRODUCTION Cerebellar ataxia is a frequent finding among patients seen in neurologic practice and may result from a wide variety of etiologies, both acquired and genetic. Inherited ataxia is a large and important subgroup of the ataxic disorders, and includes metabolic ataxias, autosomal recessive degenerative ataxias, autosomal dominant spinocerebellar ataxias (SCAs), X-linked, and maternally inherited ataxias. This section discusses predominantly the inherited causes of cerebellar ataxia, with more limited coverage of acquired and nonsyndromic congenital causes. Hereditary conditions account for the majority of ataxic syndromes in children and one-third to one-half of patients with adult-onset ataxic syndromes. Classification by mode of inheritance is a useful way of organizing the hereditary ataxias for both clinical and research purposes, and this approach will be used here.

Cucca, A., Migdadi, H. A. & Di Rocco, A. Infection-mediated autoimmune movement disorders. Parkinsonism Relat Disord 46, S83–S86 (2018). Factor, S. A. et al. Recent developments in drug-induced movement disorders: a mixed picture. Lancet Neurol 18, 880–890 (2019). Korczyn, A. D. Vascular parkinsonism-characteristics, pathogenesis and treatment. Nat Rev Neurol 11, 319–326 (2015). Lenka, A., Kamat, A. & Mittal, S. O. Spectrum of movement disorders in patients with neuroinvasive West Nile Virus Infection. Mov Disord Clin Pract 6, 426–433 (2019). Limphaibool, N., Iwanowski, P., Holstad, M. J. V. & Perkowska, K. Parkinsonism in inherited metabolic disorders: key considerations and major features. Front Neurol 9, (2018).

Joubert’s syndrome and related disorders are defined by their typical MRI findings of a ‘molar tooth sign’, which on axial images at the level of the superior cerebellar peduncles shows enlargement of the interpeduncular fossa and fourth ventricle, hypoplasia or aplasia of the cerebellar vermis, and thickened and elongated superior cerebellar peduncles (Figure 16.70).2

Etiology and pathophysiology

There are now at least 16 known genetic mutations that can lead to Joubert’s syndrome (Valente EM 2013, Handbook of Clinical Neurology). 3 All these disorders are inherited in an autosomal recessive pattern, suggesting that loss of function of the various genes is critical to pathogenesis. Most of these mutations interfere with either the structure or function of the primary cilia, which are critical for cellular migration during hindbrain development.4

CONGENITAL ATAXIAS This category includes cerebellar aplasia and hypoplasia as well as congenital structural abnormalities such as Chiari’s malformation, Joubert’s syndrome, and Dandy–Walker syndrome.1 These conditions are present at birth and are generally static in nature. Some of these defects are amenable to surgical intervention. For a number of these disorders, the condition affects multiple organ systems.

JOUBERT’S SYNDROME AND RELATED DISORDERS Definition and epidemiology

• A congenital-onset disorder of the cerebellum, with specific involvement of the cerebellar vermis. • A static and nonprogressive disorder, present from birth. • Estimated at 1:100,000 in the United States.

FIGURE 16.70  Joubert’s syndrome. Tl axial image demonstrating the ‘molar tooth’ sign that results from vermian atrophy and enlargement of the interpeduncular fossa and fourth ventricle, hypoplasia or aplasia of the cerebellar vermis, and thickened and elongated superior cerebellar peduncles. (Courtesy of William Dobyns, University of Chicago.)

Degenerative Diseases of the Nervous System Clinical features

• Static cerebellar ataxia. • Developmental delay/intellectual impairment (mild to moderate). • Hypotonia in infancy. • Characteristic facial appearance in a majority of cases (broad forehead, arched eyebrows, strabismus, ptosis, and tenting of the mouth consistent with facial hypotonia). • Abnormal eye movements, including strabismus, nystagmus, and oculomotor apraxia. • Abnormal breathing patterns, including episodic apnea and tachypnea.

The above symptoms and signs are sometimes complicated by other CNS and non-CNS organ system involvement. Other CNS changes include occipital encephalocele, agenesis of the corpus callosum, and variable brainstem anomalies. Non-CNS involvement can include: • Ocular disorders: colobomas and blindness secondary to Leber’s congenital amaurosis; a late-onset degenerative pigmentary retinopathy has also been reported in AHI1 patients.5 • Up to 30% of cases of Joubert’s syndrome are associated with renal involvement. Typical renal involvement includes either cystic dysplasia or juvenile nephronophthisis (NPHP).6

595 • A subset of patients has involvement of cerebellum, eyes, and renal system (so called cerebello-oculo-renal syndrome, CORS). • Joubert’s syndrome can also occur as a component of COACH syndrome (cerebellar vermis hypo/aplasia, oligophrenia, ataxia congenital, coloboma, and hepatic fibrosis).7 These patients can also have renal failure as in CORS.

TIP • Young patients with a ‘molar tooth’ sign should be evaluated for non-CNS involvement, particularly the renal system.

Differential diagnosis

A complete differential diagnosis for cerebellar ataxias is included in Table 16.12. • COACH and CORS syndromes, as described above. The molar tooth sign and ataxia may not be recognized until later in the course of the disorder if not explicitly evaluated.

TABLE 16.12  Differential Diagnosis for Cerebellar Ataxia CONGENITAL DISORDERS 1. Arnold–Chiari malformations 2. Congenital cerebellar hypoplasia/aplasia 3. X-linked cerebella hypoplasia 4. Pontocerebellar hypoplasia 5. Dandy–Walker cyst 6. Joubert’s syndrome and its variants (congenital absence or hypoplasia of the cerebellar vermis) 7. Gillespie’s syndrome 8. Hydrocephalus Dominant inheritance 9. The spinocerebellar ataxias (Table 16.13) 10. Dentato-rubro-pallido-luysian atrophy (DRPLA, Haw River syndrome) 11. Episodic ataxias EA-1, EA-2, EA-3, and EA-4 12. Myelocerebellar disorder 13. Adult-onset leukodystrophy Autosomal recessive inheritance 14. Freidreich’s ataxia 15. Ataxia telangiectasia 16. Ataxia telangiectasia-like disorder 17. Nijmegen breakage syndrome 18. Ataxia with oculomotor apraxia I 19. Ataxia with oculomotor apraxia II 20. Ataxia with isolated vitamin E deficiency 21. Bassen–Kornzweig disease (abetalipoproteinemia) 22. Wilson’s disease 23. Aceruloplasminemia 24. Refsum’s disease (phytanoyl-CoA hydroxylase deficiency) 25. Aminoacidurias: • Hartnup disease • Isovaleric acidemia • Maple syrup urine disease

26. Hyperammonemias: • • • •

Biotin-responsive multiple carboxylase deficiency Hypoornithinemia Argininosuccinase deficiency Argininosuccinic synthase deficiency

27. Lysosomal storage diseases: • Neimann–Pick type C • Neuronal ceroid lipofuscinosis • Adult-onset hexosaminidase-A or hexosaminidase-B deficiency 28. Leukodystrophies: • Metachromatic leukodystrophy • Adrenoleukodystrophy • Krabbe’s disease 29. Unverricht–Lundborg disease (myoclonic epilepsy and progressive ataxia due to a cystatin B deficiency) 30. Autosomal recessive ataxia type I 31. Spastic ataxia of Charlevoix–Saguenay 32. Ataxia with hypogonadism (Holmes’ ataxia) 33. Pantothenate kinase–associated neurodegeneration (formerly Hallervorden–Spatz syndrome) 34. Cerebrotendinous xanthomatosis (cholestanolosis) 35. Cockayne’s syndrome 36. Marinesco–Sjögren’s syndrome X-linked inheritance 37. Fragile X tremor ataxia syndrome (FXTAS) 38. X-linked sideroblastic anemia with ataxia 39. Adrenomyeloneuropathy 40. X-linked adrenoleukodystrophy 41. Ornithine transcarbamylase deficiency 42. Pyruvate dehydrogenase deficiency (Continued)

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596 TABLE 16.12  Differential Diagnosis for Cerebellar Ataxia (Continued) Maternal inheritance

VASCULAR ETIOLOGIES

43. Mitochondrial disorders:

74. Vertebrobasilar insufficiency, including vertebral artery stenosis, basilar stenosis, vertebral artery dissection, and subclavian steal phenomenon 75. Cerebellar stroke, either alone or with associated brainstem signs as in Wallenberg’s (lateral medulla) syndrome 76. Cerebellar hemorrhage (secondary to many causes) 77. Superficial siderosis

• • • • • • •

MELAS MERRF NARP Kearns–Sayre syndrome MIRAS Leigh’s syndrome Coenzyme Q10 deficiency

TOXIC/METABOLIC DISORDERS 44. Alcoholic cerebellar degeneration 45. Drugs (antiepileptic medications, chemotherapy) 46. Toxins: • • • • • • • •

Mercury Arsenic Lead Thallium Toluene Benzene Carbon disulfide Carbon monoxide

47. Insecticides 48. Hyperthermia 49. Hypomagnesemia 50. Hypothyroidism 51. Hypoparathyroidism 52. Extrapontine myelinolysis 53. Hepatocerebral degeneration 54. Portal-systemic encephalopathy INFECTIOUS ETIOLOGIES 55. HIV encephalitis/AIDS 56. HSV encephalitis 57. Cerebellar abscess 58. Progressive multifocal leukoencephalopathy (PML) 59. Neurocysticercosis (rarely) 60. Lyme disease 61. Tuberculosis 62. Malaria 63. Legionella 64. Mycoplasma 65. Streptococcus pneumoniae 66. Fungal meningoencephalitis 67. Congenital rubella panencephalitis 68. Subacute sclerosing panencephalitis (classically measles, rubella) 69. Viral cerebellitis (including West Nile virus, St. Louis’ encephalitis, eastern equine encephalitis and coxsackie A/B, echovirus, CMV, VZV, mumps, EBV, polio) 70. Toxoplasmosis (rare as only manifestation) 71. Syphilis (rare as only manifestation) 72. Whipple’s disease 73. Prion diseases: Creutzfeldt–Jakob disease (CJD), variant CJD, and Gerstmann–Straussler–Scheinker syndrome

VITAMIN DEFICIENCIES 78. Wernicke’s encephalopathy/thiamine deficiency 79. Vitamin E deficiency 80. B12 deficiency 81. Zinc deficiency NEOPLASTIC PROCESSES 82. Primary malignant tumors: medulloblastoma, glioma, hemangioblastoma (associated with von Hippel–Landau syndrome), ependymoma 83. Benign tumors: vestibular schwannoma and meningioma 84. Cowden’s syndrome/Lhermitte–Duclos disease (PTEN mutations leading to hemartomas in cerebellum and elsewhere) 85. Metastatic cancer: lung, breast, colon, melanoma, and renal cell carcinoma most common in adults 86. Lymphoma AUTOIMMUNE DISEASES 87. Postinfectious cerebellitis (post-VZV, EBV) 88. Multiple sclerosis (note overlap with postinfectious cerebellitis as initial presenting symptom) 89. Acute disseminated encephalomyelitis 90. Miller Fisher variant of Guillain–Barré syndrome 91. Hashimoto’s thyroiditis/encephalopathy 92. Vasculitis (Behcet’s disease, temporal arteritis, polyarteritis nodosa, among others) 93. Celiac disease (gluten enteropathy with ataxia) 94. GAD antibody-associated ataxia 95. Neurosarcoidosis 96. Histiocytosis X SPORADIC CEREBELLAR NEURODEGENERATIVE DISEASES 97. Multiple system atrophy/OPCA 98. Progressive supranuclear palsy 99. PKAN (sporadic form) 100. Neuroacanthocytosis CEREBELLAR ATAXIA MIMICS 101. Obstructive hydrocephalus 102. Normal pressure hydrocephalus 103. Large-fiber sensory neuropathy 104. Migraine headache with ataxia 105. Psychogenic conversion disorder Abbreviations: CMV, cytomegalovirus; EBV, Epstein–Barr virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibers; MIRAS, mitochondrial recessive ataxia syndrome; NARP, neurogenic weakness with ataxia and retinitis pigmentosa; OPCA, olivopontocerebellar atrophy; PTEN, phosphatase and tensin homolog; VZV, varicella-zoster virus.

Degenerative Diseases of the Nervous System • Bardet–Biedl syndrome (BBS) can present clinically with many features of Joubert’s syndrome–related disorders, including renal involvement, retinal dystrophy, cognitive delay, and ataxia, but it is not typically associated with the presence of the molar tooth sign or other structural abnormalities on MRI.8 • Dandy–Walker malformation is a congenital brain malformation that can include cerebellar hypoplasia and vermian aplasia/hypoplasia, and a retrocerebellar fluid collection. It is typically also associated with agenesis of the corpus callosum and hydrocephalus. It can be differentiated clinically based on MRI imaging. • Congenital disorders of glycosylation can present with ataxia, hypotonia, and strabismus, but other typical features on MRI are not usually seen. These can be differentiated based on transferrin isoelectric focusing, which is normal in Joubert’s syndrome–related disorders. • Congenital cerebellar hypoplasia/aplasia can occur as a component of a heterogeneous group of brain malformations.9 A typical molar tooth sign is not usually seen, and these disorders are usually sporadic.

Investigations and diagnosis

In most cases, MRI of the brain reveals the classic ‘molar tooth sign’. Genetic testing is currently clinically available for four genes: AHI1 (JBTS3), NPHP1 (JBTS4), CEP290 (JBTS5), and TMEM67 (JBTS6). Together, however, these account for only about 30–40% of cases. Targeted exome-based panels are becoming available that target upward of 94 ciliopathy genes and are thus close to definitive. Testing for involvement of systems other than the CNS is critical, including ophthalmologic evaluation with visual evoked responses, liver function tests, and monitoring of renal function. Abdominal ultrasound should be performed to evaluate for renal or hepatic abnormalities. A sleep evaluation with monitoring for apnea should be considered, as some patients require supplemental oxygen, or, rarely, bilevel positive airways pressure (BPAP) or tracheostomy.

Treatment and prognosis

Supportive. Most children survive to adulthood unless their extra-CNS symptoms are overwhelming.

AUTOSOMAL DOMINANT CEREBELLAR ATAXIAS Definition and epidemiology

Autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of dominantly inherited late-onset clinical phenotypes that include cerebellar ataxia, nystagmus, dysarthria, dysmetria, intention tremor, and ophthalmoparesis, resulting from neuronal degeneration in the cerebellum and cranial nerve nuclei. There may also be varying degrees of dysfunction of the basal ganglia, brainstem, spinal cord, optic nerves, retinas, and peripheral nerves, resulting in parkinsonism, hyperreflexia, spasticity, and visual loss. • Prevalence: about 1–5 per 100,000 throughout the world. • Age: adult onset, typically after age 20 years.

Classification

Classification is clinical, pathologic, and genotypic. The first widely accepted systematic classification of the dominantly

597 inherited ataxias was proposed by Harding in 1993. This classification scheme included: • ADCA type I: cerebellar ataxia is variably associated with other neurologic features, including involvement of the central and/or peripheral nervous system. • ADCA type II: cerebellar ataxia is associated with the presence of a pigmentary maculopathy and striking anticipation (a tendency toward earlier onset in successive generations). • ADCA type III is characterized by a pure cerebellar syndrome. Because of the large number of genes associated with the dominantly inherited ataxias, this classification scheme has limited clinical utility. SCA7 is the only dominantly inherited ataxia belonging to the class of ADCA type II. It is nevertheless useful to classify the ataxias into those that present as relatively pure cerebellar syndromes (ADCA type III) and those that are cerebellar ‘plus’ syndromes (ADCA type I). There are currently over 40 genetic loci associated with ataxia syndromes that are dominantly inherited (Table 16.13). The most common inherited ataxias (SCA1, SCA2, SCA3, and SCA6) are associated with an expansion of a glutamine-encoding trinucleotide (CAG) repeat in the respective disease-causing genes.10

Disorders of trinucleotide repeats

Five of the eight neurologic disorders caused by an increase in the number of CAG repeats result in spinocerebellar ataxia (Table 16.14). The other three are spinal and bulbar muscular atrophy (SBMA or Kennedy’s disease), HD, and DRPLA. These disorders are characterized by autosomal dominant or X-linked inheritance, onset in midlife, a progressive course, anticipation, preponderance of unstable repeats from the paternal chromosome, and correlation of increased CAG repeats with earlier age at symptom onset. The abnormal proteins in each disorder are expressed in a wide range of tissues and are not limited to the affected brain regions.

Etiology and pathophysiology

Multiple gene mutations have been identified to date (Table 16.13). As above, the most common of these result from glutamineencoding CAG repeats in the causative genes. Larger sizes of CAG repeats correlate directly with earlier ages of onset (anticipation). The repeat number increases with paternal transmission of disease (imprinting). The pathogenesis of these disorders is as diverse as the causative genes. The most common autosomal dominant ataxias result from glutamine-encoding CAG repeats. The resulting proteins are not homologous. The mechanism for pathogenesis of these proteins is diverse and includes altered gene transcription, RNA splicing, and intracellular calcium handling. Despite their individual genetic driver mutations, there is remarkable clinical similarity among multiple SCAs, raising the idea that a common downstream pathway leads to actual cellular degeneration. Recent work has shown that ion channel dysfunction is a shared mechanism in multiple SCAs (SCA1, 2, 3, and 7).11–15 Further, restoration of channel activity has shown to improve motor function and delay cerebellar atrophy.14,16 Despite these advances, it remains unexplained why cerebellar and brainstem nuclei are preferentially affected given the ubiquitous expression of these proteins.

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598 TABLE 16.13  Genetic Loci Associated with Dominantly Inherited Ataxia Syndromes Name

Locus/Gene

Protein/Mutation

SCA1

6p22-p23/ ATXN1

Ataxin 1, CAG repeats 41–81 (normal 25–36) Ataxin 2, CAG repeats 35–59 (normal 15–24)

SCA2

SCA3 (Machado–Joseph Disease/MJD)

SCA4 SCA5 SCA6

SCA7

SCA8

SCA9

SCA10

SCA11 SCA12

SCA13

SCA14 SCA15/SCA16 SCA17/Huntington’s disease–like 4 (HDL4) SCA18 Sensorimotor neuropathy with ataxia/SMNA

Pathology

Symptoms/Signs

Purkinje cells; pontine nuclei; inferior Cerebellar ataxia; dysarthria olivary nuclei ophthalmoparesis; dysphagia, amyotrophy; pyramidal signs; extrapyramidal signs 12q22–24/ Purkinje’s cells; basis pontis; inferior Cerebellar ataxia, aslow saccades, ATXN2 olivary nuclei ophthalmoplegia peripheral neuropathy; minimal pyramidal and extrapyramidal signs; dementia (rarely) 14q24.3–q31/ Ataxin 3, CAG Subthalamic nuclei; substantia nigra; Cerebellar ataxia; ophthalmoparesis; avariable pyramidal signs; extrapyramidal ATXN3 repeats 62–82 pontine nuclei, dentate nuclei; (normal 13–36) Clarke’s columns; spinocerebellar amyotrophic signs; exophthalmos tracts; anterior horn cells; dorsal root ganglia; mild Purkinje’s neuron loss 16q22 Cerebellar ataxia; asensory axonal neuropathy; pyramidal signs 11p13/SPTSN2 Pure cerebellar ataxia (late onset); β III Spectrin pyramidal signs in young-onset patients aPure cerebellar ataxia 19p13.2/ Cav2.1, CAG repeats Severe loss of Purkinje’s cells CACNA1A 21–30 (normal 6–17) 3p14.1 Ataxin 7, CAG Extensive loss of Purkinje’s cells; Progressive cerebellar ataxia with apigmentary macular degeneration; repeats dentate nuclei; inferior olivary nuclei; cone–rod dystrophy, loss of variable ophthalmoplegia; pyramidal signs retinal ganglion cells; mild loss of pontine neurons 13q21.33/ATXN8OS Toxic RNA/possible Depigmentation of substantia nigra; Spastic and ataxic dysarthria, nystagmus; polyglutamine severe loss of Purkinje’s cells limb and gait ataxia; limb spasticity; disease diminished vibration perception Cerebellar ataxia; ophthalmoplegia; dysarthria; pyramidal tract signs; weakness; extrapyramidal signs; posterior column signs; central demyelination (in one patient) 22q13/ATXN10 Intronic ATTCT repeats Ataxia; aseizures; polyneuropathy, pyramidal signs; cognitive and neuropsychiatric impairment 15q14–21.3/TTBK2 Tau tubulin kinase-2 Relatively pure cerebellar ataxia aUpper extremity tremor; hyperreflexia; 5q32/PPP2R2B Protein phosphatase PP2A, 51–78 CAG dysarthria; mild or no gait ataxia repeats (normal 7–32) 19q13.3– Kv3.3 Gait ataxia; cerebellar dysarthria; mental 13.4/KCNC3 retardation in French pedigree, pure ataxia in Filipino pedigree 3pter-q24.2/ITPR1 Protein kinase C Pure cerebellar ataxia; rare chorea and gamma cognitive deficits 6q27/TBP InsP3 receptor Pure cerebellar ataxia; rare tremor, cognitive impairment 7q22–q32/ TATA box-binding Reduction in brain weight; loss of Ataxia; dementia; psychiatric symptoms; IFRD1 protein Purkinje’s cells; neuronal inclusion extrapyramidal features; achorea; lower bodies throughout the brain gray limb hyperreflexia matter 7q22–q32 Human interferonGait difficulty; dysmetria; hyporeflexia; related amyotrophy; adecreased vibratory and developmental proprioceptive sense regulator gene-1 (Continued)

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TABLE 16.13  Genetic Loci Associated with Dominantly Inherited Ataxia Syndromes (Continued) Name

Locus/Gene

SCA19/SCA22

1p21–q21

SCA20

11p13–q11

SCA21

7p21.3–p15.1

SCA23

20p13–p12.3

SCA25

2p21–p13

SCA26 SCA27

19p13.3 13q34/FGF114

SCA28

18p11.22–q11.2

SCA29 SCA30 SCA31

Genetically heterogeneous 4q34.3–q35.1 16q21/BEAN

SCA34

ELOVL4

SCA36

NOP56

SCA37

DAB1

SCA38 SCA40 SCA41 SCA42

ELOVL5 CCDC88C TRPC3 CACNA1G

SCA43 SCA44 SCA45 SCA46 SCA47

MME GRM1 FAT2 PLD3 PUM1

Atypical cadherin

SCA48 DRPLA

STUB1 ATN1

E3 ubiquitin ligase Atrophin-1

ADCADN

DNMT1

DNA methyltransferase Beta tubulin

Hypomyelinating TUBB4A leukoencephalopathy (HL) Cerebellar atrophy FGF12 with epileptic encephalopathy Rapid-onset ataxia ATP1A3 a

Protein/Mutation

Pathology

Cerebellar vermis; dentate nuclei; inferior olives; thinning of the cerebellopontine tracts; demyelination of spinal cord posterior and lateral columns (1 patient)

Symptoms/Signs Pure ataxia or ataxia with cognitive impairment; myoclonus; postural tremor Cerebellar ataxia with aspasmodic dysphonia or aspasmodic coughing Cerebellar ataxia; akinesia, dysgraphia; hyporeflexia; postural tremor; rigidity; resting tremor; cognitive impairment Cerebellar ataxia; decreased vibration below the knees

Cerebellar ataxia; lower limb areflexia; peripheral sensory neuropathy Pure cerebellar ataxia Cerebellar ataxia, tremor, amild orofacial dyskinesias, cognitive impairment Cerebellar ataxia; lower limb hyperreflexia; rare ophthalmoparesis; ptosis aCongenital nonprogressive cerebellar ataxia Pure cerebellar ataxia Pure cerebellar ataxia; asensorineural hearing loss Skin changes in youth, disappear in adulthood Ataxia, amyotrophy, and hearing loss

Fibroblast growth factor 14

TGGAA repeat in intron

GGCCTG repeat in intron Adapter in Reelin signaling pathway

Mild atrophy of vermis Voltage-gated calcium channel

Degeneration of dentatorubral and pallidoluysian systems

Basal ganglia atrophy, hypomyelination

Fibroblast growth factor 12

Ataxia and abnormal vertical eye movements Axonal neuropathy Hyperreflexia, spasticity Pure cerebellar ataxia Cerebellar ataxia, mild pyramidal signs Sensorimotor axonal neuropathy Cerebellar ataxia, spasticity Adult-onset cerebellar ataxias Cerebellar ataxia, sensory neuropathy Cerebellar ataxia, developmental delay, seizures Ataxia, earlier-onset cognitive decline Ataxia, chorea, seizures, dementia, myoclonus Deafness, sensory loss, narcolepsy Rigidity, dystonia, chorea

Infantile seizures, intellectual deficits, microcephaly Cerebellar atrophy

These signs can sometimes be used to differentiate this form of SCA from others clinically.

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600 TABLE 16.14  Clinical Features of the Dominantly Inherited Ataxias PURE CEREBELLAR SYNDROME SCA5, SCA6, SCA11, SCA14, SCA15, SCA26, SCA30, SCA31 CEREBELLAR ATAXIA ASSOCIATED WITH OTHER CLINICAL FEATURES Eye Signs

Movement Disorders

Pyramidal Signs

Cognitive Impairment

Slow saccades SCA1, aSCA2, SCA3, SCA7

Parkinsonism SCA1, SCA2, SCA3, SCA12, SCA17, SCA21

SCA1, SCA2, SCA3, SCA1, SCA2, SCA4, SCA7, SCA8, SCA3, SCA13, aSCA17, SCA19, SCA11, SCA12, SCA13, SCA15 SCA21, aSCA27, SCA48 aDRPLA

Ophthalamoplegia SCA1, SCA2, SCA3 Pigmentary retinal degeneration aSCA7

Dystonia SCA3, SCA17, HL Limb and head tremor: SCA8, SCA12, SCA16

a

Seizures

Neuropathy

SCA10, SCA17, SCA1, SCA2, DRPLA SCA3, aSCA4, SCA6, SCA8, SCA27, SCA12, aSCA18, SCA22, aSCA25, SCA38, SCA43, SCA46

a a

Palatal tremor SCA19, SCA20 Dyskinesias aSCA27 Myoclonus SCA2, SCA19, DRPLA Chorea SCA1, SCA17, DRPLA These should be considered first when patients exhibit the indicated clinical syndromes. Modified from Manto U., The Cerebellum, 2005. a

Clinical features • • • •

Family history of similarly affected members. Slow, gradual onset. Phenotypically heterogeneous (Table 16.13). Cerebellar ataxia, dysarthria, dysmetria, and cerebellar tremor ±: • Supranuclear ophthalmoplegia. • Optic atrophy. • Pigmentary retinopathy (SCA7 only). • Dementia. • Extrapyramidal dysfunction.

The clinical syndrome may vary remarkably, even among members of the same family.

TIP • The presence of pigmentary retinopathy in a patient with dominantly inherited ataxia strongly suggests a diagnosis of SCA7.

• Wilson’s disease. • Mitochondrial cytopathy. • Paraneoplastic cerebellar degeneration: usually a subacute ataxic syndrome. • Iatrogenic cadaveric human growth hormone–induced CJD: a drug history of hormonal therapy should be taken from all young well-muscled, or previously well-muscled, patients and top athletes with signs of cerebellar dysfunction. • Sporadic cerebellar degeneration, also known as idiopathic late-onset cerebellar ataxia (ILOCA): age of onset 25–70 years (onset after 55 years: often a relatively pure midline cerebellar syndrome with marked gait ataxia, mild appendicular ataxia). • MSA of the cerebellar type (MSA-C), with sporadic cerebellar degeneration accompanied by autonomic failure (orthostatic hypotension with bladder incontinence). • Other inherited cerebellar ataxias including recessively inherited disorders (see Friedreich’s ataxia). • PSP (dementia and supranuclear ophthalmoplegia).

Investigations Differential diagnosis

• Structural cerebellar, brainstem, or spinal cord lesions (tumor, arteriovenous malformation). • Alcoholic cerebellar degeneration. • Multiple sclerosis. • Hypothyroidism. • Neurosyphilis. • Subacute combined degeneration of the spinal cord (sensory, not cerebellar ataxia).

• Blood DNA analysis using PCR for gene mutations, commonly CAG repeat expansions, on chromosomes 3, 6, 12, 14, and 16. • Cranial CT or, preferably, MRI scan of the brain and craniocervical junction: pronounced cerebellar atrophy, particularly affecting the superior vermis (Figures 16.71–16.73). • Complete blood count and sedimentation rate. • Urea and electrolytes, plasma cortisol, very-long-chain fatty acids (in males, adrenoleukodystrophy).

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FIGURES 16.71–16.73  T1W midline sagittal (Figure 16.71) and T2W axial (Figures 16.72, 16.73) MRI of the brain in a patient with autosomal dominant inherited cerebellar ataxia due to a mutation of the gene for spinocerebellar ataxia 1 on chromosome 6 causing expansion of the trinucleotide CAG repeat. Scans show pronounced atrophy of the medulla, pons, and cerebellum, particularly affecting the superior vermis.

• • • • • • • • • • • •

Thyroid function tests. Liver function tests (alcoholic cerebellar degeneration). VDRL, TPHA. Vitamin B12 and vitamin E. Plasma lactate and pyruvate, mitochondrial DNA analysis (mitochondrial cytopathy). Plasma copper, ceruloplasmin (Wilson’s disease). Alpha fetoprotein (ataxia telangiectasia). Anti-Purkinje’s cell antibodies (paraneoplastic syndrome). ECG, and if abnormal, echocardiography. Nerve conduction studies and EMG. Visual evoked potentials and somatosensory evoked potentials. Autonomic function tests (MSA).

Diagnosis

Clinical syndrome of cerebellar ataxia, positive family history, and positive DNA analysis.

Pathology

Macroscopic changes are atrophy of the brainstem and cerebellum (Figure 16.74). Microscopically, there is loss of neurons and

degenerative changes in various combinations (Figure 16.75) of sites that include: • • • •

Pontine and olivary nuclei. Cerebellar dentate nuclei. Cerebellar Purkinje’s cells. Basal ganglia (substantia nigra, subthalamic nuclei, and red nuclei). • Spinal cord (Clarke’s columns, spinocerebellar tracts, and anterior horn cells). • Peripheral nerves (dorsal root ganglia).

Treatment

No effective therapies exist currently for these disorders. Recent advances in gene-specific treatment have been made possible through development of antisense oligonucleotide (ASO) technology for gene suppression. ASO treatment has already advanced to clinical trials for the polyglutamine disorder, Huntington’s disease.17 ASO-based therapies hold great promise in the polyglutamine SCAs as suggested by improvement of motor dysfunction in mouse models of disease.18–20 A shared mechanism of neuronal dysfunction due to potassium channel

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602 SCA1

Definition and epidemiology

SCA1 is an autosomal dominant disorder due to a pathologic expansion of glutamine repeats in the ATXN1 gene. SCA1 is characterized by cerebellar ataxia associated with variable degrees of oculomotor abnormalities, pyramidal and extrapyramidal features, peripheral neuropathy, and cognitive impairment. SCA1 is one of the SCAs that can be classified on clinical grounds as ADCA type I, according to Harding’s classification. The frequency is variable depending on the population studied and ranges from 6% to 27% of dominant ataxias. It is the most frequent dominant ataxia in South Africa (41%)21 and is also common in Japan, India, Italy, and Australia. SCA1 is less common in Portugal, Brazil, and central Japan. It also is the most rapidly progressive disease, with clear correlation to repeat length, similar to other SCAs.22,23

Etiology and pathophysiology

FIGURE 16.74  Ventral surface of the brain, showing severe atrophy of the medulla, pons, and cerebellum. dysregulation has also been identified, and studies aimed to restore ion channel activity are underway.12 Current treatment remains supportive. Symptomatic medications that have been reported to be of some utility are: • Cholinergic agents: physostigmine, lecithin, and choline chloride. • GABAergic drugs: baclofen and sodium valproate. • Serotonergic compounds: L-5–hydroxytryptophan combined with a peripheral decarboxylase inhibitor, and buspirone hydrochloride.

Prognosis

Gradually progressive.

SCA1 results from expansion of a translated trinucleotide CAG repeat located within exon 8 of the SCA1 gene. The CAG repeat is highly polymorphic in the normal population and the number varies between 4 and 39 repeats. In SCA1, the CAG repeat is unstable and expands to about 40–83 repeats. CAT interruptions, though, can alter the penetrance and severity of disease. The mechanisms mediating SCA1 pathogenesis are still not completely understood. Transgenic mice expressing a mutant human SCA1 allele have shown that eventual development of ataxia is not attributable to cell death per se, but to neuronal dysfunction and morphological alterations that occur long before the onset of ataxia and cell loss. The discovery that residues in ATXN1 outside of the polyglutamine tract are crucial for pathogenesis hints that alterations in the normal function of this protein are linked to its toxicity. Biochemical and genetic studies provide evidence that the polyglutamine expansion enhances interactions that are normally regulated by phosphorylation at the amino acid serine in position 776, and a subsequent alteration in its interaction with other cellular proteins.24 ATXN1-interacting proteins are decreased in patients and animal models of the disease, suggesting that the polyglutamine expansion contributes to disease by both a gain-of-function mechanism and partial loss of function.

Clinical features

FIGURE 16.75  Brainstem from a patient with autosomal dominant cerebellar ataxia (left), showing severe atrophy of the midbrain, pons, and medulla, and a normal brainstem (right). The brainstems have been disconnected from the brains and spinal cords by cuts through the cerebellar peduncles, midbrain, and medulla.

Age at onset of the disease is usually around the third decade of life but can occur as early as 4 and as late as 74 years of age. The disease is insidiously progressive and fatal. Typical disease duration is 21–25 years from the age of onset.25 At onset, the clinical signs consist of cerebellar ataxia, pyramidal signs, which sometimes even precede ataxia, and in most patients, ophthalmoplegia. As the disease progresses, other symptoms occur in variable degrees, such as dysphagia, dysphonia, tongue atrophy, deep sensory loss, peripheral sensory–motor axonal neuropathy, pes cavus, amyotrophy, and fasciculations. Dystonia is the most common extrapyramidal symptom. Rarely, rigidity, tremor, and chorea have also been reported. At the onset of the disease, ocular movement abnormalities include gaze-evoked nystagmus, impairment of the vestibular ocular reflex, and increased amplitude of saccades with normal velocity. In one-half of the patients, the ocular movements are full, and there is upgaze or lateral gaze limitation in the remaining half.

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In later stages of the disease, there is severe ophthalmoplegia in all directions with absent nystagmus and slow velocity in saccades. Neuropsychological features in SCA1 include executive dysfunction.

dysphagia, ophthalmoplegia, incontinence, and mental deficiencies limits patient independence. Autonomic problems can be found at late stages, with vasomotor, cardiac, gastrointestinal, urinary, exocrine gland dysfunction, and malnutrition.

Differential diagnosis

Differential diagnosis

• Other autosomal dominant spinocerebellar ataxias (Table 16.13). • Recessive ataxias (Table 16.12).

Investigations and diagnosis

The diagnostic test for SCA1 is sequencing of the gene and demonstrating an increase in the CAG repeat size.

Pathology

A characteristic feature of SCA1 pathology is the atrophy and loss of Purkinje’s cells from the cerebellar cortex. As SCA1 progresses, pathology is noted in other regions of the brain, including the deep cerebellar nuclei, especially the dentate nucleus, inferior olive, pons, and red nuclei. Cranial nerve nuclei III, X, and XII can also show signs of pathology. A pathologic hallmark of SCA1, as well as most of the other polyglutamine disorders, is the presence of the large inclusions containing the mutant polyglutamine protein. Besides containing mutant ATXN1, the inclusions are positive for ubiquitin and components of the proteasome and chaperone systems.

Treatment

Treatment is supportive. No definitive treatment exists for SCA1.

SCA2 Definition and epidemiology

SCA2 is an autosomal dominant disorder resulting from a pathologic expansion of glutamine repeats in the ATXN2 gene. It can manifest either with a cerebellar syndrome or a parkinsonian syndrome. Later stages involve mainly brainstem, spinal cord, and thalamic degeneration. SCA2 was first recognized in India by Wadia and Swami, who called attention to the early and marked slowing of saccadic eye velocity.26 A large population of approximately 1000 patients in Cuba facilitated research into SCA2. Worldwide, SCA2 is among the three most frequent types of dominant spinocerebellar ataxias, together with SCA3 and SCA6.

Etiology and pathophysiology

Patients with SCA2 have an expansion of a CAG repeat located in the 5’ end of the coding region of the ATXN2 gene. Expansions of 35–64 repeats are found in affected individuals. The normal SCA2 alleles contain 17–29 repeats. There is a strong inverse correlation between the size of the CAG repeat and the age at onset of symptoms. Ataxin-2 appears to play a role in RNA metabolism, interacts with plasma membrane proteins, and has putative roles in both of these processes.

Clinical features

SCA2 overlaps clinically with other dominantly inherited ataxias, and a definitive diagnosis depends on genetic testing. Findings suggesting SCA2 include a combination of a gait ataxia/dysarthria with parkinsonian rigidity/bradykinesia with early and marked saccadic slowing, severe tremor of postural or action type, initial hyperreflexia followed by eventual hyporeflexia, early myoclonus or fasciculation-like movements, and muscle cramps. In the course of disease, immobility together with distal amyotrophy,

Other ADCAs (Table 16.13).

Investigations and diagnosis

The diagnostic test for SCA2 is sequencing of the gene and demonstrating an increase in CAG repeat size.

Pathology

Macroscopically, marked atrophy is seen in the cerebellum, pons, frontal lobe, medulla oblongata, and cranial nerves, as well as pallor of the substantia nigra. The cerebellar degeneration pattern in SCA2 is characterized by an early and pronounced degeneration of Purkinje’s neurons throughout both hemispheres and the vermis, with rarefaction of granule cells later in the course of the disease. There is a relative sparing of the dentate nucleus.

Treatment

Treatment is supportive. No definitive treatment exists for SCA2.

SCA3 Definition and epidemiology

SCA3 or Machado–Joseph disease (MJD) is a dominantly inherited ataxia. SCA3 results from expansion of a glutamine-encoding CAG repeat in the ATXN3 gene. The disease has a worldwide distribution, including families described in Portugal, the Azores, Spain, Italy, United States, Canada, Brazil, China, Taiwan, and Japan. It is likely the most prevalent dominantly inherited ataxia worldwide.10

Etiology and pathophysiology

SCA3 belongs to the class of disorders with an abnormal expansion of a glutamine-encoding CAG repeat in the 10th exon of the ATXN3 gene. In MJD/SCA3, the normal glutamine repeat range of 12–40 is expanded to a disease-causing repeat range of 60–84. Ataxin-3 is a 42 kDa, widely expressed protein that resides in both the nucleus and the cytoplasm of cells. It has been implicated in many aspects of intracellular protein quality control pathways that rely on ubiquitin, a small modifier protein. Ataxin-3 is a deubiquitinating enzyme (DUB) that cleaves ubiquitin from ubiquitinated substrates or polyubiquitin chains. Another proposed role for ataxin-3 is in the regulation of gene transcription. The link between the enzymatic action of ataxin-3 as a DUB and its role in gene transcription is unclear. One current hypothesis posits that polyglutamine expansion interferes with ataxin-3 DUB function in some manner that compromises one or more biochemical pathways dependent on ubiquitin, including the ubiquitin–proteasome protein degradation system. A consequence would be misfolding and aggregation of proteins in vulnerable neurons. No direct evidence for altered enzymatic function of glutamine-expanded ataxin-3 exists, however. It is clear that polyQ ataxin-3 resides more in the nucleus than the wild-type isoform, suggesting at least indirect, if not direct, effects on transcriptional elements.

Clinical features

Even within the same family, persons affected with MJD/SCA3 can have widely varying clinical signs and symptoms. The exact reason for this is unclear, but suspected to relate to polyQ length.

Hankey’s Clinical Neurology

604 The first description of MJD occurred in 1972 in a family (the Machado family) of Portuguese immigrants in Massachusetts, who presented a hereditary ataxia characterized by subacute onset of ataxia after age 40, associated with end-gaze nystagmus, mild dysarthria, hyporeflexia, and distal muscle atrophy. When the clinical syndrome was first described in French and German families, which later was shown to be SCA3, the disease features seemed distinct enough from those experienced by affected families with MJD to assume that it was a separate disease. MJD had already been described and mapped to chromosome 14. Only when the actual MJD mutation was discovered, it was demonstrated that SCA3 was in fact the same disease as MJD. The clinical heterogeneity of the disorder is illustrated by the classification of SCA3 into three distinct phenotypic forms, Types 1–3. Cerebellar ataxia and ophthalmoplegia are common to all types of SCA3. Facial and lingual fasciculations and staring due to lid retraction are other uncommon but helpful diagnostic features.

Type 1 MJD

• Early symptom onset, typically around 25 years. • Pyramidal signs. • Dystonic postures.

Type 2 MJD

• Most common type. • Middle age symptom onset (40 years, mean). • Ataxia and ophthalmoplegia with or without pyramidal signs.

Type 3 MJD

• Later onset (47 years, mean). • Amyotrophy prominent. • Slow progression.

In addition to these three categories, some patients present with levodopa-responsive parkinsonism that is clinically indistinguishable from idiopathic PD.

Differential diagnosis

Other autosomal dominant spinocerebellar ataxias (Table 16.13).

Investigations and diagnosis

The diagnostic test for SCA3 is sequencing of the gene and demonstrating an increase in the CAG repeat size.

Pathology

The neuropathology consists of neuronal loss and gliosis in the substantia nigra, motor cranial nuclei, dentate nucleus of the cerebellum, and variable neuronal loss with gliosis in the cerebellar cortex and neostriatum. The cerebellar cortex is significantly less affected than in SCA1 or SCA2 with typically < 30% loss of Purkinje’s neurons.27 The inferior olivary nuclei are normal. Loss of nuclei in the substantia nigra pars compacta often mimics the degeneration seen in idiopathic PD.

Treatment

Treatment is supportive. No definitive treatment exists for SCA3.

TIP • In patients presenting with a family history of heterogeneous neurologic diagnoses including cerebellar ataxia, parkinsonism, and amyotrophy, consider testing for SCA3.

SCA6 Definition and epidemiology

SCA6 is a progressive ataxic disorder caused by a CAG repeat expansion in the CACNA1A gene encoding the a1A subunit of the neuronal P/Q-type voltage-gated calcium channel (VGCC). The worldwide prevalence is variable, highest in Japan10 and moderate in Europe, although accurate absolute numbers are not available. Genetic epidemiologic studies in England have estimated the frequency of the disease-causing mutation at approximately 1 in every 10,000 individuals.

Etiology and pathophysiology

SCA6 is caused by a mutation in the C-terminus of the a1A subunit of the P/Q-type VGCC. Numerous studies have attempted to determine how the polyglutamine expansion affects the properties of the P/Q-type calcium channel, and ultimately how a small polyglutamine expansion in a VGCC may lead to cell death. Unfortunately, these results appear highly variable and depend on which expression system and auxiliary VGCC subunits are used. It was recently observed that the endogenous free C-terminal fragment localizes to Purkinje’s cell nuclei. In addition, C-terminal fragments cleaved from recombinant a1A subunits or expressed as isolated C-termini localize to nuclei in cultured cell lines and primary granule cell cultures. Cleavage and nuclear localization are not however affected by polyglutamine length. The relevance of the cleaved fragment to disease pathogenesis is unclear.

Clinical features

SCA6 is often described as a pure cerebellar ataxia, in comparison to SCAs that are complicated by cortical, subcortical, and/ or brainstem dysfunction. It is characterized by gaze-evoked nystagmus, dysarthria, progressive imbalance, and severe limb incoordination. Some patients with SCA6 experience occasional bouts of vertigo, but there is no muscle weakness or cognitive impairment. SCA6 is a late-onset disorder with an average age of onset at 50 years. The disease usually progresses slowly and does not shorten life span, but most patients do become wheelchair bound by their late 60s.

Differential diagnosis

Other autosomal dominant and recessive spinocerebellar ataxias (Tables 16.12 and 16.13).

Investigations and diagnosis

The diagnostic test for SCA6 is sequencing of the gene and demonstrating an increase in the CAG repeat size.

Pathology

Postmortem analysis of the brains from SCA6 patients demonstrates cerebellar atrophy due to selective Purkinje’s cell degeneration. These brains display a strikingly selective loss of Purkinje’s cells, with particularly high losses in the midline vermal region of the cerebellum. The surviving Purkinje’s cells frequently have decreased dendritic arborizations and decreased cytoplasmic organelles compared with normal controls.

Degenerative Diseases of the Nervous System Mild to moderate granule cell loss appears to be secondary to Purkinje’s cell loss, but basket, stellate, and Golgi’s cells of the cerebellar cortex appear largely unaffected.

Treatment

Treatment is supportive. No definitive treatment exists for SCA6.

TIPS • Since SCA1, SCA2, SCA3, and SCA6 account for over 50% of the autosomal dominant ataxias in clinical practice, consider using a tiered approach to genetic testing. Test first for these more common dominant ataxias. • In patients presenting with a mix of familial ataxia and features of HD (chorea, dementia, and neuropsychiatric symptoms), consider testing for DRPLA and SCA17.

AUTOSOMAL RECESSIVE CEREBELLAR ATAXIAS

605 long arm of chromosome 9 (9q13–q21.1). FRDA encodes a novel 210 amino acid protein, frataxin, which is involved in mitochondrial function and iron metabolism. The expanded repeat interferes with FRDA transcription, leading to lowered expression of the protein. Complete loss of the protein is incompatible with life. More than 95% of patients with classic Friedreich’s ataxia are homozygous for an expansion in their GAA repeat sequence, but a few have a combination of an increase in GAA repeats in one allele and a point mutation in the other allele, confirming that Friedreich’s ataxia is a loss-of-function disorder. Larger GAA expansions correlate with lower frataxin expression, earlier age of onset, and shorter times to loss of ambulation.

Gene expression

The GAA repeat represses transcription of frataxin mRNA by altering local chromatin structure. 32 Frataxin appears to be a nuclear encoded mitochondrial protein important for normal production of cellular energy. Reduced frataxin in spinal cord, heart, and pancreas has been postulated to cause neuronal degeneration, cardiomyopathy, and an increased risk of diabetes by altering iron homeostasis in cells and their mitochondria.

Numerous recessive ataxias have now been identified, and a description of merely the more common recessive ataxias is beyond the scope of this chapter. More than 92 recessive ataxias where ataxia is the predominant clinical feature of disease and over 82 causes of recessive disease where ataxia is a prominent symptom have now been identified. Recent work has attempted to classify the recessive ataxias based on pathogenic mechanisms and, three major themes have emerged:28 mitochondrial dysfunction, impaired DNA repair, and complex lipid homeostasis. In the following sections, a brief description of the more common recessive ataxias is provided.

Clinical features

FRIEDREICH’S ATAXIA

Physical examination

Definition and epidemiology

This is an autosomal recessively inherited disease caused by a large increase in the number of trinucleotide GAA repeats within the first intron of the FRDA gene on the proximal long arm of chromosome 9.29 This results in decreased expression of the target protein frataxin, and dysfunction of the central and peripheral nervous systems and the heart. Clinically, when it presents in classical form, Friedreich’s ataxia is characterized by onset before age 25 years of progressive limb and gait ataxia, cerebellar dysarthria, depressed deep tendon reflexes, pyramidal signs, distal vibration and proprioceptive sensory loss, axonal sensory neuropathy, and often skeletal deformities and hypertrophic cardiomyopathy. 30 Now that genetic testing has become available for this disorder, cases with onset in adult life are found commonly, and cases with onset late in life have been reported. • Prevalence: 2 per 100,000; the most common form of hereditary ataxia. 31 • Carrier frequency: 1 in 120 in European populations. • Age: adolescence and early adult life. Onset usually occurs at 8–15 years.

Etiology and pathophysiology Gene mutation

Friedreich’s ataxia results from an expanded GAA repeat in the first intron of the FRDA gene, which is located on the proximal

The clinical spectrum for Friedreich’s ataxia is broader than previously recognized.

History

Symptoms of incoordination and ataxia of the lower limbs begin in the early ‘teen’ years and progress to involve the upper limbs and cranial musculature, so that by the age of 25 years most patients have some well-established neurologic signs. However, there are cases of patients not diagnosed until their 60s or 70s.

• General: • Kyphoscoliosis (may affect posture and pulmonary function). • Foot deformity (pes cavus and extension of the metatarsophalangeal joints in about 90% of patients). • Hypertrophic cardiomyopathy. • Cranial nerves: • Reduced visual acuity. • Optic atrophy. • Eye movements: – Square wave jerks at fixation. – Saccadic intrusion upon smooth ocular pursuits (jerky pursuits). – Gaze-evoked nystagmus. – Reduced gain of vestibulo-ocular reflex. • Speech: slurred, slow, staccato, and explosive (ataxic dysarthria). • Limbs: • Wasting of the intrinsic hand and distal lower leg muscles. • Weakness (pyramidal) of the legs (paraparesis). • Ataxia of the limbs, speech, and eye movements: – Bilateral cerebellar tremor. – Dysmetria (overshoot). – Dysdiadochokinesia (poor coordination of rapid alternating movements).

Hankey’s Clinical Neurology

606 • Absent deep tendon reflexes due to axonal degeneration of afferent fibers. This is reflected neurophysiologically by absence of sensory nerve action potential (SNAPs) and loss of the H-reflex. Note that rare patients present with late-onset symptoms, retained reflexes, and spasticity. • Extensor plantar responses. • Impaired touch, pain, and temperature sensations in the feet and distal lower limbs are unusual but found in a small fraction of patients. • Impaired vibration sense in the feet and hands. • Impaired joint position sense in the distal lower limbs and hands. • Gait: spastic, ataxic (cerebellar and sensory) gait.

TIP • In adult patients, Friedreich’s ataxia can present with both ataxia and concomitant spasticity with retained reflexes.

Differential diagnosis

The differential for recessively inherited progressive cerebellar ataxias is long and includes many nonhereditary disorders (see Table 16.12 for an extensive differential diagnosis list).

Inherited ataxias with known metabolic defects Ataxia with isolated vitamin E (α-tocopherol) deficiency

• Inherited: autosomal recessive: frameshift mutations in the gene encoding α-tocopherol-transfer protein (α-TTP) on chromosome 8q (13.1–13.3). 33 • Acquired fat malabsorption syndromes: • Abeta- and hypobetalipoproteinemia (Bassen–Kornzweig syndrome). • Cholestatic liver disease. • Short bowel syndrome. • Onset in second to sixth decade of life.

Progressive ataxia, dysarthria, areflexia, extensor plantar responses, and proprioceptive loss ± ophthalmoplegia, dystonic posturing of hands/feet, bradykinesia, tongue fasciculations, and pigmentary retinal degeneration. Low serum vitamin E (11.7 μmol/l [< 5 μg/mL]). Low serum lipid concentrations, particularly cholesterol. Oral vitamin E (800–3500 mg/day [800–3500 IU]) may cause improvement or retard progression.

Hexosaminidase A deficiency (GM2 gangliosidosis)

• Onset in adolescence or early adult life. • Ataxia, tremor, supranuclear ophthalmoplegia, facial grimacing, dystonia, and proximal neurogenic muscle weakness.

Cholestanolosis (cerebrotendinous xanthomatosis). • • • •

Autosomal recessive inheritance. Defective bile salt metabolism. Onset in second decade of life. Ataxia, dementia, spasticity, peripheral neuropathy, cataracts, tendon xanthomata. • Chenodeoxycholic acid treatment may improve neurologic function. 34

Leukodystrophies

• Metachromatic leukodystrophy (arylsulfatase A deficiency). • Late-onset globoid cell leukodystrophy. • Adrenoleukomyeloneuropathy: a phenotypic variant of adrenoleukodystrophy.

Refsum’s disease

• Peroxisomal disorder characterized by retinitis pigmentosa, sensorimotor polyneuropathy, and cerebellar ataxia. ECG changes, sensorineural hearing loss, and ichthyosis are also seen. 35 • The disease usually presents in childhood but can present in early adulthood. • Results from a mutation in phytanoyl-CoA hydroxylase, an enzyme that acts as a phytanic acid oxidase. In the absence of the enzyme, phytanic acid accumulates in the tissues, resulting in toxicity. • Testing involves measuring phytanic acid levels in blood or tissue. • A diet low in phytanic acid can reduce symptoms and potentially be curative. 36

Niemann–Pick disease type C (juvenile dystonic lipidosis)

• Ataxia, supranuclear gaze palsy, and psychosis. • Can develop progressive intellectual disability. • Autosomal recessive inheritance of mutations in NPC1 (18q11.2) or NPC2 (14q24.3). • Sphingomyelinase activity is normal. • Foamy storage cells in bone marrow. • Treatment with miglustat has been shown to slow progression of neurologic symptoms. 33a

Early-onset cerebellar ataxia with retained tendon reflexes (Holmes’ ataxia)

• Optic atrophy, severe skeletal deformity, and cardiac involvement do not occur. • Deep tendon reflexes are normal or increased. • Gait may have a spastic component. • Prognosis is worse than Friedreich’s ataxia. • Associated features include: • Hypogonadism. • Myoclonus. • Pigmentary retinopathy. • Optic atrophy ± mental retardation (including Behr’s optic atrophy syndrome). • Cataract and mental retardation (Marinesco–Sjögren syndrome). • Childhood deafness. • Congenital deafness; extrapyramidal features.

Multiple sclerosis

• Relapsing and remitting course is common in young-onset cases. • Symptoms are typically subacute in onset with gradual progression and improvement. • Can involve bladder symptoms and patchy sensory loss. • CSF usually shows elevated protein and IgG and oligoclonal bands. • MRI brain usually shows multiple lesions in periventricular white matter, juxtacortical space, posterior fossa, and brainstem.

Degenerative Diseases of the Nervous System

607

Structural spinal cord lesion (spinal cord tumor or arteriovenous malformation) • • • • •

Pain, particularly nerve root pain, is common. Progressive spasticity below the level of the lesion. Progressive urgency of micturition. Sensory level. MRI (± spinal angiography) of spinal cord discloses a focal lesion.

Syphilitic pachymeningitis

• Rare. • CSF pleocytosis, raised protein and positive VDRL, TPHA, fluorescent treponemal antibody.

Subacute combined degeneration of the spinal cord

• Ataxia is predominantly sensory rather than cerebellar. • Low serum vitamin B12 level. • Antibodies to intrinsic factor and gastric parietal cell may be present. • MRI shows hyperintense T2 signal change typically in dorsal columns.

Other • • • • • •

Mitochondrial cytopathy. Wilson’s disease. Ceroid lipofuscinosis. Sialidosis. Ataxia telangiectasia, ATLD (see below). Ataxia with oculomotor apraxia I and II (see below).

Investigations

• ECG and echocardiography: many have obstructive hypertrophic cardiomyopathy. • Pulmonary function tests: may deteriorate due to kyphoscoliosis. • Nerve conduction studies: • Absent sensory nerve action potentials. • Prolonged sensory conduction velocities. • Loss of H-reflex indicative of afferent axonal neuropathy. • Somatosensory evoked potentials: absence or abnormalities of cortical responses to peroneal or tibial nerve stimulation. • Electronystagmography: fixational instability with square wave jerks. • MRI scan of brain and craniocervical junction: nonspecific, mild atrophy of the cerebellum (Figures 16.76, 16.77), the cervicomedullary junction, and upper cervical spinal cord may be present. • Molecular DNA analysis for point mutation in FRDA, or GAA trinucleotide expansion in the first FRDA intron, on the proximal long arm of chromosome 9 (9q13–q21.1): useful for diagnosis, determination of prognosis, and genetic counseling.

Tests for other disorders on differential diagnosis for reces‑ sive, metabolic, or inflammatory ataxias • Full blood count with peripheral smear for acanthocytes or sideroblasts. • Serum glucose.

FIGURES 16.76, 16.77  T1W midline sagittal (Figure 16.76) and T2W axial (Figure 16.77) MRI of the brain in a patient with Freidreich’s ataxia. Note the marked cerebellar atrophy (arrows), but the rest of the brain, including the brainstem, is normal.

• • • • • • • • • • •

Serum lipids. RPR or VDRL, TPHA. Thyroid function tests and antithyroglobulin antibodies. Vitamins B12 and E. Copper, ceruloplasmin (Wilson’s disease, copper deficiency). Cortisol and long-chain fatty acids (L C26:C22, C24:C22 ratio) if spastic paraparesis, axonal neuropathy, male (adrenoleukodystrophy). Alpha fetoprotein (ataxia telangiectasia and ataxia with oculomotor apraxia type II). Antigliadin, antitissue transglutaminase, and antiendomysial antibodies (celiac disease). Anti GAD-65 antibodies (autoimmune ataxia). Paraneoplastic antibodies, including Anti-HU, YO, and RI if subacute course (paraneoplastic). Hexosaminidase: if vertical gaze palsy, dystonia, neurogenic weakness.

Hankey’s Clinical Neurology

608 • Arylsulfatase A (metachromatic leukodystrophy). • Galactocerebrosidase: if dementia, psychiatric problems, optic atrophy, demyelinating neuropathy, radiologic evidence of white matter disease. • Plasma lactate and pyruvate, muscle biopsy and blood for mitochondrial DNA analysis: if short stature, myoclonus, retinopathy, dementia, stroke-like episodes, and fatiguable weakness. • Cholestanol: if cataracts or tendinous swellings. • Gonadotrophins: if hypogonadism. • Ammonia/amino acids: if fluctuating course, mental retardation. • Bone marrow examination for sea blue histiocytes (Niemann–Pick disease type C): if vertical gaze palsy, epileptic seizures, extrapyramidal signs, dementia. • Phytanic acid levels (Refsum’s disease): if retinitis pigmentosa, sensorimotor polyneuropathy, hearing loss, or ichthyosis (excessive dry scaly skin).

FIGURE 16.78  Normal cerebellar cortex, H&E stain, with plentiful Purkinje’s cells (two arrowed).

TIP • A number of forms of ataxia related to metabolic disorders are treatable if identified early. Thus, measuring cholestanol (cerebrotendinous xanthomatosis), phytanic acid and other long-chain fatty acids (Refsum’s disease), vitamin E (AVED, Bassen–Kornzweig syndrome), and ceruloplasmin (Wilson’s disease) should all be considered early in the work-up of patients with the correct clinical context.

Diagnosis

• Progressive limb and gait ataxia developing before the age of 25 years. • Absent deep tendon reflexes in most cases. • Electrophysiologic evidence of axonal sensory neuropathy. • Point mutation in FRDA or unstable GAA trinucleotide expansion in the first FRDA intron, on the proximal long arm of chromosome 9 (9q13–q21.1).

FIGURE 16.79  Higher magnification view of the cerebellar cortex of a patient with Freidreich’s ataxia, showing Purkinje’s cell loss. • Diabetes mellitus in about 10% of patients. • Carbohydrate intolerance in an additional 20%. • Reduced insulin response to arginine stimulation in all patients.

Pathology

• Nervous system: • Dorsal root ganglia: degeneration/loss of large sensory neurons. • Dying back of axons in: – Large myelinated sensory nerve fibers in peripheral nerves. – Posterior columns of the spinal cord. – Nucleus gracilis and cuneatus, and the medial lemniscus. – Dorsal and ventral spinocerebellar tracts. • Corticospinal tracts: demyelination, with increasing involvement caudally. • Cerebellum: – Loss of Purkinje’s cells (Figures 16.78, 16.79). – Degeneration of dentate nucleus. – Axonal loss and demyelination of superior cerebellar peduncles. • Heart: degeneration leading to hypertrophy and diffuse fibrosis. • Pancreas: degeneration, giving rise to:

Treatment

Clinical trials with idebenone have demonstrated some benefit for cardiac hypertrophy in Friedreich’s patients.37,38 There was a suggestion of possible benefit for neurologic symptoms at higher doses, especially in patients not yet wheelchair bound. 39 Clinical trials are currently underway to assess this prospectively. Symptomatic treatment with: • • • • • • • • •

Spasticity medication (e.g. baclofen, botulinum toxin). Physiotherapy. Occupational therapy. Podiatry. Speech therapy. Social work. Cardiology consultation: for hypertrophic cardiomyopathy. Pulmonary function. Orthopedic spinal surgery (Harrington’s rod); for scoliosis.

Degenerative Diseases of the Nervous System

609

Prognosis

Progressive deterioration. Most patients are unable to walk independently and safely > 5–10 years after the onset of symptoms, so almost all are confined to a wheelchair by their late 20s. Death usually occurs 10–25 years after onset of symptoms (in 40s and 50s), usually due to cardiopulmonary complications.

ATAXIA TELANGIECTASIA (LOUIS–BAR SYNDROME) Definition and epidemiology

A rare autosomal recessive disorder characterized by onset of ataxia in early childhood and subsequent progressive neuromotor degeneration, usually resulting in dependence on a wheelchair by 10 years of age.40 • Incidence: rare. • Age: early childhood. • Gender: M = F.

Etiology and pathophysiology

• Autosomal recessive inheritance. • Defective gene: ATM, mapped to chromosome 11q22–23, which encodes a protein belonging to the superfamily of phosphatidylinositol-3’ kinases. • Breaks in chromosome 14 and translocations. • Decreased synthesis of immunoglobulins. • Defective repair of DNA. • ATM homozygotes are hypersensitive to ionizing radiation and radiomimetic drugs.

FIGURES 16.80, 16.81  Conjunctival telangiectases, most evident in the outer parts of the bulbar conjunctivae, in a young man with ataxia telangiectasia.

Clinical features

• 1–2 years of age: onset with the acquisition of walking; ataxic–dyskinetic syndrome: awkward, unsteady gait. • 4–5 years of age: • Telangiectases: subpapillary venous plexuses, most evident in the outer parts of the bulbar conjunctivae (Figures 16.80, 16.81), over the ears, on exposed parts of the neck (Figures 16.82, 16.83), on the bridge of the nose and cheeks in a butterfly pattern, and in the flexor creases of the forearms (Figures 16.84, 16.85). • Ocular pursuit: jerky due to interruption by saccadic intrusions. • Saccades: slow and long latency. • Apraxia for voluntary horizontal gaze (the head, not the eyes, turn on attempting to look to the side). • Loss of optokinetic nystagmus. • Limb ataxia and dysarthric speech. • Choreoathetosis. • Grimacing. • 9–10 years of age: • Mild intellectual decline. • Mild polyneuropathy: hyporeflexia. • Growth retardation. • 10–20 years of age: • Progressive decline. • Premature aging. • Recurrent pulmonary and sinus infections due to immunologic abnormalities. • Death due to intercurrent bronchopulmonary infection or neoplasia, usually lymphoma, less often glioma.

FIGURES 16.82, 16.83  Telangiectases on exposed parts of the neck and back.

610

Hankey’s Clinical Neurology • Cockayne’s syndrome is a rare disorder with ataxia and deafness similar to XP, but also characterized by retinal degeneration and accelerated aging without an increased incidence of malignancies. It is caused by a defect in transcription-related DNA repair.

Ataxia with oculomotor apraxia type 1

• Early-onset cerebellar ataxia with oculomotor apraxia, chorea, facial and limb dystonias, sensorimotor polyneuropathy, and cognitive impairment. • Usually presents in the first decade of life, although symptom onset has been reported as late as age 25. • Associated with hypercholesterolemia and hypoalbum­inemia. • Results from a mutation in the APTX gene. APTX encodes a protein, aprataxin, that is involved in repair of singlestranded DNA breaks. • A subset of patients with ataxia with oculomotor apraxia type 1 (AOA1) have been found to have a deficiency in coenzyme Q10 and may respond to dietary supplementation.

Ataxia with oculomotor apraxia type 2

• More common than AOA1 and has a later age of onset, in the 20s to 50s. (AOA1 and AOA2 together represent ∼20% of autosomal recessive cerebellar ataxia cases.) • Cognitive impairment and oculomotor apraxia are only featured in approximately 50% of cases. • Demonstrates elevated AFP. • Results from mutations in the gene SETX which encodes a protein, senataxin, of unknown function.

Autosomal recessive spastic ataxia (of Charlevoix–Saguenay)

FIGURES 16.84, 16.85  Telangiectases in the flexor crease of the right forearm.

Differential diagnosis Ataxia telangiectasia–like diseases

• MUR-11 deficiency and Nijmegen breakage syndrome: • Present with later onset and slower progression. No telangiectasias. • Result from deficiencies of other proteins (MUR11 and NBS1, respectively) that are involved in the same DNA repair pathway as ATM. • Alpha fetoprotein (AFP) levels may be normal or slightly elevated. • Xeroderma pigmentosum (XP) is a rare, genetically heterogeneous group of disorders caused by mutations in DNA excision repair enzymes. Presents with ataxia, cognitive decline, peripheral neuropathy, sensorineural hearing loss, and choreoathetosis in addition to a variety of cutaneous lesions.

• Rare, early-onset disorder with early spasticity, peripheral neuropathy, finger and foot deformities, and hypermyelination of retinal nerve fibers. Most patients have normal intelligence until late in the disease course. • Initially described in families from Quebec, but cases in Europe and Japan have now been described. • Children are usually symptomatic by 1 year of age. • Slowly progressive with most people able to ambulate into their 20s or 30s before becoming wheelchair bound in later life. • Pathologically, patients have cerebellar vermis atrophy and an almost complete absence of Purkinje’s cells. • Autosomal recessive spastic ataxia of Charlevoix– Saguenay (ARSACS) results from a mutation in the SACS gene which encodes the protein sacsin, whose function is unknown, although it has homology to a number of heatshock proteins. • Treatment is supportive.

Autosomal recessive cerebellar ataxia type 1

• Recently described late-onset, slowly progressive cerebellar ataxia. • Onset is usually in the early 30s, with prominent dysarthria as the only other consistent finding. • Imaging studies reveal isolated cerebellar atrophy.

Degenerative Diseases of the Nervous System • The prevalence of the disorder worldwide is unknown, but it appears to be the most common inherited cause of cerebellar ataxia in Quebec where it was first identified. • Results from truncation mutations in the SYNE1 gene on chromosome 6, which encodes a large protein of unknown function.

Other differential diagnoses

• Metachromatic leukodystrophy: reduced arylsulfatase A in urine. • Neuroaxonal dystrophy (degeneration): characteristic spheroids within axons on electron microscopy of skin and conjunctival nerves. • Niemann–Pick disease (types A and B): reduced sphingomyelinase in leukocytes and cultured fibroblasts. • GM1 gangliosidosis: deficiency of β-galactosidase activity in leukocytes and cultured fibroblasts. • Neuronal ceroid lipofuscinosis: inclusions (translucent vacuoles) in lymphocytes and azurophilic granules in neutrophils. • Abeta-lipoproteinemia (Bassen–Kornzweig acanthocytosis): thorny red blood cells (acanthocytes), reduced serum low-density lipoproteins. • Friedreich’s ataxia.

Investigations

• Lymphopenia. • Immunoglobulins: IgA, IgE and isotypes, IgG2, IgG4: reduced or absent. • Failure of delayed hypersensitivity reactions. • Abnormal humoral and cell-mediated immunity. • AFP: elevated serum levels in almost all patients. • CT or MRI brain scan may demonstrate cerebellar atrophy and occasionally intracranial vascular malformations may be present.

TIP • AFP can be used as a screening test for ataxia telangiectasia and ataxia with oculomotor apraxia type II prior to formal genetic testing.

Diagnosis • • • •

Clinical features consistent with diagnosis. Abnormal humoral and cell-mediated immunity. Raised serum AFP. Genetic testing is available on a research basis only.

Pathology

• Nervous system: • Cerebellar cortex: severe degeneration; extensive loss of Purkinje’s cells. • Brain and spinal cord white matter: vascular abnormalities, like the mucocutaneous ones, are scattered diffusely in a few cases. • Substantia nigra and locus ceruleus: there may be loss of pigmented cells, with cytoplasmic inclusions (Lewy bodies) in the cells that remain. • Anterior horn cells: loss at all levels of the spinal cord.

611 • • • •

Posterior columns: loss of myelinated fibers. Spinocerebellar tracts: loss of myelinated fibers. Sympathetic ganglia cells: degeneration. Dorsal nerve root ganglion neurons: intranuclear inclusions and bizarre nuclear formations may be found in the satellite cells (amphicytes). • Posterior nerve roots: degeneration. • Peripheral nerves: loss of myelinated fibers. • Thymus: hypoplasia. • Lymph nodes: loss of follicles.

Treatment

Treatment is supportive. Case report level data suggest responses in some patients to betamethasone.41 Prophylaxis of recurrent infections due to immune defect is recommended.

Prognosis

Prognosis is poor. Median age at death is 20 years.

X-LINKED CAUSES OF ATAXIA FRAGILE X-ASSOCIATED TREMOR ATAXIA SYNDROME Definition and epidemiology

• Late onset (almost always after 50, often not until 70s or 80s) progressive neurodegenerative disorder.42 • Although the causative mutation of FXTAS is present in ∼1:813 men and ∼1:250 women,43 the prevalence appears to be low due to incomplete penetrance. • The causative mutation shows incomplete penetrance. The disorder is estimated to affect up to 40% of males with premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene who are older than 50 years.44 • Penetrance is higher in patients with longer repeats (greater than 80 CGGs) and increases with age, such that penetrance of longer repeats in men over 80 years of age is ∼75%.45 • Clinically affected females have been reported, but their frequency remains unclear. • Most commonly seen in the grandfathers or mothers of children with fragile X syndrome.

Etiology and pathophysiology

FXTAS is caused by an expanded CGG repeat in the 5’ untranslated region of the FMR1 gene on the X chromosome.46 Normally, the sequence is less than 45 CGG repeats. Expansion to greater than 200 CGG repeats (a ‘full’ mutation) leads to transcriptional silencing of the FMR1 gene and causes fragile X syndrome, the most common inherited cause of mental retardation. Patients with FXTAS have a repeat between 50 and 200 CGG repeats (a ‘premutation’ range repeat). The FMR1 gene in premutation carriers is transcribed efficiently and there is near-normal expression of the fragile X mental retardation protein, FMRP. However, there is a five- to eightfold increase in FMR1 mRNA levels.47 Pathologically, it is associated with diffuse brain atrophy with loss of cerebellar Purkinje’s cells. Microscopically, degenerating areas of the brain demonstrate large ubiquitin positive intranuclear inclusions in glia and neurons.48 The FMR1 mRNA

Hankey’s Clinical Neurology

612 containing the expanded CGG repeat is thought to elicit neurodegeneration directly via a gain-of-function mechanism. The hypothesis is that the expanded CGG repeat binds to, and sequesters, certain RNA-binding proteins involved in RNA splicing, leading to aberrant splicing of other mRNAs.49

Clinical features

• Most patients have an action tremor and cerebellar gait disorder greater than appendicular cerebellar ataxia. • Some patients have parkinsonism, which can be levodopa responsive. • Some patients have cognitive decline, including frank dementia characterized by prominent executive dysfunction. • Some patients have a sensory or sensory and motor axonal polyneuropathy. • Some patients have dysautonomia and can present with a syndrome similar to MSA. • There are reports of increased anxiety, disinhibition, depression, and apathy in FXTAS patients, but the frequency of these symptoms is unclear.

TIP • Ask older patients about a history of autism, mental retardation, and early menopause in their children and grandchildren as a hint to a diagnosis of FXTAS.

Differential diagnosis

Multiple system atrophy of the cerebellar type or parkinsonian type (MSA-C or MSA-P, also known as olivo-ponto-cerebellar atrophy, nigrostriatal degeneration, or Shy–Drager syndrome). MSA is a sporadic neurodegenerative disorder affecting the brainstem, cerebellum, and basal ganglia that usually begins in the fifth or sixth decade of life. It is the most common cause of progressive cerebellar degeneration in adults, representing 29% of cases in one large published series.50 Clinically, it is characterized by a variety of symptoms including parkinsonism, cerebellar signs including ataxia, autonomic dysfunction, pyramidal dysfunction, and, in a subset, dementia.51 Autonomic symptoms are often prominent with urinary incontinence and orthostatic hypotension leading to recurrent syncope and presyncopal events. Pathologically, it is an alpha-synucleinopathy akin to PD or Lewy body dementia, but the pathology and inclusions are seen in oligodendroglia and are often most predominant in the brainstem, basal ganglia, cerebellum, and spinal cord.52 MSA-C is a subtype of MSA in which the cerebellar signs are paramount with few other clinical findings early in the course of the disease. The diagnosis (prior to autopsy) is based on history and imaging and the exclusion of other causes discussed above.

Parkinson’s disease and other atypical parkinsonian syndromes • PSP: vertical gaze palsy uncommon in FXTAS; tremor uncommon in PSP. • Vascular parkinsonism: MRI imaging is typically different, stepwise progression.

FIGURE 16.86  The middle cerebellar peduncle (‘MCP’) sign, seen in a patient with fragile X-associated tremor ataxia syndrome (FXTAS). Axial T2 image through the cerebellum demonstrating bilateral middle cerebellar peduncle hyperintensities, seen classically in patients with FXTAS. Also note cerebellar and pontine atrophy. (Courtesy of Deborah Hall, Rush University.)

Essential tremor

Ataxia and dementia are more severe in FXTAS.

Investigations and diagnosis • MRI typically reveals multiple white matter lesions, volume loss, and T2-hyperintensities in the bilateral middle cerebellar peduncles (‘MCP’ sign) in 60% of males with FXTAS (Figure 16.86).42 • A diagnosis of definite FXTAS requires an action tremor or ataxia and an MCP sign on MRI and an expanded CGG repeat. • Probable FXTAS requires ataxia and action tremor without MCP sign or MCP sign with some minor symptom of FXTAS (parkinsonism or dementia) in the presence of an expanded CGG repeat. • Possible FXTAS is defined as action tremor or ataxia without MCP sign and with an expanded CGG repeat.

TIPS • The ‘MCP’ sign is very common in FXTAS but can also be seen in MSA and some mitochondrial conditions. In patients with sporadic cerebellar degeneration of undetermined cause, inquire about sweating, urinary function, and orthostatic symptoms. A history of absent sweating; urinary urgency, incomplete bladder emptying, or incontinence; or symptomatic orthostatic hypotension raises suspicion for MSA.

Treatment

There is no known cure for FXTAS; treatment is symptomatic only. Symptomatic treatment of tremor with primidone or propranolol has been reported. Patients with parkinsonism can respond to levodopa. Treatment of depression and other neuropsychiatric

Degenerative Diseases of the Nervous System symptoms with SSRIs can be effective. Valproate semisodium (Depakote) should be avoided.

Prognosis

FXTAS is slowly progressive. As it has been described only recently, good longitudinal natural history data are unavailable.

REFERENCES Hereditary ataxias

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613 16. Chopra, R, Bushart, DD, Shakkottai, VG. (2018). Dendritic potassium channel dysfunction may contribute to dendrite degeneration in spinocerebellar ataxia type 1. PloS One 13(5):e0198040. 17. Tabrizi, SJ, Leavitt, BR, Landwehrmeyer, GB, et al. (2019). Targeting Huntingtin expression in patients with Huntington’s disease. N Engl J Med 380(24):2307–2316. 18. Friedrich, J, Kordasiewicz, HB, O’Callaghan, B, et al. (2018). Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI Insight 3(21):e123193. 19. McLoughlin, HS, Moore, LR, Chopra, R, et al. (2018). Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice. Ann Neurol 84(1):64–77. 20. Scoles, DR, Meera, P, Schneider, MD, et al. (2017). Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature 544(7650):362–366. 21. Bryer, A, Krause A, Bill P, et al. (2003). The hereditary adultonset ataxias in South Africa. J Neurol Sci 216(1):47–54. 22. Ashizawa, T, Figueroa, KP, Perlman, SL, et al. (2013). Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study. Orphanet J Rare Dis 8:177. 23. Jacobi, H, du Montcel, ST, Bauer, P, et al. (2015). Longterm disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol 14(11):1101–1108. 24. Duvick, L, Barnes, J, Ebner, B, et al. (2010). SCA1-like disease in mice expressing wild-type ataxin-1 with a serine to aspartic acid replacement at residue 776. Neuron 67(6):929–935. 25. Klockgether T, Ludtke R, Kramer B, et al. (1998). The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 121(4):589–600. 26. Wadia NH, Swami RK (1971). A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families). Brain 94(2):359–374. 27. Durr A, Stevanin G, Cancel G, et al. (1996). Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol 39(4):490–499. 28. Synofzik, M, Puccio, H, Mochel, F, Schols, L. (2019). Autosomal recessive cerebellar ataxias: paving the way toward targeted molecular therapies. Neuron 101(4): 560–583. 29. Campuzano V, Montermini L, Molto MD, et al. (1996). Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271(5254):1423–1427. 30. Pandolfo M (1999). Friedreich’s ataxia: clinical aspects and pathogenesis. Semin Neurol 19(3):311–321. 31. Bidichandani SI, Delatycki MB (1993). Friedreich ataxia. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP (eds). GeneReviews (Internet). University of Washington, Seattle, 1993–1998 (updated 2012 Feb 02). 32. Martelli A, Napierala M, Puccio H (2012). Understanding the genetic and molecular pathogenesis of Friedreich’s ataxia through animal and cellular models. Dis Model Mech 5(2):165–176. 33. Ouahchi K, Arita M, Kayden H, et al. (1995). Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 9(2):141–145.

614 33a. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. (2007). Miglustat for treatment of Niemann-Pick C disease: A randomised controlled study. Lancet Neurol. 6(9): 765–72. 34. Donaghy M, King RH, McKeran RO, et al. (1990). Cerebrotendinous xanthomatosis: clinical, electrophysiological and nerve biopsy findings, and response to treatment with chenodeoxycholic acid. J Neurol 237(3):216–219. 35. Wanders RJA, Jansen GA, Skjeldal OH (2001). Refsum disease, peroxisomes and phytanic acid oxidation: a review. J Neuropath Exp Neurol 60(11):1021–1031. 36. Baldwin EJ, Gibberd FB, Harley C, Sidey MC, Feher MD, Wierzbicki AS (2010). The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease. J Neurol Neurosurg Psychiatry 81(9):954–957. 37. Velasco-Sanchez D, Aracil A, Montero R, et al. (2011). Combined therapy with idebenone and deferiprone in patients with Friedreich’s ataxia. Cerebellum 10(1):1–8. 38. Meier T, Perlman SL, Rummey C, Coppard NJ, Lynch DR (2012). Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich’s ataxia: data from a 6-month controlled study followed by a 12-month openlabel extension study. J Neurol 259(2):284–291. 39. Di Prospero NA, Baker A, Jeffries N, Fischbeck KH (2007). Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurol 6(10):878–886. 40. Gatti R (1993). Ataxia-telangiectasia. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP (eds). GeneReviews (Internet). University of Washington, Seattle, 1993–1998 (updated 2012 Feb 02). 41. Broccoletti T, Del Giudice E, Cirillo E, et al. (2011). Efficacy of very-low-dose betamethasone on neurological symptoms in ataxia-telangiectasia. Eur J Neurol 18(4):564–570. 42. Berry-Kravis E, Abrams L, Coffey SM, et al. (2007). Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord 22(14):2018– 2030, quiz 2140.

Hankey’s Clinical Neurology 43. Rousseau F, Rouillard P, Morel ML, Khandjian EW, Morgan K (1995). Prevalence of carriers of premutation-size alleles of the FMRI gene—and implications for the population genetics of the fragile X syndrome. Am J Hum Genet 57(5):1006–1018. 44. Jacquemont S, Hagerman RJ, Leehey MA, et al. (2004). Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 291(4):460–469. 45. Jacquemont S, Leehey MA, Hagerman RJ, Beckett LA, Hagerman PJ (2006). Size bias of fragile X premutation alleles in late-onset movement disorders. J Med Genet 43(10):804–809. 46. Hagerman RJ, Leehey M, Heinrichs W, et al. (2001). Intention tremor, parkin-sonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57(1):127–130. 47. Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfrey TE, Hagerman PJ (2000). Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragileX syndrome. Am J Hum Genet 66(1):6–15. 48. Greco CM, Berman RF, Martin RM, et al. (2006). Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129(Pt 1):243–255. 49. Todd PK, Paulson HL (2010). RNA-mediated neurodegeneration in repeat expansion disorders. Ann Neurol 67(3):291–300. 50. Abele M, Burk K, Schols L, et al. (2002). The aetiology of sporadic adult-onset ataxia. Brain 125(5):961–968. 51. Gilman S, Wenning GK, Low PA, et al. (2008). Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71(9):670–676. 52. Tu PH, Galvin JE, Baba M, et al. (1998). Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alphasynuclein. Ann Neurol 44(3):415–422.

17

NUTRITIONAL DEFICIENCIES

Deepa Bhupali, Fernando D. Testai

Contents Thiamine Deficiency: Wernicke–Korsakoff Syndrome..............................................................................................................................................616 Definition and epidemiology.....................................................................................................................................................................................616 Etiology and pathophysiology....................................................................................................................................................................................616 Clinical features............................................................................................................................................................................................................616 Korsakoff ’s amnestic–confabulatory state (Korsakoff ’s psychosis)..............................................................................................................617 Differential diagnosis...................................................................................................................................................................................................617 Investigations................................................................................................................................................................................................................617 Diagnosis........................................................................................................................................................................................................................618 Pathology.......................................................................................................................................................................................................................618 Treatment......................................................................................................................................................................................................................619 Prevention......................................................................................................................................................................................................................619 Prognosis........................................................................................................................................................................................................................619 Vitamin B12 (Cobalamin) Deficiency..............................................................................................................................................................................619 Definition and epidemiology.....................................................................................................................................................................................619 Etiology and pathophysiology....................................................................................................................................................................................619 Clinical features............................................................................................................................................................................................................620 History......................................................................................................................................................................................................................620 Physical examination...................................................................................................................................................................................................620 Differential diagnosis...................................................................................................................................................................................................621 Investigations................................................................................................................................................................................................................621 Diagnosis of vitamin B12 deficiency....................................................................................................................................................................621 Determine the cause of vitamin B12 deficiency................................................................................................................................................621 Additional investigations......................................................................................................................................................................................621 Diagnosis........................................................................................................................................................................................................................622 Pathology.......................................................................................................................................................................................................................622 Treatment......................................................................................................................................................................................................................622 Prognosis........................................................................................................................................................................................................................623 Vitamin B9 (Folic Acid or Folate) Deficiency................................................................................................................................................................623 Definition and epidemiology.....................................................................................................................................................................................623 Etiology and pathophysiology....................................................................................................................................................................................623 Clinical features............................................................................................................................................................................................................623 History......................................................................................................................................................................................................................623 Physical examination.............................................................................................................................................................................................623 Investigations................................................................................................................................................................................................................623 Treatment......................................................................................................................................................................................................................623 Vitamin E Deficiency.........................................................................................................................................................................................................624 Definition and epidemiology.....................................................................................................................................................................................624 Etiology and pathophysiology....................................................................................................................................................................................624 Clinical features............................................................................................................................................................................................................625 Differential diagnosis...................................................................................................................................................................................................625 Investigations................................................................................................................................................................................................................625 Diagnosis........................................................................................................................................................................................................................625 Pathology.......................................................................................................................................................................................................................625 Treatment......................................................................................................................................................................................................................625 Prognosis........................................................................................................................................................................................................................625 Vitamin B6 (Pyridoxine) Deficiency...............................................................................................................................................................................625 Definition and epidemiology.....................................................................................................................................................................................625 Etiology and pathophysiology....................................................................................................................................................................................625 Clinical features............................................................................................................................................................................................................626 Diagnosis........................................................................................................................................................................................................................626

615

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616

Treatment......................................................................................................................................................................................................................626 Prognosis........................................................................................................................................................................................................................626 Vitamin B3 (Niacin or Nicotinic Acid) Deficiency......................................................................................................................................................626 Definition and epidemiology.....................................................................................................................................................................................626 Etiology and pathophysiology..............................................................................................................................................................................626 Clinical features............................................................................................................................................................................................................626 Differential diagnosis...................................................................................................................................................................................................627 Investigations................................................................................................................................................................................................................627 Diagnosis........................................................................................................................................................................................................................627 Treatment......................................................................................................................................................................................................................627 Prognosis........................................................................................................................................................................................................................627 Marchiafava–Bignami Disease........................................................................................................................................................................................627 Definition and epidemiology.....................................................................................................................................................................................627 Etiology and pathophysiology....................................................................................................................................................................................627 Clinical features............................................................................................................................................................................................................627 Differential diagnosis...................................................................................................................................................................................................627 Investigations................................................................................................................................................................................................................628 Diagnosis........................................................................................................................................................................................................................628 Treatment......................................................................................................................................................................................................................628 Prognosis........................................................................................................................................................................................................................628 Vitamin D Deficiency........................................................................................................................................................................................................628 References............................................................................................................................................................................................................................628

THIAMINE DEFICIENCY: WERNICKE–KORSAKOFF SYNDROME Definition and epidemiology

Thiamine deficiency causes a range of subtle and nonspecific symptoms that may be easily overlooked. In its more severe form, it causes a neurocardiogenic syndrome called beriberi. Nonendemic thiamine deficiency can be seen in association with alcoholism where it manifests with Wernicke–Korsakoff syndrome. Wernicke’s disease (or thiamine-deficient encephalopathy) is characterized by a rather abrupt onset of any combination of nystagmus, gait ataxia, conjugate gaze palsy, and global confusional state. Korsakoff’s psychosis is a chronic amnestic disorder with both antegrade and retrograde components in an otherwise responsive patient. • Prevalence (from autopsy studies): 0.8–2.8% of autopsies; 15% in psychiatric inpatients, 24% in homeless men. • More common in adult men.

Etiology and pathophysiology1

The absorption of thiamine is impaired by both malnutrition and alcohol. In addition, liver disease has been associated with reduced body stores and impaired metabolism of thiamine. In alcoholics, thiamine deficiency may compound the situation by enhancing the neurotoxic effect of alcohol. Nevertheless, about one-third of substantial alcohol abusers do not develop Wernicke–Korsakoff syndrome. • Thiamine deficiency: • Chronic alcoholism. • Malnutrition and malabsorption. • Prolonged intravenous feeding. • Renal dialysis. • Magnesium depletion: magnesium is an essential cofactor in the conversion of thiamine into active metabolites.

Thiamine is a cofactor for: • Transketolase: This enzyme links glycolysis to the hexose monophosphate shunt (Figure 17.1). The hexose monophosphate shunt is required for the synthesis of: • Pentoses (such as ribose phosphate): necessary for the synthesis of nucleotides. • Nicotinamide adenine dinucleotide phosphate (NADP): necessary for the synthesis of fatty acids, steroids, and antioxidants. • Pyruvate dehydrogenase E1: Pyruvate dehydrogenase is a complex formed by three enzymes (E1, E2, and E3). This complex links the glycolytic pathway with the Krebs cycle. E1 requires thiamine pyrophosphate as a cofactor. • Alpha-ketoglutarate dehydrogenase: This enzyme participates in the Krebs’ cycle and is involved in the conversion of alpha-ketoglutarate to succinyl-CoA. The deficiencies of this enzyme and E1 lead to decreased adenosine triphosphate (ATP) production and cellular dysfunction. Genetic variations that may affect, for example, the affinity between thiamine and transketolase may predispose certain individuals to Wernicke–Korsakoff syndrome.

Clinical features2

Subacute onset over hours to days of one or, more often, various combinations of: • Gait ataxia. • Ophthalmoplegia: due to involvement of cranial nerves III or VI. Patient presents with supranuclear horizontal and/ or vertical gaze palsies, internuclear ophthalmoplegia, and/ or lateral rectus palsies, often causing diplopia. • Nystagmus: horizontal and/or vertical. • Mental state disturbance: global confusional state causing apathy, inattention, disorientation, minimal spontaneous speech, forgetfulness, drowsiness, and even coma.

Nutritional Deficiencies

617

TK + thiamine

Ribose-P

Nucleotide synthesis

Glucose- 6-P Fatty acids Antioxidants

NADPH

GLYCOLYSIS Pyruvate

HEXOSE MONOPHOSPHATE SHUNT

PDHC + thiamine

Cytosol

Acetyl-CoA

ATP

Mitochondrion

α-ketoglutarate KREBS CYCLE

NADH

Methylmalonic acid

α-KGD + thiamine

Succinyl-CoA

Electron Transport Chain

L-methylmalonyl-CoA

MCM

AdenosylB12

FIGURE 17.1  Sites of action of thiamine and vitamin B12 . Thiamine is a cofactor of pyruvate dehydrogenase complex (PDHC), transketolase (TK), and alpha-ketoglutarate dehydrogenase (α-KGD). Adenosylcobalamin (adenosyl-B12) is required by the l-methylmalonyl-CoA mutase (MCM) for the conversion of l-methylmalonyl-CoA into succinyl-CoA. Other features may include: • Stupor or coma as the initial manifestation. • Signs of alcohol withdrawal: agitation, hallucinations, confusion, and autonomic hyperactivity. • Hypothermia. • Postural hypotension (autonomic neuropathy). • Cardiovascular dysfunction (tachycardia, exertional dyspnea, minor electrocardiogram [ECG] abnormalities). • Impaired capacity to discriminate between odors (in the chronic stage of the disease due to a lesion of the medial dorsal nucleus of the thalamus). • Pupil abnormalities: miosis and nonreacting pupils may occur. • Ptosis. • Retinal hemorrhages, rarely. • Papilledema, rarely. • Peripheral neuropathy can be seen in up to 80% of alcoholic patients. Other features seen in this subgroup include dementia, cerebellar ataxia, macrocytosis, and abnormalities of liver function.

TIP • Beriberi is a neurocardiogenic disease secondary to thiamine deficiency. Dry beriberi is characterized by a lengthdependent, axonal, sensorimotor peripheral neuropathy in the absence of cardiac involvement. Wet beriberi is reserved for individuals with peripheral neuropathy in association with vasodilation leading to edema, increased arteriovenous shunting, and high-output heart failure (tachycardia).

Korsakoff’s amnestic–confabulatory state (Korsakoff’s psychosis)

Chronic amnestic disorder is characterized by: • Antegrade amnesia due to learning dysfunction than a defect in the retrieval mechanism. • Loss of short-term verbal and nonverbal memory (retrograde amnesia). • Long-term memory is usually maintained through multifocal networks. • Confabulation behavior and confusion.

Differential diagnosis

• Wernicke’s disease: other causes of confusional states and coma. • Korsakoff’s amnestic–confabulatory state: • Third ventricle tumors. • Temporal lobe infarction or surgical resection. • Herpes simplex encephalitis. • Hypoxic encephalopathy. • Alzheimer’s disease.

Investigations3

• Blood: • Red cell transketolase (reduced markedly, though not frequently used). • Thiamine level (reduced). • Plasma glucose and magnesium levels. • Computed tomography (CT) brain scan: widening of the third ventricle and interhemispheric fissures, and other features of long-standing alcohol abuse (generalized cerebral atrophy plus more pronounced vermian and cerebellar atrophy).

Hankey’s Clinical Neurology

618 • Magnetic resonance imaging (MRI) brain scan: areas of increased signal in the periaqueductal gray matter of the midbrain and medial portions of the thalami, atrophy of the mammillary bodies, and dilation of the third ventricle. In the chronic stage, the mammillary bodies and the anterior diencephalon may be atrophic.

TIP • The classic triad of Wernicke’s encephalopathy, including delirium, ataxia, and nystagmus or ophthalmoparesis, is seen in only 10% of the cases.

Diagnosis

The diagnosis of Wernicke–Korsakoff syndrome is missed in about 25% of cases. Physicians should have a low threshold to suspect this condition, particularly in alcoholics, even in the absence of the complete triad. Supporting data include:

Pathology

• Wernicke’s disease: • Macroscopic: loss of brain tissue (lower brain weight, increased ventricular volume, and pericerebral space) occurs, mainly in white matter. • Microscopic: neuronal loss, proliferative symmetric vasculopathy, and gliosis occur in the mammillary bodies (medial mammillary nucleus, diagnostic); thalamus (medial dorsal nucleus); hypothalamus; around the third ventricle, aqueduct in the midbrain, and floor of the fourth ventricle; and brainstem and sometimes the cerebellum (Figures 17.2–17.4). There is little or no specific pathology in the locus coeruleus, hippocampus, and cerebral cortex.

• RBC transketolase assay. In cases when thiamine deficiency is suspected, the diagnosis can be confirmed by showing a marked reduction in transketolase activity at baseline. The transketolase activity and clinical features may improve quickly, even within hours, after the administration of thiamine. Complete normalization of transketolase activity is usually attained within 24 hours. • Low thiamine level. • MRI brain. • Clinical response to thiamine.

  FIGURES 17.2, 17.3  Brain, coronal sections, showing petechial hemorrhages in the mammillary bodies (black arrows) and medial dorsal thalamus (blue arrows) of a patient with acute Wernicke’s encephalopathy.

Nutritional Deficiencies

619 • After thiamine treatment, ophthalmoplegia begins to improve within hours to days and nystagmus, ataxia, and confusion within days to weeks. The amnesic symptoms may recover slowly over 1 year or so and incompletely. Recovery of cognitive function depends on age and continuous abstinence from alcohol. • Residual nystagmus and ataxia in 60% of patients. • Residual chronic memory disorder in 80% of patients.

VITAMIN B12 (COBALAMIN) DEFICIENCY Definition and epidemiology5 FIGURE 17.4  Axial section through the medulla, showing a proliferative vasculopathy and petechial hemorrhages (arrow) in the floor of the fourth ventricle of a patient with acute Wernicke’s encephalopathy. • Acute Wernicke’s disease is characterized by small areas of petechial hemorrhage and marked vascular endothelial proliferation in the same sites listed above (i.e. mammillary bodies). • Korsakoff’s psychosis: cell loss and gliosis occur in the medial mammillary nucleus and medial dorsal nucleus of the thalamus (similar to Wernicke’s disease), but there is greater cell loss in the anterior principal nucleus of the thalamus.

Treatment4

• Correction of the underlying cause of the deficiency. • Thiamine 100–200 mg intravenously daily for 7 days because intestinal absorption is usually impaired in alcoholics. Thiamine prevents the progression of the disease and may reverse the brain abnormalities that have not resulted in fixed structural changes. • Oral vitamin maintenance, providing 10–50 mg thiamine daily until the patient is no longer at risk (usually for several months). • Magnesium replacement (if depleted). • Psychotherapy and educational efforts: ineffective in arresting the cognitive decline without abstinence.

Prevention5

The recommended daily allowance (RDA) for adults is 1.2 mg for men, 1.1 mg for women, 1.4 mg during pregnancy, and 1.5 mg for breast-feeding women. At-risk patients should be given vitamin supplements. Comatose patients or those with acute mental status changes should be treated with thiamine, especially if no obvious cause is recognized. At-risk patients should never be given a glucose load (intravenous dextrose) without vitamin supplements because glucose metabolism may consume thiamine and precipitate Wernicke’s syndrome.

Prognosis

• Depends on the stage of the disease and prompt institution of thiamine treatment. • Can be fatal if untreated: mortality rate is 10–20%, mainly due to pulmonary infection, septicemia, decompensated liver disease, and an irreversible stage of thiamine deficiency.

Vitamin B12, or cobalamin, is a cobalt-containing water-soluble vitamin that is present in meat, fish, eggs, milk products, and poultry. Vitamin B12 is generally not present in plants. The RDA is 2.4 μg for adults, 2.6 μg for pregnant women, and 2.8 μg for breast-feeding women.5 Vitamin B12 deficiency is characterized by a symmetric, distal, predominantly sensory peripheral neuropathy due to axonal degeneration, autonomic neuropathy, subacute combined degeneration of the spinal cord, optic neuropathy, dementia, and other disturbances of higher mental function. • Prevalence: • Pernicious anemia (PA): 1–3% over age 65 years. • Serum vitamin B12 levels < 150 pmol/L ( 180 mmHg and diastolic BP [DBP] > 120 mmHg) is not related to ongoing or imminent target organ damage, it is known as hypertensive urgency. The examples of hypertensive emergency and target organ damage include hypertensive encephalopathy, eclampsia, aortic dissection, acute coronary syndrome, acute renal failure, and acute left ventricular failure with pulmonary edema. • If elevated BP is resulting in ongoing acute and progressive end-organ damage, it is known as hypertensive emergency. The epidemiology of hypertensive urgency and emergency and related disorders is not known with certainty because in more than 75% of cases, elevated BP in an emergency department patient is an incidental finding. The prevalence of hypertensive urgency and emergency in patients presenting to emergency departments varies from 25 cmH2O. However, some patients with IIH and papilledema will have opening pressures < 25 cmH2O, and some asymptomatic obese women may have opening pressures > 25 cmH2O. The CSF is normal on lumbar puncture in IIH.

Treatment

• Patients need to be followed closely with repeat ophthalmoscopic examinations, visual acuity testing, and visual field testing. • Some patients respond to acetazolamide, a carbonic anhydrase inhibitor that reduces the production of CSF. Other patients may respond to furosemide used as a diuretic or topiramate, and antiepileptic that has carbonic anhydrase inhibitor properties. • Weight reduction is useful in obese patients with IIH. • When headaches are not controlled or in the setting of declining visual function, surgical intervention should be considered which includes optic nerve sheath fenestration and CSF shunting (either ventricular or lumbar shunts). • Although advocated by some, serial lumbar punctures to reduce ICP are rarely practical, especially in obese patients. • Current surgical recommendations include using lumboperitoneal shunts as an initial therapy for IIH when medical therapy with acetazolamide has failed. Ventriculoperitoneal shunting and optic nerve sheath fenestration are additional surgical options if lumboperitoneal shunting fails or is impractical.

Prognosis

Some patients with IIH remit spontaneously without prolonged medical treatment. However, in the absence of aggressive

Hankey’s Clinical Neurology

664 medical or surgical therapy as many as 17–25% of the patients with IIH will have either permanent visual loss or permanent optic atrophy. The onset of visual loss is usually gradual, but in some patients, visual loss may occur precipitously, requiring rapid surgical intervention.

INTRACRANIAL HYPOTENSION SYNDROME Definition and epidemiology

Idiopathic intracranial hypotension (also known as spontaneous intracranial hypotension) is a syndrome of orthostatic headache, worsening with upright posture, due to reduced intracranial pressure.12 Idiopathic intracranial hypotension is not rare, but its exact incidence is unknown. There are no known age or gender differences in incidence.

Etiology and pathophysiology

Intracranial hypotension syndrome is caused by reduced ICP, usually ≤ 6 cmH2O on lumbar puncture. Two theories have been proposed to explain the headache of intracranial hypotension syndrome: • Traction theory: a decrease in ICP and loss of buoyancy of the CSF causes the brain to sag in the cranium, especially in the erect position. This sagging causes traction on painsensitive structures within the head and leads to headache. • Venous engorgement theory: the drop in ICP leads to a compensatory venous engorgement, and this vascular dilation leads to headache.

• Subdural hematoma. • Posterior fossa tumor. • Hydrocephalus. Low-lying tonsils in intracranial hypotension syndrome must be differentiated from Chiari’s malformation type I.

Investigations Imaging

A frequent, but not constant, sign of intracranial hypotension syndrome is diffuse pachymeningeal (dural) enhancement with gadolinium without leptomeningeal (pia and arachnoid) enhancement on MRI (Figures 20.20, 20.21). In some symptomatic patients, meningeal enhancement resolves prior to resolution of the headache and other symptoms. Other findings on MRI include: • Diffuse thickening of the meninges, engorgement of the venous sinuses, and downward displacement of the brain. • Subdural fluid collections and enlargement of the pituitary gland may also occur. • The ventricles may be decreased in size. It is currently felt that volume depletion due to intracranial hypotension causes a compensatory venous engorgement, thickening of the meninges, and a downward displacement of the

Most cases of intracranial hypotension are due to a persistent CSF leak, often after a lumbar puncture, spinal anesthesia, or myelogram.13 CSF leaks may also develop after cranial surgery, head trauma, or after ventriculoperitoneal shunting. Spontaneous leaks without trauma or surgery may be present in the spine, cribiform plate, and paranasal sinuses. Spontaneous CSF leaks with CSF hypovolemia can be precipitated by trivial trauma such as coughing, lifting, and minor falls. Other causes of decreased ICP may include dehydration, diabetic coma, hyperpnea, and uremia. Overdrainage by a ventriculoperitoneal shunt is an important treatable cause of intracranial hypotension syndrome.

Clinical features

The hallmark of intracranial hypotension syndrome is postural headache, made worse on standing and relieved in a recumbent position. The headache may or may not be throbbing, it is usually bilateral, and may be frontal, occipital, or holocephalic in location. Other highly variable symptoms include nausea, vomiting, diplopia, altered hearing, dizziness, neck pain, blurred vision, and radicular pain in the upper extremities. Laughing, coughing, or the Valsalva maneuver can exacerbate the headache of intracranial hypotension.

Differential diagnosis

Intracranial hypotension must be differentiated from other causes of headache: • Migraine. • Meningitis.

FIGURES 20.20, 20.21  Axial (Figure 20.20) and coronal (Figure 20.21) MRI (Tl-weighted) gadolinium-enhanced images showing enhancement in dura over the surface of the brain and in the interhemispheric falx in a patient with intracranial hypotension syndrome.

Disorders of Circulation of the Cerebrospinal Fluid brain. The gadolinium enhancement of intracranial hypotension is thick, diffuse, and linear and involves the pachymeninges of both the supratentorial and infratentorial compartments of the brain. The leptomeninges, including the meninges around the brainstem, are spared. CT scanning of the brain may show obliteration of the basilar cisterns due to sagging downward of the brain. If the CSF leak is in the spinal region, CT myelography may be useful in identifying the site of leakage. Spinal MRI may also be useful in identifying leakage sites in cases of intracranial hypotension syndrome.

Other investigations

Lumbar puncture shows an opening pressure of ≤ 6 cmH2O. Analysis of the CSF is usually normal. Cultures are negative for infection. Glucose levels are usually normal. Occasionally, pleocytosis, xanthochromia, or mild increases in CSF protein may be noted. Radioisotope cisternography after injection of radioisotope into the lumbar subarachnoid space may be useful in identifying CSF leaks. Indium-111 is used as a tracer, and when a leak is present, activity does rise up above the basal cisterns to the cerebral convexities. Because of extravasation of CSF and vascular uptake, radioisotope may appear in the kidneys and bladder in < 4 hours.

Treatment

Initial treatment consists of bed rest which reduces the postural headache and presumably, the supine position reduces CSF pressure at the site of leakage and allows sealing of the leak to occur. Additional medical treatments that have been proposed for intracranial hypotension syndrome include intravenous or oral caffeine, intravenous or oral theophylline, intravenous hydration, increased salt intake, corticosteroid therapy, and carbon dioxide inhalation. Controlled studies of the efficacy of these remedies are not available and are currently unproven. When conservative remedies fail including bed rest, relief can usually be obtained with an epidural blood patch using autologous blood. The patient’s venous blood is collected at the time of the procedure and is then injected into the epidural space at the site of lumbar puncture with immediate and long-standing pain relief obtained in 85–90% of cases. Some patients may require more than one patch. When imaging demonstrates a meningeal tear, surgical repair may be useful for relief of symptoms.

Prognosis

Prognosis is good in most patients with a simple leak due to puncture of the meninges, and complete resolution of headache

665 is the rule when ICP is restored to normal. When bed rest fails, an epidural blood patch is generally effective, but larger tears in the meninges may need surgical repair.

REFERENCES

1. McLone DG (2004). The anatomy of the ventricular system. Neurosurg Clin North Am 15:33–38. 2. Kulkarni AV (2009). Hydrocephalus. Continuum 15:50–63. 3. Fukuara T, Luciano MG (2001). Clinical features of late-onset idiopathic aqueductal stenosis. Surg Neurol 55:132–137. 4. Stoquart-El Sankari S, Lehman P, Gondry-Jouet C, et al. (2009). Phase-contrast MR imaging support for the diagnosis of aqueductal stenosis. Am J Neuroradiol 30:209–214. 5. Beran A, Eide PK (2008). Prevalence of probable idiopathic normal pressure hydrocephalus in a Norwegian population. Acta Neurol Scand 118:48–52. 6. Graff-Radford NR (2007). Normal pressure hydrocephalus. Continuum 13:144–164. 7. Bergsneider M, Black PM, Klinge P, Marmarou A, Relkin N (2005). Surgical management of idiopathic normal-pressure hydrocephalus. Neurosurgery 57(3 Suppl):S29–S39. 8. Woodworth G, McGirt MJ, Williams M, Rigamonti D (2009). Cerebrospinal fluid drainage and dynamics in the diagnosis of normal pressure hydrocephalus. Neurosurgery 64:919–926. 9. Pujari S, Kharkar S, Metellus P, Shuck J, Williams M, Rigamonti D (2008). Normal pressure hydrocephalus: long-term outcome after shunt surgery. J Neurol Neurosurg Psychiatry 79:1282–1286. 10. Hankinson TC, Klimo P Jr, Feldstein NA, Anderson RCE, Brockmeyer D (2007). Chiari malformations, syringohydromyelia and scoliosis. Neurosurg Clin North Am 18:549–568. 11. Binder DK, Horton J, Lawton MT, McDermott MW (2004). Idiopathic intracranial hypertension. Neurosurgery 54:538–552. 12. Paldino M, Mogilner AY, Tenner MS (2003). Intracranial hypotension syndrome: a comprehensive review. Neurosurg Focus 15(6). Available online at http://thejns.org/toc/foc/15/6. 13. Mokri B (2004). Low cerebrospinal fluid pressure syndrome. Neurol Clin 22:55–74. 14. Michals EA, Ramsey RG (1996). Syringomyelia. Orthopaedic Nursing 15(3):33–40. 15. Beaumont TL, Limbrick DD Jr, Rich KM, Wippold 2nd FJ, Dacey RG Jr (2016). Natural history of colloid cysts of the third ventricle. J Neurosurg 125(6):1420–1430. 16. Gurol ME, St Louis EK (2008). Treatment of cerebellar masses. Curr Treat Options Neurol 10(2):138–150.

21

CRANIAL NEUROPATHIES I, V, AND VII–XII

Carlen Yuen, Helene Rubeiz

Contents Olfactory Neuropathy (Cranial Nerve I)...................................................................................................................................................................... 668 Definition...................................................................................................................................................................................................................... 668 Anatomy and physiology........................................................................................................................................................................................... 668 Etiology and pathophysiology....................................................................................................................................................................................669 Conductive impairment........................................................................................................................................................................................670 Sensorineural impairment....................................................................................................................................................................................670 Central neural impairment...................................................................................................................................................................................670 Psychiatric................................................................................................................................................................................................................670 Idiopathic.................................................................................................................................................................................................................670 Clinical features............................................................................................................................................................................................................670 Investigations and diagnosis......................................................................................................................................................................................671 Treatment......................................................................................................................................................................................................................671 Prognosis........................................................................................................................................................................................................................671 Trigeminal Neuropathy (Cranial Nerve V)...................................................................................................................................................................671 Definition and epidemiology.....................................................................................................................................................................................671 Anatomy and physiology............................................................................................................................................................................................671 Sensory and motor peripheral divisions of CN V............................................................................................................................................672 Etiology...........................................................................................................................................................................................................................673 Clinical features............................................................................................................................................................................................................674 Unilateral trigeminal lesions................................................................................................................................................................................674 Bilateral trigeminal lesions ..................................................................................................................................................................................675 Investigations..........................................................................................................................................................................................................675 Selected Conditions Affecting the Trigeminal Nerve.................................................................................................................................................675 Isolated Trigeminal Sensory Neuropathy.....................................................................................................................................................................675 Trigeminal Neuralgia (TIC Douloureux)......................................................................................................................................................................675 Definition and epidemiology.....................................................................................................................................................................................675 Etiology and pathophysiology....................................................................................................................................................................................675 Differential diagnosis...................................................................................................................................................................................................675 Clinical features............................................................................................................................................................................................................675 Investigations and diagnosis................................................................................................................................................................................676 Treatment.................................................................................................................................................................................................................676 Percutaneous procedures on gasserian ganglion.............................................................................................................................................676 Stereotactic radiosurgery (Gamma Knife)........................................................................................................................................................676 Microvascular decompression.............................................................................................................................................................................676 Numb Chin Syndrome......................................................................................................................................................................................................676 Facial Neuropathy (Cranial Nerve VII)........................................................................................................................................................................ 677 Definition and epidemiology.................................................................................................................................................................................... 677 Anatomy........................................................................................................................................................................................................................ 677 Motor component................................................................................................................................................................................................. 677 Sensory component...............................................................................................................................................................................................678 Clinical features............................................................................................................................................................................................................679 Supranuclear lesions (upper motor neuron facial palsy)................................................................................................................................679 Nuclear and fascicular lesions.............................................................................................................................................................................679 Cerebellopontine angle lesions............................................................................................................................................................................679 Facial canal lesions.................................................................................................................................................................................................679 Physical examination.............................................................................................................................................................................................679 Selected Conditions Affecting the Facial Nerve......................................................................................................................................................... 680 Bell’s Palsy........................................................................................................................................................................................................................... 680 Clinical features............................................................................................................................................................................................................681 Treatment......................................................................................................................................................................................................................681 Prognosis........................................................................................................................................................................................................................681 667

668

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Ramsay Hunt Syndrome (Herpes Zoster Oticus)........................................................................................................................................................681 Vestibulocochlear Neuropathy (Cranial Nerve VIII)................................................................................................................................................ 682 Definition and epidemiology.................................................................................................................................................................................... 682 Anatomy........................................................................................................................................................................................................................ 682 Vestibular apparatus............................................................................................................................................................................................. 682 Auditory apparatus............................................................................................................................................................................................... 682 Vestibulocochlear nerve....................................................................................................................................................................................... 683 Brainstem................................................................................................................................................................................................................ 683 Clinical features........................................................................................................................................................................................................... 683 Hearing loss............................................................................................................................................................................................................ 683 Vestibular dysfunction......................................................................................................................................................................................... 683 Differential diagnosis.................................................................................................................................................................................................. 684 Hearing loss............................................................................................................................................................................................................ 684 Vestibular dysfunction......................................................................................................................................................................................... 684 Glossopharyngeal Neuropathy (Cranial Nerve IX).................................................................................................................................................... 685 Definition and epidemiology.................................................................................................................................................................................... 685 Anatomy........................................................................................................................................................................................................................ 685 Medulla.................................................................................................................................................................................................................... 685 Base of skull (jugular foramen) .......................................................................................................................................................................... 686 Outside the skull.................................................................................................................................................................................................... 686 Clinical features........................................................................................................................................................................................................... 686 Physical examination............................................................................................................................................................................................ 686 Select Conditions Affecting the Glossopharyngeal Nerve....................................................................................................................................... 687 Glossopharyngeal Neuralgia........................................................................................................................................................................................... 687 Vagus Neuropathy (Cranial Nerve X)........................................................................................................................................................................... 687 Definition and epidemiology.................................................................................................................................................................................... 687 Anatomy.................................................................................................................................................................................................................. 687 Clinical features........................................................................................................................................................................................................... 688 Evaluation of the soft palate and uvula at rest and with phonation............................................................................................................ 688 Speech and swallowing........................................................................................................................................................................................ 688 Localization............................................................................................................................................................................................................ 688 Investigations......................................................................................................................................................................................................... 688 Spinal Accessory Neuropathy (Cranial Nerve XI)..................................................................................................................................................... 689 Definition and epidemiology.................................................................................................................................................................................... 689 Anatomy........................................................................................................................................................................................................................ 689 Cranial portion...................................................................................................................................................................................................... 689 Spinal portion......................................................................................................................................................................................................... 689 Supranuclear innervation.................................................................................................................................................................................... 689 Clinical features........................................................................................................................................................................................................... 689 Localization.................................................................................................................................................................................................................. 690 Investigations............................................................................................................................................................................................................... 690 Hypoglossal Neuropathy (Cranial Nerve XII)............................................................................................................................................................. 690 Definition and epidemiology.................................................................................................................................................................................... 690 Anatomy........................................................................................................................................................................................................................ 690 Clinical features........................................................................................................................................................................................................... 690 Unilateral hypoglossal nerve palsy..................................................................................................................................................................... 690 Bilateral hypoglossal nerve palsies..................................................................................................................................................................... 690 Localization.............................................................................................................................................................................................................691 Investigations................................................................................................................................................................................................................691 References............................................................................................................................................................................................................................691

OLFACTORY NEUROPATHY (CRANIAL NERVE I) Definition

Disorder of the olfactory nerve.

Anatomy and physiology

Nerve fibers mediating the sense of smell have their cells of origin in the mucous membranes of the upper and posterior parts of the

nasal cavity. The olfactory mucosa contains three types of cells (Figure 21.1): • Olfactory or receptor cells. • Sustentacular or supporting cells. • Basal cells, which are stem cells and the source of both olfactory (receptor) cells and sustentacular cells during regeneration. The olfactory or receptor cells are bipolar neurons that have a single peripheral dendritic process (the olfactory knob) that

Cranial Neuropathies I, V, and VII–XII

669

Anterior commissure

Media olfactory stria Lateral olfactory stria

Cribriform plate of skull Basal cell

Olfactory epithelium

Olfactory tract Secondary sensory axon Anterior olfactory cell

Left and right olfactory bulbs Tufted and mitral cells (secondary olfactory cells) Glomeruli Olfactory gland

Supporting cell (sustentacular) Primary olfactory cell Primary axon Mucus Aromatic molecule

FIGURE 21.1  Schematic illustration of olfactory epithelium, bulb, and tract. (Adapted from Cranial Nerves in Health and Disease by Linda Wilson-Pauwels.) extends to the epithelial surface and from which project 10–30 fine hairs or cilia, and an axon which transmits signals centrally. Axons of olfactory cells form nerve bundles (olfactory filia), which are unmyelinated fibers that converge to form small fascicles enwrapped by Schwann’s cells to constitute the olfactory nerve that passes through openings in the cribriform plate of the ethmoid bone into the olfactory bulb. In the olfactory bulb, the axons of the receptor cells synapse with mitral and tufted cells, the dendrites of which form brushlike terminals or olfactory glomeruli. The axons of the mitral and tufted cells form the olfactory tract, which courses along the olfactory groove on the orbital surface of the frontal lobe. The olfactory tract divides into medial and lateral olfactory striae. The medial stria contains fibers from the anterior olfactory nucleus, which pass to the contralateral hemisphere via the anterior commissure. Fibers in the lateral stria give off collaterals to the anterior perforated substance and terminate in the primary olfactory cortex, which comprises the anterior olfactory nucleus, the piriform cortex, the anterior cortical nucleus of the amygdaloid complex, and the entorhinal cortex.1 Thus, olfactory impulses reach the cerebral cortex without relay through the thalamus, which is a unique feature among the sensory systems.2 From the primary olfactory cortex, fibers project to the hypothalamus and to the orbitofrontal cortex (secondary olfactory cortex) via the medial dorsal nucleus of the thalamus (Figure 21.2). During quiet breathing, little of the air entering the nostrils reaches the olfactory mucosa; sniffing carries the air into the olfactory crypt. To be perceived as an odor, an inhaled substance must be volatile, i.e. spread in the air as very small particles, and be soluble in water or lipid. The intensity of olfactory sensation is determined by the frequency of firing of afferent neurons. The quality of an odor is likely determined by ‘cross-fiber’ activation, since the individual receptor cells are responsive to a wide range of odors and exhibit different types of responses to stimulants.

Etiology and pathophysiology

Reduced sense of (hyposmia) or complete loss of (anosmia) smell can be congenital (as a result of absence of olfactory epithelium or hypoplasia/aplasia of the olfactory bulb) or more commonly,

acquired. Olfactory disorders may be caused by local disease in the nose or by a lesion along the olfactory pathway. A unilateral lesion distal to the decussation of the olfactory fibers is usually asymptomatic due to bilateral cortical representation.3 Approximately two-thirds of cases of anosmia and hyposmia are secondary to prior upper respiratory infections, nasal or sinus diseases, or head injury. Other factors include age, tobacco smoking, neurodegenerative conditions, nasal or intracranial neoplasms, prior nasal surgical procedures, and chemical exposure. Hyperosmia is heightened sense of smell. Dysosmia (or parosmia) is abnormally perceived sense of smell. Phantosmia (olfactory hallucination) is smell perception in the absence of an odor stimulus. Olfactory agnosia is the inability to recognize olfactory sensory information in the setting of intact olfactory function. Olfactory dysfunction can be classified into three different impairment categories: conductive, sensorineural, and central. Olfactory bulb Anterior commissure Rhinal sulcus Optic tract (cut) Uncus

Olfactory tract

Amygdaloid body Entorhinal area

Pyriform area

Lateral olfactory stria

FIGURE 21.2  Schematic illustration of the olfactory pathway (inferior view).

Hankey’s Clinical Neurology

670 Conductive impairment

• Odorants do not reach the olfactory receptors: upper respiratory infections, nasal obstruction, or inflammation (rhinosinusitis) are by far the most common causes.

Sensorineural impairment

• Damage to olfactory epithelium: • Upper respiratory infections. • Exposure to chemicals and toxins: herbicides, pesticides, solvents, and heavy metals (cadmium, chromium, nickel, and manganese). • Impairment at the level of receptor neurons or their axon filaments: • Congenital absence or hypoplasia of primary receptor neurons: – Kallmann’s syndrome (congenital anosmia and hypogonadotropic hypogonadism). – Albinism. • Ciliopathy disorders resulting in congenital anosmia: Bardet–Biedl syndrome (retinitis pigmentosa, obesity, polydactyly, hypogonadism, renal dysfunction, and cognitive deficits), Meckel–Gruber syndrome (occipital encephalocele, polydactyly, and cystic renal disease), and Joubert’s syndrome (hypoplasia of the cerebellar vermis, hypotonia, oculomotor apraxia, dysregulation of breathing pattern, developmental delay, retinal dystrophy, and renal anomalies).4 • Disruption of the delicate filaments of the receptor cells as they pass through the cribriform plate: – Head injury, particularly if severe enough to cause skull fracture but may occur without a fracture. The damage may be unilateral or bilateral. This accounts for 20% of cases of anosmia/hyposmia. – Complications of cranial surgery. – Complications of nasal and sinus surgery. – Subarachnoid hemorrhage. – Chronic meningitis. • Nutritional causes: vitamin deficiency (B12), copper and zinc deficiency.

Central neural impairment

• Inferior frontal tumor compressing the olfactory tracts (e.g. olfactory groove meningioma, Figure 21.3). • Large aneurysm of the anterior cerebral or anterior communicating artery. • Anterior meningoencephalocele (cerebrospinal fluid [CSF] rhinorrhea may be present in certain head positions). • Meningitis. • Refsum’s disease. • Sarcoidosis. • Neurodegenerative diseases: olfactory deficit is present in 90% of patients with early-stage Parkinson’s disease and Alzheimer’s disease (AD).5,6 Most patients are unaware of their deficit. Anosmia has also been described in multiple system atrophy, Lewy body dementia,7,8 Huntington’s disease, and spinocerebellar ataxias.9 • Multiple sclerosis:10 olfactory dysfunction may wax and wane with disease activity11 and is related to the presence of plaques in the inferior frontal and temporal regions. • Temporal lobe epilepsy: patients with complex partial seizures may have olfactory hallucinations (phantosmia) as auras.12 • Alcoholic Korsakoff’s syndrome: loss of olfactory discrimination has been described in alcoholics with Korsakoff’s psychosis due to degeneration of neurons in the

FIGURE 21.3  Olfactory groove meningioma (coronal view). (From Welge-Luessen A, et al. ‘Olfactory function in patients with olfactory groove meningioma,’ J Neurol Neurosurg Psychiatry 2001; 70(2); 218–221.) higher-order olfactory systems of the medial temporal and thalamic regions. • Migraine: can be associated with olfactory hallucinations or hyperosmia.13 • Stroke: may be associated with olfactory agnosia (inability to recognize odors though olfactory system is intact).14

TIP • Olfactory deficit is present in 90% of patients with earlystage Parkinson’s disease and AD.

Psychiatric

• Hysteria: anosmia can be unilateral or bilateral. If unilateral, anosmia may be ipsilateral to other symptoms such as anesthesia, blindness, or deafness. Hysterical anosmics do not usually complain of loss of taste (whereas true anosmics do) and show normal taste sensation on testing. • Depression and schizophrenia: patients can have complaints of dysosmia, olfactory hallucinations, or delusions.

Idiopathic

Usually bilateral but can be unilateral.

Clinical features

• Bilateral anosmia or hyposmia: the patient commonly, but not always, recognizes this. It may present as impaired taste, because the perception of flavor is a combination of smell and taste, and taste depends largely on the volatile particles in foods and beverages which reach the olfactory receptors through the nasopharynx. However, these patients have no impairment of the elementary taste sensations (sweet, sour, bitter, and salty). • Unilateral anosmia, hyposmia: seldom, if ever, recognized by the patient.

TIP • Olfactory impulses reach the cerebral cortex without relay through the thalamus. This is a unique feature among the sensory systems.

Cranial Neuropathies I, V, and VII–XII • Dysosmia or parosmia may be due to foul odors within the nasal cavity in association with nasal infections. • Spontaneous sensation of smell in the absence of a stimulus (phantosmia). • Associated signs, such as unilateral optic atrophy and contralateral papilledema (Foster–Kennedy syndrome) may be present in conditions such as olfactory groove or sphenoid ridge meningiomas which extend posteriorly to involve the ipsilateral optic nerve (resulting in optic atrophy) and also cause raised intracranial pressure (ICP) and contralateral papilledema.15,16

Investigations and diagnosis

Smell should be tested in each nostril separately with a nonirritating substance, and not with an acrid substance such as ammonia. The etiology of olfactory deficits is determined by the clinical presentation, and the following diagnostic work-up is indicated based on the clinical presentation: • ENT evaluation with nasal endoscopy. • Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain. • CSF analysis. • Electroencephalogram (EEG).

Treatment

Treat the underlying cause, if possible. Rhinosinusitis can be treated with steroids and antibiotic therapy. Structural causes can be treated with surgery. Smoking cessation can improve tobacco-related causes. Nutritional deficiency can be treated with repletion,14 but symptoms may not be responsive to treatment.17

671 Prognosis

Prognosis depends on the cause and the severity of olfactory impairment.14 Anosmia due to head injury is dependent on the severity of the trauma and recovers in about one-quarter of patients.18

TRIGEMINAL NEUROPATHY (CRANIAL NERVE V) Definition and epidemiology

Disorder of the trigeminal nerve is a common disorder.

Anatomy and physiology

The trigeminal nerve is the largest cranial nerve (CN). It is a mixed nerve that provides sensation to the face, mucous membranes of the mouth, nose, cornea, and dura through three sensory branches (V1, V2, and V3), and motor innervation to the muscles of mastication.2 The motor nucleus is located in the mid-pons. The branches of V1–V3 have their cell bodies located in the gasserian (or semilunar) ganglion, which overlies the apex of the petrous portion of the temporal bone (Meckel’s cave). From the ganglion, the sensory fibers enter the pons and terminate on three major sensory nuclei that are located in the brainstem and upper cervical spinal cord. In a rostral to caudal direction, the trigeminal sensory nuclei are distributed as follows (Figure 21.4):1 • Mesencephalic nucleus (lower midbrain/upper pons). • Principal sensory nucleus (mid-pons). • Spinal nucleus (lower pons/medulla/upper cervical spinal cord).

Midbrain

Mesencephalic nucleus

Mesencephalic nucleus

Motor (masticatory) nucleus

Motor (masticatory) nucleus Pontine trigeminal (principal sensory) nucleus Spinal nucleus of trigeminal nerve

Pontine trigeminal (principal sensory) nucleus Mandibular nerve Spinal nucleus of trigeminal nerve

Dorsal horn

Dorsal view

CN III CN IV CN IX CN XII

Dorsal gray matter of spinal cord Mesencephalic nucleus Pontine trigeminal (principal sensory) nucleus Spinal nucleus of trigeminal nerve

Ventral view

CN X CN XI

Lateral view

FIGURE 21.4  Cranial nerve V nuclei. (Adapted from Cranial Nerves in Health and Disease by Linda Wilson-Pauwels.)

Hankey’s Clinical Neurology

672 Sensory and motor peripheral divisions of CN V Sensory (Figure 21.5) First (ophthalmic) division or V1  Innervates the skin of the ipsilateral scalp, forehead, upper eyelid and nose, the upper half of the cornea, conjunctiva, and iris, in addition to the frontal sinuses and dura, via four branches: the lacrimal nerve (skin of lateral eyelid/brow and conjunctiva); the frontal nerve and its branches: the supratrochlear nerve (conjunctiva, medial upper eyelid, forehead, and side of the nose) and supraorbital nerve (medial upper eyelid and conjunctiva, forehead and scalp up to vertex, and frontal sinuses); the nasociliary nerve (skin of the top of the nose and medial canthus, nasal cavity, conjunctiva, ciliary body, iris, and cornea); the tentorial branch (dura of cavernous sinus, sphenoid wing, anterior fossa, petrous ridge, tentorium, posterior falx, and venous sinuses). The first division carries most of the afferent pathway of the corneal reflex, with some contribution from the second division for the lower half of the cornea. V1 enters the orbit and passes through the superior orbital fissure, lateral wall of the cavernous sinus (below the abducens nerve) and eventually reaches the trigeminal sensory ganglion.

TIP • The ophthalmic (V1) and maxillary (V2) nerves are purely sensory. The mandibular (V3) nerve has both sensory and motor functions. Second (maxillary) division or V2  Innervates the skin of the ipsilateral lower eyelid, lateral nose, upper lip, cheek sparing the skin over the angle of the mandible (which is innervated by the C2–C3 nerve roots), the lower half of the cornea, conjunctiva and iris, the mucous membranes of the maxillary sinus, palate, nasopharynx, upper gum, the upper teeth, and the dura of the middle cranial fossa (via middle meningeal artery). V2 enters the skull through the foramen rotundum and then passes in the inferolateral wall of the cavernous sinus to the trigeminal sensory ganglion.

C2 V1

C2, C3

V2 C3 C2, C3 V3

C4 C2, C3

C3, C4

FIGURE 21.5  Dermatomal distribution of cranial nerve V branches. V1, ophthalmic nerve; V2, maxillary nerve; V3, mandibular nerve. Spinal nerve roots C2–C4 innervate the skin of the posterior scalp and the neck.

Third (mandibular) division or V3  This division has three main branches: auriculotemporal, lingual, and inferior alveolar nerves. V3 innervates the skin of the lower lip, chin, lower jaw, upper ear, external auditory canal and tympanic membrane, the mucous membranes of the lower oral cavity, lower gums, anterior two-thirds of tongue (not taste), the teeth of the lower jaw, and the dura of the posterior cranial fossa. V3 joins the motor root to form the mandibular nerve. V3 enters the skull through the foramen ovale (with the motor fibers) and passes inferior to the cavernous sinus to the trigeminal sensory ganglion.

TIP • V1 enters the skull through the superior orbital fissure, V2 enters the skull through the foramen rotundum, and V3 enters the skull through the foramen ovale.

Motor

The motor nucleus is in the mid-pons. The motor root passes through the posterior fossa, enters Meckel’s cave, and leaves the base of the skull through the foramen ovale. After leaving the skull, it joins the V3 division to form the mandibular nerve, which supplies the muscles of mastication: masseter, temporalis, medial and lateral pterygoids, tensor tympani, tensor veli palatini, mylohyoid, and the anterior belly of digastric. Course of sensory fibers: gasserian ganglion to cortex  From the gasserian ganglion, sensory fibers enter the pons and terminate on the three sensory nuclei. The principal sensory nucleus mediates pressure and light touch from the face and oral cavity and contains second-order neurons that project to the ipsilateral and contralateral ventral posteromedial (VPM) nuclei of the thalamus via the dorsal trigeminothalamic tract (Figure 21.6). The spinal trigeminal tract and nucleus mediate pain and temperature from V1 to V3. Fibers in the spinal trigeminal tract descend from the pontomedullary junction to the C2–C4 level of the spinal cord; second-order neurons project to the contralateral VPM nucleus via the ventral trigeminothalamic tract.19 The mesencephalic nucleus, which is located at the midbrain–pontine junction, contains first-order neurons that receive proprioceptive input from V3.20 This nucleus also provides the afferent limb of the jaw jerk reflex. After the trigeminothalamic tracts synapse in the thalamus, third-order neurons from the thalamus project on the somatosensory cortex. Trigeminal reflexes  The trigeminal nerve constitutes the afferent limb in five monosynaptic reflexes; in one of them, jaw jerk reflex, it also constitutes the efferent limb (Table 21.1).

Jaw jerk

This is a monosynaptic myotatic reflex in which the trigeminal nerve constitutes both the afferent limb (sensory division of V3) and the efferent limb (motor division of V3) of the reflex arc. Its first-order neuron is not in the gasserian ganglion, but located centrally in the mesencephalic nucleus in the midbrain: • Afferent limb: Ia fibers in V3 division that carry proprioceptive sensory information from facial muscles and masseter. Collateral fibers synapse with the motor nucleus of CN V. • Efferent limb: mandibular fibers that originate in the motor nucleus of CN V. Efferent (motor) fibers are sent to masticatory muscles via the motor division of V3.

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Ventral posteromedial nucleus of thalamus

Caudate nucleus Internal capsule (posterior limb)

Face area of postcentral gyrus

Dorsal trigeminothalamic tract

Ventral trigeminothalamic tract

Mesencephalic nucleus of CN V Principal sensory nucleus of CN V Sensory branch of CN V1 Sensory branch of CN V2 Sensory branch of CN V3 Motor branch of CN V3

Midbrain Pons Motor nucleus of CN V Spinal trigeminal nucleus

Spinal trigeminal tract Medulla Spinal cord

FIGURE 21.6  Trigeminothalamic pathways. (Adapted from High Yield Neuroanatomy, 3rd edition, by James D Fix.)

Etiology

• Brainstem: lesions are often associated with other CN deficits and long tract involvement: • Stroke (lateral medullary syndrome). • Multiple sclerosis (MS). • Tumor (brainstem glioma, lymphoma, and metastases). • Syringobulbia. • Hemorrhage from hypertension, ruptured vascular anomalies. • Inflammatory conditions: sarcoidosis, connective tissue diseases, and vasculitis. • Infectious conditions. • Cerebellopontine angle: • Vestibular schwannoma compressing CN V (although CN VII is most commonly affected). • Trigeminal schwannoma (second most common cause of schwannomas affecting CNs). • Meningioma (multiple CNs are usually affected). • Glossopharyngeal schwannoma (rare). • Epidermoid/dermoid tumor. • Chordoma. • Chloroma. • Metastases. • Aberrant vessels, basilar artery ectasia, or aneurysm.

TABLE 21.1  Trigeminal Reflexes Reflex Corneal reflex Blink reflex Tearing (lacrimal) reflex Oculocardiac reflex Jaw jerk

Afferent Limb

Efferent Limb

CN V1 CN V1 CN V1 CN V1 CN V3

CN VII CN VII CN VII CN X CN V3

• Meckel’s cave: • Schwannoma. • Meningioma. • Nasopharyngeal cancer and other head and neck malignancies. • Sarcoidosis. • Petrous apicitis.

TIP • Trigeminal schwannomas are the second most common cause of schwannomas affecting the cranial nerves.

• Base of the skull: • Meningitis (infectious, inflammatory, and carcinomatous). • Sarcoidosis. • Meningovascular syphilis. • Chordoma. • Metastases to skull base, nasopharyngeal cancer, and other head and neck cancers. • Osseous lesions (e.g. Paget’s disease). • Cavernous sinus (V1, V2)/superior orbital fissure (V1): • Aneurysm of carotid siphon or ophthalmic artery. • Carotid–cavernous fistula. • Cavernous sinus thrombosis. • Sarcoidosis. • Tolosa–Hunt syndrome: a rare condition that manifests as subacute onset of severe unilateral orbital pain which may be accompanied by a sensory disturbance in V1 and sometimes V2 distribution, and ocular motor (III, IV, and VI cranial) nerve palsies. It is caused by a chronic inflammation behind and/or within the orbit.

Hankey’s Clinical Neurology

674 • Infectious etiologies. • Tumors (Figure 21.7). • Orbit (V1): • Inflammation. • Cellulitis. • Tumor. • Mandible (V3): • Inflammation. • Tumor: often metastatic (e.g. numb chin syndrome). • Other: • Autoimmune trigeminal sensory neuropathy: undifferentiated and mixed connective tissue diseases, scleroderma, and Sjögren’s syndrome. • Guillain–Barré syndrome and other peripheral neuropathies. • Herpes zoster (usually first sensory division) (Figure 21.8). • Skull trauma. • Trichloroethylene (organic solvent) toxicity: bifacial numbness. • Isolated trigeminal sensory neuropathy.

Clinical features Unilateral trigeminal lesions

• Motor involvement: • Difficult to detect. • Wasting of the ipsilateral temporalis and masseter muscles may be evident. • The open jaw deviates to the side of the lesion, due to pterygoid muscle weakness. • Sensory loss: sensory disturbance in any or all of the three sensory divisions, ipsilateral or contralateral to the lesion, can occur, depending on the location of the lesion (see below).

FIGURE 21.8  Varicella-zoster V1 distribution. (From eMedicine Neurology: Varicella Zoster by Wayne E Anderson.)

Lesion in the brainstem

Sensory disturbance in all three sensory divisions can occur, with or without motor loss: • A lesion in the pons can result in ipsilateral or contralateral facial pain, temperature, touch, and corneal reflex loss, with or without motor loss. • A lesion in the medulla can cause ipsilateral or contralateral facial pain and temperature loss only. • Symptoms are usually associated with other brainstem (e.g. lower cranial nerve and long tract) and cerebellar signs.

Cerebellopontine angle and base of skull

• Ipsilateral facial sensory disturbance (pain [and temperature] and touch [and corneal reflex] loss) in all three sensory divisions and motor loss occur. • Symptoms may be associated with other ipsilateral cranial neuropathies (e.g. VI, VII, VIII, and IX), brainstem, and cerebellar signs.

Petrous temporal bone apex (Gradenigo’s syndrome)15

• Initially described in children with petrous apicitis as a complication of otitis media and mastoiditis. • May affect all three divisions of CN V (decreased ipsilateral corneal reflex, ipsilateral facial pain, ear pain, and motor loss in masticatory muscles) and CN VI (ipsilateral abducens paresis).

Cavernous sinus/superior orbital fissure lesion

FIGURE 21.7  Intracavernous schwannoma of V1. Brain MRI (axial T2 image) showing a large area of increased signal intensity, due to an intracavernous schwannoma of the ophthalmic division of the right trigeminal nerve, extending from the right cavernous sinus into the retro-orbital space (causing proptosis), and compressing the medial right temporal lobe.

• Sensory disturbance occurs in the first division of CN V, and sometimes in the second division; the third division is spared. • Symptoms are associated with ocular motor (III, IV, and VI) cranial nerve palsies, Horner’s syndrome, optic nerve or chiasm compression, and pain above and within the orbit. • Proptosis, eyelid and conjunctival edema (chemosis), episcleral vasodilation, and papilledema may be present if there is venous obstruction (e.g. cavernous sinus thrombosis). With a carotid–cavernous fistula, there is additionally pulsating exophthalmos and an orbital bruit.

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Orbital lesion

Sensory disturbance in the first division exclusively associated with ophthalmoplegia.

TRIGEMINAL NEURALGIA (TIC DOULOUREUX)

Foramen ovale or mandibular lesion

Definition and epidemiology

Sensory disturbance in the third division exclusively; sometimes only unilateral chin numbness.

Bilateral trigeminal lesions

• Motor involvement: more obvious symptoms are usually evident, with weakness and wasting of the temporalis and masseter muscles bilaterally. If severe, the jaw hangs open. • Sensory loss: • Bilateral facial sensory loss occurs, which may not be complete (e.g. it may be in an ‘onion skin’ distribution as may occur with syringobulbia). • Can occur with exposure to trichloroethylene (an organic solvent in glue, paint stripper, and paint) and connective tissue diseases (such as undifferentiated and mixed connective tissue diseases, scleroderma, and Sjögren’s syndrome).

Investigations

Diagnostic testing based on the clinical syndrome and likely localization and etiology: • Direct examination of the nasopharynx and larynx. • MRI or CT scan of brain, base of skull, and orbits (with and without contrast). • CSF examination (evaluation for infectious, malignant, or inflammatory process). • Complete blood count and erythrocyte sedimentation rate (ESR). • Fasting blood glucose. • Autoantibody screen. • Chest X-ray (evaluating for malignancy or sarcoidosis). • Electrophysiologic testing of the blink reflex may help in lesion localization and in distinguishing classical from symptomatic trigeminal neuralgia. • CT or conventional angiography if a carotid–cavernous fistula is suspected.

SELECTED CONDITIONS AFFECTING THE TRIGEMINAL NERVE ISOLATED TRIGEMINAL SENSORY NEUROPATHY • Uncommon. • It may begin as a small patch of facial numbness, which spreads to the territory of a whole division and eventually to adjacent divisions and possibly the entire face. • Severe loss of pain sensation in the face may lead to ulcerative lesions around the nose and in the cornea. • Certain etiologies need to be excluded, such as a skull base tumor, Sjögren’s syndrome, and other connective tissue diseases, but can be idiopathic.21 • Recovery sometimes occurs after weeks or months.

Trigeminal neuralgia (TN) is a painful condition caused by irritation of the trigeminal nerve. The most common cause is neurovascular compression by a redundant or tortuous arterial loop impinging on the trigeminal nerve root adjacent to its entry zone into the pons causing focal demyelination. The superior cerebellar artery is the most frequently implicated vessel. TN is characterized by severe, paroxysmal, sharp lancinating pain in the distribution of one or more divisions of the trigeminal nerve (typically affecting V2 > V3). The condition is known as tic douloureux because of the typical lightning-like jabs of pain that may result in wincing. • Incidence: 2–8 per 100,000 per year. • Lifetime prevalence: 0.7% (95% confidence interval [CI]: 0.4–1.0%); 4% of MS patients. • Age: usually starts after the age of 50 years, most commonly in the sixth and seventh decades. • Gender: F > M (1.5:1).

Etiology and pathophysiology

TN is divided into three categories: Idiopathic TN: no identifiable cause. Classic TN: because of neurovascular compression of the trigeminal nerve, most commonly by an aberrant superior cerebellar or anterior inferior cerebellar artery. Secondary TN:22 Because of an underlying cause other than neurovascular compression, including: • MS due to a plaque of demyelination at the root entry zone in the pons, and can cause bilateral TN.22,23 This accounts for 2–3% of all cases of TN and up to 8% in younger patients. • Cerebellopontine angle (CPA) tumor arising from or compressing the trigeminal nerve (epidermoid, acoustic or trigeminal schwannoma, and meningioma). • Arteriovenous malformations, aneurysms, and herpes zoster.

Differential diagnosis • • • • •

Temporomandibular joint (TMJ) disorders. Atypical dental pain. Phantom tooth pain. MS (TN may be bilateral). Glossopharyngeal neuralgia: extremely rare. Pain is similar in nature (i.e. severe, unilateral, lancinating, and episodic), but at a different site: pain arises from the throat, larynx, pharynx, or pinna of the ear (i.e. in the distribution of the glossopharyngeal nerve).

Clinical features

Pain occurs in the face or mouth. It commonly starts in the cutaneous distribution of the second or third division of the trigeminal nerve; only 5% occur in the first division. Trigger factors include talking, chewing, swallowing, shaving, brushing the teeth, and wind blowing on the face. Trigger points are areas around the nose, lips, or mouth which, when touched, evoke a paroxysm of pain. When sites are inside the mouth, patients become hesitant about eating, drinking, and brushing their teeth. The pain

676 is described as brief (lasting for seconds) stabbing/lightning or electric shock–like/penetrating jabs of pain or clusters of stabbing pain followed by a refractory period lasting for seconds to minutes.23 The pattern is episodic: pain may recur several times a day for weeks or months, and then may remit for months or years. Oral hygiene may suffer and weight loss may occur as patients attempt to avoid triggering the pain; anxiety, depression, dehydration, and even suicide can occur in severely afflicted patients.

Investigations and diagnosis

Diagnosis is clinical, based on clinical history. Physical examination is normal in idiopathic and classic TN. If there are abnormalities on examination, such as ipsilateral trigeminal distribution sensory loss, depressed corneal reflex, deafness, or if an aching pain persists between the characteristic stabs, then investigation into a secondary cause should take place. Neuroimaging using high-resolution brain MRI with gadolinium along with brain MRA is helpful for determining the anatomy of the trigeminal nerve and to identify neurovascular compression. MRI is also useful to evaluate secondary causes of TN such as MS and CPA lesions. In one study, neurovascular compression was present on the symptomatic side in 89% of patients compared to 78% on the asymptomatic side while severe neurovascular compression was highly prevalent on the symptomatic side compared to the asymptomatic side (53% vs. 13%).24 On pathology, focal demyelination and microneuromas are often present at the site of microvascular compression of the trigeminal nerve, but these features may also be found in asymptomatic subjects.

Treatment

Most patients can be managed medically. The most effective firstline treatment is carbamazepine, followed by oxcarbazepine, both of which reduce the excitability of neurons by blocking sodium channels. Carbamazepine 400–1200 mg daily in divided doses is effective in about three-quarters of patients.25 A small dose of 50–100 mg nightly is the usual starting dose (to avoid drowsiness), escalating the dose as tolerated until pain relief is achieved (or adverse effects occur). A slow-release preparation can also be used. The dose is continued for weeks to months, and can then be tapered slowly, with reloading if the pain recurs. Most responders will experience about 6–12 months of respite before recurrence. Up to one-third of patients cannot tolerate carbamazepine in the doses required to alleviate the pain due to adverse effects such as rash, nausea, drowsiness, and ataxia. Carbamazepine may also cause hyponatremia, megaloblastic anemia (folate interaction), aplastic anemia, agranulocytosis, hepatotoxicity, and hypersensitivity reactions. Oxcarbazepine (900 mg/day to 1800 mg/day) is generally better tolerated.

TIP • Brain imaging studies for work-up of TN should be used in young patients (< 40 years), if bilateral pain is present, and/or in the presence of neurologic signs/deficits. Second-line medical therapy includes: • Phenytoin 200–400 mg/day. It has the same mechanism of action as carbamazepine, but is less effective. • Baclofen, a γ-aminobutyric acid (GABA) B-receptor agonist, 10–20 mg three times daily.

Hankey’s Clinical Neurology • Gabapentin or pregabalin, which attenuates neuronal hyperexcitability by binding to the α2δ subunit of voltagegated calcium channels. • Lamotrigine, which is as potent as carbamazepine in inactivating sodium ion currents with fewer adverse effects, is effective in some cases. Lamotrigine is a potent antiglutamatergic agent, which may depress excitatory transmission in the spinal trigeminal nucleus. It may cause initial ataxia, diplopia, nausea, vomiting, and blurred vision in 15–35% of patients, but these are often dose-related. An allergic skin rash is seen in 3–17% of patients. Some patients require more than one medication for symptom control, and 25–50% of patients eventually stop responding to drug therapy. For these patients, one of several surgical procedures can be undertaken. These include percutaneous procedures on the gasserian ganglion, and procedures performed on the trigeminal root including stereotactic radiosurgery and microvascular decompression (MVD).22 MVD offers the longest duration of pain relief; however, no clinical trials have established the efficacy of any of these surgical procedures.26

Percutaneous procedures on gasserian ganglion

These procedures include lesioning of the gasserian ganglion with radiofrequency thermocoagulation, glycerol injection, or balloon microcompression under fluoroscopic guidance. In all three procedures, a cannula is inserted lateral to the corner of the mouth and aimed at the foramen ovale, through which it penetrates the skull base to reach the gasserian ganglion in Meckel’s cave. With percutaneous procedures, pain relief is immediate and complete in a high percentage of cases, however follow-up studies report pain relief in 70% at 1 year, 60% at 3 years, and 50% at 5 years.22 Trigeminal sensory deficits can occur after these procedures. These are usually transient with balloon microcompression and glycerol injection and more severe and longer-lasting after radiofrequency gangliolysis.

Stereotactic radiosurgery (Gamma Knife)

This targets the trigeminal root immediately prior to its entrance into the pons. Pain relief is not immediate with this procedure and generally develops 6–8 weeks later. Per the 2008 AAN/EFNS guidelines on trigeminal neuralgia, complete pain relief occurs in up to 69% of patients at 1 year after stereotactic radiosurgery and falls to 52% at 3 years.27 Facial numbness occurs in 9–37% of patients, and troublesome sensory loss or paresthesia is reported in 6–13%.

Microvascular decompression

With this procedure, performed via craniotomy, a sponge is inserted between the nerve and the offending artery. According to the AAN/EFNS guidelines, 90% of patients obtain pain relief.27 More than 80% of patients remain pain free at 1 year, 75% at 3 years, and 73% at 5 years. The average mortality associated with MVD is 0.2%. Complications include ipsilateral hearing loss, CSF leak, infarct or hematoma, aseptic meningitis, diplopia, and facial palsy. Sensory loss occurs in 7% of patients.27

NUMB CHIN SYNDROME Numb chin syndrome is usually seen in patients with systemic malignancy (lymphoreticular neoplasms, breast, lung, prostate, colon, and thyroid cancer), but may be seen with noncancerous

Cranial Neuropathies I, V, and VII–XII etiologies including dental procedures, dental infection, connective tissue disease, or trauma. The mental nerve is a branch of the inferior alveolar nerve, which arises from V3. It exits through the mental foramen and supplies sensation to the chin and lower lip. The nerve may be compressed by a metastasis to bone at the mental foramen or along its course; it may also be infiltrated by tumor. Sensory loss extending beyond the chin and lower lip may indicate a more proximal V3 lesion or leptomeningeal involvement. Evaluation should include MRI of the brain with contrast with special attention to the trigeminal nerve and its branches, dedicated MRI of the mandible if brain MRI is nonrevealing, and CSF examination.15,28

FACIAL NEUROPATHY (CRANIAL NERVE VII) Definition and epidemiology Disorder of the facial nerve. • Common. • Age: any. • Gender: M = F.

Anatomy

The facial nerve has motor, somatosensory, and secretomotor functions. The motor component of the facial nerve innervates the muscles of facial expression; this component represents approximately 70% of the facial nerve fibers. The remaining 30% are contained in the nervus intermedius and constitute the somatosensory and secretomotor components of the nerve.2 There are five functional components of the facial nerve (Figure 21.9): • Special visceral efferent: innervates the muscles of facial expression, the stapedius, stylohyoid, and posterior belly of the digastric. • General visceral efferent: parasympathetic fibers that innervate the lacrimal, submandibular, and sublingual glands in addition to the mucous membranes of the nasopharynx and palate.

677 • Special visceral afferent: taste sensation from the anterior two-thirds of the tongue. • General somatic afferent: sensory innervation (touch, temperature, and pain) from the auricle, pinna of the ear, and retroauricular region. • General visceral afferent: light touch, temperature, and pain sensation from the soft palate and surrounding pharyngeal wall.

Motor component Supranuclear control

• Precentral gyrus: the innervation of the facial muscles begins in the most lateral and inferior aspect of the precentral gyrus, near the sylvian fissure. A branch of the middle cerebral artery supplies this region. • Corticobulbar fibers course in the corona radiata, the genu of the internal capsule, and the medial aspect of the cerebral peduncle before reaching the pons. • In the pons, most descending fibers decussate and project on the contralateral facial motor nucleus. The facial motor nucleus is divided into a dorsal and a ventral half. The ventral portion innervates the lower two-thirds of the face and receives crossed supranuclear control. The dorsal portion supplies the upper one-third of the face and has bilateral supranuclear control. As a result, a unilateral hemispheric lesion impairs only the lower facial muscles.15

Nuclear and infranuclear control (Figures 21.9 and 21.10)

The facial motor nucleus lies ventral and lateral to the abducens nucleus in the lower pons. From the facial nucleus, all the nerve fibers that innervate the ipsilateral facial muscles ascend posteriorly and medially to loop around the abducens nucleus (genu of the facial nerve) before travelling ventrally (immediately lateral to the corticospinal tract) to emerge from the ventrolateral aspect of the pons. The motor division of the facial nerve and the nervus intermedius (see below) then proceed laterally in the CPA along with CN VIII before entering the internal auditory canal of the temporal bone (with CN VIII). The nerve has four segments within the temporal bone:

Spinal nucleus of the trigeminal nerve (general sensory) Abducens nucleus (CN VI – somatic motor) Pons CN VII CN VIII Nervus intermedius portion of VII

Nucleus solitarius, rostral portion (special sensory) Motor nucleus of CN VII (branchial motor) Superior salivatory (lacrimal) nucleus (visceral motor/ parasympathetic) Nucleus solitarius, caudal portion (visceral sensory)

FIGURE 21.9  Cranial nerve VII brainstem nuclei. (Adapted from Cranial Nerves in Health and Disease by Linda Wilson-Pauwels.)

Hankey’s Clinical Neurology

678

Greater petrosal nerve to pterygopalatine ganglion

Superior salivatory nucleus Motor nucleus VII Solitary nucleus

Motor root Nervus intermedius Internal auditory meatus Geniculate ganglion Stylomastoid foramen Digastric branch Stylohyoid branch Posterior auricular branch

Lesser petrosal nerve to otic ganglion Nerve to stapedius Chorda tympani nerve Lingual nerve

Taste fibers To sublingual gland To submandibular gland Temporal Zygomatic Buccal Mandibular Cervical

Facial motor branches

FIGURE 21.10  Anatomy of cranial nerve VII. (Adapted from Shapiro. EMG.) • Meatal segment: this segment extends from the porus of the internal auditory canal to the meatal foramen. There are no major branches from this facial nerve segment. • Labyrinthine segment: this segment extends from the meatal foramen to the geniculate ganglion. The labyrinthine segment is the narrowest part of the facial nerve and is susceptible to compression as a result of edema. In this section, which is 3–5 mm in length, the facial nerve changes direction to form the first genu and ends at the geniculate ganglion where the cell bodies of the general somatic and special visceral afferent neurons are located. The greater superficial petrosal nerve, which is the first major branch of the facial nerve, arises from the upper portion of the geniculate ganglion. • Tympanic segment: this section is 10 mm in length and has no major nerve branches. It extends from the geniculate ganglion to the horizontal semicircular canal. The tympanic segment ends where the facial nerve makes its second genu. • Mastoid segment: this is the final intracranial portion of the facial canal. The nerve proceeds vertically to the stylomastoid foramen where it exits the cranium. The nerve to the stapedius originates near the upper portion of this segment. The chorda tympani is another branch arising from this segment; it joins the lingual nerve and carries preganglionic parasympathetic fibers (from the superior salivatory nucleus), which innervate the submandibular and sublingual glands and afferent taste fibers from the anterior two-thirds of the tongue. A sensory branch exits the nerve immediately below the stylomastoid foramen and innervates the posterior wall of the external auditory canal and a portion of the tympanic membrane. Once it has exited the facial canal at the stylomastoid foramen, the facial nerve gives off several rami before it divides into its main branches. Near the exit site at the stylomastoid foramen, the

facial nerve gives off the posterior auricular nerve, which supplies auricular muscles and the occipitalis, the digastric branch, and the stylohyoid branch. The facial nerve then pierces the parotid gland where it divides into five branches that supply muscles of facial expression and the platysma: temporal, zygomatic, buccal, marginal mandibular, and cervical (Figure 21.11).

Sensory component

The sensory and parasympathetic component of the facial nerve is the nervus intermedius (of Wrisberg). This division of the facial nerve carries:

1

2

3 4

5

FIGURE 21.11  Motor branches of the facial nerve. 1, temporal; 2, zygomatic; 3, buccal; 4, mandibular; 5, cervical.

Cranial Neuropathies I, V, and VII–XII • Sensory fibers that carry taste sensation from the anterior two-thirds of the tongue, afferents from the pharyngeal, nasal, and palatal mucosae, and from the skin of the external auditory canal, lateral ear, and postauricular region. The taste fibers from the anterior two-thirds of the tongue first traverse the lingual nerve (a branch of the mandibular nerve) then diverge to join the chorda tympani (a branch of CN VII); they then pass through the pars intermedia and geniculate ganglion of the seventh nerve to the rostral part of the nucleus of the tractus solitarius in the medulla. Somatic afferent fibers from the external auditory canal and postauricular region end in the spinal nucleus of cranial nerve V. • Parasympathetic fibers to the submandibular and sublingual glands (through the submaxillary ganglion) and to the lacrimal, palatal, and nasal glands (through the pterygopalatine ganglion). The preganglionic parasympathetic fibers originate in the superior salivatory nucleus at the level of the caudal pons; fibers that control lacrimation arise from the adjacent lacrimal nucleus. These fibers exit the brainstem as part of the nervus intermedius and divide into two groups: • One group of fibers synapses with the pterygopalatine ganglion through the greater superficial petrosal nerve. Postganglionic fibers innervate the lacrimal, palatal, and nasal glands. • Another group of fibers will synapse with the submaxillary ganglion through the chorda tympani and branches from the lingual nerve. Postganglionic fibers innervate the sublingual and submaxillary glands.

Clinical features

Facial neuropathy can occur at any age and is nearly always unilateral. It is bilateral in 1–2% of cases.29 Unilateral facial weakness of acute onset may be secondary to a facial neuropathy or a central lesion. 30 A central facial weakness spares the upper face, is not associated with hyperacusis or taste abnormalities, and is often accompanied by other findings referable to the site of the lesion. Causes of facial neuropathy are listed in Table 21.2. Bilateral facial neuropathy is most commonly caused by Bell’s palsy; other etiologies include (but are not limited to) sarcoidosis, Guillain–Barré syndrome, and Lyme disease (Table 21.3).29

Supranuclear lesions (upper motor neuron facial palsy)

A supranuclear lesion affecting the corticobulbar tract results in contralateral weakness of the lower facial muscles.31 The most severely affected muscles are the ones surrounding the mouth with occasional involvement of the orbicularis oculi. The muscles of the forehead are spared and there is no hyperacusis, or dysgeusia.

TIP • Facial paresis from a central lesion spares the upper face and is not associated with hyperacusis or taste abnormalities.

Nuclear and fascicular lesions

Lesions in the pons affecting the facial motor nucleus or facial nerve fascicles result in an ipsilateral peripheral (or lower motor

679 neuron) facial nerve palsy with upper and lower facial weakness. This manifests with weakness of frowning, eye closure, and elevation of the eyebrow in addition to involvement of muscles of the lower face. Pontine lesions involving the facial nucleus/fascicles generally affect neighboring structures including CN VI nucleus and fascicles (reduced abduction in ipsilateral eye), paramedian pontine reticular formation (impaired conjugate horizontal gaze to ipsilateral side), corticospinal tract (contralateral arm and leg weakness), CN V spinal tract and nucleus (ipsilateral facial numbness), and spinothalamic tract (contralateral hemibody numbness).20

Cerebellopontine angle lesions

A lesion in the CPA may involve the motor fibers of the facial nerve (ipsilateral upper and lower facial weakness), nervus intermedius (loss of taste over the ipsilateral anterior two-thirds of the tongue), and CN VIII (vertigo, ipsilateral tinnitus, and hearing loss).

Facial canal lesions

• A lesion in the meatal segment has a similar presentation to CPA lesions. • A lesion between the end of the meatal segment and the take-off of the nerve to stapedius results in involvement of the motor division of the facial nerve (ipsilateral peripheral facial weakness and hyperacusis) and the nervus intermedius (loss of taste over the ipsilateral anterior two-thirds of the tongue). Lacrimation is impaired if the lesion is proximal to the greater superficial petrosal nerve. • A lesion between the nerve to stapedius and the chorda tympani results in ipsilateral peripheral facial weakness and loss of taste over the ipsilateral anterior two-thirds of the tongue, without hyperacusis. • A lesion distal to the chorda tympani results in ipsilateral peripheral facial weakness without hyperacusis or alteration of taste. • There is impairment of sensation in the ipsilateral earlobe with lesions proximal to the stylomastoid foramen.

Physical examination

• Unilateral facial droop with flattening of the forehead creases, widening of the palpebral fissure, flattening of the nasolabial fold, lowering of the corner of the mouth, and impaired smiling and grinning are observed at rest. The patient is unable to elevate the eyebrow, wrinkle the forehead, and close the eye on the affected side. • The ipsilateral eye may be red and dry as a result of impaired blinking or decreased lacrimation. • Air escapes between the lips on the affected side when the cheeks are puffed with air. • Corneal reflex is impaired because the lesion affects the efferent limb of this reflex arc. • Taste may be impaired if the facial nerve lesion is proximal to the chorda tympani branch, within the temporal bone. • Speech may be slurred (flaccid dysarthria). • Otoscopy of the external auditory canal may reveal findings that could be relevant (e.g. vesicles which may suggest herpetic facial neuropathy [Ramsay Hunt syndrome]).

Hankey’s Clinical Neurology

680 TABLE 21.2  Causes of Unilateral VII Cranial Neuropathy Pontine • • • • • •

Infarct Multiple sclerosis Brainstem tumor Encephalitis Abscess Hemorrhage

Congenital/postnatal • Möbius’ syndrome • Facial neuropathy from forceps/birth trauma • Hemicranial microsomia • Congenital lower lip paralysis • Kawasaki’s disease • Albers–Schoenberg disease (osteopetrosis) • Infantile hypercalcemia • Cardiofacial syndrome Tumor • • • • • •

Acoustic neuroma Meningioma Cholesteatoma Metastatic Neurinoma Parotid tumor

Meningitis • Infectious • Bacterial • Fungal • Tuberculous • Syphilis • Lyme disease/ borreliosis • Parasitic (trichinosis, neurocysticercosis) • Inflammatory • Sarcoidosis • Neoplastic • Carcinomatous • Lymphomatous • Leukemia (children)

Infections • • • • • • • • • • • •

Ramsay Hunt syndrome (VZV) Herpes simplex virus HIV seroconversion Osteomyelitis of skull base Otogenic infections Parotitis/abscess Mastoiditis Lyme disease Leprosy Poliomyelitis Mycoplasma Influenza

Miscellaneous • Benign intracranial hypertension • Trauma • Melkersson–Rosenthal syndrome • Amyloidosis • Wegener’s granulomatosis • Polyarteritis • Diabetes mellitus • Sjögren’s syndrome • Pregnancy • Human T-cell lymphotropic virus type 1 • Hereditary neuropathy with pressure palsies • Familial Bell’s palsy • Guillain–Barré syndrome • Chronic inflammatory demyelinating polyneuropathy • Charcot–Marie–Tooth disease • Histiocytosis X • Interferon therapy • Sclerosteosis • Ethylene glycol intoxication • Wernicke–Korsakoff syndrome • Stevens–Johnson syndrome

TABLE 21.3  Diseases Most Likely to Cause Bilateral Facial Neuropathy Bell’s palsy Guillain–Barré syndrome Miller Fisher syndrome Multiple cranial neuropathies Brainstem encephalitis Neoplastic meningitis Pontine glioma Prepontine tumors Syphilis Leprosy Infectious meningitis Lyme disease Herpes simplex virus, herpes zoster virus Sarcoidosis Sclerosteosis Amyloidosis Ethylene glycol intoxication Möbius’ syndrome HIV Infectious mononucleosis Poliomyelitis Head injury (especially children)

SELECTED CONDITIONS AFFECTING THE FACIAL NERVE BELL’S PALSY This condition presents with the acute onset of unilateral facial weakness (Figure 21.12) and accounts for up to 70% of cases of facial neuropathy. The incidence is 20–30 per 100,000 persons per year. Diabetes, hypertension, and pregnancy are often cited

Abbreviations:  HIV, human immunodeficiency virus; VZV, varicella-zoster virus.

• Examination of the oral cavity may also reveal vesicles on the ipsilateral palate in patients with Ramsay Hunt syndrome. • Associated central nervous system (CNS), CN, or peripheral nervous system signs may be present such as contralateral hemisensory loss or gaze palsy ipsilateral to the lower motor neuron facial weakness (suggesting a low pontine lesion), multiple cranial neuropathies (suggesting basilar meningitis or vasculitis), or sensory disturbances in the distal extremities or muscle wasting (which may indicate an underlying neuropathy).

FIGURE 21.12  Patient with left Bell’s palsy.

Cranial Neuropathies I, V, and VII–XII as risk factors. Facial paralysis in Bell’s palsy can be incomplete (type I) or complete (type II). 31 There is evidence supporting reactivation of herpes simplex virus (HSV) type 1 infection in the geniculate ganglion as the major cause of Bell’s palsy, resulting in inflammation, edema, and demyelination of the nerve in the facial canal and in some cases, axonal loss. Other viruses that have been implicated include varicella-zoster virus (VZV), cytomegalovirus (CMV), coxsackie, Epstein–Barr virus (EBV), mumps, influenza, and human immunodeficiency virus (HIV).18

Clinical features

• A viral prodrome is present in about 60% of patients. • Pain behind the ear may precede the facial weakness by up to 2 weeks, evolving over about 48 hours before reaching a plateau. • Unilateral facial weakness of lower motor neuron type follows the pain, and may be associated with excessive tearing due to weakness of the orbicularis oculi (which normally holds the puncta lacrimalia against the conjunctiva) or decreased lacrimation due to impaired innervation of the lacrimal gland. • Ipsilateral facial numbness is a common symptom, but objective sensory testing is normal. • Taste may be altered. • Sensitivity to sound may be increased (hyperacusis). • Presence of vesicles in the ear canal, behind the ear, or in the palate, is suggestive of Ramsay Hunt syndrome (see below). • Brain imaging is not indicated unless a structural lesion is suspected. A large percentage of patients with Bell’s palsy have facial nerve enhancement on MRI.

Treatment

• The AAN evidence-based guideline on treatment of Bell’s palsy with steroids and antivirals (acyclovir or valacyclovir) was last updated in 2012, largely based on two Class I studies that showed an increased rate of complete recovery with steroids with no additional benefit from antivirals. The AAN evidence-based review granted a level A recommendation for the use of steroids for treatment of Bell’s palsy within 72 hours of onset. Additionally, the guideline states that although adding an antiviral to a steroid offers no significant benefit, the two Class I studies could not rule out a modest increase in recovery with the addition of an antiviral and granted a level C recommendation for the combination.32

681 Prognosis

Most patients with Bell’s palsy have a favorable prognosis. Approximately 85% of patients recover completely within 1 year. 34 In these cases, recovery usually begins within 8 weeks and is complete by 6–12 months. The most favorable prognostic sign is an incomplete rather than complete facial palsy. If weakness is severe or complete, recovery commencing within 3 weeks is a favorable sign. The longer the delay in return of movement, the poorer the recovery. Recurrence occurs in around 7% of patients. If this occurs, alternative causes should be excluded, such as diabetes, sarcoidosis, tumor, or infection.18,28 From a prognostic standpoint, the amplitude of the facial motor response on electrodiagnostic testing can be helpful in the case of a unilateral facial palsy, by comparing side-to-side amplitude difference 5–7 days after onset of symptoms. On rare occasions, recovery from Bell’s palsy may be associated with persistent dysfunction including synkinesis, myokymia, or hemifacial spasm. 35 Predictors of incomplete recovery are: • Complete facial weakness. • Pain other than in or around the ear (i.e. back of head, cheek, etc.). • Older age. • Hyperacusis. • Decreased lacrimation. Residual deficits include: • Persistent facial weakness. • Motor synkinesis caused by aberrant reinnervation of the muscles of facial expression by regenerating facial nerve fibers. This includes simultaneous contraction of the ipsilateral lower face or platysma with blinking or simultaneous contraction of the orbicularis oculi when smiling. • Gustatory tearing (‘crocodile tears’) and gustatory sweating (Frey’s syndrome) due to misdirection of regenerating nonmotor fibers of the facial nerve.

RAMSAY HUNT SYNDROME (HERPES ZOSTER OTICUS)

There is insufficient evidence regarding the effectiveness of surgical facial nerve decompression in this condition. 32

This is an acute unilateral facial neuropathy associated with a vesicular rash in the ipsilateral ear canal, external ear, and/or oropharynx:

• Avoid complications, such as exposure keratitis: • Occurs if the cornea is not adequately protected. • Can be avoided by using artificial tears, instilling lubricating paraffin ointment, and taping (rather than padding) the eye closed at night. • Dark glasses should be worn outdoors. • Ophthalmological evaluation should be sought if the patient reports eye discomfort, or the eye becomes irritated despite the above measures. • Botulinum toxin injection into the eyelid levator to weaken it may be considered if conservative measures fail. • Tarsorrhaphy is rarely necessary in cooperative patients. • Facial electrostimulation has not been shown to provide benefit. 33

• Peripheral facial neuropathy, hyperacusis, ipsilateral taste alteration, and ear pain accompanied by a vesicular rash on the auricle, external auditory meatus or palate, in addition to erythema of the external ear. • Because of reactivation of the VZV in the geniculate ganglion of CN VII, 36 which may be due to diminished VZVspecific cell-mediated immunity. • Can be associated with other cranial neuropathies, most frequently CN VIII due to the juxtaposition of the geniculate ganglion to the vestibulocochlear nerve in the facial canal, resulting in hearing loss, tinnitus, and vertigo. 36 Other cranial neuropathies may be present involving CN IX, X, V, and VI. • Condition can occur in children or adults.

Hankey’s Clinical Neurology

682 • More severe and unfavorable prognosis compared to Bell’s palsy. VZV polymerase chain reaction (PCR) from the geniculate zone of the ear may differentiate early Ramsay Hunt syndrome from Bell’s palsy. 36 • There is a lack of prospective, randomized controlled trials in Ramsay Hunt syndrome. Recommended treatment is with prednisone and antiviral agents such as acyclovir, famciclovir, or valacyclovir.

VESTIBULOCOCHLEAR NEUROPATHY (CRANIAL NERVE VIII) Definition and epidemiology

A common disorder of the vestibulocochlear nerve.

Anatomy

The vestibulocochlear nerve is a special somatic afferent nerve consisting of two functional divisions: the vestibular nerve, mediating equilibrium and balance information from the vestibular apparatus (semicircular canals, saccule, and utricle), and the cochlear nerve, mediating auditory information from the cochlear apparatus (organ of Corti in the spiral ganglion). Both of these structures are in the inner ear, which is located deep in the temporal bone within a space called the bony labyrinth (Figure 21.13). The bony labyrinth contains the membranous labyrinth and is filled with perilymph, a fluid with a chemical content similar to that of CSF and plasma. The membranous labyrinth is filled with endolymph, a highly specialized fluid with high protein content. The membranous labyrinth is further divided in two portions: vestibular and cochlear. The hair cells are the sensory receptors for both the vestibular and the cochlear systems.2

Vestibular apparatus

The first-order sensory neurons of the vestibular pathway are bipolar cells located in Scarpa’s ganglion (vestibular ganglion), in the fundus of the internal auditory meatus. The vestibular portion of the membranous labyrinth is divided into two

External acoustic meatus (ear canal) Auricle (pinna)

Tympanic membrane (eardrum) Middle ear Round window

FIGURE 21.13  Anatomy of the ear.

sections: kinetic labyrinth (formed by the semicircular canals), and the static labyrinth (formed by the saccule and utricle). The vestibular bipolar neurons send peripheral projections to the hair cells in the semicircular canals, saccule, and utricle. Their central projections are to the four vestibular nuclei in the brainstem (lateral, medial, superior, and inferior) located in the caudal pons and rostral medulla. From the vestibular nuclei, central fibers are projected to the nuclei of the CNs responsible for extraocular movements (through the medial longitudinal fasciculus), the spinal cord (via the lateral and medial vestibulospinal tracts), and the flocculonodular lobe of the cerebellum. 37

Semicircular canals

The semicircular canals (SCCs) sense angular acceleration of the head. There are three SCCs in each ear, which contain endolymphatic fluid, and are oriented at right angles to each other: lateral (horizontal), posterior, and anterior (superior). Each SSC terminates at an expanded end called crista ampullaris that contains hair cells and a gelatinous structure called cupula overlying the stereocilia of the hair cells. During head movement, the endolymph inside the SCCs displaces the cupula, and this in turn causes the stereocilia of the hair cells to bend. The mechanical movement of the hair cells is converted into an electrical signal. Neural activity generated by the canals is transmitted in the vestibular nerve to the vestibular nuclei in the ipsilateral brainstem.

Otolith organ: utricle and saccule

The utricle and saccule sense linear acceleration of the head. Both are expansions of the membranous labyrinth and contain a macula, which consists of hair cells covered by an otolithic membrane (lying on top of the hair cells) and otoconia (composed of calcium carbonate crystals or otoliths) on the surface. The movement of the otoliths deflects the hair cells.

Auditory apparatus

The first-order sensory neurons of the cochlear pathway are bipolar cells and their cell bodies are located in the spiral ganglion (lying in Rosenthal’s canal). They project peripherally to the hair Malleus Incus Crura of stapes Footplate of stapes in oval window

Semicircular canals Facial nerve Vestibular nerve Internal acoustic meatus Cochlear nerve Cochlea Cochlear duct Scala vestibuli Scala tympani Eustachian tube

Cranial Neuropathies I, V, and VII–XII cells in the organ of Corti and centrally as the cochlear nerve to the anteroventral, posteroventral, and dorsal cochlear nuclei in the brainstem. Central fibers arising from these nuclei then project through the different relays of the auditory pathway before reaching the primary auditory cortex (Brodmann’s area 41) located in the transverse temporal gyri of Heschl.

Cochlea

The cochlea has the shape of a tapering helix. Inside, portions of the membranous labyrinth (vestibular and basilar membranes) divide this spiraling tunnel structure into three channels called scalae. The scala vestibuli and scala tympani are filled with perilymph and are contiguous at the tip of the cochlea in a part called helicotrema, whereas the scala media (also known as cochlear duct) lies between the other two scalae, is filled with endolymph, and contains the organ of Corti.

Organ of Corti

The organ of Corti contains receptor hair cells overlying the supporting tissue that arises from the basilar membrane in the cochlea. The hair cell processes are embedded in a thin membrane that bridges across the organ of Corti, known as the tectorial membrane. Sound waves are transmitted by the pump-like effect of the stapes in the oval window, which creates shock waves that are passed to the round window where the energy dissipates. The pressure wave is transmitted through the perilymph, and leads to vibration of the basilar membrane, depending on the frequency of the sound. When the basilar membrane oscillates, the tectorial membrane has a shearing effect across the hair cells, stimulating the cochlear nerve fibers. Hair cells located in the apex of the cochlea are stimulated by low-frequency tones, whereas hair cells located at the base are stimulated by high-frequency tones.

Vestibulocochlear nerve

The vestibulocochlear nerve emerges from the temporal bone to enter the posterior fossa through the internal auditory canal along with the facial nerve. Both nerves pass through the CPA to enter the brainstem at the anterolateral pontomedullary junction.

Brainstem Vestibular nuclei

These occupy much of the lower lateral pontine tegmentum, with vertical ramifications over the entire brainstem from the midbrain down to the cervical spinal cord. Consequently, vestibular symptoms and signs are almost always present in brainstem disease but are of limited intrinsic localizing value within the brainstem.

Cochlear nuclei

These receive fibers from the cochlear nerve as it enters the pons, and transmit auditory information to the superior olives bilaterally (mainly contralaterally), from which fibers ascend in the lateral lemniscus to the inferior colliculus (midbrain), medial geniculate, and temporal cortex (Heschl’s gyrus).1

Clinical features Hearing loss

Abnormalities in the auditory pathways manifest as hearing impairment. Sensorineural hearing loss is a deficit caused by a lesion at the level of the cochlea or CN VIII. Conductive hearing

683 loss is due to a dysfunction in transmission of sound to the cochlea (in the external or middle ear). Patients with sensorineural hearing loss often have tinnitus. Tinnitus is rarely an isolated symptom of neurologic disease unless it is pulsatile and associated with a bruit that is audible to the examiner. Pulsatile tinnitus may be indicative of a dural arteriovenous fistula, arteriovenous malformation in the neck or head, stenosis of the distal internal carotid artery extra- or intracranially, carotid–cavernous fistula, giant intracranial aneurysm, glomus jugulare tumor, intracranial hypertension, or high cardiac output (e.g. pregnancy, thyrotoxicosis, and anemia).28 Select conditions that present with hearing impairment include: • Sudden sensorineural hearing loss: sudden deafness caused by pathology in the cochlea or CN VIII. This is almost always unilateral. The etiology is often unclear, and recovery is variable. Prognosis is poor if hearing loss is profound. • Stroke: hearing loss can occur with anterior inferior cerebellar artery (AICA) distribution infarcts. The vascular supply of the inner ear comes from the internal auditory artery, which is a branch of the AICA. • CPA lesion: symptoms include progressive hearing loss, tinnitus, vertigo, and loss of balance. Other symptoms may include facial neuropathy (due to involvement of CN VII) and facial pain (CN V). The most common tumors in this location include vestibular schwannoma followed by meningioma. Evaluation of the auditory system may include: • Examination of the ear. • Bedside testing of hearing: rubbing fingers or whispering in one ear. • Differentiating sensorineural, conductive, and mixed hearing loss with bedside testing (Weber’s and Rinne’s test) and quantitative audiologic testing. • Brain imaging if a central lesion is suspected.

Vestibular dysfunction

Vestibular dysfunction usually presents with symptoms of vertigo, which is an illusion of motion in the form of a spinning or whirling sensation. It may be associated with nausea, vomiting, oscillopsia, hearing loss, and tinnitus. The presence of associated unilateral hearing loss or fullness in the ear suggests inner ear pathology. Signs and symptoms referable to the brainstem, CNs, or cerebellum are indicative of a central lesion. 37 Evaluation of the vestibular system may include: • Neuro-otological evaluation: • This frequently includes assessment for the presence of nystagmus. This can be done with Frenzel’s goggles which are essential to eliminate ocular fixation that can hinder nystagmus. In peripheral vertigo, the nystagmus characteristically has horizontal and torsional components and may be present in primary gaze. Peripheral vertigo is not direction-changing and becomes more pronounced in the direction of the fast phase of the nystagmus. In central vertigo, the nystagmus can be direction-changing and may exhibit a vertical component. • Electronystagmography/videonystagmography (ENG/ VNG) to characterize the nystagmus.

684

Hankey’s Clinical Neurology

• Provocative testing to induce vertigo and nystagmus: Dix– Hallpike test. • HINTS testing is helpful in a patient with acute vertigo to differentiate a vestibulopathy from a central lesion such as a stroke. 38

TIP • Peripheral nystagmus usually is horizontal and torsional and the direction of the nystagmus does not change. Central nystagmus can be purely horizontal and/or purely vertical, and the direction of the nystagmus may change.

Differential diagnosis Hearing loss

• Brainstem (pontomedullary junction): • Infarct or hemorrhage. • MS. • Tumor. • Central pontine myelinolysis. • CPA: • Vestibular schwannoma (Figures 21.14, 21.15). • Meningioma. • Arachnoid cyst. • Epidermoid/dermoid tumor. • Chordoma. • Metastases. • Basilar artery ectasia or aneurysm, AICA aneurysm. • Arteriovenous malformation. • Peripheral nerve lesions: • Infectious meningitis: bacterial, viral. • Carcinomatous meningitis. • Sarcoidosis. • Meningovascular syphilis. • Herpes zoster oticus/Ramsay Hunt syndrome. • Refsum’s disease. • Chordoma. • Nasopharyngeal carcinoma. • Metastases. • Paget’s disease of the skull: obstruction of foramina. • Trauma, base of skull fractures. • Sensorineural deafness:

FIGURE 21.14  Axial section through the pons and cerebellum showing a vestibular schwannoma.

FIGURE 21.15  Brain MRI, coronal view, showing an acoustic schwannoma. (Courtesy of Dr. Laughlin Dawes, University of Sydney.) • Ototoxins: aminoglycosides, loop diuretics, quinine, high-dose salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs), and cisplatinum. • Meniere’s disease. • Cranial radiation. • Cogan’s syndrome. • Susac’s syndrome. • Conductive hearing loss: • Middle ear diseases. • Cerumen impaction. • Otosclerosis.

Vestibular dysfunction Peripheral causes of vertigo

Peripheral vestibular syndromes usually present with severe vertigo, often associated with tinnitus, hearing loss, and nystagmus. There are no other abnormalities to suggest a central etiology. Nystagmus is unidirectional with the fast phase away from the side of the lesion, characteristically horizontal with a rotatory component. • Benign paroxysmal positional vertigo (BPPV): this is a common inner ear disorder characterized by brief attacks of vertigo precipitated by head movement and associated with nystagmus and autonomic symptoms. The vertigo typically lasts < 30 seconds. Symptoms may occur repeatedly throughout the day. BPPV is due to canalithiasis (otoconia dislodge from the macule of the utricle and become free floating in a SCC) or cupulolithiasis (otoconia become adherent to the matrix gel of the cupula). Most cases of BPPV are due to posterior canalithiasis. The diagnosis of BPPV is confirmed with the Dix–Hallpike maneuver. In posterior canal BPPV, after head tilt toward the affected

Cranial Neuropathies I, V, and VII–XII ear, vertigo develops with concomitant nystagmus with an upbeat and torsional component. The nystagmus develops a few seconds after positioning the patient, fatigues within 30 seconds, and habituates with repeated attempts. Symptoms may last for weeks and may recur. 39 With a central lesion, symptoms develop when the head is turned to either side during the testing maneuver; the vertigo is usually mild and brief; the nystagmus changes direction when the head is turned from one side to the other, and is not fatigable. Treatment of BPPV consists of repositioning maneuvers40 (Epley’s and Semont’s maneuvers). • Vestibular neuronitis: this is usually associated with a viral infection or is the result of postviral inflammation of the vestibular portion of CN VIII. Patients present with severe vertigo that lasts several days, associated with nausea, vomiting, and at times unilateral hearing loss. Examination may show horizontal nystagmus with a torsional component. Treatment is symptomatic with antiemetics, vestibular therapy,41 and benzodiazepines. Use of betahistine in the treatment of peripheral vertigo requires further studies.42 • Other causes of peripheral vertigo: trauma, perilymphatic fistula, Meniere’s disease, superior semicircular canal dehiscence, middle ear disease, syphilis, geniculate zoster, and viral and bacterial labyrinthitis.

Central causes of vertigo

Vertigo of central origin is typically less severe than peripheral vertigo and usually constant. It is associated with abnormalities referable to the brainstem or cerebellum, and hearing impairment is less frequent. Nystagmus can be bidirectional. Etiologies include: • Posterior circulation stroke or transient ischemic attack (TIA) (lateral medullary syndrome, AICA distribution stroke), cerebellar hemorrhage, and migraine with brainstem aura. • MS. • Wernicke’s encephalopathy. • CPA tumors. • Temporal lobe seizures. Nucleus solitarius (rostral portion) Axon of tractus solitarius CN IX and jugular foramen

Tractus solitarius Tract of spinal trigeminal nucleus Nucleus solitarius (visceral sensory portion)

685

GLOSSOPHARYNGEAL NEUROPATHY (CRANIAL NERVE IX) Definition and epidemiology

Disorder of the glossopharyngeal nerve. It is a rare disorder.

Anatomy

The glossopharyngeal nerve contains sensory, motor, special visceral afferent, and parasympathetic fibers1.

Medulla (Figure 21.16) Motor fibers

The glossopharyngeal motor fibers arise from the upper part of the nucleus ambiguus in the medulla, and supply the stylopharyngeus muscle (which cannot be tested clinically). The nucleus ambiguus is the main motor nucleus of cranial nerves IX, X, and XI; it receives bilateral supranuclear innervation from corticobulbar fibers.2

Sensory fibers

• Taste fibers from the posterior third of the tongue and pharynx terminate (via the glossopharyngeal nerve) in the nucleus of the tractus solitarius. • General somatic afferent fibers (pain, temperature, and tactile sensation) from the posterior one-third of the tongue, tonsils, soft palate, tympanic membrane, and eustachian tube terminate in the nucleus of the spinal tract of the trigeminal nerve. • Chemoreceptive (from the carotid body) and baroreceptive (from the carotid sinus) fibers are carried by the glossopharyngeal nerve via the carotid sinus nerve and terminate in the solitary nucleus.

Parasympathetic fibers

These fibers originate in the inferior salivatory nucleus in the medulla and travel via the tympanic nerve (Jacobson’s nerve) to the middle ear from which they continue as the lesser superficial petrosal nerve that synapses in the otic ganglion. Postganglionic fibers supply the parotid gland. Nucleus solitarius surrounds tractus solitarius Inferior salivatory nucleus Inferior cerebellar peduncle Spinal nucleus of trigeminal nerve Nucleus ambiguus (branchial and visceral motor) CN IX CNX Olive Rootlet of CN XII Rootlet of CN XI Pyramid

FIGURE 21.16  Cross-section of medulla at the point of entry of cranial nerve IX. (Adapted from Cranial Nerves in Health and Disease by Linda Wilson-Pauwels.)

Hankey’s Clinical Neurology

686 Greater petrosal nerve and foramen (CN VII) Carotid canal Foramen lacerum

Foramen ovale Lesser petrosal foramen and nerve (CN IX) Otic ganglion Internal carotid artery

CN V

CN IX CN X CN XI

Pons Internal auditory meatus CN VII (visceral motor fibers) Tympanic plexus (sensory) and visceral motor nerve in the middle ear cavity

Internal jugular vein Jugular foramen

FIGURE 21.17  Sagittal section through the jugular foramen, showing the relationship of cranial nerves IX, X, and XI with the jugular vein. (Adapted from ‘Cranial Nerves in Health and Disease’ by Linda Wilson-Pauwels.)

Base of skull (jugular foramen) (Figure 21.17)

The glossopharyngeal nerve emerges from the posterior lateral sulcus of the medulla in line with the vagus and the bulbar fibers of the spinal accessory nerve and enters the internal part of the jugular foramen lying on the medial side of the sigmoid sinus. The foramen angles forward and laterally under the petrous bone, which is excavated by the slight ballooning of the sigmoid sinus as the sinus exits through the skull to become the jugular bulb. The glossopharyngeal, vagus, and accessory nerves exit anterior to the jugular bulb from the jugular foramen.

Outside the skull

The glossopharyngeal nerve descends between the jugular vein and internal carotid artery, which ascends to enter the carotid canal just anterior to the jugular vein as it emerges from the jugular foramen. Nearby is the hypoglossal nerve (CN XII), which exits the skull through the anterior condylar canal posteromedial to the jugular foramen, and comes into close contact with CNs IX, X, and XI outside the skull. The glossopharyngeal nerve then loops forward and medially to reach the soft tissues of the oropharynx, posterior tongue, and palate.

Clinical features

Isolated lesions of the glossopharyngeal nerve are rare. CN IX lesions typically occur in combination with CN X lesions.43 • Supranuclear lesions: a unilateral supranuclear lesion does not result in a neurologic deficit due to bilateral supranuclear input. • Nuclear and medullary lesions: these lesions usually result in involvement of other structures in the brainstem. These include infarcts, demyelinating lesions, tumors, and syringobulbia. • CPA lesions: the glossopharyngeal nerve may be involved in lesions of the CPA along with CNs V, VII, and VIII.

• Jugular foramen lesions: these lesions at the level of the jugular foramen involve CNs IX, X, and XI (Vernet’s syndrome). The clinical presentation includes ipsilateral weakness of the trapezius and sternocleidomastoid, ipsilateral anesthesia and paralysis of the pharynx and larynx resulting in dysphonia and dysphagia, palatal droop on the affected side and ipsilateral vocal cord paralysis, and loss of taste from the ipsilateral posterior one-third of the tongue. Lesions at the jugular foramen may result from skull base fractures, neoplasms (e.g. glomus jugulare, neurofibroma, metastatic lesions, meningioma, and cholesteatoma), osteomyelitis, or vascular processes (internal carotid artery dissection).15,18 • Retropharyngeal lesions: lesions in the retropharyngeal space may result in symptoms referable to the ipsilateral CNs IX, X, and XI in addition to the hypoglossal nerve resulting in ipsilateral tongue weakness, and the ascending sympathetic chain resulting in ipsilateral Horner’s syndrome (Villaret’s syndrome). Causes of lesions in this location include neoplasms, infections/abscesses, surgical procedures, and trauma.15

Physical examination

The only muscle supplied by CN IX (stylopharyngeus) cannot be tested clinically. The glossopharyngeal nerve does not provide motor innervation to the palate. When the gag reflex is tested, the sensory stimulus is relayed via the glossopharyngeal nerve, and the resulting visible palatal movement is mediated by the vagus nerve. The gag reflex therefore cannot differentiate between a glossopharyngeal lesion and a vagal lesion. The only method of accurately testing the integrity of the glossopharyngeal nerve is to test pharyngeal sensation by gently touching each side of the palate and, while the patient is phonating, touching the posterior pharyngeal wall on each side. The patient is then asked to compare these stimuli. Evaluation of taste sensation over the posterior third of the tongue has no proven value in clinical diagnosis.15,20

Cranial Neuropathies I, V, and VII–XII These are clues to the site of involvement (e.g. intracranial vs. extracranial): • Long tract signs indicate an intracranial lesion.15 • An isolated ipsilateral Horner’s syndrome (with a concomitant glossopharyngeal palsy) is suggestive of an extracranial lesion, as the cervical sympathetic fibers ascend near the area of the jugular foramen.

SELECT CONDITIONS AFFECTING THE GLOSSOPHARYNGEAL NERVE GLOSSOPHARYNGEAL NEURALGIA Glossopharyngeal neuralgia is a rare condition characterized by recurrent brief episodes of unilateral sharp lancinating pain in the throat, ear, base of tongue, or neck, usually in response to chewing, coughing, yawning, or swallowing due to a ‘trigger point’ in the throat. The pain is stereotyped lasting seconds to minutes. Occasionally, bradycardia and syncope occur (associated with swallowing or coughing), possibly due to cross-stimulation of the carotid sinus via the carotid nerve. This neuralgia is usually idiopathic; however, it may also be a result of a structural lesion along the course of the glossopharyngeal nerve such as tumor, infection, or neuroma. Unlike trigeminal neuralgia, MS is a very rare cause of this syndrome.44 Symptoms may respond to carbamazepine,45 oxcarbazepine,46 phenytoin, gabapentin, or baclofen. In refractory cases, surgical options such as microvascular decompression,47 nerve resection, tractotomy, or Gamma Knife radiosurgery48 may relieve symptoms.

Nucleus solitarius (rostral portion)

687

VAGUS NEUROPATHY (CRANIAL NERVE X) Definition and epidemiology

An uncommon disorder of the vagus nerve.

Anatomy

The vagus nerve is the most widely distributed CN. It carries motor, sensory, and parasympathetic fibers that innervate the head, neck, thorax, and abdomen. The nerve leaves the medulla in the region of the posterior lateral sulcus in close proximity to CN IX. The nerve exits the skull through the jugular foramen (Figure 21.17). In the region of the jugular foramen are two vagal ganglia: the jugular ganglion (superior vagal ganglion) and the nodose ganglion (inferior vagal ganglion) (Figure 21.18).1 The motor fibers of the vagus nerve arise from the nucleus ambiguus, which receives bilateral supranuclear innervation. These fibers supply all striated muscles of the larynx and pharynx, except the stylopharyngeus (supplied by CN IX) and the tensor veli palatini (supplied by V3 division of CN V). 2 Three motor branches arise from the vagus nerve: the pharyngeal nerve, the superior laryngeal nerve, and the recurrent laryngeal nerve. The pharyngeal nerve travels between the internal and external carotid arteries, forms the pharyngeal plexus with the glossopharyngeal nerve, and innervates muscles of the pharynx and palate. The superior laryngeal nerve takes off distal to the pharyngeal branch and descends lateral to the pharynx. The external branch of the superior laryngeal nerve supplies the cricothyroid muscle. The third motor branch arising from the vagus nerve is the recurrent laryngeal nerve. The right and left recurrent laryngeal nerves follow different courses: the right recurrent laryngeal nerve descends anterior to the right subclavian artery and turns posteriorly under the

Dorsal vagal motor nucleus Spinal nucleus of trigeminal nerve

Nucleus solitarius (caudal portion)

Inferior cerebellar peduncle

Tract of spinal trigeminal nucleus

Nucleus ambiguus

CN X Jugular fossa and foramen

CN IX CN X Olive Rootlet of CN XII Rootlet of CN XI Superior vagal ganglion

Pyramid

Inferior vagal ganglion

FIGURE 21.18  Cross-section of the medulla at the point of entry of cranial nerve X. (Adapted from Cranial Nerves in Health and Disease by Linda Wilson-Pauwels.)

Hankey’s Clinical Neurology

688 artery to ascend in the tracheoesophageal sulcus, whereas the nerve on the left turns posteriorly around the aortic arch and ascends in the same sulcus on the left. Both recurrent branches then enter the larynx and supply all intrinsic muscles of the larynx except the cricothyroid muscle (supplied by the external branch of the superior laryngeal nerve).

TIP • Motor fibers from vagus nerve supply all striated muscles of the larynx and pharynx except the stylopharyngeus (supplied by the CN IX) and the tensor veli palatini (supplied by the V3 branch of CN V). The sensory fibers carried in the vagus nerve have their cell bodies in the jugular and nodose ganglia. The vagus nerve receives general visceral sensory input from the larynx, pharynx, linings of the trachea, bronchi, heart, aortic arch, and abdominal viscera; these fibers originate in the nodose ganglion and project to the nucleus solitarius. The vagus nerve (through the nodose ganglion) also carries taste sensation from the epiglottis, pharynx, and palate; these fibers terminate in the nucleus solitarius. The vagus nerve (through the jugular ganglion) also receives sensory input from the concha of the ear and the dura of the posterior fossa; these fibers terminate in the spinal nucleus of CN V. The vagus nerve supplies parasympathetic innervation to smooth muscle and glands of the pharynx, larynx, and thoracic and abdominal viscera. Preganglionic parasympathetic fibers arise from the dorsal nucleus of the vagus.

Clinical features

Patients with vagal nerve lesions present with symptoms of hoarseness, dysphagia, and dyspnea.

Evaluation of the soft palate and uvula at rest and with phonation

Normally with phonation, there is symmetric palatal elevation without deviation of the uvula. With a unilateral vagus nerve lesion, there is flattening of the ipsilateral palate at rest, and with phonation, there is no elevation of the ipsilateral palate and deviation of the uvula to the opposite side. There is also depression of the ipsilateral gag reflex (efferent limb is through the vagus nerve). With bilateral vagus nerve lesions, there is bilateral drooping of the palate and no palatal movement to phonation.18

Speech and swallowing

With a unilateral vagal lesion, there may be mild dysphagia and nasal voice quality. With bilateral lesions, there is severe dysphagia, nasal speech, hoarseness, markedly impaired cough, and dyspnea. An otolaryngological evaluation is essential to assess the larynx/vocal cords.

Localization Supranuclear lesions

A unilateral supranuclear lesion rarely results in vagal dysfunction due to bilateral supranuclear input. However, dysphagia is not

uncommon with a unilateral hemispheric stroke. Bilateral corticobulbar tract lesions result in pseudobulbar palsy. Symptoms include dysarthric speech and dysphagia along with emotional lability.

Nuclear and brainstem lesions

Lesions in the medulla involving the nucleus ambiguus result in ipsilateral weakness of the palate, pharyngeal, and laryngeal muscles. This is often associated with involvement of other CN nuclei and descending/ascending tracts. Etiologies include infarcts, demyelinating lesions, tumors, infectious and inflammatory conditions, syringobulbia, and motor neuron disease.

Posterior fossa, skull base, and jugular foramen

The vagus nerve can be involved in lesions in these anatomical locations along with other cranial nerves (IX, XI). Lesions in the CPA can affect the vagus in addition to causing hearing loss and vertigo (CN VIII), and peripheral facial weakness (CN VII). Lesions at the skull base (infectious, neoplastic, vascular, and traumatic) involving the jugular foramen result in symptoms referable to CNs IX, X, and XI. Skull base lesions can also affect other contiguous CNs. The vagus nerve can also be affected in the setting of a diffuse leptomeningeal process (infectious, carcinomatous, and inflammatory), trauma, and Guillain–Barré syndrome.28

Extracranial vagus nerve lesions

The vagus nerve may be involved along its extracranial course by lesions in the neck and chest. Patients with isolated vagus nerve lesions present with hoarseness as their primary symptom. The presence of other associated symptoms is helpful in additional localization. Proximal vagal lesions present with dysphagia, hoarseness, and ipsilateral palatal droop. Vagal lesions distal to the pharyngeal branch or lesions of the recurrent laryngeal nerve result in isolated hoarseness.

Lesions of recurrent laryngeal nerve

The recurrent laryngeal nerve is longer on the left than the right and is therefore more susceptible to injury.43 Both nerves, however, can be damaged due to their course through the upper chest. Etiologies include thoracic malignancies, lymphadenopathy, aneurysms, tumors, and operative injuries. Iatrogenic recurrent laryngeal nerve injury accounts for one-third of cases of vocal cord paralysis (thyroidectomy, carotid endarterectomy, and anterior cervical discectomy). A unilateral recurrent laryngeal lesion results in paralysis of all ipsilateral laryngeal muscles except the cricothyroid (innervated by the superior laryngeal nerve) and manifests as hoarseness. Bilateral recurrent laryngeal nerve lesions (postoperative, peripheral neuropathy, and malignancy) result in bilateral vocal cord abductor paralysis with inspiratory stridor and aphonia.

Neuromuscular junction disorders

Patients with myasthenia gravis can present with fatigable ocular symptoms, generalized weakness, and bulbar weakness including hoarseness, dysarthria, and dysphagia.

Investigations

CT or MRI can be used to diagnose proximal or distal lesions. CT is less sensitive than MRI in the detection of proximal lesions in the brainstem, basal cisterns, and skull base.

Cranial Neuropathies I, V, and VII–XII

689 Cranial root Jugular foramen Vagus nerve Internal branch of recurrent laryngeal nerve to laryngeal muscles

FIGURE 21.19  Nucleus and course of the spinal accessory nerve. (Adapted from Massey EW Spinal Accessory Nerve Lesions Seminars in Neurology. 2009; 29(1); 82–84. Thieme.)

Corticobulbar fibers Nucleus ambiguus Foramen magnum Spinal nucleus of accessory nerve Spinal root

Accessory nerve, external branch Sternocleidomastoid muscle Trapezius muscle

SPINAL ACCESSORY NEUROPATHY (CRANIAL NERVE XI)

Supranuclear innervation

The spinal accessory nerve is a motor nerve arising partly from the nucleus ambiguus in the medulla and partly from upper cervical segments. It supplies two muscles: the sternocleidomastoid and the trapezius (Figure 21.19).49

Supranuclear innervation of the sternocleidomastoid is likely ipsilateral, because hemispheric lesions (e.g. stroke) cause weakness of the sternocleidomastoid on the same side as the lesion (i.e. weakness turning head to the side of the hemiparesis) and partial epileptic seizures originating in the frontal lobe cause the head to turn away from the side of the lesion and the epileptic focus, indicating that the ipsilateral sternocleidomastoid is contracting. Supranuclear innervation from the contralateral hemisphere supplies the trapezius.

Cranial portion

Clinical features

Definition and epidemiology

An uncommon disorder of the spinal accessory nerve.

Anatomy

• Arises predominantly from the lower part of the nucleus ambiguus. • The nerve rootlets emerge from the lateral medulla in line with the vagus nerve. • The cranial rootlets are joined by the ascending spinal component, then run laterally to enter the jugular foramen. • The cranial portion merges with the vagus nerve to supply the pharynx and larynx.

Unilateral sternocleidomastoid muscle weakness results in impaired head rotation to the opposite side and slight rotation of the head to the unaffected side with neck flexion. Bilateral sternocleidomastoid weakness causes neck flexion impairment. Trapezius weakness causes shoulder droop at rest as well as downward and lateral scapular displacement with slight winging of the scapular vertebral border. The patient cannot raise the abducted arm above the horizontal plane (Figure 21.20).

Spinal portion

• Motor innervation to the sternocleidomastoid and trapezius. • Arises from a column of cells in the ventral horn of the spinal cord extending from C1–C5 (the accessory nucleus). • The C1–C5 spinal root fibers emerge from the upper cervical cord laterally between the anterior and posterior spinal nerve roots to form a separate nerve trunk, which ascends into the skull through the foramen magnum. • Once inside the skull, the spinal and cranial roots of CN XI unite and exit by way of the jugular foramen in the same dural sheath as the vagus nerve. • Upon emerging from the jugular foramen, the spinal portion enters the neck between the internal carotid artery and the internal jugular vein. It then penetrates and supplies the ipsilateral sternocleidomastoid, emerges midway through the posterior border of the sternocleidomastoid, and crosses the posterior triangle of the neck to supply the ipsilateral trapezius. • As the spinal accessory nerve courses through the neck, it receives a contribution from branches of the C3–C4 ventral motor roots.

FIGURE 21.20  Wasting and weakness of the left trapezius muscle due to transection of the accessory nerve in the process of a lymph node biopsy.

Hankey’s Clinical Neurology

690 Proximal spinal accessory nerve lesions result in trapezius and sternocleidomastoid weakness. Nerve damage in the posterior triangle of the neck spares the sternocleidomastoid. Spinal accessory nerve lesions do not cause a sensory disturbance.

Localization

• Nuclear lesions: these lesions are rare and are associated with involvement of other structures in the medulla or upper cervical spinal cord. These can occur with parenchymal lesions, syringomyelia/syringobulbia, and motor neuron disease. • Skull and foramen magnum lesions: these lesions usually also involve contiguous cranial nerves (IX, X, XI, and XII) and may also affect the medulla or upper cervical cord. Possible etiologies include neoplasms (meningiomas, dermoids), meningeal processes, and traumatic injuries. • Jugular foramen lesions: see glossopharyngeal nerve section. • Spinal accessory nerve lesions in the neck: these can result from surgical procedures in the posterior triangle of the neck such as lymph node excision or biopsy (most common cause), jugular vein cannulation, and carotid endarterectomy. Other etiologies include blunt trauma, neuralgic amyotrophy, and radiation therapy (Figure 21.20).

Investigations

Imaging studies including MRI (to assess the brainstem and craniocervical junction), CT (to assess the skull base), and electromyography to confirm denervation of the sternocleidomastoid and trapezius muscles can be helpful in diagnosis.

HYPOGLOSSAL NEUROPATHY (CRANIAL NERVE XII) Definition and epidemiology

A rare disorder of the hypoglossal nerve.

Anatomy

• The hypoglossal nerve fibers arise from a nuclear column located under the floor of the fourth ventricle (Figure 21.21). • Fascicular fibers traverse the full sagittal diameter of the medulla to exit from the ventral surface between the medullary pyramid and the inferior olive. • Numerous rootlets located medial to cranial nerves IX, X, and XI combine to form two main bundles with their own dural sleeves. • The two bundles leave the skull through the hypoglossal canal and unite after passing through the canal. The nerve

Vestibular nuclei Dorsal motor nucleus Hypoglossal nucleus Spinal tract (V) Nucleus of spinal tract (IV)

• • •

•

then descends in the neck in close proximity to the internal carotid artery and the jugular vein, crosses the inferior vagal (nodose) ganglion, and ascends anteriorly on the hyoglossus muscle, distributing branches to the ipsilateral intrinsic (longitudinal, transverse, and vertical) and extrinsic (styloglossus, hyoglossus, geniohyoid, and genioglossus) muscles of the tongue. The hypoglossal nerve receives sympathetic fibers from the superior cervical ganglion and some fibers from the vagus. The hypoglossal nerve is joined for a short distance by fibers from the C1 nerve root. The descending C1 fibers after branching off from the hypoglossal nerve are joined by fibers from C2 and C3 roots to form the ansa cervicalis; fibers from the ansa supply the sternohyoid, sternothyroid, omohyoid, thyrohyoid, and geniohyoid. Supranuclear innervation of tongue muscles is usually bilateral but may be predominantly contralateral. An exception is the genioglossus, which primarily receives contralateral corticobulbar innervation.

Clinical features

The tongue should be evaluated both at rest and with movement.

Unilateral hypoglossal nerve palsy

• Wasting, furrowing, fasciculations, and weakness of one side of the tongue (ipsilateral to the lesion), with deviation of the tongue to the side of the paresis. With tongue protrusion, the normal contralateral muscles force the tongue forward and to the opposite side (which is toward the side of the weak muscle). • Minimal dysarthria and dysphagia. • Laryngeal shift to one side on swallowing (contralateral to the lesion) due to failure of the hyoid to elevate on the paralyzed side.

Bilateral hypoglossal nerve palsies

• Bilateral weakness, atrophy, and fasciculations. • Weakness of tongue protrusion. • Difficulty manipulating food in the mouth, chewing, and swallowing. • Difficulty speaking (flaccid dysarthria). • Difficulty breathing due to the flaccid tongue.

Fourth ventricle Cerebellar peduncle Medial longitudinal fasciculus Medial lemniscus Vagus nerve (CN X)

Nucleus ambiguus Olivocerebellar tract Inferior olivary nucleus

Hypoglossal nerve (CN XII) Pyramid

FIGURE 21.21  Cross-section of medulla showing the hypoglossal nucleus/nerve. (Adapted from Localization in Clinical Neurology, 5th edition. Brazis, Biller, et al.)

Cranial Neuropathies I, V, and VII–XII

691

Localization Supranuclear lesions

These are lesions affecting the corticobulbar tract in the cerebral cortex, corona radiata, internal capsule, or brainstem. They result in deviation of the tongue away from the side of the lesion and toward the hemiparesis (if present) without tongue atrophy or fasciculations. Dysarthria may occur. With bilateral corticobulbar lesions affecting fibers to the hypoglossal nuclei, the tongue is paretic with slow lateral movements and spastic dysarthria; other signs of pseudobulbar palsy may be present including emotional lability, brisk jaw jerk (with bilateral lesions above the mid-pons), and bilateral corticospinal tract signs.15 Etiologies of supranuclear lesions may include stroke, hemorrhage, tumor, abscess, motor neuron disease, inflammatory/demyelinating conditions, central pontine myelinolysis, and multiple system atrophy.50

• A lesion in the retroparotid or retropharyngeal space may involve CNs IX, X, XI, XII, and the sympathetic chain resulting in an ipsilateral Horner’s syndrome (Villaret’s syndrome). • The distal hypoglossal nerve may be involved in the neck resulting in ipsilateral weakness and hemiatrophy of the tongue. Etiologies include carotid artery aneurysm, internal carotid artery dissection, carotid endarterectomy, trauma, abscess, radiation to the neck, and tumors in the neck, retropharyngeal space, or at the tongue base. • Tongue weakness associated with dysarthria and dysphagia can be seen with myasthenia gravis. Symptoms often fluctuate in severity.

Investigations

• Suspected intracranial lesion: • MRI and CT scan of brain and base of skull. • CT or MR angiography to evaluate for vascular lesions. • CSF examination. • Suspected extracranial lesion: • Direct examination of the nasopharynx/larynx. • MRI or CT of the soft tissues of the neck.

TIP • Supranuclear lesions of CN XII result in deviation of the tongue away from the side of the lesion and toward the hemiparesis (if present). There is no associated tongue atrophy or fasciculations.

Nuclear and fascicular lesions

Pathologic processes such as demyelinating disease, motor neuron disease, syringobulbia, Chiari’s malformation, tumor, arteriovenous malformation, hemorrhage, ischemia, and inflammatory and infectious conditions may affect the hypoglossal nuclei in the dorsal medulla, resulting in tongue weakness and atrophy. A unilateral ischemic lesion in the medulla in the territory of the vertebral or anterior spinal artery (medial medullary syndrome) may result in involvement of the hypoglossal nerve fibers coursing ventrally in the medulla (ipsilateral tongue weakness and atrophy), the pyramid (contralateral arm and leg weakness), and the medial lemniscus (contralateral impairment of position and vibration sense). Lesions in the medulla can also result in involvement of other cranial nerves (CNs X and XI).50

Peripheral lesions

The hypoglossal nerve may be involved in lesions of the meninges, posterior fossa, skull base, retropharyngeal space, or neck. • Leptomeningeal processes, which may include infectious, inflammatory (e.g. sarcoidosis), or carcinomatous etiologies, may result in cranial neuropathies. • In the posterior fossa, the hypoglossal nerve is in close proximity to CNs IX, X, and XI. The nerve may be involved with meningiomas or neurofibromas. • A skull base lesion involving the jugular foramen and the hypoglossal canal may affect CNs IX, X, XI, and XII (Collet– Sicard syndrome).15 This presents with ipsilateral deficits including weakness of the trapezius and sternocleidomastoid, vocal cord and pharyngeal weakness, hemi-tongue weakness and atrophy, loss of taste in the posterior third of the tongue, and diminished sensation in the palate, pharynx, and larynx. A skull base lesion may also affect CN XII in isolation. Etiologies include infection, trauma/fracture, and malignancies. A lesion at the level of the clivus may involve multiple cranial nerves including CNs VI and XII; this is seen with malignancy such as nasopharyngeal carcinoma. The occipital condyle may be involved in a neoplastic or inflammatory process, which presents with unilateral occipital pain and ipsilateral hypoglossal neuropathy.18

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692 14. Doty RL (2003). Handbook of Olfaction and Gustation, 2nd edn. Marcel Dekker, New York. 15. Brazis PW, Masdeu JC, Biller J (2016). Localization in Clinical Neurology, 7th edn. Lippincott Williams & Wilkins. 16. Welge-Luessen A, Temmel A, Quint C, Moll B, Wolf S, Hummel T. Olfactory function in patients with olfactory groove meningioma. J Neurol Neurosurg Psychiatry. 2001;70(2):218–21. 17. Russell RM, Cox ME, Solomons N. Zinc and the special senses. Ann Intern Med. 1983;99(2):227–39. 18. Samii M, Jannetta PJ (1981). The Cranial Nerves, 1st edn. Springer-Verlag. 19. Fix JD (2005). High Yield of Neuroanatomy, 3rd edn. Lippincott Williams & Wilkins, Philadelphia. 20. Blumenfeld H (2010). Neuroanatomy through Clinical Cases, 2nd edn. Sinauer Associates. 21. Gonella MC, Fischbein NJ, So YT. Disorders of the trigeminal system. Semin Neurol. 2009;29(1):36–44. 22. Cruccu G. Trigeminal Neuralgia. Continuum (Minneap Minn). 2017;23(2, Selected Topics in Outpatient Neurology):396–420. 23. Cruccu G, Finnerup NB, Jensen TS, Scholz J, Sindou M, Svensson P, et al. Trigeminal neuralgia: new classification and diagnostic grading for practice and research. Neurology. 2016;87(2):220–8. 24. Maarbjerg S, Wolfram F, Gozalov A, Olesen J, Bendtsen L. Significance of neurovascular contact in classical trigeminal neuralgia. Brain. 2015;138(Pt 2):311–9. 25. Bennetto L, Patel NK, Fuller G. Trigeminal neuralgia and its management. BMJ. 2007;334(7586):201–5. 26. Zakrzewska JM, Akram H. Neurosurgical interventions for the treatment of classical trigeminal neuralgia. Cochrane Database Syst Rev. 2011(9):CD007312. 27. Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K, et al. 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. 2008;71(15):1183–90. 28. Ropper A, Samuels M, Klein J, Prasad S (2019). Adams and Victor’s Principles of Neurology, 11th edn. McGraw-Hill Education. 29. Keane JR. Bilateral seventh nerve palsy: analysis of 43 cases and review of the literature. Neurology. 1994;44(7):1198–202. 30. Gilden DH. Clinical practice. Bell’s Palsy. N Engl J Med. 2004;351(13):1323–31. 31. Adour KK. Diagnosis and management of facial paralysis. N Engl J Med. 1982;307(6):348–51. 32. Grogan PM, Gronseth GS. Practice parameter: steroids, acyclovir, and surgery for Bell’s palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001; 56(7):830–6. 33. Teixeira LJ, Valbuza JS, Prado GF. Physical therapy for Bell’s palsy (idiopathic facial paralysis). Cochrane Database Syst Rev. 2011(12):CD006283. 34. Gronseth GS, Paduga R, American Academy of Neurology. Evidence-based guideline update: steroids and antivirals for Bell palsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2012;79(22):2209–13. 35. Preston DC, Shapiro BE (2012). Electromyography and Neuromuscular Disorders: Clinical-Electrophysiologic Correlations, 3rd edn. Saunders.

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Further reading

Felten DL, O’Banion MK, Maida MS, Netter FH (2016). Netter’s Atlas of Neuroscience, 3rd edn. Elsevier, Philadelphia, PA. Finsterer J. Management of peripheral facial nerve palsy. Eur Arch Otorhinolaryngol. 2008;265:743–52. Gilchrist JM. Seventh cranial neuropathy. Semin Neurol. 2009; 29(1):5–13. Pinto JM. Olfaction. Proc Am Thorac Soc. 2011;8(1):46–52. Reich SG. Bell’s palsy. Continuum (Minneap Minn). 2017;23:447–66. Stino AM, Smith BE, Temkit M, Reddy SN. Hypoglossal nerve palsy: 245 cases. Muscle Nerve. 2016;54(6):1050–4. Wilson-Pawels L, Stewart PA, Akesson EJ, Spacey SD (2002). Cranial Nerves in Health and Disease, 2nd edn. BC Decker Inc.

22

CRANIAL NEUROPATHIES II, III, IV, AND VI

Tanyatuth Padungkiatsagul, Heather E. Moss

Contents Optic Neuropathies (Cranial Nerve II)..........................................................................................................................................................................694 Definition.......................................................................................................................................................................................................................694 Anatomy.........................................................................................................................................................................................................................694 Clinical assessment......................................................................................................................................................................................................695 History......................................................................................................................................................................................................................695 Examination.............................................................................................................................................................................................................695 Differencing between causes of monocular vision loss........................................................................................................................................696 Retinal diseases of interest to the neurologist........................................................................................................................................................697 Susac’s syndrome....................................................................................................................................................................................................697 Mitochondrial diseases.........................................................................................................................................................................................698 Etiologies of optic neuropathies................................................................................................................................................................................698 Inflammatory optic neuropathies.......................................................................................................................................................................698 Ischemic optic neuropathies................................................................................................................................................................................699 Papilledema (due to high intracranial pressure)..............................................................................................................................................701 Pseudopapilledema................................................................................................................................................................................................702 Compressive optic neuropathies.........................................................................................................................................................................702 Optic nerve neoplasms..........................................................................................................................................................................................703 Congenital optic neuropathies........................................................................................................................................................................... 704 Hereditary optic neuropathies............................................................................................................................................................................ 704 Nutritional and toxic optic neuropathies......................................................................................................................................................... 704 Traumatic optic neuropathies..............................................................................................................................................................................705 Cranial Nerve III, IV, and VI Palsies..............................................................................................................................................................................705 Definition.......................................................................................................................................................................................................................705 Ocular motility anatomy.............................................................................................................................................................................................705 Clinical assessment of diplopia or ocular misalignment......................................................................................................................................705 History......................................................................................................................................................................................................................705 Examination............................................................................................................................................................................................................ 706 Symptomatic treatment of diplopia..........................................................................................................................................................................707 Common etiologies of isolated cranial nerves III, IV, or VI palsy......................................................................................................................707 Trauma.....................................................................................................................................................................................................................707 Microvascular.........................................................................................................................................................................................................707 Giant cell arteritis...................................................................................................................................................................................................707 Tumors......................................................................................................................................................................................................................707 Recurrent painful ophthalmoplegic neuropathy..............................................................................................................................................707 Other.........................................................................................................................................................................................................................707 Etiologies of combined cranial nerve III, IV, VI palsies........................................................................................................................................707 Cranial Nerve III (Oculomotor Nerve).........................................................................................................................................................................707 Anatomy.........................................................................................................................................................................................................................707 Clinical features............................................................................................................................................................................................................708 Investigations................................................................................................................................................................................................................709 Etiologies........................................................................................................................................................................................................................709 Fascicular lesions of the cranial nerve III..........................................................................................................................................................709 Compression...........................................................................................................................................................................................................709 Cranial Nerve IV (Trochlear Nerve)..............................................................................................................................................................................710 Anatomy.........................................................................................................................................................................................................................710 Clinical features............................................................................................................................................................................................................710 Etiologies........................................................................................................................................................................................................................711 Pediatric cranial nerve IV palsy...........................................................................................................................................................................711

693

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Cranial Nerve VI (Abducens Nerve)..............................................................................................................................................................................711 Anatomy.........................................................................................................................................................................................................................711 Clinical features............................................................................................................................................................................................................711 Etiology...........................................................................................................................................................................................................................711 Fascicular lesions....................................................................................................................................................................................................711 False localizing sign of high intracranial pressure...........................................................................................................................................711 Apex of the petrous temporal bone (Gradenigo’s) syndrome.......................................................................................................................713 Pediatric cranial nerve VI palsies........................................................................................................................................................................713 Pupillary Pathways and Common Disorders................................................................................................................................................................713 Horner’s syndrome due to sympathetic dysfunction............................................................................................................................................713 Anatomy...................................................................................................................................................................................................................713 Clinical features......................................................................................................................................................................................................713 Etiology.....................................................................................................................................................................................................................713 Investigations..........................................................................................................................................................................................................714 Parasympathetic dysfunction....................................................................................................................................................................................714 Anatomy...................................................................................................................................................................................................................714 Clinical features and investigations....................................................................................................................................................................714 Etiologies..................................................................................................................................................................................................................715 References............................................................................................................................................................................................................................715

OPTIC NEUROPATHIES (CRANIAL NERVE II) Definition

intraorbital optic nerve is redundant as not to restrict eye movement. The intraorbital optic nerve derives its blood supply from anastomoses between pial perforating capillaries that branch from the ophthalmic artery and the central retinal artery, which

This is a disorder of the cranial nerve (CN) II, or optic nerve resulting in visual disturbance when using the eye on the affected side. This can be perceived as blurred vision, decreased visual acuity, loss of certain part of vision (visual field defect), or abnormal perception of color (dyschromatopsia). Strictly speaking, the optic nerve extends from the eyeball to the chiasm. However, any disease that impacts the retinal ganglion cells (RGCs) including those of the optic chiasm and optic tract can have structural and functional effects on the optic nerves.

Cones

Anatomy

The optic nerve consists of approximately 1.2 million RGC axons,1 that originate in the inner retina, where they receive information from the rods and cones that is modified by amacrine, bipolar, and horizontal cells (Figure 22.1). The ganglion cell axons sweep toward the optic nerve head where they coalesce to form the optic nerve. Axons from the superior retina, carrying vision from the inferior field enter the optic nerve head superiorly, inferior axons, carrying vision from the superior field, enter inferiorly, nasal fibers, carrying vision from the far temporal field, enter nasally, and the papillomacular bundle, which carries central, nasal, and near temporal vision enters temporally (Figure 22.2).2 RGC in the retina are unmyelinated. The RGCs in the retina derive their blood supply from the central retinal artery. The optic nerve head is supplied by a circular anastomosis of the posterior ciliary arteries called the circle of Zinn–Haller. These anastomoses are variable and scant, so the optic nerve head can be a watershed area. 3 The posterior ciliary arteries and the central retinal artery are both branches of the ophthalmic artery, which is the first branch of the internal carotid artery. The RGCs exit the eye by passing through the lamina cribrosa, a porous region of sclera, after which they become myelinated by oligodendrocytes (in contrast to other cranial nerves). The myelinated retrobulbar optic nerve is surrounded by meningeal layers including cerebrospinal fluid (CSF) in the subarachnoid space and a tough dural sheath, the optic nerve sheath. The

Rods Pigment epithelium Axons travelling to optic nerve

Fovea

Ganglion cell Bipolar cell Amacrine cell Horizontal cell Ganglion cell layer

Photoreceptor layer

FIGURE 22.1  Layers of the retina, showing the projection of the photoreceptors that convert light into action potentials to the retinal ganglion cells whose axons ultimately become the optic nerve.

Cranial Neuropathies II, III, IV, and VI

695 Temporal

Nasal

Nasal

Temporal

* A B A

C

B

FIGURE 22.2  Retinotopic organization of retinal ganglion cell axons in the retina with the optic nerve (yellow circle) located nasally to the fovea (*), where central vision is projected (right eye, as seen by the examiner).

D

F

enters the nerve approximately 10 mm behind the globe. The remaining 20 mm of the nerve receives its blood supply from the pial perforating vessels of the ophthalmic artery. Some collateral blood supply from the external carotid artery may exist. The intraorbital optic nerve travels within the cone formed by the extraocular muscles and exits the orbit through the optic canal, which is situated in the lesser wing of the sphenoid. The dura covering the optic nerve becomes invested in the periosteum of the optic canal at the annulus of Zinn at the orbital apex. After leaving the canal, the intracranial optic nerve slants upward at a 45-degree angle to reach the optic chiasm where the RGCs redistribute by visual field. Above the nerves are the anterior cerebral and anterior communicating arteries, and below the nerves is the pituitary gland. The optic nerves pass medially to the internal carotid arteries above the ophthalmic artery takeoffs. The intracranial optic nerve receives its blood supply from a pial plexus of vessels arising from the internal carotid artery, the anterior cerebral, and anterior communicating arteries.

Clinical assessment History

Even in an era of advanced investigations, history-taking remains paramount to diagnosis of optic neuropathy etiology. Most optic neuropathies cause vision loss in one eye (Figure 22.3), though a condition that affects both optic nerves can cause vision loss in both eyes. Many people don’t differentiate visual loss in one eye from one-sided visual field defect, and comparing the vision between eyes may be necessary to clarify if eyes or fields are affected. The tempo of the visual loss is an important point to consider: was it sudden, episodic, or gradual? Associated ocular symptoms such as pain, proptosis, redness, photophobia, and positive visual phenomena and associated neurologic symptoms such as headache, double vision, and paresthesias or weakness should be inquired about. Past medical history including oncologic, rheumatologic, or vasculopathic diseases is relevant. History of visual loss or neurologic diseases that runs in family is also important.

TIP • Unilateral optic neuropathy causes vision loss in one eye; bilateral optic neuropathy causes vision loss in both eyes.

C D E F

E G

G

FIGURE 22.3  Patterns of common visual field defects related to lesions along the visual pathway. Anterior to the chiasm defects these field defects are monocular. At the chiasm, the orientation of visual field defects begins to line up along the vertical meridian. Since the nasal retinal fibers, representing the temporal visual fields, cross at the chiasm, field defects here produce a bitemporal defect that affects both eyes and often respects the vertical midline. Retrochiasmal defects involve fibers from both eyes, affecting the nasal fibers from the contralateral eye and the temporal fibers from the ipsilateral eye. This produces field defects in both eyes that affect the same side of the visual field. These are homonymous visual field defects that respect the vertical midline, contralateral to the side of injury.

Examination

The hallmark signs of optic neuropathy include reduced visual acuity, visual field defects, color vision loss, relative afferent pupillary defect (if asymmetric), abnormal optic nerve head appearance (if the anterior nerve is involved or there is RGC death), and no other ophthalmic findings accounting for vision loss. Each of these components must be characterized in the assessment of optic neuropathy; however, each is not always present.

Visual acuity

Visual acuity is the ‘ocular vital sign’; measurement can be performed at the bedside with handheld cards, provided the patient is wearing their corrective lenses for near vision. A pinhole is also useful to correct for refractive error. Visual acuity impairment is highly variable. Normal visual acuity does not exclude optic neuropathy.

TIP • Normal visual acuity does not exclude optic neuropathy.

Hankey’s Clinical Neurology

696 Color vision

Color perception can be affected by retinal, optic nerve, or cortical lesions. Optic neuropathies often cause acquired dyschromatopsia in the affected eye(s). Discordance between severe dyschromatopsia and mildly impaired visual acuity is a unique characteristic of optic neuropathy which can be useful in differentiating optic neuropathy from other causes of visual loss. Color testing can be done using pseudoisochromatic plates which are available in both print and electronic forms. In the hospital setting, the red desaturation test is a quick and easy method to detect dyschromatopsia. This test is performed by holding up a red object and asking the patient to compare color saturation subjectively between the two eyes.

Visual field testing

Generally, three types of visual defects may be seen with optic neuropathies. The most common is generalized constriction of the peripheral field.4 This type of visual field defect can also be caused by other ophthalmic conditions including cataract, retinal degenerations, and nonorganic visual loss. The second type of defect is central visual field loss including central, paracentral, and cecocentral scotomas. These are typically described as a blur, spot, or missing central vision. These also occur in maculopathies. Finally, nerve fiber bundle defects can be seen. They follow the retinotopic pattern of the nerve fibers as they enter the optic nerve, flipped due to the optics of the eye (i.e. superior retina – inferior visual field) (Figure 22.2). They respect the horizontal meridian of the visual field and are termed arcuate defects, nasal steps, or altitudinal defects. This is in contrast to visual field defects due to visual pathway injury at the chiasm or behind the chiasm that respect the vertical meridian (Figure 22.3). Confrontation visual field testing is easily performed at the bedside. The examiner stands an arm’s length away from the patient and directs the patient to cover one eye while the examiner closes their opposite eye. The patient is asked to look at the examiner’s nose, who monitors the fixation by watching the patient’s eyes for movements during the examination. The examiner presents one, two, or five fingers in the upper and lower right and left quadrants of the visual field within 30 degrees of fixation and asks the patient to identify the number of fingers displayed. The examination then switches to the other eye. Variations include asking if the patient can see the examiner’s entire face while fixated on the nose to test the central field, moving wiggling fingers in from the outside to assess the far periphery, or holding a red target in the upper and lower visual fields to assess for color desaturation across the horizontal meridian. While these examinations are reasonably specific, they are not very sensitive except in cases of dense visual field loss.

TIP • Visual field defects that respect the vertical meridian suggests injury at or behind the optic chiasm. Ophthalmology clinics use formal visual field testing, which is more sensitive and specific for visual field loss. Humphrey’s visual field testing is static automated perimetry that evaluates the central 20–60 degrees of the visual field. It presents a standardized static point of light of varying intensity to establish a threshold of vision at multiple points in the visual field. Goldmann’s perimetry varies stimulus size and intensity and evaluates the entire

180-degree field of vision. The stimuli are typically presented in a kinetic fashion with the examiner moving the stimulus from a nonseeing part of the field to a seeing part of the field to locate the boundary of perception. Both kinds of formal visual fields are helpful for detecting optic neuropathy improvement or worsening.

Relative afferent pupillary defect (Marcus Gunn pupil)

The relative afferent pupillary defect (RAPD) is an important sign of asymmetric optic neuropathy. It relies on the direct and indirect pupil responses as a marker of light transmission to the brainstem. Though, any pathology anterior to the optic chiasm as well as contralateral optic tract injury can potentially produce this sign, it is particularly sensitive to ipsilateral optic nerve injury. It is assessed using the ‘swinging flashlight test’. The examiner uses a pen light and rhythmically moves the light back and forth between the visual axes of each eye, pausing briefly to observe pupil change. Since the pupillary fibers project bilaterally to the Edinger–Westphal subnuclei of the third nerve, the efferent arc for pupillary constriction is equal between the two eyes regardless of which eye the light is shining in (Figure 22.4). If both eyes, optic nerves, and efferent pupillary pathways are normal, the amount of pupillary constriction should remain constant, regardless of which eye is stimulated. If the left eye, for example, has optic nerve damage, the pupils will constrict symmetrically to a light shone in the right eye or the left eye. However, the amount of constriction will be less when the light is shone in the affected eye (in our example, the left eye). Therefore, when the flashlight is passed from the left eye to the right eye, both pupils will constrict further, and conversely, when the light travels from the right eye to the left eye, both pupils will dilate. This is a result of poorer conduction of light signal to the Edinger–Westphal subnuclei from the optic nerve of the affected eye (Figure 22.5).

TIP • A patient with bilateral, symmetric optic neuropathies will not have a relative afferent pupillary defect because there is no ‘relative’ difference between the optic nerves.

Optic nerve head examination

The optic nerve head can be viewed on the funduscopic examination. Normal optic nerve heads are orange/pinkish in color with sharp margins (Figure 22.6A). Abnormalities relevant to detecting optic neuropathies include swelling, which causes blurring of the margins between the optic nerve head and surrounding retina. Sometimes, there can be hemorrhages (red), ischemia (cotton wool spots, white), and obscuration of the vessels when the swelling is severe. Optic atrophy or pallor is evident as a yellow or cream color of the optic nerve head (Figure 22.6B). This is indicative of permanent RGC injury.

Differencing between causes of monocular vision loss

The differential diagnosis of monocular vision loss is large, including optic neuropathies and pathology of other ophthalmic structures. Most of the ophthalmic causes are readily appreciated on ophthalmic examination. The exception is maculopathies, damage to the central retina, which shares symptomatic features with optic neuropathies and can be occult, even on dilated fundoscopic

Cranial Neuropathies II, III, IV, and VI

697 Light

CN II

Pupillary constrictor muscle

Optic chiasm

Ciliary ganglion (parasympathetic)

Optic tract

CN III

Edinger–Westphal nucleus

Brachium of superior colliculus

Lateral geniculate nucleus

Posterior commissure

Pretectal nucleus

Optic radiation

Visual cortex

FIGURE 22.4  The pupillary light reflex. The signal from the light shone in one eye projects to the pretectal nuclei bilaterally due to the decussation of the nasal fibers from each eye at the chiasm. In addition, each pretectal nucleus projects to both the right and left Edinger– Westphal nuclei which contain preganglionic parasympathetic neurons. These, via the oculomotor nerves, reach the ciliary ganglia and synapse with the postganglionic parasympathetic neurons which innervate the papillary constrictor muscles to cause constriction of both pupils. examination. Symptom of metamorphopsia (distortion of image) or photopsia (perception of flashing lights) are unusual for optic neuropathies but suggestive of maculopathies. On the contrary, perception of dimness, pain on eye movement, and heat-induced

Right

Left

transient visual loss (Uhthoff’s phenomenon) are well described in optic neuropathies. Although both may cause reduced visual acuity, disproportionally severe dyschromatopsia and presence of RAPD suggest optic neuropathy. Functional visual pathway testing such as visual evoked potential (VEP) or electroretinogram (ERG), and structural retinal imaging with optical coherence tomography (OCT) can help distinguish between these two causes of central vision loss.

Retinal diseases of interest to the neurologist Susac’s syndrome

Susac’s syndrome presents with vision loss due to branch retinal artery occlusions. It is a microangiopathy of the brain, retina, and inner ear that occurs most often in young women with a mean age of onset at 30 years. About 90% of patients have retinal arterial occlusions, and 66% have sensorineural hearing loss. In

FIGURE 22.5  Swinging flashlight test to assess for relative afferent pupillary defect. When the light is moved from the affected (left) eye to the unaffected (right) eye, both pupils constrict, and when the direction is reversed, both pupils dilate. This is because of reduced signal conduction along the visual pathway by the optic nerve on the affected side.

FIGURE 22.6  Panel A: Normal optic disc appearance with sharp margins, orange in color, and normal size cupping (white dotted line). Panel B: Atrophic optic disc. The neuroretinal rim appears pale (area between arrowheads).

698 the patients with retinal arterial occlusions, 60% have bilateral retinal ischemia. Autoimmune endothelial cell damage has been implicated as the underlying cause although pathogenesis has not been determined.

Mitochondrial diseases

Multiple mitochondrial diseases are associated with retinal pigmentary changes. These include Kearns–Sayre syndrome and mitochondrial encephalopathy with lactic acidosis and strokelike episodes (MELAS syndrome). This type of retinal pigmentary change can also be seen in the mucopolysaccharidoses, spinocerebellar ataxia type 7, and Gaucher’s disease.

Etiologies of optic neuropathies

Optic neuropathies can result from various causes including inflammatory, ischemic, oncologic, congenital, hereditary, toxic/ metabolic, and traumatic. Clinical findings, treatment, and long-term prognosis are determined by the underlying etiology. Therefore, timely determination of etiology is critical for proper management.

Inflammatory optic neuropathies

Inflammation can affect the optic nerve itself or the surrounding nerves, in which case it is called perineuritis. Optic neuritis is the most common cause of inflammatory optic neuropathy, typically causing acute, unilateral vision loss with retrobulbar pain that is worse during eye movement. This used to be categorized as demyelination (associated with multiple sclerosis [MS]) or idiopathic. However, during the past two decades, identification of novel immunologic markers, specifically anti-aquaporin-4-IgG (AQP4IgG), associated with neuromyelitis optica spectrum disorder (NMOSD), and anti-myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) have expanded the classification. Optic nerve inflammation can also be caused by infectious agents such as syphilis, Lyme, or tuberculosis. Rarely, it is associated with rheumatologic disease such as lupus. Prolonged inflammation of the optic nerve in the absence of a connective tissue disease despite extensive rheumatologic or vasculitic work-up is termed autoimmune optic neuropathy.

Optic neuritis related to multiple sclerosis

Optic neuritis affects approximately 70% of MS patients and is the initial presentation in one-fourth of cases. Some optic neuritis patients will not develop MS. The optic neuritis treatment trial (ONTT)5 has provided excellent data regarding the clinical presentation, treatment, outcomes, and risk of development of MS patients diagnosed with optic neuritis. Patients were randomized to treatment with oral steroids, intravenous (IV) steroids followed by an oral taper, or observation. Clinical features  Visual loss is usually acute, unilateral, and develops over few days reaching nadir in approximately 1 week. Progressive visual loss beyond 2 weeks is unusual. Ocular pain, typically worsening on eye movement, was reported in 92% of ONTT patients. Presenting vision loss ranged from 20/20 to no light perception, with the majority of patients (54%) between 20/25 and 20/200. Using static threshold automated perimetry, 45% of patients had diffuse visual field loss and 55% had localized defects, the most common of which was an altitudinal defect.6 On ophthalmoscopy, only one-third of cases had optic disc swelling, while the rest had normal appearance of optic nerve since

Hankey’s Clinical Neurology the affected part was behind the eye. Disc swelling, when present, was mild. Findings of hemorrhagic disc edema, exudate, or vitreous cells were related to a reduced risk for MS.7 Investigations and diagnosis  The diagnosis of optic neuritis is made based on clinical presentation. Magnetic resonance imaging (MRI) shows segmental gadolinium enhancement of the optic nerve in over 90% of cases. Magnetic resonance imaging (MRI) of the brain is important to evaluate for risk of current or future MS. ONTT 15-year follow-up data showed that patients who had one or more white matter lesions on their initial MRI had a 72% risk of developing MS at 15 years, while those with no lesions on the baseline MRI had a risk of 25%.7 Per the most recent MS diagnostic criteria, MS can be diagnosed in a patient with optic neuritis who has both enhancing and non-enhancing brain MRI lesions or has both non-enhancing brain lesions and CSF oligoclonal bands (OCBs).8 ‘Atypical’ features of optic neuritis include presenting vision worse than 20/200, simultaneous bilateral involvement, marked disc swelling with hemorrhages and exudates, progressive visual loss beyond 2 weeks, persistent pain, or no recovery at 1 month, blood tests, and CSF analysis should be performed to evaluate for alternate causes of optic neuropathy.9 Treatment and prognosis  According to ONTT, visual prognosis of optic neuritis is favorable regardless of treatment option. Most of the patients had nearly complete recovery (visual acuity [VA] 20/40 or better). Secondary analysis of ONTT cohort found black race associated with worse contrast sensitivity and visual acuity outcomes.10 Intravenous methylprednisolone 1000 mg/ day for 3 days followed by oral prednisolone (1 mg/kg/day for 11 days) hastened visual recovery and reduced the risk of developing definite MS for 2 years in patients with white matter lesions. Lowdose oral prednisolone (1 mg/kg/day or less) alone was associated with increased risk of recurrent optic neuritis.5, 7 Patients who are diagnosed with MS or high risk for MS based on MRI brain should be offered treatment with MS disease-modifying therapies. Patients who do not meet threshold for MS treatment should be monitored for development of MS.

Optic neuritis related to neuromyelitis optica

Optic neuritis is the presenting symptom in roughly half and eventually occurs in the majority of patients with NMO, an inflammatory central nervous system (CNS), distinct from MS that is related to AQP-4-IgG. It is important to maintain a high index of suspicion for NMO in patients with optic neuritis, since the morbidity and mortality rates are higher than for MS and the treatment is different. Clinical features  Features that distinguish NMOSD optic neuritis from MS optic neuritis include more severe vision loss (VA of 20/400 or worse) and bilateral involvement in 20% of patients.11 Lesions are more often posterior and chiasmal. Investigation and diagnosis  MRI criteria for NMOSDassociated optic neuritis include an inflammatory optic nerve involving more than half of optic nerve length or involving optic chiasm.12 According to 2015 international consensus criteria, NMOSD can be diagnosed in patients with optic neuritis and serum AQP-4-IgG positivity.12 Seronegative cases require a secondary core clinical characteristic to make a diagnosis (e.g. acute myelitis or area postrema syndrome). CSF is more likely to have pleocytosis of greater than 50 cell/mm3, and oligoclonal bands are less likely to be present in NMOSD than MS.13

Cranial Neuropathies II, III, IV, and VI Treatment and prognosis  Vision recovery is worse in NMO than MS optic neuritis following treatment with high-dose intravenous corticosteroid with only 36% having good recovery.14 Plasma exchange has also been used as both second-line treatment and initial treatment combined with IVMP. In patients diagnosed with NMOSD, long-term immunosuppressive treatment is recommended due to high risk of relapse and devastating outcomes. Some immunomodulatory agents designed for MS may worsen NMOSD disease.15, 16

TIP • Due to the unfavorable prognosis and distinct acute and long-term therapeutic needs, it is crucial to differentiate optic neuritis in NMOSD from that in MS. In addition, certain immunomodulatory agents approved for MS including interferon beta, fingolimod, and natalizumab, may worsen the course of NMOSD.

Myelin oligodendrocyte glycoprotein antibody-associated optic neuritis

Myelin oligodendrocyte glycoprotein IgG (MOG-IgG) has been identified as a novel serologic marker associated with optic neuritis, which is termed MOG-associated disorder (MOGAD). This appears to be a distinct spectrum of CNS inflammatory diseases including phenotypes of seronegative NMOSD and acute disseminated encephalomyelitis (ADEM), the latter is more common in children.17 Myelin oligodendrocyte glycoprotein optic neuritis (MOG-ON) is more likely to affect bilateral optic nerves and has a higher risk of having recurrent clinical course.18 Visual loss on initial presentation is often severe, and optic disc swelling is more common and severe than in NMO- and MS-associated optic neuritis. Similar to NMO, MRI commonly reveals longitudinal extensive optic nerve inflammation. Unlike MS and NMO, there is often perineural enhancement.18 Diagnosis is based on association with positive serum testing for MOG-IgG. Visual outcomes in MOG-ON generally favorable. MOG-ON is typically steroid responsive and can be steroid dependent. The choice of long-term immunosuppressive agent in patients with relapsing disease is an area of active study.

699 Ischemic optic neuropathies

Blood flow loss to the optic nerve causes acute vision loss whether the anterior (i.e. optic nerve head) or posterior nerve is affected. Categorizations are based on anatomy (anterior vs. posterior) and cause (arteritic vs. nonarteritic).

Arteritic ischemic optic neuropathy

Arteritic ischemic optic neuropathy (AION) can affect the anterior or posterior optic nerve, most commonly in association with giant cell arteritis (GCA).20, 21 Visual loss is frequently the symptom that brings patients to medical attention. It is estimated that visual loss occurs in 7–60% of patients with GCA, from either AION, central retinal artery occlusion, or, less frequently, occipital infarction. Arteritic anterior ION is the most common cause of visual loss in patients with GCA.22 GCA involves large and mid-sized arteries which have an elastic lamina. The vasculitis preferentially targets the superficial temporal, vertebral, ophthalmic, and posterior ciliary arteries. This explains the frequency of blindness and neurologic findings seen in these patients. Less commonly involved vessels include the internal carotid, external carotid, and central retinal arteries as well as the aorta. Symptoms occur due to systemic inflammation (fatigue, fever, and weight loss) and focal ischemia (headaches, jaw claudication, loss of vision, and scalp tenderness). It occurs almost exclusively in the older population. Clinical features  AION can present as transient visual loss similar to that seen with carotid artery disease or cardiac valvular disease. This can stutter and progress to permanent vision loss. Sometimes, there is no prodrome, and vision loss happens suddenly. It is usually unilateral with second eye involvement occurring within 5–6 days after the first eye involvement if the diagnosis is not recognized and treated. The visual loss is typically profound with the majority of patients having acuities of 20/200 or worse.23, 24 In anterior cases, the affected optic nerve shows pallid edema that may be associated with intraretinal hemorrhages and/or cotton wool spots (Figure 22.7). Posterior ischemic optic neuropathy (PION) can also occur in GCA. These patients have normalappearing fundi with sudden visual loss and afferent pupillary

Sarcoidosis

Sarcoidosis in a multisystem disorder without a known etiology that is diagnosed pathologically by finding noncaseating epithelioid cell granulomas on biopsy. Ocular involvement is present in 25% of patients with sarcoidosis.19 The majority of these patients have anterior uveitis. However, optic nerve involvement can present as an optic nerve head granuloma, optic perineuritis (inflammation of the nerve sheath), or retrobulbar optic neuritis. Compared to MS or idiopathic optic neuritis, these patients have less pain and progressive vision loss beyond 2 weeks. In addition, the visual loss may respond rapidly to steroid therapy, in contrast to idiopathic/MS-associated optic neuritis where recovery can be delayed. If any of these signs are present, suspicion of sarcoidosis should prompt chest imaging, testing for angiotensin-converting enzyme, and lysozyme. In addition, a history of rashes, adult-onset asthma, joint pain, or arthritis should be inquired about. Treatment with systemic steroids is often needed for long periods of time; therefore, a tissue diagnosis should be sought, if possible, by using skin biopsy, bronchoalveolar lavage, or conjunctival biopsy.

FIGURE 22.7  Pallid edema of the optic nerve is seen in giant cell arteritis.

Hankey’s Clinical Neurology

700 defects. Central retinal artery occlusion (CRAO) from GCA can also cause monocular vision loss. This is less frequent than AION. Other visual symptoms in GCA include homonymous visual field defects from cerebral infarction, diplopia due to vasculitic occlusion and/or ischemia of the ocular motor cranial nerves, the extra ocular muscles, or brainstem ischemia. Most patients with GCA will have premonitory systemic symptoms prior to their visual symptoms. These may include new-onset headache, jaw claudication, weight loss, malaise, fever, scalp tenderness, anemia, tongue claudication, tinnitus, or vertigo. Jaw claudication is one of the most specific systemic symptoms associated with GCA and may predict a higher risk of visual loss.23

TIP • It is important to differentiate jaw claudication from temporomandibular joint (TMJ) pain by history. Patients with jaw claudication will describe crescendo pain in the masseter muscles that begins after a period of chewing and abates when chewing ceases. Patients with TMJ report maximal pain when opening the jaw or immediately upon chewing.

Diagnosis and investigations  Various diagnostic criteria have been proposed for GCA with the gold standard being arterial pathology, typically via temporal artery biopsy (TAB). In addition to clinical history consistent with ischemia, presence of systemic symptoms and age over 50 years, GCA is suggested by high erythrocyte sedimentation rate (ESR) or high C-reactive protein (CRP). Fluorescein angiography demonstrating reduced perfusion in more than one retinal circulation is also suggestive. The diagnosis can be challenging because some patients lack systemic symptoms, and elevated ESRs (defined as greater than age [+10 if female] divided by 2) are nonspecific and have suboptimal sensitivity. Elevated CRP is more sensitive than ESR and the combination of an elevated ESR and CRP has been shown to be 97% specific for the diagnosis of GCA.25 Platelet count may also be informative, and thrombocytosis may have a higher specificity, positive predictive value, and negative predictive value for GCA than ESR alone.26 Though the American College of Rheumatology has published a list of diagnostic criteria for GCA that permit diagnosis in the absence of TAB, 27 a TAB, deemed 95% sensitive and 100% specific for GCA, is a low-risk test that is prudent to confirm the diagnosis and support long-term steroid therapy. Since the pathology of the vasculitis can be scattered (skip areas), it is important to ensure the biopsy specimen be of sufficient length to reduce the risk of missing the involved portion of the vessel. Disruption of the internal elastic membrane is diagnostic of GCA. Obliteration of the lumen and epithelioid giant cells may also be seen but are not necessary for diagnosis. Attempts should be made to undertake TAB within the first week of starting corticosteroid therapy. However, experienced pathologists can make the diagnosis of ‘healed arteritis’, characterized by lymphocytic infiltration and scarring, even after several weeks of therapy with corticosteroids. In patients for whom there is a high suspicion of GCA, but first TAB is negative, a second TAB can be considered. Yield after initial negative result ranges from 5% to 13%.28

TIP • About 20% of patients with visual symptoms due to GCA can have no associated systemic symptom, ‘occult GCA’, in addition, ESR and CRP can be both negative in 10%. Therefore, high clinical suspicion is crucial in diagnosis.

Treatment and prognosis  When patients present with vision loss, and there is high suspicion for GCA, therapy should be initiated as soon as possible, even prior to confirming the diagnosis, with the goal of preventing additional ischemic events including second eye involvement. A typical regimen is intravenous methylprednisolone (typically 1 g/day for 3 days) followed by high-dose oral prednisone, though some practitioners use high-dose oral prednisone initially. A steroid dose taper can be initiated after about 1 month provided that the ESR and CRP remain normal without re-emergence of systemic symptoms. This taper is very slow and may last 6–12 months or longer. Tocilizumab, an interleukin-6-inhibitor, has been shown to increase the rate of sustained steroid-free remission at 1 year and may be added as adjuvant therapy.29

Nonarteritic anterior ischemic optic neuropathy

Nonarteritic anterior ION (NAION) is the most common cause of unilateral optic disc edema and optic neuropathy in patients over 50 years old. 30 The definite cause of NAION is not known. Histologic studies have demonstrated infarction at the level of retrolaminar optic nerve, which points to insufficiency of short posterior ciliary arteries in this watershed area. 31 Nocturnal hypotension may contribute. A structural risk factor for NAION is a crowded ONH or so-called ‘disc at risk’, which it thought to contribute a compartment syndrome as the initially injured swollen fibers compress the blood supply and surrounding fibers. Disruption of autoregulation may also play a role with identified risk factors that may worsen autoregulation including hypertension, diabetes mellitus, obstructive sleep apnea and possibly dyslipidemia, and anemia. The Ischemic Optic Neuropathy Decompression Trial (IONDT) found that patients without systemic risk factors, including hypertension and diabetes, did not have visual loss as severe as that seen in patients with systemic risk factors. 32 External factors, particularly medications, may trigger onset of disease in certain conditions. Amiodarone and phosphodiesterase-5 inhibitors have been linked to NAION. 33 Clinical features  A typical presentation is sudden nonprogressive monocular visual loss, most commonly noticed upon awakening. Unlike GCA, systemic symptoms are rare. Typically, patients describe a painless loss of vision; however, pain has been reported in up to 10% of patients. 34 Patients present with decreased visual acuity at any range, although it is typically not as profound as that seen with GCA. In the IONDT, 49% of patients had acuity better than 20/64, and 34% had acuity worse than 20/200. In addition, to findings of optic neuropathy, the classic visual field defect is an altitudinal defect (Figure 22.8). However, the visual field defect can be any ‘optic neuropathy’ type defect, ranging from a central scotoma to arcuate or altitudinal defects. Ophthalmoscopy must reveal optic disc swelling in the acute phase to make the diagnosis of NAION. A typical appearance is sectoral optic disc swelling, with hyperemia, and splinter hemorrhages (Figure 22.9). Additionally, the finding of ‘disc at risk’ in fellow eye can support diagnosis of

Cranial Neuropathies II, III, IV, and VI

701 Treatment and prognosis  There is no proven treatment that reduces or reverses visual loss. The IONDT showed a worse outcome in patients treated with optic nerve decompression. Aspirin has not been shown to change the visual outcome, nor does it affect the risk of second eye involvement. Many other off-label treatments have been tried without consistent success. Oral steroids are sometimes given. Though a recent randomized controlled trial did not demonstrate improvement in visual outcome with oral steroids, they were associated with faster resolution of optic disc edema and improved electrophysiologic measures. 35 Most patients have a fixed deficit; however, some patients have a progressive course or spontaneous recovery. In the IONDT, 43% of nontreated patients recovered three or more lines of vision, while approximately 10–15% of patients have a progressive loss of vision over the first month after diagnosis. There is a lifetime risk of 30–40% of second eye involvement.36 Untreated severe sleep apnea may increase this risk. Control of vascular risk factors is generally recommended, as is avoiding nocturnal hypotension and diagnosis/treatment of obstructive sleep apnea.

TIP FIGURE 22.8  Automated visual perimetry demonstrating superior altitudinal visual field defect corresponding in a case of NAION. This corresponds to the inferior sectoral optic disc swelling as shown in Figure 22.9. NAION in affected eye. Over time, as edema resolves, patients are left with pallor of the optic nerve head. Diagnosis and investigations  There is no diagnostic test for NAION. GCA should be considered and ESR and CRP evaluated if appropriate. In atypical patients (e.g. younger without vascular risk factors), MRI orbit and hypercoagulability work-up can be considered.

• It is prudent to distinguish NAION from other causes of acute visual loss with optic disc swelling. Arteritic anterior ION is always on the differential diagnosis in patients over 50 years old. CBC, ESR, and CRP can help guide evaluation for this.

Postoperative ischemic optic neuropathy

Visual loss after nonocular surgery is a relatively uncommon complication. The incidence of ION after nonocular surgery is approximately 1/60,000–1/125,000. 37 A wide variety of surgical interventions have been associated with perioperative visual loss (POVL). The most commonly reported settings are cardiac surgery and spinal fusion surgery. The incidence of all causes of POVL has been observed to be as high as 4.5% in cardiac surgery. In spine surgery, reported incidences are as high as 0.2%. There are several causes of POVL after nonocular surgery. AION and PION are most frequently described.38 In addition, central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) have been noted, particularly in cases with ocular or orbital compression. Cortical blindness is another cause of POVL.

Papilledema (due to high intracranial pressure)

Papilledema is swelling of the optic nerve due to elevated intracranial pressure (ICP). Appearance can range from mild c-shaped swelling that spares the temporal margin to severe 360-degree swelling with hemorrhages, cotton wool spots, and obscuration of the blood vessels on the disc surface (Figure 22.10). It can be considered a compressive optic neuropathy where compression is caused by high CSF pressure in the optic nerve sheath.

Clinical features

FIGURE 22.9  Sectoral swelling of the inferior optic nerve head with splinter hemorrhages in nonarteritic anterior ischemic optic neuropathy.

Vision is preserved in papilledema, with about 50% of patients not having vision loss. When it is impacted, it typically affects peripheral vision, with central vision not being involved until optic nerve injury is advances. Transient vision loss for a few seconds can occur with head movement. This is thought to be related to transient ischemia of the swollen optic nerve. The disc swelling is bilateral, though can be asymmetric in some cases. Associated symptoms include those related to high ICP including headaches and pulsatile tinnitus.

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FIGURE 22.11 Optic pseudopapilledema. FIGURE 22.10  Papilledema, diffuse optic disc swelling due high intracranial pressure. Note obscuration of peripapillary vessels along swelled optic disc margin (arrows).

Diagnosis and investigations

Papilledema is a medical emergency due to the underlying cause of elevated ICP. Neuroimaging, cerebral venous imaging, and lumbar puncture (LP) are useful for excluding secondary causes of high ICP. LP is also important for measurement of opening pressure to confirm ICP. If high ICP is confirmed, and no secondary cause of high ICP is identified, the patient can be diagnosed with idiopathic intracranial hypertension (IIH). Because central vision is typically not affected, formal visual field testing is helpful for assessing and monitoring visual dysfunction. Ophthalmic imaging including OCT is helpful for monitoring optic nerve swelling and RGC injury.

Treatment and prognosis

Treatment of any identified secondary causes of ICP is important but should not preclude directed management of ICP in cases with vision loss or evidence of RGC injury. Options for lowering ICP include medications such as acetazolamide, topiramate, or furosemide and CSF diversion surgeries. Optic nerve sheath fenestration is a surgical technique for lowering pressure in the optic nerve sheath. Cerebral venous sinus stenting is a technique for lowering cerebral venous pressure when there is a stenosis contributing to pressure elevation. Generally, surgical treatment is reserved for patients with vision loss unresponsive to medical treatment, RGC injury, or severe vision loss. In patients with IIH, weight loss is associated with disease improvement. Symptomatic management of symptoms such as headache can supplement disease-directed treatment.

Pseudopapilledema

Pseudopapilledema refers to an elevated optic nerve not due to RGC axon swelling. This differentiation can sometimes be made clinically. Fluorescein angiography can help differentiate because it shows leakage in the case of true disc edema. Optic nerve drusen is the most common cause.

nerve

head

drusen

causing

Optic nerve drusen

Optic disc drusen are calcium deposits below the surface of the optic nerve head present in 2% of the population. There are bilateral deposits in two-thirds of cases. They cause an elevation of the optic nerve head that can be mistaken for optic nerve head edema. As patients get older and undergo some involution of the RGC axons, the calcific deposits become more visible (Figure 22.11). Up to 70% of patients will have a visual field defect. 39 The majority of these never progress although progression can occur in some cases. The central visual acuity is rarely affected in these patients; if central acuity is affected, other causes of visual loss should be pursued even in the presence of disc drusen. Occasionally, because of the crowding of the axons as they pass through the lamina cribrosa into the orbit, ischemic optic neuropathy can occur.

Compressive optic neuropathies

Compressive optic neuropathies have a typical presentation with slowly progressive visual loss. On occasion, unilateral vision loss may present as ‘pseudo-sudden visual loss’ when the good eye is temporally occluded and the patient notices that the affected eye has visual loss. The typical features of optic neuropathy are present including visual loss, dyschromatopsia, visual field loss, and afferent pupillary defects. Often at the time of diagnosis there is optic atrophy, though if RGC damage has not occurred, the optic nerve head can appear normal. If there is compression of the optic nerve in the orbit, the optic nerve head can be swollen. Causes of compressive optic neuropathies can be intraorbital, intracanalicular, or intracranial. Intraorbital causes include primary orbital tumors such as cavernous hemangiomas or schwannomas, secondary tumors such as metastatic or sinus lesions, or enlarged muscles due to thyroid-associated orbitopathy, orbital pseudotumor, or neoplasm of perioptic nerve sheath complex such as optic nerve sheath meningioma. Intracranial etiologies of compressive optic neuropathies include aneurysms, chiasmal lesions, meningiomas, metastatic tumors, or fibrous dysplasia of the skull among others. If the lesion becomes large enough to increase the ICP, the fellow eye may be swollen as a result of increased ICP (papilledema). The

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703 Radiation is currently the first-line treatment reserved for adult patients with progressive vision loss. Stereotactic fractioned radiotherapy reported to be better tolerate than conventional therapy.41 Surgical excision is not recommended, as removal of the arachnoid strips the pial vessel supply to the nerve, and visual loss is worsened. Therefore, surgery is reserved for blind and painful or unsightly eyes or decompression of the optic canal in the case of intracanalicular extension.

Thyroid-associated ophthalmopathy

FIGURE 22.12  Computed tomography of optic nerve meningioma showing calcification – the ‘tram track’ sign (arrow). pale compressed nerve is atrophic and therefore will not swell in response to increased ICP. This phenomenon is known as Foster– Kennedy syndrome.

Optic nerve sheath meningiomas

Optic nerve sheath meningiomas classically present with unilateral insidious visual loss. Bilateral and multifocal cases are associated with neurofibromatosis type 2 (NF-2). Visual acuity is usually within the 20/40 to 20/200 range and can be normal. The appearance of the optic nerve is almost always abnormal either atrophic or swollen. Optociliary shunt vessels are visible on the optic nerve head in up to 33% of patients.40 Mass effect can also lead to proptosis, ophthalmoplegia, and diplopia. Neuroimaging shows calcification on computed tomography (CT) scans in a so-called ‘tram track’ appearance because the sheath on either side of the nerve is involved (Figure 22.12). On MRI the tumor is isointense with brain on T1- and T2-weighted images with homogeneous gadolinium enhancement. The progression is slow, but intracranial extension can occur. Visual acuity has been reported to remain stable for many years.

Graves’ eye disease or thyroid-associated ophthalmopathy (TAO) is the most common orbital disorder in adults. It may occur in hyperthyroid, euthyroid, or hypothyroid patients. It causes inflammation and a restrictive myopathy of the extraocular muscles and levator palpebrae in the eyelids. The most common finding is lid retraction; however, proptosis, limited eye movements, and diplopia are not uncommon. Optic neuropathy due to compression by the swollen muscles occurs in about 9% of TAO patients42 (Figure 22.13). Vision loss associated with TAO requires immediate management with steroid therapy and, sometimes, surgical orbital decompression. Radiation to the posterior orbit with concomitant steroid treatment can also be helpful but does not generally produce immediate results.

Optic nerve neoplasms

Primary tumors of the optic nerve are rare. More common is infiltrative disease due to leukemia, lymphoma, or metastatic disease. These are typically apparent on neuroimaging. A tissue diagnosis can be challenging unless there are other anatomical regions involved. Sometimes CSF analysis can provide guidance.

Optic nerve gliomas

In children, optic nerve gliomas are typically benign and slowly progressive. Most children present within first decade of life. About 25% of these children diagnosed with neurofibromatosis type 1 (NF-1). On the contrary, only 15% of patients with NF-1 developed optic nerve gliomas.43 Neuroimaging typically shows kinking and fusiform enlargement of the nerve with enhancement. MRI is the preferred

FIGURE 22.13  Panel A: Compression of the optic nerve (arrow) by extraocular muscle bellies (red dashed line) at the orbital apex in thyroid-associated ophthalmopathy. Panel B: Comparison with normal orbital study. There is a space between the optic nerve (arrow) and the extraocular muscle bellies (red dashed line).

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704 imaging modality because it can assess intracranial extension. The diagnosis can be made radiographically, and biopsy is generally not necessary. The clinical course is variable. The tumors typically have slowgrowing nature and may even have self-limited growth. Patients with small lesions confined within orbit usually have preserved vision. Generally, non-NF cases have a worse prognosis. Tumors should be surveilled for clinical or radiographic progression. Meanwhile, coexisting amblyopia should be treated to achieve best possible vision. Glioma usually do not require treatment unless progression occurs. In this case, chemotherapy is the first-line treatment in most cases. Radiation is currently not considered appropriate due to endocrinologic and neurologic adverse outcomes. Surgical resection is only considered in prechiasmatic lesions with poor vision (nearly blind or worse) and disfiguring proptosis. Malignant optic nerve gliomas are much rarer and affect middle-aged and older adults. Rapid progression to blindness often occurs. Life expectancy is usually months after diagnosis.

Congenital optic neuropathies

Congenital optic neuropathies are structurally abnormal optic nerves present at birth. Often, but not always, there is visual impairment. Typically, these do not progress. Several of these findings have neurologic associations and will be discussed here.

Optic nerve hypoplasia

This is the most common congenital anomaly of the optic nerve. Visual function is widely variable, but smaller nerves are associated with worse function. MRI typically reveals small optic nerves and chiasm. It may occur in isolation or associated with other midline abnormalities such as thin or absent corpus callosum, absence of the septum pellucidum, and hypopituitarism. This septo-optic dysplasia or de Morsier’s syndrome can also be associated with schizencephaly. Optic nerve hypoplasia can also be seen in association with congenital suprasellar tumors and teratomas.

Morning glory discs

Morning glory discs result from a weakness of the posterior globe that allows uveal tissues to protrude through the sclera, in this case involving the optic nerve. The nerve appears large and vessels radiate in a spoke-like manner from the center of the nerve, like a morning glory flower. The disc itself is filled with white glial tissue. This congenital anomaly can be associated with moyamoya disease and/or transsphenoidal basal encephaloceles.

Colobomas

Colobomas occur when there is incomplete closure of the embryonic fetal fissure that forms the optic cup and stalk. This results in incomplete formation of certain part of the eye. When the optic nerve is involved, the disc appears excavated usually inferiorly, with normal vessels and a normal superior rim. These patients need to be investigated radiographically for associated basal encephaloceles. Coloboma also known to be associated with tuberous sclerosis and CHARGE syndrome.44

Hereditary optic neuropathies

In contrast to congenital optic neuropathies, hereditary optic neuropathies are due to genetic mutations and are associated with progressive vision loss.

Leber’s hereditary optic neuropathy

Leber’s hereditary optic neuropathy (LHON) is an inherited mitochondrial disorder with incomplete penetrance that occurs more frequently in men. It commonly presents in the second or third decade with bilateral sequential painless visual loss causing central scotomas and decreased visual acuity in both eyes. The average interval between eye involvement is several months. Visual acuity is typically severely affected to 20/200 or worse in both eyes.45 Some patients note that they have Uhthoff’s phenomenon, and a disease resembling MS has been described as occurring with LHON. In addition, cardiac conduction defects have been described. Skeletal abnormalities including hip dislocation, pes cavus, and kyphoscoliosis have also been associated with the disease. Diagnosis is made based on the clinical picture. There are now several mitochondrial mutations that can be tested to make the diagnosis. Treatment and prophylaxis have not been effective for LHON. There is a suggestion that smoking, alcohol, or certain medications may contribute to the development of the disease, so these should be avoided.

Dominant optic atrophy

Dominant optic atrophy usually presents in the first decade of life. Patients typically develop central visual field defects and visual acuity loss with normal peripheral vision. Vision loss progresses slowly and is usually not severe with visual acuity remaining 20/60 or better in 40% of the patients.46 The optic nerve develops a wedge-like atrophy with temporal loss of the neuroretinal rim. The disease has been linked to the long arm of chromosome 3. Currently, there is no known effective treatment.

Recessive optic atrophy

Recessive optic atrophy presents with severe visual loss in early childhood. Parental consanguinity is often present. In some cases, it can be associated with spinocerebellar degeneration (characterized by cerebellar ataxia and pyramidal tract dysfunction) and mental retardation; in these cases, it is referred to as Behr’s syndrome.47 There are several metabolic and degenerative neurologic diseases associated with optic atrophy such as spinocerebellar degeneration (e.g. Friedreich’s ataxia), Charcot–Marie–Tooth disease, and olivopontocerebellar atrophy. Recessive optic atrophy may also be associated with mucopolysaccharidoses (including Hurler’s, Scheie’s, Hunter’s, Sanfilippo’s, Morquio’s, and Maroteaux–Lamy variants) and lipidoses (such as Tay–Sachs, adrenoleukodystrophy, metachromatic leukodystrophy, Niemann–Pick, and Krabbe’s disease).

Nutritional and toxic optic neuropathies

These diseases involve gradual painless loss of vision that is bilateral and tends to impact central vision causing decreased visual acuity. Patients typically have bilateral cecocentral visual field loss, normal optic nerve appearance early in the disease, and no metamorphopsias (as associated with maculopathies). Improvement in vision can be seen with removal of the offending agent or correction of the nutritional deficit, but this is not always the case. These diseases can be recognized by the patient’s exposure history including treatment with chemotherapy, recreational drug use, antibiotics, or malnutrition.

Cranial Neuropathies II, III, IV, and VI Vitamin B12 deficiency

This can be seen with pernicious anemia, status post resection of the stomach or small intestine, and in very strict vegans. It can occur in association with posterior spinal column symptoms. Diagnosis is made in the setting of low vitamin B12 level or elevated homocysteine or methylmalonic acid. Treatment is with vitamin B12 replacement.

Malnutrition (tobacco/alcohol amblyopia)

This is the most common nutritional/toxic optic neuropathy. Tobacco/alcohol amblyopia is a misnomer since it is not direct toxicity, but lack of micronutrients due to predominant caloric intake in the form of alcohol. Asking the patient to detail a typical daily breakfast, lunch, and dinner can shed light on the potential for malnutrition. If tobacco alcohol amblyopia is suspected, testing for vitamin B12 and folate levels should be performed. Counseling the patient to reduce alcohol and tobacco use, though frequently unsuccessful, should be documented, and the appropriate referrals made. Supplementation with vitamins and folate should be instituted even in the absence of documented deficiencies.

Methanol toxicity

Methanol causes a dramatic toxic optic neuropathy characterized by sudden visual loss and disc swelling as well as metabolic acidosis. Very small doses of methanol can lead to optic nerve damage. Exposure tends to occur in suicide attempts or accidental ingestion from contamination of ethyl alcohol. The exact mechanism of optic neuropathy by methanol is not well understood. Methanol is a direct depressant of the CNS and, on ingestion, it is rapidly absorbed and metabolized in the liver by the alcohol dehydrogenase to formaldehyde, which is then transformed into formic acid; this causes cellular hypoxia via mitochondrial inhibition. Treatment includes dialysis to control the acidosis and IV ethyl alcohol, which competitively inhibits the binding of methanol to alcohol dehydrogenase.

Other causes of toxic optic neuropathies

Include ethambutol, carmustine, busulfan, chloramphenicol, cisplatin, disulfiram, fludarabine, interferon, isoniazid, lead, methotrexate, quinine, toluene, and vincristine.

Traumatic optic neuropathies

Traumatic optic neuropathy (TON) can be direct or indirect. Direct injuries are a result of objects penetrating the orbit and lacerating or compressing the optic nerve. Indirect injuries are a result of forces transmitted through the skull (often with frontal impact) to the optic nerve where it passes through the boney canal, shearing due to rapid deceleration injuries or avulsion, which occurs due to forceful rotation of the eye and leads to separation of the nerve from the globe. The vision loss associated with indirect TON ranges from 20/20 to no light perception. Patients will initially have no ophthalmoscopic signs of damage to the optic nerve. CT scan with 1-mm slices of the orbits is important to rule out a canalicular fracture or hematoma. Fractures can be repaired or decompressed with the possibility of visual improvement. There is currently no recommended treatment for TON, and the likelihood of recovery is low. Pallor of the nerve will develop over weeks to months after the injury.

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CRANIAL NERVE III, IV, AND VI PALSIES Definition

Dysfunction of the nerves that control eye movements, including cranial nerves III (oculomotor), IV (trochlear), and/or VI (abducens), leads to ocular misalignment and often diplopia.

Ocular motility anatomy

Smooth pursuits are generated from the parietal eye fields, while saccades are generated from the frontal eye fields. Vestibular outputs stimulate reflexive eye movements to stabilize gaze during head movement. Multiple brainstem nuclei are involved in eye movement initiation and gaze maintenance including coordination between the eyes. Cranial nerves III, IV, and VI carry the neural signals to the extraocular muscles, which move the eyes. The horizontal saccade pathway is clinically relevant, starting from the frontal eye fields and decussating to the contralateral paramedian pontine reticular formation (PPRF). The PPRF projects to the CN VI nucleus which projects to the ipsilateral lateral rectus and sends interneurons through the medial longitudinal fasciculus (MLF) to the contralateral CN III medial rectus subnucleus. This achieves coordinated contralateral gaze. Internuclear ophthalmoplegia (INO) results from damage to the MLF and causes an adduction deficit on the ipsilateral side with a contralateral abducting nystagmus. Stroke and MS are the most common causes (Figure 22.14). Descending vestibular pathways are also clinically relevant with disruption leading to skew deviation causing horizontal ocular misalignment.

TIP • Though diplopia is typically due to a cranial nerve, neuromuscular junction, or extraocular muscle problem, parenchymal lesions causing internuclear ophthalmoplegia or skew deviation must be considered.

Clinical assessment of diplopia or ocular misalignment History

Symptoms of diplopia or observation of ocular misalignment, anisocoria, or ptosis should prompt consideration of cranial nerves III, IV, and VI localization among others. When taking a history from a patient with diplopia, the most important question is whether the diplopia resolves when either eye is closed. If closing either eye relieves the diplopia, then it is a binocular process, meaning the diplopia is occurring because the eyes are pointing in two different directions with one image is coming from each eye. This is typically a neurologic or orbital process with a few congenital exceptions. If the diplopia persists when one of the eyes is closed, it is a monocular process. Monocular diplopia is almost always related to refractive, ocular surface, or intraocular problems such as cataract or macular edema. Usually, if the patient is instructed to view an object through a pinhole, this type of diplopia resolves or at least improved. Very rarely, patients have monocular diplopia that does not resolve with pinhole viewing, due to occipital lobe lesions causing cerebral polyopia.48 Other important questions are the orientation of the images relative to each other (i.e. horizontal, vertical, or oblique) and whether orientation and spacing between the images change in

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706 Interpeduncular fossa

Starting point Lateral gaze center (PPRF)

Abducens nucleus (CN VI)

Lateral rectus muscle

ABDUCTION

Oculomotor nucleus (CN III) ventral lateral subnucleus

Lesion in MLF

Medial longitudinal fasciculus (MLF)

Medial rectus muscle

NO ADDUCTION

FIGURE 22.14  A lesion of the medial longitudinal fasciculus on the left leads to a defect in conjugate eye movement to the right. PPRF, paramedian pontine reticular formation.

different directions of gaze. This can help to localize which muscles are paretic or restricted. For example, vertical diplopia suggests CN IV palsies, CN III palsies, skew deviations, thyroid eye disease, and myasthenia gravis. Other accompanying neurologic symptoms, including ptosis, anisocoria, and facial numbness, as well as orbital symptoms such as proptosis, also guide localization. Beyond CN III, IV, and VI palsies, the differential diagnosis for diplopia also includes central, neuromuscular junction, and muscular causes. Central causes of horizontal diplopia include internuclear ophthalmoplegia, one and a half syndrome, and skew deviation. Intermittent diplopia in a changing pattern that is worse at the end of the day or with fatigue can suggest myasthenia gravis. Ocular muscle inflammation (e.g. thyroid ophthalmopathy), tumors, and myopathies (e.g. chronic progressive external ophthalmoplegia) are orbital causes.

Examination

Examination of ocular motility should begin with observing the patient for obvious misalignment of the eyes, also called a manifest tropia. The ductions should be tested. Ductions are the movements of both eyes in all the directions of gaze and are tested by asking the patient to look in a direction, follow an object, or localize a sound with their eyes. How the movement is stimulated does not matter as this is a motor test, not a sensory test. Limitations of motility of any of the muscles may be noted during this examination. Testing the eyes separately can be helpful when there is

misalignment present. Vergences are the result of the eyes moving in opposite directions such as convergence and divergence and are testing by having the patient look at an object moving toward them and away from them. The oculocephalic maneuver can be performed when the patient is unable to cooperate or to test the supranuclear pathways controlling eye movements. If the limitation of eye movements is overcome by the oculocephalic maneuver, the lesion is supranuclear in nature. Next, the relative alignment of the eyes should be determined in different directions of gaze. A convenient way to evaluate ocular alignment is shining a light between the patient’s eyes and asking them to look at it while observing the corneal light reflex. If the eyes are aligned, the corneal light reflex should be in the center of both pupils. In some cases, it will be necessary to do more subtle measurement of misalignment of the eyes using Maddox’s rod or cover/uncover and alternating cover testing. These techniques can help with determining pattern of deviation and are especially helpful when the amplitude of misalignment is small. Any patients complaining of diplopia should be closely examined for signs of pupillary involvement or ptosis, as can be seen with CN III palsies or Horner’s syndrome as well as facial numbness, which suggest orbital or intracranial localization. It should be stressed that although management of each of these palsies in isolation will be discussed, if a combination of cranial nerve palsies is seen, or if one cranial nerve palsy occurs in the presence of other neurologic signs or symptoms, neuroimaging and further investigation are warranted.

Cranial Neuropathies II, III, IV, and VI Symptomatic treatment of diplopia

In addition to diagnosing and treating the underlying etiology, double vision can be managed by patching, closing, or covering one eye. If the patient wears glasses, this can be easily accomplished by covering one lens with partially opaque tape. In children, this should be alternated between eyes to prevent development of amblyopia. In adults, one eye can be covered. Prism glasses can optically align the disparate images. However, these are typically not very helpful for CN III, IV, or VI palsies due to incomitance, with varying alignment in different directions of gaze. If recovery is incomplete, eye muscle surgery can be used to realign the eyes.

Common etiologies of isolated cranial nerves III, IV, or VI palsy

Some etiologies are common across all three ocular motor nerves and are discussed here.

Trauma

Though head trauma can cause isolated palsies of cranial nerves III, IV, or VI, CN IV palsies are the most common. CN III and VI nerve palsies are usually associated with substantial head trauma, while CN IV palsies can be associated with more moderate trauma insufficient to cause fractures or intracranial hemorrhage. Aberrant regeneration can subsequently develop after traumatic CN III palsy. Traumatic CN IV palsies generally have a good prognosis and recovery spontaneously.

Microvascular

Vasculopathic palsies are from reduced perfusion of the microvasculature that supply the nerve fascicles. They typically occur in patients over 50 years old with vascular risk factors including hypertension, diabetes mellitus, advanced age, smoking, and hyperlipidemia, causing sudden onset or rapidly progressive mononeuropathy associated with pain localized around the orbit. There is no confirmatory diagnostic test. Treatment is supportive as the majority of patients with vasculopathic CN III, IV, or VI palsies recover spontaneously in 3–4 months. If no resolution is seen in this period, further evaluation is recommended.

TIP • Microvascular palsies are a common cause of diplopia in people over 50 years with vascular risk factors. There is no confirmatory test, and resolution is usually spontaneous over 3–4 months.

Giant cell arteritis

In patients over 50 years with diplopia and systemic inflammatory symptoms, ESR and CRP are useful to evaluate for GCA as a contributing cause.

Tumors

Tumors of the cranial nerves include neurinomas and schwannomas. These typically appear on neuroimaging with thickening of the nerve and enhancement in the subarachnoid space or cavernous sinus. They are slow growing and benign and can be observed in most cases. Other neoplasms of the nerve include malignant meningioma or glioblastoma multiforme.

707 Skull base neoplasms such as meningiomas and chordomas can cause isolated cranial nerve palsies through compression.

Recurrent painful ophthalmoplegic neuropathy

Previously classified as a form of childhood migraine (ophthalmoplegic migraine), this syndrome is characterized by ipsilateral headache or retrobulbar pain associated with CN III, IV, or VI palsy, with CN III being the most common. This is a diagnosis of exclusion based on lack of other diagnosis and no permanent neurologic deficit between attacks. Neuroimaging may show cranial nerve enhancement. Steroids may hasten recovery.

Other

Herpes zoster, infections, sinus mucoceles.

Etiologies of combined cranial nerve III, IV, VI palsies

Certain combination findings together with CN III, IV, or VI palsies have localizing value. • Cavernous sinus: CN III, IV, or VI palsies associated with V1 and V2 numbness or ipsilateral Horner’s syndrome. Can be caused by parasellar lesions, nasopharyngeal lesions, vascular lesions, or thrombosis. • Sellar lesions such as pituitary tumors can involve both cavernous sinuses and the optic chiasm. • Pituitary apoplexy is an emergent cause of ocular motor palsies and vision loss. • Orbital apex: CN III, IV, or VI palsies associated with V1 numbness, Horner’s syndrome, or optic neuropathy. • Superior orbital fissure: lesions are anterior to the orbital apex. It presents with similar findings to the orbital apex syndrome, except that the optic nerve is not affected. • Other causes of combined CN III, IV, or VI palsies include infiltrative processes (e.g. carcinomatous or lymphomatous meningitis), inflammatory disorders (e.g. sarcoidosis, granulomatosis with polyangiitis, etc.), infections (e.g. tuberculosis), Wernicke’s encephalopathy, and Miller Fisher syndrome. • The differential diagnosis includes neuromuscular junction disorders (e.g. myasthenia gravis, botulism), muscular dystrophies (e.g. oculopharyngeal muscular dystrophy), and mitochondrial myopathies.

CRANIAL NERVE III (OCULOMOTOR NERVE) Anatomy

The CN III nucleus lies in the midbrain, anterior to the cerebral aqueduct. There is a specific subnucleus for each muscle innervated by the CN III (Figures 22.15, 22.16). Most of the subnuclei subserve the ipsilateral muscles; however, there are several anatomic tricks to the CN III nuclei: • One subnucleus that is shared between the right and left CN III nuclei subserves both levator palpebrae muscles. • Each superior rectus subnucleus crosses over to innervate the contralateral superior rectus. • The Edinger–Westphal nuclei, which ultimately innervate sphincter of the pupil, send projections to the sphincter bilaterally.

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Midbrain

Superior colliculus

Red nucleus

Oculomotor nuclear complex

Pons

Interpeduncular fossa

Posterior communicating artery

Posterior cerebral artery Superior cerebellar artery Region of the cavernous sinus Superior orbital fissure Superior division of CN III Levator palpebrae superioris muscle Superior rectus muscle Inferior division of CN III Inferior rectus muscle Medial rectus muscle Inferior oblique muscle

Levator palpebrae superioris muscle Superior rectus muscle Short ciliary nerves Nerve to pupillae constrictor muscle Nerve to ciliary muscle Nerve to medial rectus muscle

Superior division of CN III

Nerve to inferior oblique muscle

Inferior division of CN III

Nerve to inferior rectus muscle

Ciliary ganglion

Somatic motor nucleus Oculomotor nuclear complex: Edinger– Westphal nucleus Oculomotor nerve (CN III)

FIGURES 22.15, 22.16  Course of the cranial nerve III. Somatic motor efferents provide innervation of muscles of the eye; visceral motor parasympathetic efferents (blue) for constrictor pupillae and ciliary muscles.

The fascicles of the CN III nuclei pass through the red nuclei and the cerebral peduncles before entering the interpeduncular fossa. Once in the subarachnoid space, the fascicles pass between the superior cerebellar artery and posterior communicating artery. Each CN III enters the cavernous sinus just posterior to the clinoid processes and travels to the orbit in the wall of the cavernous sinus. At the orbital apex, the CN III enters via the superior orbital fissure. At this point, it splits into a superior division which innervates the levator and the

superior rectus. The inferior division innervates the inferior and medial recti, the inferior oblique, and the pupillary sphincter.

Clinical features

The CN III innervates the medial, inferior, and superior recti muscles as well as the inferior oblique, along with the levator muscle of the eyelid, and the pupillary sphincter. Therefore, a complete CN III palsy causes limitation in ipsilateral elevation,

Cranial Neuropathies II, III, IV, and VI

709 of onset. Additional work-up should be guided by other neurologic or systemic symptoms and signs.

Etiologies

The CN III can be affected by lesions anywhere along its length. Intra-axial lesions usually consist of infarction of the paramedian penetrating vessels from the posterior cerebral artery, metastatic tumors, MS, or compressing vascular malformations. Nuclear third nerve lesions are very rare. The causes below are in addition to the common etiologies discussed above.

Fascicular lesions of the cranial nerve III FIGURE 22.17  Cranial nerve III palsy in primary gaze. There is severe ptosis of the left eye, and the eye is in the ‘down and out’ position.

adduction, and depression. The eye classically appears ‘down and out’, with ipsilateral ptosis and mydriasis (Figure 22.17). Diplopia is oblique and resolves in ipsilateral gaze. Patients may not complain of diplopia if the ptosis blocks vision in one eye. The mydriasis can cause blurry vision at near if accommodation is also impaired. When evaluating patients with CN III palsies, the key examination points to pay attention to are whether the palsy is complete or partial, whether the pupil is involved or spared, and whether the superior or inferior division is involved in an isolated fashion. Aberrant regeneration is suggested when attempted third nerve action of one kind (e.g. adduction) prompts a different third nerve action (e.g. lid opening, pupillary constriction). Aberrant regeneration is not seen after vasculopathic CN III palsies and should alert the examiner to the possibility of a compressive lesion. Other causes of aberrant regeneration include trauma, ophthalmoplegic migraine, or inflammation.

Investigations

A third nerve palsy due to aneurysmal compression is a medical emergency and must be assessed for using high-quality neurovascular imaging, typically CT or MR angiography and sometimes catheter angiography. Any partial palsy, complete palsy with pupil involvement or evidence of aberrant regeneration, is concerning for this. Historically, the differentiation of microvascular from aneurysmal third nerve palsies was based on pupillary involvement as microvascular palsies usually spare the pupil due to ischemia at the terminus of penetrating vessels preferentially impacting the inside of the nerve. However, some studies have suggested that mild pupillary involvement may exist in patients with vasculopathic CN III palsies up to 40% of the time. Exceptions to the rule of the pupil along with ready availability of high-quality noninvasive neuroimaging have shifted practice toward excluding aneurysm in most cases of third nerve palsy due to the high morbidity and mortality of this etiology. In a patient with isolated third nerve palsy who is young, without vascular risk factors, or has medical history of cancer or immunosuppression, additional neuroimaging of the orbit, cavernous sinus, and skull base is warranted to exclude a lesional basis. This is also the case in older patients with presumed microvascular palsies in whom there is no recovery within 2–3 months

These may be isolated or may occur in conjunction with symptoms caused by damage to surrounding structures. The fascicular syndromes include: • Claude’s syndrome, which is ipsilateral CN III palsy with contralateral ataxia due to dentatorubrothalamic involvement. • Weber’s syndrome, which includes a lesion of the cerebral peduncle with contralateral hemiparesis and ipsilateral CN III palsy. • Benedikt’s syndrome, which is ipsilateral CN III palsy with the additional involvement of the red nucleus, giving the additional finding of contralateral tremor. • Nothnagel’s syndrome which involves the cerebellar peduncle and results in cerebellar ataxia. In addition, the CN III fascicles may be involved in dorsal midbrain syndrome with vertical gaze paresis, lid retraction, skew deviation, and convergence retraction nystagmus with or without a homonymous hemianopia if the posterior cerebral arteries are involved.

Compression

Compression in the subarachnoid space, cavernous sinus, or orbit is unnerving due to the high morbidity and mortality associated with some compressive causes. Acute compression is more likely cause early pupil involvement because the pupil fibers run on the outside of the nerve. An important clue to chronic compression is aberrant regeneration.

Uncal herniation

• Begins with ipsilateral pupil dilation and altered mental status before progressing to complete CN III palsy. • Caused by compression of the nerve under the tentorial edge, compression by the posterior cerebral artery, or compression of the nerve over the clivus.

Aneurysms

• Posterior communicating artery (PCom) aneurysms may compress the CN III. • In this case, the pupil is almost always involved because the position of the pupillary fibers is dorsomedial at this point in the course of the nerve, making them prone to compression from aneurysms. However, pupil involvement is not absolute. • Typically, the patients complain of pain with complete or incomplete CN III palsy with pupil dilation. However, pain is not a strong indicator for etiology determination. • CN III palsies related to aneurysm are important to identify early as greater than 90% of patients with subarachnoid hemorrhage as a result of PCom aneurysms have signs of a CN III palsy prior to rupture.49

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Pediatric cranial nerve III palsies

In children, CN III palsies can be congenital or acquired. • Acquired: • The most frequent cause of acquired CN III palsies is trauma. • PCom aneurysms are unusual in children. • Infections such as with Haemophilus influenzae or pneumococcal meningitis can result in CN III palsy. • Compressive CN III palsy can be caused by different etiologies along the course. For example, posterior fossa tumors include astrocytomas or gliomas, and orbital apex tumor such as rhabdomyosarcoma are reported. • Congenital: • Often associated with neurologic damage. • Aberrant regeneration of the CN III is often seen in congenital palsies. • Aplasia of the nucleus of the CN III with malformation of the midbrain may be seen on MRI. Tendon of superior oblique muscle Trochlea CN IV through superior orbital fissure Superior oblique muscle

CRANIAL NERVE IV (TROCHLEAR NERVE) Anatomy

The cranial nerve IV (CN IV) nucleus is located in the pontomidbrain junction, caudal to the CN III nucleus (Figure 22.18). The axons from the nuclei decussate near the roof of the aqueduct and exit the brainstem on the dorsal side below the inferior colliculi. The CN IV has the longest course of all the cranial nerves through the subarachnoid space. In addition, it is the smallest of the cranial nerves, containing only 1500 axons. As a result, it is very prone to shearing injuries and trauma.

Clinical features

The cranial nerve IV innervates the contralateral superior oblique muscle of each eye. The superior oblique is a depressor, abductor, and intorter of the eye. Palsies of the CN IV result in a vertical diplopia with the higher eye and lower image on the side with the affected superior oblique (Figure 22.19). The image in the affected eye is often tilted. The hypertropia and diplopia worsen when the patient attempts to adduct, (i.e. look away from the affected side). This is because when the eye is adducted, the superior oblique has its greatest vertical action. In addition, the other depressor of the eye, the inferior rectus, is not active in adduction. The diplopia will also be

MIDBRAIN

• Basilar artery aneurysms can also cause CN III or IV palsies. Other signs of brainstem compression can be seen, such as hemiparesis, homonymous hemianopias, or obstructive hydrocephalus.

Trochlear nucleus Inferior colliculus CN IV Superior medullary velum Superior cerebellar peduncle

Tendinous ring Central retinal artery

Trochlear nucleus Trochlear nerve CN IV Midbrain – level of inferior colliculus

Superior oblique muscle Superior rectus muscle Trochlea

FIGURE 22.18  Course of the cranial nerve IV.

Posterior cerebral artery Superior cerebellar artery Superior orbital fissure Levator palpebrae superioris muscle

Cranial Neuropathies II, III, IV, and VI A

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Right gaze

C

Primary position

Left gaze

FIGURE 22.19  Left cranial nerve IV palsy. In primary position, patient is fixing with the right eye. The left eye is elevated and hypertropic, corneal light reflex (*) falls in the center of pupil in the right eye but inferior to the pupil in the left (B). In right gaze, left eye adducted, left hypertropia is more pronounced, since the superior oblique has its greatest action in adduction of the eye (A). In left gaze, left hypertropia is less pronounced (C). worse when the head is tilted to the ipsilateral side. This is called Bielschowsky’s head tilt test. The reason the diplopia becomes worse in this gaze is because when the head is tilted, the intorters of the ipsilateral eye must come to action in order to maintain an object on the macula. Patients with symptomatic CN IV palsies may have very subtle vertical deviation that is difficult to discern on examination. Thus, a patient with binocular vertical diplopia with one image tilted likely has a fourth nerve palsy even if the eyes appear aligned to the examiner. Tools such as the Maddox rod are useful to measure the deviation in these cases.

TIP • Neuroimaging should always be requested in acute multiple cranial nerve palsies. In order to determine whether CN IV is still intact in the setting of CN III palsy (unable to adduct affected eye), examiner should ask patient to attempt downgaze and observe if there is any intorsion movement in affected eye. Intact CN IV can be deduced from the presence of intorsion.

Etiologies

The causes below are in addition to the common etiologies discussed above.

Pediatric cranial nerve IV palsy

Pediatric palsy of the CN IV is usually congenital. This may be unnoticed in childhood and present in adulthood when patients with congenital CN IV palsies may have ‘decompensation’ of the palsy. This can also occur during illness or are under the influence of alcohol or drugs. Decompensation of the palsy leading to diplopia is not a result of progressive weakness of the nerve, rather the reduced ability of the brain to fuse the vertically dissociated images on the retina. These patients can be identified by several factors including: • Long-standing head tilt to the contralateral side seen in photographs or by history. • No inciting event. • Increased vertical fusional amplitudes identified as a larger misalignment when one eye is covered than when both eyes are open.

CRANIAL NERVE VI (ABDUCENS NERVE) Anatomy

The nucleus of the CN VI is located in the dorsal pons (Figures 22.20, 22.21). The genu of the CN VII fascicle wraps around it, corresponding with facial colliculus on external surface of the pons. The CN

VI fascicles travel through the body of the pons ventrally, passing through the cortical spinal tracts. In the posterior fossa, the CN VI ascends from the pontomedullary junction along clivus and passed under Gruber’s ligament into Dorello’s canal and the cavernous sinus. While in the cavernous sinus, the postganglionic sympathetic fibers to the pupil join the CN VI for a short distance. Ultimately, it innervates the ipsilateral lateral rectus muscle in each eye. In addition, the nucleus of the CN VI contains the interneurons that ascend through the medial longitudinal fasciculus to innervate the contralateral medial rectus muscles in order to perform coordinated horizontal gaze. Thus, a lesion of the PPRF or CN VI nucleus causes a gaze palsy. If there is concomitant damage to the contralateral MLF, one-and-a-half syndrome occurs, which is a gaze palsy to one side with an ipsilateral INO on gaze to the other side. This is also known as paralytic pontine exotropia.

Clinical features

The CN VI is responsible for abduction of each eye. Patients experience horizontal diplopia, worse at distance, and in ipsilateral gaze. Diplopia typically resolves in contralateral gaze. Nuclear lesions of the CN VI result in a gaze palsy to the affected side (Figure 22.22). In dorsal pontine lesions, there may be associated facial weakness if the fibers from the CN VII are affected as they wrap around the CN VI nucleus. The CN VI travels freely in the body of the cavernous sinus and is often the first nerve impacted in cavernous sinus disease.

Etiology

The causes below are in addition to the common etiologies discussed above.

Fascicular lesions

Fascicular lesions of the sixth nerve often affect surrounding structures resulting in several syndromes: • Gasperini’s syndrome involves the paramedian pontine reticular formation, CNs VI and VII, the spinothalamic tract, and vestibular neurons. • Raymond’s syndrome involves the cerebellar peduncles and the corticospinal tract with the CN VI, resulting in contralateral hemiparesis. • Millard–Gubler syndrome is similar to Raymond’s syndrome in that the corticospinal tract and the CN VI are involved, but it also involves a CN VII palsy. • Foville’s syndrome includes the CNs VI and VII, the corticospinal tract, and the ciliospinal tract, resulting in the addition of Horner’s syndrome.

False localizing sign of high intracranial pressure

High ICP can cause CN VI palsies in isolation. The CN VI is fixed along the clivus and over the petrous apex; any increased pressure

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Internal carotid artery

Abducens nucleus Superior orbital fissure Lateral rectus muscle

CN VI exiting at the pontomedullary junction Pons Petrous temporal bone (cut)

Facial colliculus Abducens nucleus Pons Middle cranial fossa Internal carotid artery Region of cavernous sinus Superior orbital fissure CN VI Lateral rectus muscle

FIGURES 22.20, 22.21  Course of the cranial nerve VI. Figure 22.20 is the upper one and Figure 22.21 is the lower one.

in the cranial vault, whether idiopathic intracranial hypertension, supratentorial masses, or hydrocephalus, can lead to stretch on the nerve resulting in unilateral or bilateral CN VI palsies that are nonlocalizing. Low ICP can also result in downward pressure on the

brain leading to nonlocalizing CN VI palsies in the subarachnoid space. Therefore, when seeing a patient with a CN VI palsy, it is important to ask about other symptoms of increased or decreased ICP, as well as carefully examining the fundus for papilledema.

FIGURE 22.22  Left cranial nerve VI palsy. In primary gaze, the eyes are very slightly esotropic, corneal light reflex (*) falls in the center of pupil in the fixating right eye but temporal to the pupil in the left eye (B). In gaze to the left eye does not fully abduct (C). There is normal adduction of the left eye in right gaze and full abduction of the right eye in right gaze (A). Notice how the sclera is buried in abduction of the right eye, whereas the temporal sclera is still visible in abduction of the left eye.

Cranial Neuropathies II, III, IV, and VI Apex of the petrous temporal bone (Gradenigo’s) syndrome

This is characterized by pain in distribution of V1/V2 dermatomes, and CN VI palsy. This syndrome is a result of involvement of the apex of petrous bone, usually seen as a complication of middle ear infection or mastoiditis.

Pediatric cranial nerve VI palsies Duane’s syndrome

The absence or hypoplasia of the CN VI nucleus leads to aberrant innervation of the lateral rectus. Patients can have reduced abduction, adduction, or both, as different subtypes have been described. Unique clinical characteristic is cocontration of ipsilateral medial and lateral rectus resulting in narrow palpebral fissure with globe retraction in attempted adduction. Duane’s syndrome can be distinguished from an acquired CN VI or lateral rectus palsy in that the patients are not esotropic in primary gaze. They typically do not experience diplopia.

Mobius’ syndrome

Considered to be much rarer than Duane’s syndrome, this is characterized by bilateral facial diplegia and bilateral abducens weakness with an esotropia. A significant proportion of the time, children with Mobius’ syndrome have total external ophthalmoplegia.

Acquired in childhood

Acquired CN VI palsies in children are most frequently associated with posterior fossa tumors. These lesions affect the midline structures in the pons and may also present with gaze palsies. If the fourth ventricle is obstructed, there may be associated papilledema due to high ICP. If the cerebellar pathways are associated, ataxia and/or nystagmus may be seen. All children with acquired CN VI palsies must be evaluated with imaging of the posterior fossa and LP to rule out potentially fatal causes of CN VI palsy.

Acute acquired comitant esotropia

Acute acquired comitant esotropia (AACE) is characterized by sudden-onset diplopia and comitant esotropia in a child previously regarded to have straight eyes. This is sometimes mistaken for bilateral CN VI palsies. Although not technically a CN VI palsy, it merits discussion because of its associations. It is a benign condition most of the time. However, there have been several reports of medulloblastomas, pontine gliomas, or astrocytomas causing acquired comitant esotropia in children. There are usually signs of increased ICP or cerebellar or brainstem involvement in these children, and they must be looked for in all children presenting with new-onset acquired esotropias.

PUPILLARY PATHWAYS AND COMMON DISORDERS Efferent pupillary function is governed by two autonomic systems. The sympathetic system produces pupillary dilation through oculosympathetic pathway, which controls iris dilator muscles. The parasympathetic system causes iris constriction via iris constrictor muscles. In normal function, the size of the pupils is equal, governed by the relative tone of the two systems. In addition, the pupil sizes adjust to light and near focus. Efferent pupillary dysfunction presents as anisocoria. Which side is abnormal depends on whether the anisocoria is more pronounced in light

713 (big pupil is abnormal) or in dark (small pupil is abnormal). Isolated pupillary dysfunction is usually asymptomatic. However, it is important to identify because it can be a sign of underlying life-threatening condition. Mild anisocoria ( bowel incontinence.

Classification of spinal cord lesions

• Extramedullary (includes extradural and intradural): • Degenerative spine disease. • Epidural collection (hematoma, abscess). • Neoplastic (metastatic vs. primary). • Intramedullary: • Inflammatory. • Infectious. • Metabolic/toxic. • Vascular. • Genetic/hereditary. • Structural. • Neoplastic. • Heredodegenerative.

Clinical myelopathy syndromes

Clinical myopathy syndromes may be due to intrinsic or extrinsic processes.

Complete cord transection or transverse myelopathy

• Weakness below the level of the lesion: • UMN signs below the lesion and, possibly, LMN signs at the level of the lesion (anterior horn cells affected). • Complete anesthesia to all sensory modalities below the level of the lesion.

Brown–Sequard syndrome (hemicord)

• Ipsilateral weakness below the level of the lesion. • “Split” sensory loss below the level of the lesion: • Contralateral pain, temperature, light touch loss. • Ipsilateral discriminating touch, vibration, proprioception loss. • Autonomic function may be spared, depending on the etiology of the lesion. • Prototypical disorder: trauma or inflammatory myelopathy.

Myeloradiculopathy syndrome

• Weakness: • LMN pattern in one or more myotomes (distribution of motor nerve). • UMN pattern below the level of the lesion. • Pain and sensory changes in one or more dermatomes. • Prototypical disorder: extradural spinal tumor.

Central cord syndrome (cervical cord)

• Weakness: • Distal > proximal upper extremities. • Lower extremities less severely affected or normal. • “Dissociated” sensory loss below the level of the lesion: • Pain, temperature, light touch loss. • Discriminating touch, vibration, proprioception preserved. • Autonomic function may be affected (urinary dysfunction). • Prototypical disorder: syringomyelia.

Posterolateral column degeneration

• Weakness due to corticospinal tract dysfunction below the level of the lesion: • Although weakness may be in a UMN pattern with spasticity and hyper-reflexia, some manifestations of this syndrome are associated with peripheral neuropathy, leading to depressed deep tendon reflexes. • Sensory loss below the level of the lesion: • Posterior columns: discriminating touch, vibration, proprioception loss. • Spinothalamic tracts (pain, temperature, light touch): spared. • Prototypical disorder: B12 deficiency (“subacute combined degeneration” [SCD]).

Posterior column syndrome

• Loss of discriminating touch, vibration, proprioception only. • Prototypical disorder: syphilis (“tabes dorsalis”).

Anterior horn cell syndrome

• Weakness only in an LMN pattern: • May be diffuse or segmental (e.g. “monomelic” or one limb). • May involve cranial nerve nuclei (motor only). • Prototypical disorder: spinal muscular atrophy (SMA).

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Combined anterior horn cell and corticospinal tract syndrome

Clues to an extrinsic lesion may include:

Anterior spinal artery syndrome

Clinical findings depend on the cord level and tracts affected (see syndromes described above):

• Weakness only with both UMN and LMN features: may involve cranial nerve nuclei (motor only). • Prototypical disorder: amyotrophic lateral sclerosis (ALS). • Weakness below the level of the lesion: flaccid/areflexic acutely, progressing to spastic weakness. • Sensory loss below the level of the lesion: • Loss of pain, temperature, light touch. • Preserved discriminating touch, vibration, proprioception. • Prototypical disorder: anterior spinal artery occlusion.

EXTRAMEDULLARY SPINAL CORD LESIONS (EXTRINSIC MYELOPATHY) Definition

Any spinal cord syndrome caused by compression of the cord rather than pathology within the cord itself.

Etiology and pathophysiology Extradural

• Degenerative spine disease: • Herniated disc. • Vertebral bone spurs. • Acquired central spinal stenosis. • Nondegenerative process: • Congenital central spinal stenosis. • Hypertrophic ligamentum flavum. • Posterior longitudinal ligament ossification. • Epidural lipomatosis. • Trauma: vertebral fracture. • Vertebral body infiltration: • Osteomyelitis (bacteria, tuberculosis [TB; Pott’s disease of the vertebral body]). • Malignancy (plasmacytoma, primary bone tumor, metastatic lesions – most common to metastasize to vertebral body: prostate, breast).

Intradural • • • •

Epidural abscess. Epidural hematoma. Spinal arachnoiditis. Spinal arteriovenous malformation (AVM).

Clinical features

Clinical features of an extrinsic cord lesion depend on both the level of the spinal cord involved and the etiology of the compression.

TIP • Due to the somatotopic organization of the spinal cord tracts, compression can lead to lumbosacral motor fiber dysfunction prior to the onset of arm weakness. Dorsal column organization, however, is opposite, and cervical fibers are most superficial, leading to loss of discriminating touch, vibration, or proprioception prior to similar findings in the lower body. Pain and temperature loss are expected to be contralateral to the site of compression and affecting sacral fibers earlier.

• Early loss of sacral sensation. • Early involvement of bowel and bladder function. • Pain in a radicular pattern (due to nerve root involvement).

• Brown–Sequard (hemicord). • Complete transection. • Anterior spinal artery or posterior column – if ventral or dorsal compression, respectively.

Differential diagnosis Cervical spondylotic myeloradiculopathy Definition and epidemiology

The most common type of extrinsic myelopathy in which the spinal cord (myelopathy) and/or nerve roots (radiculopathy) are damaged, either directly by traumatic compression and abnormal movement, or indirectly by ischemia due to arterial compression, venous stasis, or other consequences of the proliferative changes that characterize spondylosis, such as ligamentum flavum hypertrophy with associated canal narrowing. Most people older than 50 years have some degree of cervical spondylosis. Most have no symptoms apart from reduced mobility of the cervical spine. • Age: middle-aged and elderly; peak incidence in the age group 50–54 years. • Gender: M > F (3:2 ratio).

Etiology and pathophysiology Predisposing factors include:

• Narrowing of the spinal canal in the sagittal (anteroposterior [AP]) plane: 50% of cases of suspected spinal cord infarct. • CSF: • Cells: normal or moderate leukocytosis ( distal). Preserved sensation. Reduced or absent deep tendon reflexes. Normal cognitive function. Distal tremors of extremities (adult patients).

SMA I (Werdnig–Hoffman disease)

• Severe generalized muscle weakness and hypotonia at birth or within the first 6 months of life (“floppy infant” syndrome). • Death from respiratory failure usually occurs within the first 2 years. • Paradoxical respirations due to initial sparing of diaphragm strength with weak intercostal muscles (bell-shaped chest). • Lower cranial nuclei involvement leads to poor suck and swallow, resulting in dependence on tube feeding and tongue weakness with fasciculations.

SMA II (intermediate or childhood onset) • • • •

Children can sit, but cannot stand or walk unaided. Survive beyond 2 years. Bulbar weakness may compromise nutritional status. Scoliosis and joint contractures are common with advancing age.

SMA III (juvenile onset: Kugelberg– Welander disease)

• Onset is in childhood or adolescence (18 months–18 years) with difficult walking due to hip-girdle weakness. • Bulbar musculature is spared. • Scoliosis and joint contractures often develop during the course of the disease. • Variable course of progression with loss of walking in childhood or preservation of ambulation into early adulthood. • Compatible with a normal life span.

Type IV (adult onset)

• Uncommon ( 1 μm in diameter in the PNS. • Largest and fastest conducting fibers. • Motor and sensory nerves have myelinated fibers. The sensory modalities include proprioception, position sense, and touch sensation. Unmyelinated fibers: • 8–15 small axons (0.1–1.3 μm) contained within the infolding of a single Schwann cell. The axons are separated by a constant periaxonal space. • Responsible for pain and temperature sensation and autonomic functions.

765 feet) are affected first. As the symptoms progress and move up the leg, numbness and paresthesias are noticed in the distal fingers. Upper extremity symptoms usually begin when the lower extremity symptoms reach the knees. In most cases, the sensory and motor nerves are both involved (sensorimotor). However, there are certain polyneuropathies that selectively affect only the sensory nerves or the motor nerves. • Axonal – damage to the axons. Most common type of polyneuropathy. • Demyelinating – disturbance of the structure and function of the myelin sheath or Schwann cell with sparing of the axons. Epidemiology of polyneuropathy is as follows:1 • Overall prevalence is approximately 1–3%. • In the elderly, the prevalence rises to approximately 7%. • After a polyneuropathy is diagnosed, many patients undergo evaluation for a secondary cause (see Investigation section below). However, in one-quarter of cases, a cause is not discovered and the polyneuropathy is considered idiopathic.2

Small arteries located in the epineurium are termed the vasa nervorum. They branch into arterioles that penetrate the perineurium to form capillary anastomoses in the endoneurium.

Mononeuropathy is dysfunction of an individual peripheral nerve (see below). Mononeuropathy multiplex is dysfunction of multiple individual peripheral nerves. If many nerves are involved, the neuropathies may coalesce into a pattern that resembles a polyneuropathy. In order to distinguish between these two entities, a thorough history of present illness is essential.

Classification of disease

Etiology and pathophysiology

Polyneuropathy is diffuse dysfunction of multiple nerves, usually creating a ‘stocking-glove’ pattern of numbness, paresthesias, and weakness (Figure 25.2). The most distal nerves (e.g. in the

Types of nerve damage (Figure 25.3) include: • Neurapraxia: • Failure of nerve conduction due to metabolic or microstructural dysfunction. • Usually reversible. • No permanent damage to the axon, though axonal swelling and constriction often occur. • May result from compression and ischemia. • Most severe form results in segmental demyelination. – Disturbance of the Schwann cells/myelin associated with significant reduction of nerve conduction velocity and/or conduction block. – Axonal degeneration cannot create the same degree of conduction velocity slowing.

TIP • In demyelination, conduction block causes motor weakness. Slowing does not do this.

Mononeuropathy multiplex

Polyneuropathy (‘stocking–glove’ pattern)

FIGURE 25.2  Mononeuropathy multiplex versus polyneuropathy, illustrating differing patterns of sensory change and weakness (red/blue areas).

• Axonotmesis: • Disruption of the axon and myelin sheath. • Supporting connective tissue (endoneurium and epineurium) is preserved. • Axonal degeneration distal to the injury site.

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b

c

d Degenerating cell body

Axon

Degenerating axon

Myelin sheath Wallerian degeneration

Motor end plate

Neurogenic muscular atrophy

Muscle

Neurogenic muscular atrophy

FIGURE 25.3  Schematic representation of different types of nerve damage: (a) normal nerve; (b) segmental demyelination; (c) axonal degeneration; (d) neuronal degeneration/cell death.

• Nerve sprouts regenerate from the proximal stump in attempts to reinnervate muscle or skin. • Rate of regrowth is quite slow at 1 mm/day. • Functional improvement can take months to a few years, depending on the length of the injured nerve. • Neurotmesis: • Partial or complete severance of a nerve. • Disruption of the axons, myelin sheaths, and supporting connective tissue. • Degeneration of the axons distal to the injury site. Because the supporting connective tissue is no longer intact, regeneration is difficult and portends a poor prognosis for recovery. • Wallerian degeneration: structural alterations in the normal nerve distal to injury or transection of the nerve.

TIP • NCS only assess large nerve fibers. Therefore, a patient with a small fiber neuropathy will have normal NCS.

In, waveforms resulting from stimulation of motor nerves are referred to as compound muscle action potentials (CMAPs) (Figure 25.4). A recording electrode is placed over a muscle supplied by the nerve of interest. A stimulus is given at different points along the nerve, in a distal to proximal fashion.

Amplitude

• Maximum voltage difference between the baseline of the action potential and the peak. • The amplitude is a reflection of the number of functioning axons.

Investigations Nerve conduction studies

Nerve conduction studies (NCS) involve the recording and analysis of electric waveforms of the peripheral nerves elicited in response to electric or physiologic stimuli. Sensory, motor, and autonomic nerves can be evaluated. The waveforms which result from stimulation of sensory nerves are referred to as sensory nerve action potentials (SNAPs). Recording electrodes are placed on the skin over a sensory or mixed nerve. A stimulus is given at different points along the nerve, in a distal to proximal fashion. Total current flow across the nerve membrane is dependent on the membrane’s surface area. Thus, the small myelinated and unmyelinated fibers contribute little to the SNAP. Although sensory abnormalities may be an initial sign of polyneuropathy, such abnormalities may not be reflected in sensory NCS unless changes occur in the very largest sensory axons. Therefore, a neuropathy involving only the small fibers will have normal NCS.

Amplitude (mV)

Distal latency (ms)

FIGURE 25.4  Compound muscle action potential.

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• For the CMAP, the amplitude is an estimate of the number of viable axons and the muscle fibers they innervate. Significant muscular atrophy from a primary muscle or neuromuscular junction disease can cause the CMAP amplitude to be reduced or absent, despite an intact supplying nerve. • Reduced amplitudes are indicative of axonal loss, most commonly from polyneuropathies.

Distal latency

• Interval between the onset of a stimulus and the onset of the resulting response. • For the CMAP, the measurement is taken from the onset of the stimulus to the onset or takeoff of the response. • For the SNAP, the measurement is taken from the onset of the stimulus to the peak. • Delayed distal latency is associated with demyelinating neuropathies and can also occur to a lesser degree with marked axonal loss.

500 µV 10 ms

Nerve conduction velocity

• Speed of propagation of an action potential along a particular segment of a nerve. • Two points of stimulation are obtained (e.g. for the ulnar nerve, stimulation at the wrist and just below the elbow). • The distance between the two points is divided by the difference between the corresponding distal latencies. The calculated velocity signifies the conduction velocity of the fastest fibers. • Measured in meters/second (m/s). • Important measure for demyelination: • Uniformly reduced conduction velocities are a hallmark of hereditary demyelinating neuropathies. • Can identify nerve damage at compression sites (e.g. slowing of the median nerve response at the carpal tunnel or the ulnar nerve across the elbow).

F-waves

• A supramaximal stimulus is delivered resulting in the primary response, the CMAP. • The CMAP is derived from orthodromic conduction of the action potential. Additionally, the initial nerve depolarization also produces an antidromic response, which travels toward the spinal cord. When the response reaches the corresponding anterior horn cells, a second (backfiring) action potential is propagated in an orthodromic direction along the entire length of 1–5% of the same motor axons. This second response is then recorded from the original muscle as the F-wave (Figure 25.5). • With multiple stimulations, the CMAP morphology remains stable due to activation of all responsive muscle fibers. The F-waves, on the other hand, have different latencies and morphologies due to activation of different motor units with subsequent stimulations. • Prolongation or absence of response may indicate very proximal demyelination (i.e. at the level of the nerve root in polyradiculopathies or at proximal sites of nerve entrapment).

Technical factors

• Decreased temperature of the skin may result in falsely increased amplitude of CMAP and SNAP, reduced conduction velocities, and prolonged F-waves. Hand

FIGURE 25.5  Diagram to demonstrate analysis of a nerve conduction study, showing tibial nerve F-waves. temperature should be > 33°C (91.4°F) and foot temperature > 31°C (88°F). • Patient movement during the testing. • External electrical interference from the room.

Electromyography

Electromyography (EMG) is performed by inserting a needle electrode into a muscle, recording insertion activity, spontaneous activity, and voluntary electric activity of the muscle. Recordings are visualized on a computer screen and heard through a speaker system. EMG determines the type of abnormality within a specific muscle (i.e. neurogenic vs. myopathic processes). EMG results are used in conjunction with the NCS results.

Insertion activity

• Transitory burst of electrical activity recorded within the muscle as a result of insertion or movement of the needle electrode. • Related to disruption of muscle fibers. • Increased insertion activity (prolonged) can occur in neurogenic disorders and muscle disorders with membrane instability. • Insertion activity may be decreased (less activity upon insertion) in long-standing nerve or muscle disorders, where the muscle is fibrotic or replaced by fat.

Spontaneous activity

Electric activity recorded from muscle at rest after insertion activity has subsided. Normal muscle should be electrically silent, with the exception of needle movement. Positive sharp waves and fibrillations (denervation potentials) are the most common forms of (abnormal) spontaneous activity. Their presence suggests disruption of the continuity between the muscle fiber and its axon in the acute or chronic phase of the disorder. These occur most commonly in neurogenic disorders involving axon loss (anywhere from the anterior horn cell to the terminal nerve). Positive sharp waves and fibrillations may also

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500 µV 10 ms

FIGURE 25.6  Electromyography. Spontaneous activity: positive sharp waves with a few fibrillations in the first dorsal interosseous. be observed in certain primary muscle disorders, presumed to be due to muscle membrane instability (Figure 25.6). Fasciculations are random and spontaneous twitching of a group of muscle fibers or a motor unit that is often grossly visible in a limb or the tongue. A fasciculation potential is a recording often associated with clinical fasciculations. This has the configuration of a motor unit action potential (MUP) but occurs spontaneously. Fasciculation potentials can occur in any nerve disorder, but are most notoriously associated with motor neuron disease. Complex repetitive discharges are activity that originates from a reverberating circuit that has developed within contiguous myofibers. Its sound is machinery-like with an abrupt onset and cessation. Complex repetitive discharges can occur in chronic nerve and muscle disorders. Myokymic discharges originate from the peripheral nerve and result from ephaptic transmission between damaged contiguous axons. These discharges are often seen clinically and described as a bag of worms. These can occur in a variety of nerve disorders including Isaac’s syndrome (acquired neuromyotonia) and Morvan’s syndrome (limbic encephalitis with peripheral nerve hyperexcitability) due to anti–voltage-gated potassium channel complex antibodies and episodic ataxia type 1 due to mutations in the neuronal potassium channel Kv1.1 but are most commonly associated with radiation-induced nerve injury and other demyelinating disorders. 3 Facial myokymia may be seen in multiple sclerosis, pontine glioma, and spinal and bulbar muscular atrophy. Eyelid myokymia is a common and generally benign occurrence.

Motor unit action potential recruitment

The electromyographer asks the patient to activate gradually the muscle being tested. This allows for evaluation of the number of MUPs the patient is capable of activating (recruitment). In normal recruitment, as isometric tension in the muscle intensifies, an increasing number of MUPs are seen and heard on the EMG machine display. With minimal effort, the first MUP is recruited and fires at a rate of approximately 5–7 Hz. As the effort in contraction increases, the first MUP begins to fire faster. When the firing rate reaches 10 Hz, the second MUP should appear. With normal recruitment, multiple MUPs are appreciated. Each has its own distinctive sound and configuration due to its relationship with the recording needle (i.e. MUPs that are closer to the recording needle have a crisper sound and sharper rise time in initial deflection) (Figure 25.7). In neurogenic recruitment, with axon loss there is a reduced number of motor units available to recruit. The remaining motor units need to fire at a greater frequency in order to compensate for this loss. During the study, a single MUP may be observed to fire at a rate greater than 15 Hz with no other MUP recruited. Normal MUPs have a triphasic configuration (Figure 25.7). In neurogenic MUPs: • Polyphasia occurs: extra turns and phases are incorporated into an individual MUP. Noticeable within weeks to months of injury and occurs in myopathies, axon loss, and demyelinating nerve disease. Polyphasia occurs when the single-fiber MUPs become desynchronized.

500 µV 10 ms

FIGURE 25.7  Electromyography. Multiple motor unit action potentials during moderate recruitment.

Diseases of the Peripheral Nerve and Mononeuropathies • Large-amplitude (> 2 mV), long-duration (> 15 ms) MUPs: occur when a muscle fiber deprived of its own axon supply is reinnervated by a collateral nerve twig belonging to a neighboring viable motor axon. Thus, a single motor axon may be supplying many more muscle fibers than it had prior to the nerve insult. This MUP morphology occurs within months of the onset of neuropathies, motor neuron disease, or radiculopathies.

Laboratory tests

Recommended screening blood tests for the evaluation of polyneuropathy include HgBA1C, vitamin B12 with metabolites (methylmalonic acid with or without homocysteine), thyroid function tests, rapid plasma reagin (RPR), HIV serology, and serum protein immunofixation electrophoresis. If HgBA1C is normal, testing for impaired glucose tolerance (i.e. glucose tolerance test) should be considered. Cerebrospinal fluid (CSF) analysis should be considered (lumbar puncture) for the assessment of demyelinating polyneuropathies or polyradiculopathies (see section on chronic inflammatory demyelinating polyneuropathy [CIDP]). Any polyneuropathy may produce a mild elevation in total protein levels.

Nerve biopsy

Nerve biopsy can be used as a diagnostic measure to further delineate the specific form of neuropathy. The biopsy site is chosen based on the following criteria:4 • Is affected by the neuropathy, based on clinical and electrophysiological evidence. • Constant in its location and readily accessible. • Pure sensory nerve: fewer postoperative complications compared with a pure motor or mixed nerve. • A nerve that is long enough so that 6 cm of the same fascicle can be removed. • Located away from a common site of compression. According to the above criteria, the sural nerve is considered to be the most suitable nerve for biopsy. However, in certain clinical circumstances (e.g. vasculitic neuropathy, amyloid or sarcoid), the combination of biopsies from a sensory nerve and muscle may have higher diagnostic value (pairings include the sensory branch of the superficial peroneal nerve and the peroneus brevis muscle, the sural at the calf and gastrocnemius, the radial nerve and brachioradialis)(see section on vasculitic neuropathy). If motor nerve is required, the nerve to the gracilis can be biopsied. Superficial radial nerve (a pure sensory branch of the radial nerve) with or without brachioradialis may be considered for biopsy if the clinical symptoms mostly involve the upper extremities and the NCS show involvement of that nerve.5 Nerve biopsies should only be performed in carefully selected patients after a thorough clinical work-up, due to high complication rates. The indications for nerve biopsy are mostly commonly for evaluation for suspected vasculitic neuropathies, leukemic or lymphomatous infiltration, or amyloid. Hereditary neuropathies may rarely be considered, however, molecular genetic testing is available in most cases.

Muscle biopsy

Muscle biopsy is not indicated for most nerve disorders. However, in the event that muscle tissue is obtained, certain muscle

769 patterns occur in the setting of nerve damage. Axonal degeneration of motor nerves results in muscle pathology referred to as neurogenic atrophy. Denervated muscle fibers become atrophic and angulated in appearance. Nerve sprouts reinnervate the surrounding denervated muscle fibers. The muscle fibers then take on the fiber type of the new nerve (i.e. type 1 vs. type 2 muscle fibers). This results in fiber type grouping and loss of the muscle’s mosaic pattern.

DIABETIC NEUROPATHY Definition and epidemiology

Neuropathic complications from diabetes mellitus or impaired glucose tolerance. Diabetes mellitus is the most common cause of polyneuropathy in the developed world. At least half of all patients with diabetes will develop neuropathy.6 However, only 20% are symptomatic. In one study of patients with painful idiopathic sensory neuropathy, 65% had evidence of abnormal glucose metabolism (diabetes or impaired glucose tolerance).7

TIP • The old clinical saw that ‘diabetes can be the cause of any clinical pattern of peripheral neuropathic dysfunction’ is only a slight overstatement.

Etiology and pathophysiology

The pathogenesis of neuropathy in the setting of hyperglycemia is unknown. Theories include a metabolic process, microangiopathic ischemia, or an immunologic disorder.

Clinical features

Neuropathy may be the presenting feature of diabetes.

Distal symmetric sensory and sensorimotor polyneuropathy

This is the most common form of diabetic neuropathy (Figure 25.8). It begins with sensory loss in the toes (length dependent) and gradually progresses up the feet, ankles, and legs in a symmetric

FIGURE 25.8  Toluidine blue stain of a nerve. Two fascicles are pictured. There is loss of myelinated nerve fibers (dark blue circles). (Courtesy of Tibor Valyi-Nagy, MD, PhD).

Hankey’s Clinical Neurology

770 fashion. The progression occurs over years. When the symptoms roughly reach the knees, the fingertips become involved with numbness and paresthesias. Pain can be a bothersome feature, particularly at night. Patients may comment that they cannot tolerate the bedsheets touching their feet. Pain exacerbation at night may be due to lack of daytime activity distractions. The polyneuropathy associated with impaired glucose tolerance often affects the small fibers resulting in painful paresthesias. Sensory ataxia occurs in advanced polyneuropathy. Intrinsic foot and hand muscle atrophy may occur, but should prompt investigation for other processes (i.e. median, ulnar, or peroneal compressive mononeuropathies, concurrent inflammatory or hereditary neuropathy). Lower extremity involvement may present as foot dorsiflexion weakness creating a foot drop and steppage gait. Other etiologies such as a superimposed peroneal neuropathy or L5 radiculopathy should be considered. In NCS, sensory responses are often affected with reduced or absent amplitudes. Motor responses are less frequently affected and may have slowing within a demyelinating range.

Autonomic neuropathy

Autonomic neuropathy is often associated with distal symmetric sensorimotor polyneuropathy. Features include abnormal sweating, dry eyes and mouth, pupillary abnormalities, cardiac arrhythmias, orthostatic hypotension, gastroparesis, postprandial bloating, erectile dysfunction, urinary incontinence, chronic diarrhea, or constipation. Treatment includes fludrocortisone or midodrine for orthostatic hypotension, metoclopramide for gastroparesis, and PDE5 inhibitors (sildenafil, vardenafil) for erectile dysfunction.

Mononeuropathy

Patients with diabetic polyneuropathy are at risk of developing mononeuropathies. The most common mononeuropathies and their corresponding sites of compression are as follows: • Median neuropathy at the wrist. • Ulnar neuropathy at the elbow. • Peroneal neuropathy at the fibular head. • Lateral femoral cutaneous neuropathy (meralgia paresthetica) at the inguinal ligament. • Cranial nerves: • Most common is facial neuropathy, then oculomotor and abducens neuropathy. • Less frequently, trochlear neuropathy. • Multiple mononeuropathies may give the appearance of mononeuropathy multiplex (most commonly associated with vasculitic neuropathy).

Diabetic lumbosacral radiculoplexus neuropathy

Other monikers include diabetic amyotrophy, Bruns–Garland syndrome, or proximal diabetic neuropathy. It predominantly affects individuals with type 2 diabetes. The pathogenesis is believed to be a T-cell–mediated microvasculitis involving small epineurial and perineurial vessels.8 It usually begins with sudden onset of severe aching of the hip and thigh area that may last for days or weeks. This is followed by weakness of the proximal lower extremity that may spread distally to involve the entire lumbosacral plexus. About 50% of patients have spread of symptoms to the contralateral leg. Weight loss without other constitutional symptoms is a common feature.

The natural course is monophasic, but recovery may be slow and some patients may be left with residual deficits. Treatments such as intravenous immunoglobulin (IVIG), IV methylprednisolone, and other immunosuppressants may be helpful in hastening recovery, but the literature does not provide clear evidence that these treatments are beneficial.9 IV methylprednisolone may be most effective in pain control, allowing for necessary physical therapy, and physical therapy is probably the most important intervention.

Chronic inflammatory demyelinating polyneuropathy

Diabetic patients, particularly type 1, may have a higher risk of developing CIDP than the general population.10 These cases seem to respond to the standard CIDP treatments. (See section on CIDP.) Elevated CSF protein and demyelinating features on NCS can be characteristic of diabetic polyneuropathy without CIDP. If conduction block is present on NCS, there is a higher likelihood of CIDP. Conduction block is a rare finding in diabetic polyneuropathy.10 CIDP with diabetes may not respond as well to treatment. In one study comparing idiopathic CIDP to CIDP with diabetes, those with diabetes presented with a higher frequency of autonomic dysfunction, associated axonal loss, and a poorer outcome at 6 months.11

Differential diagnosis

Other etiologies for neuropathy, although less likely, should be ruled out. These include: • • • • •

Alcohol use. Vitamin deficiencies. Toxic/drug-induced. Monoclonal gammopathy. Renal or hepatic insufficiency.

Investigations

• NCS should be performed to further define the type of neuropathy. • EMG can assist in determining the degree of axonal involvement. • Fasting blood glucoses and hemoglobin A1c to evaluate glycemic control. Diabetes is defined as a fasting blood glucose > 1.26 g/L (126 mg/dL) or a HgBA1c ≥6.5%. • Glucose tolerance test: impaired glucose tolerance is defined as 2-hour glucose between 1.4 g/L (140 mg/dL) and 1.99 g/L (199 mg/dL). Impaired glucose tolerance has been linked to peripheral neuropathy.

Neuropathy may be associated with metabolic syndrome (obesity, hypertriglyceridemia, hypertension, insulin resistance).12

Treatment

• Adequate blood glucose control is important for prevention of neuropathies or preventing worsening of existing neuropathies. • Impaired glucose tolerance: diet and exercise intervention with weight loss, low-density lipoprotein and triglyceride reduction, and improved glucose control. Glucose control may be more effective in arresting progress of neuropathy in type 1 diabetes than in type 2 diabetes.6 • Small uncontrolled trials suggest light exercise may improve neuropathy symptoms. Symptomatic treatment: burning pain and paresthesias can be bothersome and debilitating features of neuropathy. Many medications are available for symptom relief (Table 25.1).

Diseases of the Peripheral Nerve and Mononeuropathies TABLE 25.1  Treatment Options for Neuropathic Pain Medication

Dosing

FIRST LINE Tricyclic 10–250 mg qhs antidepressant (e.g. amitriptyline, nortriptyline) Gabapentin 100–1200 mg tid Pregabalin

50–100 mg tid

Duloxetine

60–120 mg daily

SECOND LINE Carbamazepine Lamotrigine Tramadol

Venlafaxine THIRD LINE Topiramate

Side Effects Anticholinergic (i.e. urinary retention, constipation, dry mouth and eyes, sedation) Cognitive abnormalities, sedation, limb edema Cognitive abnormalities, sedation, limb edema Cognitive abnormalities, sedation, nausea, diarrhea, constipation, diaphoresis

200–400 mg tid

Cognitive abnormalities, vertigo, leukopenia, liver dysfunction 200–400 mg daily Stevens–Johnson syndrome (slow titration to prevent) 25–50 mg every Cognitive abnormalities, 4–6 hours as gastrointestinal upset needed 150–225 mg daily Sedation, nausea 200–400 mg bid

Cognitive abnormalities (particularly memory and language impairment), sedation, weight loss, glaucoma, metabolic acidosis, nephrolithiasis Arrhythmias

Mexiletine 200–300 mg tid TOPICAL AGENTS Capsaicin cream Apply to feet 3–4 Warn patients that initial times daily applications may exacerbate neuropathic pain which should improve with subsequent applications Lidocaine 5% patch 1–3 patches or Skin irritation or gel applications per 12–24 hours

TIP • Polyneuropathy may improve with better glycemic control, but it is generally not reversible.

TOXIC NEUROPATHY Definition

Neuropathic complications from the toxic effects of drug or environmental exposures.

TIP • Neuropathies tend to improve when offending agents/ exposures are removed, but this is not always the case. Some neuropathies may worsen over time.

771 Etiology and pathophysiology Alcohol

Alcoholics may develop a generalized axonal sensorimotor polyneuropathy. There may also be a more acute axonal polyneuropathy (similar to Guillain–Barré syndrome [GBS]), though this has been disputed.13 The more acute neuropathy typically has normal or only slightly elevated CSF total protein. The pathogenesis of nerve injury is not known. It may be related to nutritional deficiency or a direct toxic effect to the nerves. Treatment involves abstaining from alcohol and maintaining a balanced diet. Recovery depends on initial severity of the polyneuropathy.

Chemotherapeutic agents

The risk of developing a neuropathy increases with higher doses and concomitant use of other potentially neurotoxic drugs. Neuropathies are usually an axonal polyneuropathy that is length dependent with greater sensory involvement or a sensory neuronopathy. Medication withdrawal or dose reduction at an early stage of the neuropathy can prevent progression to a more severe grade and may result in functional resolution. However, if treatment is continued and high cumulative doses are received, residual neuropathic deficits are inevitable.

ARA-C (cytosine arabinoside)

• An antimetabolite used for treatment of leukemia and lymphoma. • Sensory neuropathy and severe sensorimotor polyneuropathy resembling GBS may begin within hours to weeks after treatment initiation. • Pathogenesis is unknown. Hypotheses include inhibition of proteins involved in myelin production, axonal structure, or axonal transport or the immunomodulating effects of the medication predisposing peripheral nerves to immune attack.

Bortezomib

• A selective, reversible inhibitor of the proteasome that has been approved for multiple myeloma. • New-onset neuropathy or symptomatic worsening of a neuropathy occurred in 35% of patients in treatment trials. • NCS usually reveal a length-dependent axonal sensory polyneuropathy. • The neuropathy usually improves with dose reduction or drug discontinuation. • Pathogenesis is possibly related to a build-up of proteins that impairs neuronal function in the dorsal root ganglia, leading to a retrograde axonopathy of small nerve fibers followed by larger nerve fibers.

Check point inhibitors

• May cause an acute demyelinating, axonal motor sensory neuropathy, vasculitis, mononeuropathy (e.g. Bell’s palsy) or pure sensory neuropathy. • May be associated with myositis (often including cardiac involvement) or myasthenia gravis. • May also cause CNS demyelination.

High-dose steroids are a mainstay of treatment, which may include plasma exchange IVIG and other immunosuppressive agents.

Hankey’s Clinical Neurology

772 Etoposide

• Semisynthetic derivative of podophyllotoxin used to treat lymphoma, leukemia, small-cell lung cancer, and testicular carcinoma. • Mechanism of action is inhibition of the deoxyribonucleic acid (DNA)-unwinding enzyme topoisomerase II. • 4–10% of patients develop a predominantly sensory axonal polyneuropathy. • The neuropathy resolves several months after drug discontinuation.

Ifosfamide

• An alkylating agent used for treatment of testicular and cervical carcinomas, sarcomas, lymphomas, and lung cancers. • A sensory neuropathy occurs in 3% of patients taking highdose therapy with onset 1–2 weeks after treatment. The symptoms gradually resolve, but do tend to recur if rechallenged with the medication.

Misonidazole

• Used as an hypoxic cell sensitizer before radiation therapy for various malignancies, particularly pharynx, larynx, and lung. • Painful paresthesias and occasional distal weakness in a length-dependent pattern may occur after 3–5 weeks of drug administration. The neuropathy usually improves after drug discontinuation.

Platinum agents: cisplatin

• Platinum compound used for a wide variety of malignancies, most notably ovarian, testicular, lung, bladder, head and neck, and germ cell cancers. Cisplatin kills malignant cells by disruption of DNA function. • There is an 85% incidence of neuropathies with doses > 300 mg/m 2 of body surface and neuropathy is practically universal with doses > 600 mg/m 2. The pathogenesis for neuropathy is not known, but a proposed mechanism involves DNA binding of the drug and impairing axonal transport. • The induced neuropathy is usually a symmetric sensory neuropathy or neuronopathy, which is related to total cumulative dose. At higher cumulative doses, severe proprioceptive defects may appear such as sensory ataxia and pseudoathetosis (see section on Sensory Neuronopathy). • Cisplatin-induced neuropathies have an important characteristic of off-therapy deterioration, known as coasting. The neuropathic symptoms may not appear for up to 8 weeks after therapy has been stopped. In 30% of patients, the neuropathy continues to progress for as long as 6 months after medication withdrawal. With time, the neuropathy may subside. However, long-term follow-up studies reveal 40% of patients noting residual sensory symptoms, likely due to its neuronopathic effects.

Platinum agents: Oxaliplatin

• Platinum chemotherapy agent designed to have fewer side effects. However, it has actually been associated with a unique, but frequent, sensory neuropathy, which is triggered or exacerbated by cold exposure. The neuropathy is rapidly reversible without persistent impairment of sensory function.

Suramin

• Hexasulfonated naphthylurea that is active against hormone-refractory prostate cancer, malignant thymoma, non-Hodgkin’s lymphoma, and other solid tumors such as adrenocortical, ovarian, and renal cell carcinoma. • Peripheral neuropathy, occurring in 25–90% of patients, is a dose-limiting side effect. There are two distinct types of toxic neuropathy – a dose-dependent, distal, axonal sensorimotor polyneuropathy and a subacute demyelinating polyradiculoneuropathy, which may be immune mediated. The latter type is less common but can be quite severe, resulting in mechanical ventilation in up to 25% of affected patients. Plasmapheresis has been used, but with mixed results. The neuropathy may progress for 1 month following discontinuation and can take several months to recover.

Taxanes: Paclitaxel, docetaxel

• Used in the treatment of ovarian, breast, lung, bladder, cervical, head and neck cancers, and non-Hodgkin’s lymphoma. Mechanism of action is promotion of microtubule assembly that leads to accumulation of disordered microtubular bundles. Accumulation may also occur in the axons and the dorsal root ganglion neuronal cell body. • When treatment is combined with granulocyte colonystimulating factor, peripheral neurotoxicity becomes the dose-limiting factor. Usually, myelosuppression is the dose-limiting factor. • A dose-dependent, predominantly sensory neuropathy may occur. Most patients improve 1–2 months after chemotherapy cessation, but symptoms have potential to worsen for several months after discontinuation.

Thalidomide

• Older therapy currently being utilized for new therapeutic indications (multiple myeloma, graft-versus-host disease, erythema nodosum leprosum, autoimmune diseases). • It can be associated with a painful, axonal sensorimotor neuropathy that often persists years after drug discontinuation.

Vinca alkaloids: Vincristine, vinblastine, vindesine, vinorelbine

• Mechanism of action involves inhibition of microtubule formation by binding to tubulin, which can also impair axoplasmic transport and leads to cytoskeletal disarray and axonal degeneration. • Most commonly used to treat leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma. It is also utilized for lung cancers, breast carcinomas, and childhood tumors. • Neurotoxicity is vincristine’s dose-limiting side effect, while myelotoxicity limits the use of vinblastine and vinorelbine. • The neuropathy is usually a symmetric sensorimotor polyneuropathy that commonly includes autonomic symptoms and less frequently involves cranial nerves. • The median duration of symptoms after stopping vincristine is approximately 3 months.

Other medications Amiodarone

• A neuromyopathy may develop after taking the medication for 2–3 years.

Diseases of the Peripheral Nerve and Mononeuropathies • Severe proximal and distal weakness can develop primarily in the legs, combined with distal sensory loss, tingling, and burning pain. • Presumed mechanism for neuropathy: amphiphilic properties of the medication lead to drug–lipid complexes that result in accumulation of autophagic vacuoles. • NCS show absent sensory responses and reduced or normal CMAPs. Also, conduction velocities may be significantly reduced, suggesting a demyelinating component. EMG reveals denervation in the distal muscles and myopathic-appearing MUPs in the proximal muscles due to the accompanying toxic myopathy. • Other clinical features include myopathy or rhabdomyolysis, tremor, optic neuropathy, thyroid dysfunction, keratitis, pigmentary skin changes, hepatitis, pulmonary fibrosis, and parotid gland hypertrophy.

Chloroquine/hydroxychloroquine

• Similar mechanism of action to amiodarone. • A toxic myopathy or a distal sensorimotor axonal polyneuropathy may develop. The myopathy and neuropathy may occur simultaneously, manifesting as both proximal and distal weakness (neuromyopathy). • The signs and symptoms are usually reversible with discontinuation of the medication.

Colchicine

• Used to treat gout. • Mechanism of action involves inhibition of the polymerization of tubulin into microtubules. Axoplasmic flow can be impaired leading to neurotoxicity. • The neuropathy is length-dependent, involving large-fiber modalities. • A superimposed myopathy may occur, which leads to proximal weakness and is often more severe than the neuropathy. • Muscle biopsies reveal a vacuolar myopathy, and sensory nerve biopsies show axonal degeneration.

Dapsone

• Used for the treatment of leprosy and various dermatologic conditions. • A primary motor neuropathy can develop between 1 week and 5 years after initiating treatment. • The hands tend to be more affected. • Discontinuation of the drug results in marked improvement. • The risk of developing neuropathy is greatest in individuals with a slower acetylation rate of dapsone.

Disulfiram

• Used to aid in the detoxification of patients with chronic alcoholism. • A neuropathy with distal weakness (i.e. foot drop) and sensory loss may occur at various times throughout the treatment (10 days–18 months after initiation). • The pathogenesis of the neuropathy may be due to toxicity from carbon disulfide, which is a metabolite of disulfiram. • Histological feature: axonal swellings caused by accumulation of neurofilaments (see Carbon disulfide below).

HMG-CoA reductase inhibitors (‘statins’)

• Used to treat hyperlipidemia. • Case reports of axonal sensorimotor neuropathy or purely small-fiber neuropathy, with the former improving after

773 withdrawal of the medication. The small-fiber neuropathic symptoms may be persistent. Currently, the neuropathy appears to be a rare phenomenon.14 • Hypothetical mechanisms for nerve injury include inhibition of guanosine triphosphate signaling-related binding proteins, inhibition of the formation of selenoproteins, and reduction of antioxidant defense pathways.

Isoniazid

• Used for the treatment of tuberculosis, peripheral neuropathy is one of the most common side effects. • The usual presentation is numbness and paresthesias in hands and feet. • The neuropathy can develop within a few weeks on higher doses. • The symptoms resolve after discontinuing the medication. • The neuropathy is due to pyridoxine deficiency (isoniazid inhibits pyridoxal phosphokinase). Patients with slow acetylation (i.e. elderly or those with the autosomal recessive trait) maintain a higher serum concentration of the drug and are at greater risk for developing neuropathy. • Prophylactic pyridoxine 100 mg daily can prevent neuropathy.

Metronidazole

• Used to treat protozoan infections (trichomoniasis, giardiasis, and amebiasis) and anaerobic infections (Clostridium difficile). Also used in higher doses for Crohn’s disease. • There are several reports of a sensory neuropathy or neuronopathy that developed on high doses. Doses of < 12 g over 5 days are unlikely to cause a neuropathy.

Nitrofurantoin

• Used to treat a wide range of gram-positive and gramnegative organisms, most frequently for urinary tract infections. • An acute, severe sensorimotor polyneuropathy may develop. Paresthesias are painful. Occasionally, quadriparesis occurs. • Elderly and patients with renal insufficiency are at greatest risk for neuropathy. • There is slow improvement after drug discontinuation.

Phenytoin

• Used to treat several types of epilepsy. • A rare side effect is a mild sensory neuropathy, which improves after drug discontinuation.

Tacrolimus

• An immunosuppressive agent used to prevent solid organ transplant rejection, and to treat graft-versus-host disease and various autoimmune diseases. • Mechanism of action involves modulation of T-cell function. • Although neuropathy is a rarely reported side effect, the best-characterized peripheral nerve disorder is a chronic demyelinating neuropathy, which may resemble CIDP with NCS demonstrating demyelinating features. • Patients do improve with plasmapheresis or IVIG. • Another syndrome is an acute, severe, motor-predominant axonal polyneuropathy that commences 1–2 weeks into the treatment regimen. Onset is abrupt with progression to flaccid quadriparesis occurring in a few days. Other features include ptosis, bilateral facial weakness, lethargy, and

Hankey’s Clinical Neurology

774 foot pain. Symptoms should improve with discontinuation of the drug, but may require additional treatment with plasmapheresis or IVIG. The neuropathy may relapse if rechallenged with tacrolimus. • The pathogenesis of neuropathy may be mediated by a dysimmune process. Tacrolimus may enhance autoreactive T cells directed against peripheral nerve myelin.

Human immunodeficiency virus medications See section on Infectious neuropathy.

Industrial agents Acrylamide

• A vinyl monomer used in soil grouting for stabilization, in waterproofing, and as a flocculator. • Oral, dermal, and respiratory absorption. • Accumulates distally in the nerves. Acrylamide has been used in animal models of distal axonal neurotoxic injury. • Chronic exposure may lead to an axonal polyneuropathy; potential recovery when exposure is eliminated.

Carbon disulfide

• Used to make rayon and cellophane. • Dermal or respiratory absorption. • Chronic exposure can result in a length-dependent axonal polyneuropathy. • Histological feature: giant axonal swellings (neurofilamentous debris within axons).

Ethylene oxide

• Used to sterilize heat-sensitive materials. • Absorbed across respiratory membranes. • Sensorimotor polyneuropathy is the most common neurotoxic effect, which can occur at exposure levels that do not affect other tissues.

Hexacarbons

• Water-insoluble organic solvents, used in industrial and household glues. • Dermal absorption or through inhalation (i.e. glue sniffing). • A subacute sensorimotor polyneuropathy may progress over 4–6 weeks, leading to quite extensive weakness with sparing of respiratory muscles. • Pathogenesis of neuropathy is hypothesized to involve crosslinking between axonal neurofilaments, resulting in aggregation, impaired axonal transport, swelling of the axons, and axonal degeneration (similar to carbon disulfide). • Histological feature: loss of large myelinated fibers and swollen axons filled with neurofilaments.

• Dermal, respiratory, and gastrointestinal tract absorption. • Clinical features include organophosphate-induced delayed neurotoxicity: • Rapidly progressive axonal sensorimotor polyneuropathy developing a few weeks after acute exposure to a large quantity. • Pathogenesis of the neuropathy stems from phosphorylation of neurotoxic esterase. • Reduced erythrocyte acetylcholinesterase activity. • Neuropathy may slowly improve with no further exposure.

Heavy metals Arsenic

• Exposure can occur from intentional poisoning or from industry such as smelting. • Toxicity may result in a sensorimotor polyneuropathy with onset within 5–10 days of ingestion. The neuropathy may progress for several weeks and can mimic GBS. Severe intoxication can involve the proximal muscles and cranial nerves. • Respiratory muscles may be affected necessitating mechanical ventilation. • Skin examination may reveal Mee’s lines (transverse lines at the base of fingernails and toenails that appear after 1–2 months of exposure) (Figure 25.9). Mee’s lines can also be a feature of exposure to thallium. • NCS reveal an axonal pattern with demyelinating features. • CSF studies may show elevated protein with normal cell count. These features, in addition to the clinical presentation, may lead to the misdiagnosis of GBS. • Slow recovery of the neuropathy with removal of the exposure. British anti-Lewisite (BAL) chelation therapy has yielded inconsistent results.

Lead

• Intoxication from accidental ingestion (e.g. children eating lead-based paint chips) and industrial exposure to leadcontaining products. • Most common presentation of lead poisoning is encephalopathy. • A motor neuropathy can occur, which often presents with a wrist drop (i.e. radial neuropathy). Foot drop (i.e. peroneal neuropathy) may also occur. Bluish discoloration of the gums is an associated feature.

Nitrous oxide

• Used as an inhaled dental anesthetic. • Interferes with vitamin B12 metabolism and may produce a syndrome similar to the subacute combined degeneration associated with vitamin B12 deficiency. In these cases, the vitamin B12 concentrations are normal. • A single exposure can cause a myeloneuropathy in those with underlying subclinical B12 deficiency. Onset of symptoms may be delayed between 2 and 6 weeks after exposure.15

Organophosphates

• Used in insecticides/pesticides, flame retardants, chemical weapon agents, and suicide attempts.

FIGURE 25.9  Mee’s lines on the fingernails after exposure to arsenic.

Diseases of the Peripheral Nerve and Mononeuropathies • Other investigations reveal a microcytic anemia with basophilic stippling of erythrocytes and an elevated serum coproporphyrin level. • Treatment requires removal of the exposure source. Chelation therapy with calcium disodium ethylenediamine tetraacetate, BAL, and penicillamine has shown some efficacy in neuropathy improvement.

Mercury

• Elemental mercury can be found in older thermometers. • Organic: • Contaminated fish. • Paresthesias in hands and feet and may involve the face and tongue. Encephalopathy, hearing loss, and vision loss may also occur. • Due to its low water solubility, it remains in the body, may have limited urinary excretion, and is difficult to measure. • Inorganic: • Found in batteries and used in industrial procedures (plating processes, felt manufacturing). • Primary symptoms include gastrointestinal symptoms and nephritic syndrome. Encephalopathy and a sensorimotor polyneuropathy may also develop. • Measured in 24-hour urine sample. • Remove the source of exposure. Chelation treatment has been tried, but with variable success.

Thallium16

• Used in the manufacture of glass and optical lenses, semiconductors, cardiac scans, artists’ paints, gamma radiation detectors, low temperature thermometers, and fireworks. (In the past, it was found in insecticides and rodenticides). Toxicity most often occurs in relation to its use in criminal activity or after exposure to contaminated food, water, illicit drugs, or herbal products. • After a few weeks of exposure, clinical features include diffuse alopecia, gastrointestinal symptoms including abdominal distension and hepatic dysfunction and Mee’s lines. Burning foot pain, distal muscle atrophy, and weakness occur. With severe intoxication, proximal weakness and cranial nerve involvement may be observed. Respiratory muscles may be affected. Death can occur within 48 hours after a significantly high dose. • As blood and urine thallium concentrations decrease, the neuropathy slowly improves, but may leave a residual sensory neuropathy. Treatments include administration of Prussian blue and hemodialysis or plasmapheresis.17

NUTRITION-RELATED NEUROPATHY Definition and epidemiology

Neuropathic disorders due to nutritional deficiency or toxicity. Patients at risk include those with impaired gastrointestinal absorption (status-post gastric bypass surgery or partial gastrectomy or with autoimmune malabsorption) or decreased nutritional intake (alcoholics, chronic illness, extreme diets, or anorexia).

Etiology and pathophysiology Vitamin B12 (cobalamin) deficiency Etiology

• Pernicious anemia is the most common cause. • Gastrectomy, disease of the terminal ileum.

775 • Vegan diet (no meat, dairy products, or eggs). • Nitrous oxide exposure can produce a B12 deficiency syndrome in those with marginal stores.

Clinical features

• May present as a myeloneuropathy (involvement of both the posterior columns of the spinal cord and the peripheral nerves). • Symptoms include numbness, sensory ataxia, spastic weakness, reduced vibratory sense and proprioception, abnormal Romberg’s sign, and absent ankle jerks with hyperreflexia elsewhere. • Hand numbness may be more severe than the leg numbness due to the myelopathy.

Investigations

• Measure serum vitamin B12 levels. • For low normal levels of B12 (< 300 pg/mL), check methylmalonic acid and homocysteine levels to improve diagnostic sensitivity.

Treatment

• B12 1000 μg intramuscularly per day for 1 week then weekly for 1 month, followed by monthly treatments. This treatment is recommended in severe cases. • Oral replacement may be just as effective (though with slower effect) at a dose of 1000–2000 mg daily.9 • Improvement in the neuropathy depends on duration of symptoms.

Folate deficiency Etiology • • • •

Poor diet. Partial gastrectomy, duodenojejunal resections. Celiac disease. Medications that interfere with utilization of folic acid (phenytoin, phenobarbital, sulfasalazine, and colchicine).

Clinical features

Folate deficiency may predispose to peripheral neuropathy. In the young, < 40 years, peripheral neuropathy is about twice as common in those with folate deficiency as it is in those with normal folate. This effect is not seen in those > 40 years of age.18

Investigations

• Check serum folate and vitamin B12.

Treatment

• Supplementation usually results in good clinical recovery.

Vitamin B6 (pyridoxine) deficiency or toxicity19 Etiology

• Deficiency: malnutrition, chronic peritoneal dialysis, medications such as isoniazid, penicillamine, cycloserine, or hydralazine. • Toxicity: high-dose supplementation (recommended daily dose for adults is 2–4 mg and 10–25 mg when using B6 depleting medications).

Clinical features

• Deficiency: axonal sensorimotor polyneuropathy with more prominent sensory symptoms. Severe toxicity causes neuronopathy.

Hankey’s Clinical Neurology

776 • Toxicity: • Sensory neuropathy with paresthesias and sensory ataxia resulting in a wide-based gait. • Sensory loss may be more pronounced in the upper extremities. • Normal muscle strength. • Absent or reduced reflexes.

Investigations

• Serum vitamin B6 level. • Toxicity: NCS show reduced or absent sensory responses and preserved motor responses.

Treatment

• Deficiency: 50–100 mg daily of vitamin B6. • Toxicity: stop B6 supplementation.

Vitamin B1 (thiamine) deficiency Etiology

• Decreased intake or abnormal absorption: • Poor nutrition in alcoholism. • Chronic vomiting (e.g. hyperemesis gravidarum). • Total parental nutrition. • Gastric bypass surgery. • Restrictive diets. • Hyperthyroidism: increased metabolism and utilization of thiamine may result in a relative deficiency.

Clinical features

• Sensorimotor polyneuropathy generally occurs with chronic deficiency (dry or neuritic beriberi). • May overlap with wet beriberi (high output cardiac failure) or gastrointestinal manifestations. • Oculomotor abnormalities, mental status change, ataxia and hemorrhagic/necrotic lesions in mamillary bodies, thalamus or other deep brain structures are also seen.

Investigations

• Thiamine level may not be reliable for the diagnosis. • Measure erythrocyte transketolase activity and the percentage increase in activity after adding thiamine pyrophosphate.

Treatment

• For isolated neuropathy, intravenous thiamine 100 mg daily for 3 days, then 50 mg oral daily until after resolution of symptoms. Consider lifelong supplementation in at-risk patients. • Slow recovery is expected, but deficits persist with severe neuropathy.

Copper deficiency Etiology

• Gastric surgery. • Excessive zinc intake (from supplementation or certain denture creams) may cause copper deficiency by decreasing copper absorption.20

Clinical features

• Myeloneuropathy similar to vitamin B12 deficiency. Numbness and paresthesias in the lower extremities with brisk reflexes and gait abnormalities.

• Copper deficiency may also cause neutropenia or pancytopenia.

Investigations

• Low serum copper levels. • Microcytic anemia, neutropenia, or pancytopenia. Bone marrow biopsy may show a myelodysplastic syndrome. • Magnetic resonance imaging (MRI) of the cervical spine may show abnormal T2-weighted signal in the dorsal columns.

Treatment

• Intravenous or oral copper supplementation: • Oral: 8 mg of elemental copper daily for 1 week, 6 mg daily for the second week, 4 mg daily for the third week, and 2 mg daily thereafter. • IV: 2 mg daily for 5 days and then periodically if necessary. • Discontinue zinc source. • Hematological and bone marrow abnormalities respond promptly to treatment. Neurologic symptoms may not improve, but symptom progression may be halted.

NEUROPATHY IN SYSTEMIC DISEASE Definition

Neuropathies associated with systemic disease that are not the result of treatment. Vasculitic neuropathies, even those associated with systemic disease, are dealt with in a later section.

Neuropathies associated with metabolic or inflammatory diseases Hypothyroidism

• Mononeuropathy at the wrist (carpal tunnel syndrome): occurs in 2–20%, possibly due to weight gain, edema compressing the carpal tunnel, or joint effusions. Usually resolves with thyroid replacement therapy. • Rarely, a sensory polyneuropathy with painful paresthesias and numbness may occur and improves with treatment.

Hepatic disease

• Length-dependent predominantly axonal sensorimotor polyneuropathy with demyelinating features, with sensory complaints prevailing. • The exact mechanism for neuropathy is not known, but possibly related to accumulation of toxins secondary to liver disease that damage the nerve. Also, alcoholism or viral hepatitis may coexist as an etiology.

Renal insufficiency Polyneuropathy

• Approximately 60% of patients with renal failure (glomerular filtration rate < 12 mL/min) develop a length-dependent axonal sensorimotor polyneuropathy. The pathogenesis may be related to accumulation of medium-sized proteins, which may be toxic to the nerves.

Mononeuropathy

• Median mononeuropathy at the wrist (carpal tunnel syndrome): most often associated with hemodialysis and deposition of β 2-microglobulin in the transverse carpal ligament.

Diseases of the Peripheral Nerve and Mononeuropathies • Ischemic monomelic neuropathy: complication of arteriovenous shunt placed in the forearm for dialysis, affecting the median, ulnar, or radial nerves.

Celiac disease (gluten-induced enteropathy)

• Intolerance to gluten, in that gluten exposure results in a malabsorption syndrome. • About 10% of patients develop neurologic complications, most commonly ataxia and neuropathy. The neuropathy usually presents with distal sensory loss, paresthesias, and unsteadiness. A small fiber neuropathy or autonomic neuropathy may also occur. The neuropathy may be the presenting feature of celiac disease. • Serum antitissue transglutaminase and antiendomysial antibodies are often positive. (These antibodies have the same antigen but are assayed differently; antiendomysial antibody testing is more specific). Antigliadin antibodies are sensitive but are not as specific.21,22 Referral to gastroenterology for biopsy is recommended prior to initiating gluten-free biopsy. • The pathogenesis of the neuropathy may be due to vitamin malabsorption or immune mediated. • A gluten-free diet does not necessarily result in neuropathy improvement. • Vitamin B12 and vitamin E supplementation should be considered.

Inflammatory bowel disease (ulcerative colitis and Crohn’s disease)

• These disorders may be associated with a variety of neuropathies such as acute or chronic demyelinating polyneuropathy, axonal sensory or sensorimotor polyneuropathy, small fiber neuropathy, or brachial plexopathy. • Overall incidence is not well documented.

Neuropathies associated with Neoplasia Paraproteinemia

• There is an association between immunoglobulin (Ig)M, IgG, and IgA monoclonal proteins and polyneuropathy. Most cases are a benign form called monoclonal gammopathy of unknown significance. In other cases, the neuropathy may be part of a syndrome such as primary systemic amyloidosis, osteosclerotic myeloma/POEMS, multiple myeloma, lymphoma, Waldenstrom’s macroglobulinemia, or cryoglobulinemia. • The neuropathy is usually a slowly progressing sensorimotor polyradiculopathy or polyneuropathy that resembles CIDP. The sensory deficit appears earlier and is more prominent than the motor deficit. CSF total protein is elevated, often > 1 g/L (100 mg/dL). • Patients, especially those with Waldenstrom’s macroglobulinemia, may have an IgM anti–myelin-associated glycoprotein (anti-MAG) antibody causing a chronic predominantly distal demyelinating neuropathy. • Treatment: plasmapheresis, corticosteroids, and chemotherapy have been used with variable success. Anti-MAG syndromes may be treated with rituximab.

Primary amyloid

• 20–40% of multiple myeloma patients, most commonly with light chains (2:1 λ–κ). Painful sensory or motor sensory neuropathy with a prominent small fiber component causing pain and autonomic dysfunction.

777 • Other organ system involvement (e.g. cardiac or renal) is common. • Several therapeutic regimens including intensive chemotherapy have been proposed.23

Vasculitis

• Associated with type 1 cryoglobulinemia; often has systemic involvement. Treatment is aimed at the underlying malignancy with the possible addition of rituximab.

POEMS24

(Polyneuropathy, organomegaly, endocrinopathies, M-protein, skin changes, including thickening and hyperpigmentation, and clubbing of the fingers.) • A syndrome that presents with a slowly progressive, mainly motor demyelinating neuropathy. Diagnosis requires the presence of Castleman’s disease, sclerotic bone lesions, or increased vascular endothelial growth factor, as well as one additional minor criterion.23 • Most common endocrinopathies include hypogonadism, diabetes, and hypothyroidism. • Usually IgG or IgA (mostly λ) monoclonal protein. • Responses to plasmapheresis, corticosteroids, or IVIG are typically absent or minimal. More aggressive regimens including high-dose chemotherapy may be useful when plasma cell proliferation is systemic. Treatment of solitary plasmacytoma with radiation is recommended.

Paraneoplastic neuropathy23

• This refers to peripheral neuropathic complications of cancer due to remote effect of the tumor. Here, we separate paraprotein-associated neuropathies from other paraneoplastic neuropathies though this is likely an artificial distinction. Manifestations often precede the diagnosis of the underlying malignancy. • Most malignancies are detected within 4–12 months of symptom onset. However, there have been reports of malignances discovered after 8 years or more. • Paraneoplastic neurologic syndromes are rare and occur in < 1% of patients with cancer.25 Small-cell lung carcinoma (SCLC) is the most common malignancy associated with a paraneoplastic syndrome. It is believed that there is antigenic similarity between proteins expressed in the tumor cells and the neuron cells, resulting in an immune response directed against both types of cells. Other associated malignancies include carcinoma of the esophagus, breast, ovaries, kidney, and lymphoma.

Sensory neuronopathy/ganglionopathy

• Patients present with acute–subacute numbness and paresthesias in the distal extremities, often beginning in the hands and/or face (to be distinguished from a lengthdependent polyneuropathy). On neurologic examination, all sensory modalities are affected, and reflexes are depressed. Sensory ataxia and pseudoathetosis may be present. • Usually associated with anti-Hu antibodies, but antiamphiphysin or CV2/CRMP5 antibodies may be present. • In some cases associated with motor neuronopathy. • Early removal of the tumor offers best chance for stabilization. Immunosuppressant treatments have not been effective.

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778 Autonomic neuropathy

• Patients present with severe gastrointestinal dysmotility. Often associated with another neurologic syndrome such as limbic encephalitis or sensory ganglionopathy. • Associated antibodies include anti-Hu and CRMP5. However, negative antibody tests do not exclude the diagnosis of a paraneoplastic neuropathy.26

Other neuropathies without an M-band

• Rare cases of axonal, demyelinating, or mixed neuropathies with or without antibodies. • Vasculitis.

Neoplastic neuropathy

• Carcinomatous/lymphomatous meningitis due to subarachnoid spread of neoplastic cells may lead to root involvement. • Due to infiltration of the peripheral nerve by lymphoma or carcinoma cells. May occur due to extension of tumor from roots to periphery. • Can have axonal or demyelinating features on EMG. • Very difficult to diagnose or treat. Treatment generally consists of aggressive chemotherapeutic regimens.

GUILLAIN–BARRÉ SYNDROME/ACUTE INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY Definition and epidemiology

Acute onset of extremity paresthesias, numbness, and progressive weakness, with potential risk of respiratory insufficiency due to a demyelinating process involving the nerve roots and peripheral nerves (polyradiculoneuropathy). • Worldwide incidence of 0.6–4 cases per 100,000. • Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (demyelinating form) accounts for about 90% of North American and European cases; 5–10% of cases constitute an axonal subtype, acute motor axonal neuropathy (AMAN). • Two-thirds of cases have an antecedent infection within 6 weeks of symptom onset, most commonly an upper respiratory infection or gastroenteritis. Usual infections include Epstein–Barr virus, Mycoplasma pneumoniae, Campylobacter jejuni, and cytomegalovirus (CMV). • Reports of GBS occurring after vaccinations, surgery, and head trauma.

Pathophysiology27

Caused by an aberrant immune response that damages peripheral nerves. • Activated macrophages invade intact myelin sheaths resulting in myelin damage and demyelination. Mechanisms may be explained by the following: • Activated helper T cells react against antigens on the surface of Schwann cells and direct activated macrophages to this region. • Humoral immunity: antibodies bind to epitopes on the surface of Schwann cells inducing complement activation and subsequent myelin destruction. • In severe cases, inflammatory mediators may induce axonal damage in addition to the demyelination.

• In AMAN, the macrophages are believed to invade the space between the Schwann cell and axon, leaving the myelin sheath intact.

Clinical features

• Initial symptoms are pain, numbness, paresthesias, or weakness in the limbs. The severity of symptoms varies greatly among individuals. • The main feature of GBS is rapidly progressive bilateral and relatively symmetric weakness of the limbs, usually affecting the lower extremities first. Classically, both proximal and distal muscles are involved simultaneously. This may also be accompanied by respiratory and/or cranial nerve involvement. • The facial nerve is the most common cranial nerve affected. Facial neuropathy occurs in 50% of cases and is frequently bilateral.27 • About 25% of patients have severe respiratory involvement warranting mechanical ventilation. • Dysautonomia (cardiac arrhythmia, hypertension or hypotension, ileus, urinary retention) occurs in up to 15% of patients. • Reflexes are almost always depressed or absent. • Many patients have back pain during the course of the disease.

Variants

• AMAN presents similarly to AIDP, but has a more rapid and severe course, often resulting in mechanical ventilation. Autonomic involvement is mild. • Miller Fisher syndrome (MFS): • Clinical triad of ophthalmologic abnormalities, ataxia, areflexia. • Ophthalmologic abnormalities include acute ophthalmoplegia, internuclear ophthalmoplegia, Parinaud’s syndrome, convergence failure, divergence paralysis, optic neuritis, ptosis, and isolated abducens nerve palsy. • Rare respiratory failure. • Generally, recovery is good. There are no randomized controlled trials for IVIG or plasmapheresis in the treatment of MFS. However, if symptoms are severe (limb weakness, autonomic symptoms, respiratory involvement, or dysphagia), patients may benefit from a course of IVIG.28 • Bickerstaff’s brainstem encephalitis: a similar syndrome that presents with cranial or peripheral nerve involvement and may evolve to altered consciousness and even coma. Plasmapheresis should be considered.

Differential diagnosis • • • •

Vasculitic neuropathy. Acute intermittent porphyria. Heavy metal intoxication (arsenic poisoning). Acute onset of chronic inflammatory demyelinating polyneuropathy (CIDP). • Tick paralysis. • Vitamin B1 deficiency.

Investigations NCS

Motor NCS determine diagnostic criteria. Sensory NCS help to differentiate various forms of axonal GBS, for example AMAN, from acute motor and sensory axonal neuropathy (AMSAN).27

Diseases of the Peripheral Nerve and Mononeuropathies Neurophysiological criteria for AIDP

• CMAP amplitude (measured in mV) may be normal or reduced, depending on the degree of axonal involvement. • Conduction block; must occur at a noncompression site, such as between the wrist and below elbow when testing the ulnar nerve (Figure 25.10): • Definite conduction block is defined by > 50% reduction in the proximal CMAP amplitude compared with the distal CMAP amplitude. • Probable conduction block is > 30% reduction. • Conduction block cannot be diagnosed if CMAP amplitude is < 1 mV. • Temporal dispersion is diagnosed by > 30% increase in proximal negative peak CMAP duration. • Motor conduction velocity, measured in m/s, is < 70% of the lower limit of normal. • Distal motor latency, measured in ms, is > 150% of the upper limit of normal. • F-wave latency, measured in ms, is > 120% of the upper limit of normal. At least 85% of patients with AIDP have evidence of demyelination on NCS. For patients with normal NCS, repeat studies in 1–2 weeks may be required for diagnosis confirmation.27 Since AIDP initially affects the very proximal (nerve roots) and very distal nerve fibers, the first abnormalities noted on NCS may be prolonged F responses and normal sural responses. The latter finding is termed sural sparing. As the disease progresses, the sural response becomes reduced or absent.

Other tests

• EMG: used to assess the degree of axonal loss, which is primary in AMAN or secondary in AIDP. • CSF studies:

Wrist

779 • In 80% of cases, CSF studies reveal increased total protein with a normal white blood cell count. This finding is referred to as albuminocytologic dissociation. If white blood cells are present in the CSF, there should be < 50 cells/mm. If there are > 50 cells/mm in the CSF, other diagnoses such as HIV polyradiculopathy should be considered.27 • CSF studies are often normal 1 week after disease onset. However, by the end of the second week, 90% of patients will have elevated total protein. • Serum antibodies:28 in about 50% of patients with GBS, serum antibodies to various gangliosides have been found: • Pure motor or axonal variants are associated with GM1, GM1b, GD1a, and GalNAc-GD1a. • MFS and GBS overlapping syndromes (Bickerstaff’s brainstem encephalitis) are associated with GQ1b, GD3, and GT1a. • The antibodies associated with AIDP are not known.

Treatment

Severe cases can lead to respiratory distress and autonomic dysfunction. These patients should be admitted to intensive care units with close monitoring for respiratory and cardiac status (respiratory failure, cardiac arrhythmias, blood pressure instability, urinary retention). Respiratory monitoring should utilize frequent [q2–q6] hours depending on acuity) functional measures of respiratory competence (i.e. negative inspiratory force [NIF] and vital capacity [VC]) and should not rely on blood gas monitoring. Clinical evidence of respiratory difficulty or low ventilatory parameters (NIF < 15–18, VC, 15–20 mL/kg) should trigger intubation

TIP • If respiratory parameters are not immediately available, asking the patient to count after a maximum inspiration allows for an estimate of VC. VC ≅ 100 mL × highest number reached. For example, counting to 20 means VC ≅ 2 liters.

36 mA

Plasmapheresis or plasma exchange (PE) and IVIG are proven effective treatments for GBS.

Below elbow

68 mA

Above elbow

51 mA

Plasma exchange

• Mechanism of action is unknown. It is hypothesized to remove autoantibodies, immune complexes, complement, or other humoral factors. • Side effects: hypotension during the procedure, depletion of clotting factors that usually correct afterward. • Usual course is 4–6 alternate day exchanges of 2–4 L each. • The ideal number of exchanges is not known.

5 mV 30 ms

FIGURE 25.10  Nerve conduction study in acute inflammatory demyelinating polyradiculoneuropathy. Conduction block at a noncompression site (between the wrist and below-elbow stimulation sites) and temporal dispersion noted in the left ulnar nerve. Wrist CMAP amplitude: 7.5 mV; below-elbow CMAP amplitude: 4 mV; above-elbow CMAP amplitude: 2.8 mV.

Intravenous immunoglobulin

• Proven to be as effective as PE. IVIG is readily available at most centers, while PE may only be available at tertiary care centers. • IVIG may inhibit the binding of ganglioside antibodies to their respective antigens, preventing complement activation. • Common side effects include headaches and flu-like symptoms that can occur during the infusion or within the next few days following treatment. Renal failure is a risk with

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780 preparations containing sucrose. Rare side effects include strokes and myocardial infarctions, but this risk is significantly reduced with slower rates of infusion (should never exceed 300 mL per hour). • IVIG dosing is 2 g/kg body weight infused over 2–5 days. Younger patients in good health usually tolerate 2-day treatment. Patients who are older, have other comorbidities (e.g. cardiovascular disease), or are intolerant of side effects may do better with 4- or 5-day treatment. Treatment with either IVIG or PE should ideally be initiated within the first 7–10 days of symptoms but should be initiated for nonambulant patients presenting within 4 weeks of onset. Improvement can be delayed 1 week to 1 month. About 10% of responders have a limited relapse after either treatment. At the time, it is not known which of these patients will go on to develop CIDP. An additional course of IVIG or PE should be given though we favor PE. Treating patients who are mildly affected (defined by being able to walk with or without assistance) and present in the first 2 weeks is recommended due to the tendency for this order to progress after presentation. There is some evidence that treating these patients with PE may hasten motor recovery.28 Corticosteroids do not appear to be beneficial and some patients actually notice worsening of their symptoms.

Prognosis

• Nadir should be around 2–4 weeks, followed by progressive recovery over weeks to months. GBS is usually a monophasic illness, although 7–16% of patients have a recurrence in symptoms.27 • During recovery, 10–20% of patients experience disabling motor deficits. Up to 15% of patients die by 1 year after onset. • Adverse prognostic factors include older age at onset (> 50 years old), severe disease at nadir (bed-bound or on mechanical ventilation), rapid onset of disease, infection with C. jejuni or CMV, and evidence of axonal loss on neurophysiologic studies.27

TIP • If symptoms continue to worsen after 8 weeks, consider the acute onset of CIDP rather than GBS.

CHRONIC ACQUIRED DEMYELINATING POLYNEUROPATHY A group of demyelinating peripheral nerve disorders that share common clinical and pathologic features. These polyneuropathies often respond to immunomodulatory therapy.29

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY Definition

• Immune-mediated neuropathy with a relapsing or progressive course that is characterized by both proximal and distal weakness. • Considered to be the ‘chronic variation’ of AIDP. • Most common of the chronic acquired demyelinating polyneuropathies.

Epidemiology

• 2 per 100,000. • Usual onset 40–60 years of age. • Slight male predominance.

Etiology and pathophysiology

• Immune-mediated process for which the specific antigens are not known. • Certain comorbidities may make people more susceptible to acquiring CIDP, including Charcot–Marie– Tooth disease (CMT), hepatitis C, diabetes, or a paraproteinemia.

Clinical features

• Most cases present with progressive, symmetric proximal and distal weakness of arms and legs. • Up to 80% of cases have both motor and sensory symptoms. • Sensory abnormalities on examination are predominantly the large fiber modalities (i.e. vibration, position sense, and touch). Sensory ataxia and unsteady gait may be a presenting symptom. • Diffuse areflexia or hyporeflexia. • Symptoms must be present for at least 2 months to distinguish from AIDP. • Infection and pregnancy may trigger an exacerbation.

TIP • CIDP presents with both proximal and distal weakness.

Differential diagnosis

• Diabetic CIDP. • Toxic (cyclosporine, tacrolimus, tumor necrosis alpha blockers). • HIV neuropathy.

Investigations Motor NCS

The American Academy of Neurology (AAN) has developed research criteria for the diagnosis of CIDP, which involve mandatory and supportive findings on electrophysiologic studies. 30

Mandatory

There must be three of the following four criteria, which indicate acquired, segmental demyelination of the nerves. • Reduction in conduction velocity in two or more motor nerves: • < 80% of lower limit of normal (LLN) if amplitude > 80% of LLN (indicating disruption of the myelin with intact and functioning axons). • < 70% of LLN if amplitude < 80% of LLN (both demyelinating and axonal features). • Partial conduction block or abnormal temporal dispersion occurring at a noncompression site in one or more motor nerves (i.e. peroneal nerve between ankle and below fibular head, median nerve between wrist and elbow, ulnar nerve between wrist and below elbow): • Partial conduction block is defined by > 20% amplitude drop between proximal and distal stimulation sites. • Temporal dispersion is defined by > 15% increase in duration after proximal stimulation. This occurs from

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781

desynchronization of components of the CMAP due to different rates of conduction. • Prolonged distal latencies in two or more motor nerves: • > 125% of upper limit of normal (ULN) if amplitude > 80% of LLN. • > 150% of ULN if amplitude < 80% of LLN. • Absent F-waves or prolonged minimum F-wave latencies (10–15 trials) in two or more nerves: • > 120% of ULN if amplitude > 80% of LLN. • > 150% of ULN if amplitude < 80% of LLN.

Supportive

• Reduction in sensory conduction velocity < 80% of LLN. • Absent H reflexes.

Sensory NCS

• Low amplitude or absent SNAPs in both upper and lower extremities. • If SNAPs are obtained, distal latencies may be prolonged and conduction velocities slowed. • Median, ulnar, and radial SNAPs may be abnormally low amplitude compared with the sural SNAP, which suggests a nonlength-dependent process. If this phenomenon does occur, the differential diagnosis should include a demyelinating neuropathy or sensory neuronopathy.

EMG

• Spontaneous activity such as fibrillations may be noted if secondary axonal degeneration has occurred. • Myokymic discharges (cross-talk between demyelinated nerve fibers) may be noted. • MUPs appear morphologically normal, but have reduced recruitment with rapid firing. This may be one of the earliest abnormalities.

CSF studies

• 85–90% of cases have an elevated protein with a mean of 1.35 g/L (135 mg/dL). • Cell count is usually normal (up to 10% may have pleocytosis with greater than 5 lymphocytes/mm3). • Oligoclonal bands may be present.

Other tests

• Lumbar spine MRI. Enhancement of the nerve roots may be observed (Figures 25.11–25.13). • Nerve biopsy (not essential for the diagnosis): • Segmental demyelination and remyelination. However, because of the multifocal process, this finding may be missed on biopsy. • Onion bulbs: – Formed from proliferation of the surrounding Schwann cells, due to chronic demyelination and remyelination. – Usually not a prominent feature on biopsy. • Inflammatory cell infiltrate may be evident in the epineurium, perineurium, or endoneurium, but is usually subtle or absent.

FIGURES 25.11–25.13  Lumbar spine MRI in chronic inflammatory demyelinating polyneuropathy (CIDP). (Figure 25.11) Noncontrast Tl-weighted image; (Figures 25.12, 25.13) contrast Tl-weighted images which show enhancement of the nerve roots in a case of CIDP. • Teased fiber preparations may demonstrate segmental demyelination, remyelination, and/or axonal degeneration (Figures 25.14, 25.15).

Treatment

Corticosteroids, IVIG, and PE are acceptable first-line treatments for CIDP.

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782

Etiology and pathophysiology

• Immune-mediated process that is a distinct entity from CIDP. • Antigens presumed to be specific to the motor nerve.

Clinical features

• Painless asymmetric limb weakness usually in the distribution of an individual nerve with normal or diminished reflexes. • Muscle fasciculations may be present, a finding that can lead to a misdiagnosis of motor neuron disease. • Radial neuropathy is the most common presentation.

Differential diagnosis

• Vasculitic neuropathy, although pain is usually a prominent feature. • Immune-mediated brachial plexus neuropathy. • Amyotrophic lateral sclerosis; usually presents with hyperreflexia in the affected limbs. In MMN cases, reflexes are usually normal or diminished in the affected limbs.

Investigations Motor nerve conduction studies   FIGURES 25.14, 25.15  Teased nerve fiber preparation showing segmental demyelination; (Figure 25.14) in a case of chronic inflammatory demyelinating polyneuropathy; (Figure 25.15) in the lower half of the image. (Courtesy of Tibor Valyi-Nagy, MD, PhD.)

Corticosteroids

• Usually start with 60–100 mg daily for up to 4 weeks. When strength has improved, a slow taper can be initiated (5 mg every 2–3 weeks). • Most patients require some type of immunosuppressive therapy to prevent relapses. A steroid-sparing agent, such as azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, or methotrexate (Table 25.2), may be necessary if symptoms flare during the taper.

IVIG

• After an initiation dose of 2 g/kg, dosing is usually 1 g/kg monthly. However, dosing can range from every 2 weeks to every 8 weeks, depending on symptoms.

PE

• Use may be limited by availability. • Because the effect of PE only lasts for a few weeks, it is difficult to use as a chronic therapy. Can be helpful during disease flares.

MULTIFOCAL MOTOR NEUROPATHY Definition

• An immune-mediated neuropathy only affecting the motor nerves.

Epidemiology

• 1 per 100,000 with predilection for young adults.

Conduction block at a noncompression site is the electrophysiologic hallmark of MMN. However, it does not need to be present to make the diagnosis. In one series, 31% of patients with MMN had conduction block, while 94% had other electrophysiologic features of demyelination (prolonged distal latencies, temporal dispersion, slowed conduction velocity, and prolonged or absent F responses).29 • Normal sensory responses on NCS. • EMG: denervation may be present if secondary axonal loss has occurred. • CSF studies: total protein is normal in most cases (as opposed to CIDP). • Serum antibodies:29 • 40–80% of MMN cases have polyclonal IgM antibodies directed against GM1. • Very high titers of anti-GM1 are specific for MMN, but low titers can be present in other disorders such as GBS, CIDP, or motor neuron disease.

Treatment29

Typically, patients have a good response to IVIG, which begins within several days and lasts several weeks. Serial IVIG (administered approximately monthly) is the mainstay treatment for MMN. If a patient is going to respond to IVIG, it is often apparent after the first treatment. Nonresponders to the first treatment generally will not respond to subsequent doses. For nonresponders to IVIG, other treatments such as cyclophosphamide, rituximab, or mycophenolate mofetil are less studied options.

OTHER VARIANTS Distal acquired demyelinating symmetric neuropathy

Predominantly sensory symptoms and signs including gait ataxia and occasional tremor. Despite mostly sensory findings on examination, the motor NCS are abnormal. Distal latencies are significantly prolonged resulting in a short terminal latency index. This indicates the conduction velocity slowing is most prominent in the distal nerve segments.

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TABLE 25.2  Immunosuppressant Medications Side Effects and Management Potential Side Effects

Management/Monitoring of Side Effects

AZATHIOPRINE

• Less nausea if taken in divided doses • Baseline complete blood count with platelets and liver transaminases, then weekly the first month, twice monthly the next 2 months, then monthly while on treatment • Discontinue drug or reduce dose if white blood cell count < 3000/mL • Measure thiopurine methyltransferase: low activity may lead to bone marrow toxicity • Warn patients of allergic reaction, which requires drug discontinuation

• • • • •

Nausea, vomiting Pancytopenia Hepatic toxicity Increased risk of infection and malignancy Hypersensitivity reaction occurring within the first several weeks (nausea, vomiting, rash, fever, malaise, myalgias, elevation of liver transaminases)

CYCLOPHOSPHAMIDE • • • • •

Hemorrhagic cystitis, risk of transitional cell carcinoma of bladder Dose-related bone marrow suppression Increased risk of infection associated with leukopenia Gonadal toxicity, permanent infertility Teratogenicity

METHOTREXATE • • • • •

Bone marrow toxicity Hepatic fibrosis and cirrhosis, elevated liver function tests Increased risk for opportunistic infections Stevens–Johnson syndrome, toxic epidermal necrolysis Pulmonary fibrosis

MYCOPHENOLATE MOFETIL • Pancytopenia • Malignant epithelial neoplasm of the skin (nonmelanoma) • Diarrhea PREDNISONE • • • • • • • •

Increased susceptibility to infections Increased appetite, weight gain Hyperglycemia, hypertension Insomnia Avascular necrosis of femoral heads Osteoporosis Peptic ulcer disease Cataracts

RITUXIMAB • • • • •

Bone marrow suppression Severe infusion reactions Arrhythmia, cardiogenic shock Angioedema Flu-like symptoms

There is a strong association with antibodies against myelinassociated glycoprotein (anti-MAG). This is often discovered after finding an elevated IgM level on serum immunofixation electrophoresis. Patients respond poorly to immunomodulatory therapy.

Multifocal acquired demyelinating sensory and motor neuropathy

Insidious onset of motor and sensory loss in the distribution of individual nerves with accompanying pain and paresthesias. Arms are usually involved initially with eventual spread to the legs. Reflexes are diminished or absent in accordance with the

• Routine urinalysis to evaluate for hematuria (may indicate bladder carcinoma) • Ample fluids following dosing • Complete blood counts with platelets weekly for the first month and then monthly while on treatment; total leukocyte counts < 3500/mL mandates taper or suspension of the medication • Birth control measures • Baseline complete blood count with platelets and liver function tests, then repeated every 3 months; should be checked if fever develops • Prophylactic trimethoprim/sulfamethoxazole twice weekly • Discontinue medication if rash develops • Baseline pulmonary function tests

• Complete blood count with platelets weekly during first month, twice monthly for next 2 months, then monthly through the first year on medication

• Monitor diet and weight, regular exercise program • Periodic serum glucose and blood pressure monitoring • Supplemental calcium with vitamin D, may require bisphosphonates if abnormal bone density testing • Proton pump inhibitor • Ophthalmology evaluation

• Baseline complete blood count, repeat at 2 and 4 weeks, then monthly • Caution in patients with a history of coronary artery disease or arrhythmias • Discontinue in cases of severe reactions

involved nerves. As the disease progresses, diffuse areflexia may develop. Like MMN, motor NCS may reveal conduction block, temporal dispersion, prolonged distal latencies, slowed conduction velocities, and prolonged F responses. Unlike MMN, sensory responses may also be abnormal. CSF total protein is elevated in a majority of cases. There may be improvement with IVIG or corticosteroid treatment.

CIDP with neurofascin-155 immunoglobulin G4 autoantibodies31

Neurofascin-155 (NF155) belongs to the L1 family of adhesion molecules and is expressed at paranodes by terminal loops of

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784 myelin. It is also associated with axonal cell adhesion molecules contactin 1 (CNTN1) and contact-associated protein-1 (Caspr1), which play a role on rapid propagation of nerve impulses along axons. One study found that about 7% of patients diagnosed with CIDP were found to have anti-NF155 IgG4 antibodies. These patients were younger at symptom onset, had sensory ataxia, tremor, and central nervous system (CNS) demyelination, and had poor response to IVIG. Poor response to IVIG is thought to be due to low affinity of IgG4 antibodies to Fc receptors and C1q. Beneficial response was found with treatment of plasma exchange and rituximab infusion.

VASCULITIC NEUROPATHY32 Definition and epidemiology

Ischemia and infarction of one or more peripheral nerves due to vasculitis (destruction of the blood vessel wall from inflammatory cell infiltration) of the vasa nervorum. • Peripheral nerve involvement can occur in up to 30% of systemic vasculitidies.8 • Of all cases of vasculitic neuropathy, approximately 30% have no other organ involvement (nonsystemic vasculitic neuropathy). 33

Etiology Systemic vasculitic neuropathy

The vasculitidies most commonly associated with vasculitic neuropathy are those affecting small- to medium-sized vessels. The vasa vasorum contains vessels ranging from 50 to 400 μm in diameter. • Primary systemic vasculitic neuropathy occurs in the setting of a disorder with mainly vasculitic manifestations: • Eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome): neuropathy is common, occurring in 65–80% of cases. • Microscopic polyangiitis occurs in > 50% of cases. • Polyarteritis nodosa: up to 75% of patients. • Granulomatosis with angiitis (Wegener’s granulomatosis): 14–40% of patients. • Secondary systemic vasculitic neuropathy occurs in the setting of a disorder with nonvasculitic manifestations such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjögren’s syndrome. Vasculitic neuropathy is uncommon in SLE and rheumatoid arthritis, but is a relatively common occurrence in Sjögren’s syndrome.

Other vasculitic neuropathies

• In nonsystemic vasculitic neuropathy, vasculitis is isolated to the peripheral nerves with no other systemic manifestations. However, in 6–37% of these cases, systemic vasculitis is discovered later on in the course of the disease. • Hypersensitivity and infectious vasculitic syndromes with associated neuropathy are rare: • Infectious: hepatitis C (often associated with cryoglobulinemia), HIV, CMV, herpes zoster, Lyme disease, syphilis, tuberculosis, beta-hemolytic streptococci. • Drug-induced: sulfonamides, amphetamines, cocaine. • Paraneoplastic vasculitic neuropathy from an underlying malignancy (rare etiology).

Pathophysiology

• An inflammatory process with unknown triggering events. Altered expression and function of adhesion molecules and leukocyte and endothelial cell activation appear to play a role in pathogenesis. 34 • Drug-induced: most likely related to a complement-mediated leukocytoclastic reaction.

Clinical features

Mononeuropathy multiplex is the classic presentation of peripheral nerve involvement. Symptoms occur in multiple individual nerve distributions. The first symptom is often the sudden onset of severe, throbbing pain localized to the region of acute nerve infarction, which usually occurs in the upper arm or thigh due to watershed areas of the vasa nervorum. The absence of pain is rare and should raise concern for an alternative diagnosis. The pain is followed by sensory abnormalities and weakness in the distribution of the affected nerves. Nerves that are particularly susceptible to injury include the peroneal nerve (90%), tibial nerve (38%), ulnar nerve (35%), and median nerve (26%).8 Mononeuropathies may occur within days or weeks of each other. However, in the event that only one nerve is clinically symptomatic, vasculitic neuropathy should be included in the differential diagnosis if the mononeuropathy was preceded by severe limb pain. In clinical practice, the majority of patients have a confluence of multiple mononeuropathies, which appears as a generalized and asymmetric polyneuropathy at the time of presentation. It is important to ask the patient direct questions regarding the onset and progression of symptoms. They may describe a stepwise progression of individual nerve involvement coalescing into a diffuse pattern (e.g. right foot drop followed by left foot drop later on). Again, pain should be a prominent feature. Occasionally, symptoms may worsen rapidly over days and evolve into a painful quadriparesis.

TIP • Mononeuropathy multiplex – think vasculitis.

Signs and symptoms associated with systemic vasculitis

• Weight loss, malaise, fevers/chills, and night sweats. • Signs of other end-organ dysfunction (skin, lung, bowel, kidney, joints, CNS). • Eosinophilic granulomatosis with polyangiitis syndrome usually presents with asthma, pulmonary infiltrates, fevers, and eosinophilia. However, an initial presentation of vasculitic neuropathy occurs in more than 20% of cases. • Most common pattern of nerve involvement in polyarteritis nodosa is mononeuropathy multiplex. Cranial neuropathies and CNS involvement occur in < 2% of patients. The neuropathy is commonly associated with hepatitis B, which portends a more aggressive disease course. • Granulomatosis with angiitis is a necrotizing vasculitis of the respiratory tract and kidneys. Early symptoms include nasal discharge, coughing, and hemoptysis. Neuropathy usually occurs in the setting of severe renal involvement.

Diseases of the Peripheral Nerve and Mononeuropathies

• •

•

•

•

Cranial neuropathies occur in 5–10% of cases as a result of extension of nasal granulomas rather than vasculitis. Skin rash of erythematous macules or purpuric papules associated with cryoglobulinemia (Figure 25.16). Sicca symptoms (dry mouth, dry eyes) associated with Sjögren’s syndrome. Sjögren’s syndrome may present with a sensory neuronopathy (dorsal root ganglionopathy) or distal sensory neuropathy. Cranial neuropathies, such as trigeminal neuropathy, can occur. Rheumatoid vasculitis occurs as a late manifestation of severe seropositive disease. With advancements in effective treatment, this is declining in incidence. Many patients with rheumatoid arthritis develop a mild, symmetrical polyneuropathy, which is distinct from vasculitic neuropathy. Median mononeuropathy at the wrist (carpal tunnel syndrome) and other compressive neuropathies are quite common. Nonsystemic vasculitic neuropathy usually presents with mononeuropathy multiplex. Individual attacks of mononeuropathy are less frequent than systemic vasculitic neuropathy. Most affected nerves recover gradually. When considering drug-induced vasculitic neuropathy, there should be a temporal relationship with drug ingestion.

Differential diagnosis

• Compression or entrapment neuropathies; however, conduction block in vasculitic neuropathy is not located at common compression sites. • Multifocal motor neuropathy: usually not painful. • Malignant infiltration of individual nerves.

785 • Diabetic lumbosacral radiculoplexus neuropathy may present with similar clinical features.

Investigations NCS

• Sensory and motor responses are absent or have reduced amplitudes (axonal degeneration). Pattern of nerve involvement is often multifocal and asymmetric and can be nonlength dependent. • Usually, demyelination features are not present. However, conduction blocks (not at common compression sites) can be identified if the NCS are performed within a few days after nerve infarction and prior to wallerian degeneration. This phenomenon has been labeled pseudoconduction block due to the ‘disappearance’ of the conduction block on follow-up studies performed after 1 week or more. At that time, the motor responses have reduced amplitude due to the axon loss.

Blood and CSF

• CSF studies are often not helpful other than ruling out other etiologies (infections, inflammatory, carcinomatous). 34 • Routine blood and urine tests: complete blood count, metabolic panel (electrolytes, glucose, blood urea nitrogen, creatinine), erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, urinalysis. • Other blood tests that should be included in the work-up for a systemic vasculitis: • Rheumatoid factor, anticyclic citrullinated peptide (CCP) antibody (rheumatoid arthritis). Rheumatoid factor can be positive in other autoimmune diseases, infections (hepatitis C), and following chemotherapy and radiation treatment for cancer. However, antiCCP antibody has a high specificity for rheumatoid arthritis. 35 • Antineutrophil cytoplasmic antibodies (ANCAs) are positive in 90% of granulomatosis with angiitis (anticANCA, usually against the PR3 antigen) and 50% of eosinophilic granulomatosis with polyangiitis (antipANCA usually against the myeloperoxidase [MPO] antigen). • Serum complement levels, anti–double-stranded DNA antibodies (SLE). • Anti-Ro/SSA, anti-La/SSB (Sjögren’s syndrome). • Hepatitis B and C panel. • Cryoglobulins.

Nerve biopsy

FIGURE 25.16  Skin rash associated with cryoglobulinemia.

Evaluating for vasculitic neuropathy is an important indication for nerve biopsy. In most cases, the diagnosis of vasculitic neuropathy is established by nerve biopsy, although the onset of neuropathy following a diagnostic biopsy of another affected organ (e.g. kidney, lung) can practically secure the diagnosis (systemic vasculitic neuropathy). Nerve biopsy is mandatory to confirm the diagnosis of nonsystemic vasculitic neuropathy. Combined nerve and muscle biopsy is recommended as this improves the diagnostic yield (e.g. sensory branch of the superficial peroneal nerve and peroneus brevis muscle). The frequency of a diagnostic nerve biopsy or combined nerve/muscle biopsy (with a mandatory finding of vessel wall disruption) is approximately 60%.

Hankey’s Clinical Neurology

786

1 g/m2, respectively. In severe cases, IV methylprednisolone can be used instead of oral prednisone. Cyclophosphamide seems to be the most effective medication for induction of remission. Most patients require 3–12 months of cyclophosphamide before transitioning to a maintenance immunosuppressant (i.e. azathioprine, methotrexate, rituximab, mycophenolate mofetil). After 1–2 months a slow prednisone taper can be started. The daily dose can be reduced by 5–10 mg every month with an even slower taper when doses reach < 20 mg daily.

Nonsystemic vasculitic neuropathy

FIGURE 25.17  Sural nerve biopsy showing inflammation of a blood vessel wall and surrounding epineurial connective tissue and fascicles. (Courtesy of Tibor Valyi-Nagy, MD, PhD.) Characteristic histopathological findings include: • Inflammatory cell infiltration of blood vessels: T cells and macrophages invading epineurial arteries (Figures 25.17, 25.18). • Necrosis of the vessel wall leading to structural damage. Immunohistochemically, immunoglobulin (IgM, IgG), complement, membrane attack, and complex deposition on blood vessels are seen. A supportive feature is multifocal, asymmetric nerve fiber loss with variable degrees of axon degeneration among different nerve fascicles.8 EMG shows denervation in muscles supplied by affected nerves.

Treatment Systemic vasculitic neuropathy

There are currently no controlled treatment trials. Thus, treatment regimens are derived from studies in patients with systemic vasculitis without neuropathy. Initial treatment includes prednisone 1 mg/kg/day and oral or IV pulse cyclophosphamide with doses of 1–2 mg/kg/day and

The neurologic deficits often spontaneously resolve over time. The disease may remit for many years before returning. Therefore, the risks of immunosuppressive therapies should be thoroughly weighed against the potential benefits prior to initiation. Prednisone monotherapy is often adequate, at a dose of 40–60 mg daily for 2–3 months. If there is an adequate clinical response, a slow taper can be initiated with transition to alternate day dosing.34 A retrospective study indicated that combination therapy of prednisone and cyclophosphamide had a superior response after 6 months and fewer relapses compared with patients taking prednisone alone. However, the patients treated with cyclophosphamide had a greater incidence of pneumonia, herpes zoster, and sepsis.8 Other options for corticosteroid nonresponders or those with tapering difficulties include azathioprine or methotrexate.

Prognosis

If left untreated, systemic vasculitic neuropathy may be fatal. Thus, therapeutic intervention is almost always indicated. Unlike systemic vasculitic neuropathy, untreated nonsystemic vasculitic neuropathy is not usually fatal. Long-term follow-up studies have shown that most patients with nonsystemic vasculitic neuropathy can walk without assistance.

IMMUNE-MEDIATED BRACHIAL PLEXUS NEUROPATHY Definition and epidemiology

Acute to subacute injury to the brachial plexus or individual nerves of the upper extremity resulting in severe arm pain, weakness, and sensory changes. Other terminologies include Parsonage–Turner syndrome, acute brachial plexitis, and neuralgic amyotrophy. • Annual incidence: 1.64 per 100,000 population. • Male to female ratio: 2:1. • Age: any age group, but most commonly occurs in ages 20–50 years. 36

Etiology and pathophysiology

• Unknown. Possibly an autoimmune reaction to a preceding trigger such as immunizations, infections, or surgery. • Post surgical inflammatory neuropathy, may also affect the lower extremities, especially the sciatic nerve and lumbosacral plexus. • Most cases occur in healthy individuals. • Some reports hypothesize the production of antibodies against the peripheral nerve.

FIGURE 25.18  Sural nerve biopsy from a patient with ischemic neuropathy due to polyarteritis nodosa, showing infiltration by neutrophils and fibrinoid necrosis of the vessel wall.

Clinical features

Usually presents with an acute onset of severe pain in the shoulder, which is often described as a ‘hot poker’ jabbed into the

Diseases of the Peripheral Nerve and Mononeuropathies shoulder. Movement of the shoulder or arm exacerbates the pain. The pain lasts for several days to a few weeks, but a dull ache can last for years. When the pain somewhat subsides, weakness and sensory changes are noted. Because the pain is so severe initially, arm weakness may go unnoticed, as arm movement may not even be attempted. Weakness and sensory changes depend on the distribution of nerve involvement (i.e. upper or lower trunk, specific cords, or terminal nerves). The most common pattern involves the upper trunk or a single mononeuropathy or multiple mononeuropathies, primarily the suprascapular, long thoracic, or axillary nerves. Less likely, the phrenic nerve or anterior interosseous nerve may be affected. In cases involving individual nerves, it has been proposed that the pathology is probably within the corresponding fascicle of the brachial plexus rather than a separate trunk of the respective nerve. Most cases are unilateral, but up to 10% can have bilateral involvement.

Hereditary neuralgic amyotrophy

• Inherited as an autosomal dominant trait. • Associated with a mutation in the gene septin 9. • Genetically distinct from hereditary neuropathy with liability to pressure palsies. • Episodes consist of pain, weakness, and sensory loss in the distribution of the brachial plexus and may be precipitated by pregnancy, infection, and other physical stressors and tend to recur. • Congenital anomalies, such as syndactyly and hypotelorism, are common associated features.

Differential diagnosis

• Multifocal motor neuropathy: NCS may show conduction block and other demyelinating features. immune-mediated brachial plexus neuropathy (IBPN) is usually axonal. • Vasculitic neuropathy. • Nerve sheath tumors. • Radiation-induced brachial plexopathy versus tumor invasion of the brachial plexus (neoplastic plexopathy): • Radiation-induced brachial plexopathy: – Malignancies such as breast cancer, lung carcinoma, and lymphoma are often treated with radiation therapy to the chest. The brachial plexus often falls within this radiation plane. – Radiation results in direct toxic effects on axons and on the vasa nervorum (secondary microinfarction of the nerve). Fibrosis of the surrounding tissues may also affect the nerves. – Risk of injury is dose-dependent. Pathologic changes of the Schwann cells, endoneurial fibroblasts, and vascular and perineural cells are noted with doses above 1000 cGy. – Overall frequency of radiation-induced brachial plexopathy in treated patients is 1.8–4.9%. 37 – Can occur months to years following therapy. – Usually affects the upper trunk and is painless. – Strongly associated with myokymic discharges on EMG. • Neoplastic plexopathy: – Less common than radiation-induced. – Painful and usually affects the lower trunk. May have associated Horner’s syndrome.

787 – MRI appears to be more sensitive than computed tomography (CT) in detecting tumor invasion. The presence of a mass compressing a portion of the brachial plexus is the most helpful feature distinguishing tumor invasion from radiation injury.38 Increased T2 signal may be present in radiation injury. Usually, there is no contrast enhancement of the brachial plexus with radiation-induced plexopathies.37

Investigations NCS

Abnormalities depend on which sites of the brachial plexus are involved. In most cases, the upper trunk is affected resulting in abnormal motor responses recorded from the deltoid (axillary nerve) and biceps (musculocutaneous nerve), median and radial sensory responses, and lateral antebrachial cutaneous response. Lower trunk involvement results in abnormal median and ulnar motor responses, ulnar sensory response, and medial antebrachial cutaneous response.

Other tests

• EMG: denervation of the muscles supplied by the affected nerves. • CSF; occasional abnormalities of elevated protein or pleocytosis. • MRI with and without contrast of the brachial plexus to evaluate for a mass lesion (i.e. tumor invasion, lymphoma, neurofibroma, schwannoma). In IBPN, there may be increased T2 signal suggestive of inflammation or edema.

Treatment

• Pain can be treated with high-dose prednisone and taper. However, there is limited evidence for efficacy. Physical and occupational therapy are important to initiate immediately to prevent joint contractures (i.e. ‘frozen shoulder’).

Prognosis

IBPN is usually monophasic, although attacks can occasionally recur. One large study found that 36% of patients recovered most functions within the first year, 75% within the second year, and 89% within the third year. 39

INFECTIOUS NEUROPATHY LEPROSY Definition, epidemiology, and etiology • • • •

Leading cause of peripheral neuropathy worldwide. 15–20% of affected individuals will develop neuropathy. Most prevalent in southeast Asia and other tropical areas. In the United States, cases of leprosy have been found in Hawaii and some southern states.

Pathophysiology

Caused by Mycobacterium leprae, an acid-fast organism that reproduces best in cool temperatures, which explains its attraction to cooler areas of the body (skin, superficial nerves, nose, testes, and ears). It is probably spread by the respiratory route.

Clinical features

Primarily affects the skin and nerves. There are two main clinical presentations, which depend on the immunologic status of the patient: tuberculoid and lepromatous.

Hankey’s Clinical Neurology

788 Variants Tuberculoid leprosy

• Host with good immune status. Clinical syndrome is due to the intense immune response produced by the bacterial exposure. • Well-localized disease process that produces sharply demarcated, raised skin lesions with a hypopigmented anesthetic center. Skins lesions occur on the extensor surfaces of the arms, legs, face, and buttocks. • Good prognosis with lesions often healing spontaneously.

Lepromatous leprosy

• Host with poor immune status. • Extensive bacterial infiltration of the skin, nerves, and dissemination through the blood. • Skin lesions include nodules, bullous lesions, ulcers, macules, and papules. • Diffuse, symmetric disease with solitary lesions only occurring in the initial stages. • Poor prognosis if left untreated.

Borderline leprosy

• Clinical syndrome that lies between tuberculoid and lepromatous. • If treated, may move toward tuberculoid. • If left untreated, prognosis is poor and tends to transition into lepromatous.

Neuropathy

• Most common symptom is such severe sensory loss that painless injuries to the skin occur. • Mononeuropathy can occur if a particular nerve trunk passes through an area of inflammation. • Frequently involved nerves include the ulnar nerve at the elbow, median nerve in the forearm, peroneal nerve at the fibular head, and facial nerves. • In tuberculoid, patchy sensory loss occurs, primarily affecting small fiber nerves. • In lepromatous, diffuse polyneuropathy occurs later on in the disease process (months to years). • Examination findings: • Tender enlargement of one or more peripheral nerves over part of their superficial course (e.g. the superficial radial sensory nerve at the wrist). • Hypopigmented areas of skin may be present, but can be difficult to detect in Caucasians. Loss of pain sensation and often anhidrosis in the affected skin areas. • Painless ulcerations of the fingers and toes may be present.

Differential diagnosis

Thickening of the nerves may be noted in the following: • Hypertrophic forms of hereditary neuropathies. • Neurofibromatosis. • Phytanic acid deficiency (Refsum’s disease). • Amyloidosis. • CIDP.

Investigations and diagnosis

• NCS: nerves most affected are ulnar nerve at the elbow and median nerve in the distal forearm.

• May find more diffuse disease when clinical examination only reveals single nerve involvement. • Diagnosis of leprosy is confirmed by identifying acid-fast organisms in a skin biopsy from affected areas. • Sensory nerve biopsy can be informative if skin biopsy is indeterminate. • Serum assay for phenolic glycolipid-1 (PGL-1) antibodies is very sensitive and correlates with bacterial load.

Treatment

Patients are divided into two groups: • Paucibacillary: • Fewer bacilli on biopsy. • World Health Organization (WHO) recommendations: rifampicin 600 mg monthly, dapsone 100 mg daily for 6 months; single-lesion paucibacillary: single dose of rifampicin 600 mg, ofloxacin 400 mg, and minocycline 100 mg (ROM). • Multibacillary: • Infiltrating disease, many bacilli on biopsy. • WHO recommendations: rifampicin 600 mg and clofazimine 300 mg monthly; dapsone 100 mg and clofazimine 50 mg daily for 12 months.

Prognosis

Risk of relapse is negligible, so posttreatment surveillance is not recommended.

LYME DISEASE Definition, epidemiology, and etiology

Caused by the spirochete Borrelia burgdorferi and transmitted by Ixodes dammini (a deer tick endemic in some areas of the United States) as a primary vector. The tick must be attached for about 12–24 hours to transfer the spirochete to the human host.

Pathophysiology

• Target organs are skin, heart, nervous system, and joints. • Peripheral nerve injury may be due to an indirect immunologic response or a type of vasculopathy.

Clinical features

There are three stages of disease: early, disseminated, and late.

Early infection

• Skin lesion (erythema migrans) appears within a few days to a few weeks of the bite. • An erythematous circular area appears around the original bite site and gradually expands with a central clearing, creating a ‘bull’s eye’ appearance. This lasts for about 1 month and resolves spontaneously. • Some patients may not develop erythema migrans.

Disseminated infection

• Spirochetes spread through body, and systemic symptoms develop (fever, chills, fatigue, myalgias, headaches). • Patients may have pericarditis and inflammatory arthritis. • Neurologic complications can occur including facial neuropathy (bilateral in approximately 50% of cases) and polyradiculoneuropathy similar to GBS.

Diseases of the Peripheral Nerve and Mononeuropathies Late-stage infection

• Arthritis worsens. • Acrodermatitis chronica atrophicans: bluish discoloration of the skin. • 40–60% of patients develop a polyneuropathy many years after the original infection.

Investigations

NCS may show an axonal polyneuropathy. If the facial nerve is involved, patients may have reduced facial nerve CMAP and an abnormal blink reflex. CSF studies show increased protein and lymphocytic pleocytosis if there are cranial neuropathies or polyradiculitis.

Diagnosis

• Detection of antibody to B. burgdorferi in serum and/or CSF. • False-positive antibodies have been identified in rheumatoid arthritis, tuberculous meningitis, mononucleosis, and Rocky Mountain spotted fever.

Treatment

• Early infection without evidence of CSF involvement; oral doxycycline or amoxicillin for 3 weeks. • Late infection or clinically severe disease: intravenous ceftriaxone or cefotaxime for 2–4 weeks.

DIPHTHERIA Definition, epidemiology, and etiology

Caused by the bacteria Corynebacterium diphtheriae. Diphtheria has been eliminated in most developed countries through childhood immunization programs. • Children who have not been immunized are at risk (primarily in developing countries). • Adults who were previously immunized in childhood and now have lost the immune protection are at risk during epidemics. • 20% of infected patients develop a polyneuropathy.

Pathophysiology

• Inhaled or permeates through the skin (e.g. in warfare). • Polyneuropathy is caused by a toxin that is released from the bacteria: • The toxin disrupts the Schwann cells’ production of myelin. • The clinical effects of demyelination do not occur until the cells recycle and myelin cannot be produced.

Clinical features

• Initial infection presents with flu-like symptoms including fatigue, headaches, myalgias, and fever within 1 week of exposure. The pharynx may be covered in a white membranous exudate resulting in dysarthria and regurgitation of liquids from palatal paralysis. Within 1 month, development of blurred vision occurs from failure to accommodate. The phrenic nerve may be involved causing respiratory distress.

Polyneuropathy may develop over the next 2–3 months, manifesting as progressive numbness, paresthesias, and weakness of the arms and legs. Weakness may progress to inability to ambulate over the course of weeks.

Differential diagnosis

Distinguish from GBS, which has less severity of bulbar involvement compared with diphtheria.

789 Investigations and diagnosis NCS

• Demyelinating polyneuropathy. • Initially, increased distal latencies and prolonged F responses, normal SNAPs. • As the weakness progresses, conduction velocity slowing worsens and SNAP amplitude decreases. • There is a dissociation between electrodiagnostic and clinical findings (i.e. weakness may be improving, but electrodiagnostic abnormalities continue to worsen).

CSF

• Elevated protein with or without lymphocytic pleocytosis.

Diagnosis is from culturing bacteria from throat swabs or elevated serum diphtheria antibody titers.

Treatment

Antitoxin should be administered within 48 hours of symptom onset. Treatment beyond 48 hours does not affect development of polyneuropathy or prevent death.

Prognosis

About 80% of people will have resolution of the polyneuropathy 1 year following the infection.

HUMAN IMMUNODEFICIENCY VIRUS Epidemiology and pathophysiology

Approximately 20% of HIV patients will develop some type of neuropathy, either due to the virus itself, secondary infections, or toxicity from antiretroviral medications. The pathophysiology is unknown, but does not appear to be due to infection of the nerves. Neuropathies may be immune-mediated and caused by the release of cytokines.

Clinical features40

The types of neuropathy include distal symmetric polyneuropathy (DSPN), AIDP or CIDP, mononeuropathy multiplex, motor neuronopathy, and sensory ganglionopathy. DSPN is the most common type of neuropathy associated with HIV and is often found in patients with acquired immunodeficiency syndrome (AIDS).

AIDP

• Usually occurs at the time of seroconversion. • Progressive weakness, sometimes evolving to respiratory insufficiency.

CIDP

• Can occur anytime. • May follow a progressive or relapsing course.

Other HIV associated neuropathies

• Mononeuropathy multiplex due to vasculitis is rare in HIV. • Motor neuronopathy presentations have been similar to primary lateral sclerosis, amyotrophic lateral sclerosis, and bibrachial diplegia and respond to antiretroviral therapy. • Sensory ganglionopathy results in abnormalities in all sensory modalities and gait ataxia.

Hankey’s Clinical Neurology

790 Differential diagnosis

• For mononeuropathy multiplex, consider coinfection with hepatitis C (cryoglobulinemia) or CMV. • Progressive polyradiculopathy due to CMV-infected cauda equina. • Neurosyphilis. • Lymphomatous meningitis. • Sensory ganglionopathy: Sjögren’s syndrome, paraneoplastic.

Investigations

• CD4 lymphocyte count and serum viral load. • NCS and EMG to further define the specific type of neuropathy. • Nerve biopsy is indicated if vasculitis or an infiltrative process of the nerve is likely. • Lumbar spine MRI with and without contrast to evaluate for enhancement of nerve roots. • CSF to evaluate for pleocytosis, increased protein, and/or viral polymerase chain reaction (PCR) for CMV.

Treatment

Initiation of highly active antiretroviral therapy (HAART) is necessary to suppress viral replication, but the associated neuropathy is usually not responsive to this treatment. Neuropathy (particularly DSPN) has been a disabling side effect of dideoxynucleoside antiretrovirals (d-drugs), which are suspected to cause a neuropathy through direct toxicity on mitochondrial DNA replication. Elevated lactate levels may help distinguish d-drugs neuropathy from HIV-induced neuropathy with a specificity and sensitivity of 90%.41 The associated neuropathic pain has limited the use of these medications in the developed world. Protease inhibitors may have a small risk of DSPN, but this should be weighed against the importance of treatment.42 Medications should be given for neuropathic pain. Treatments for AIDP, CIDP, mononeuropathy multiplex, and sensory ganglionopathy are similar to those used in the HIV-negative population. CMV infection should be treated with ganciclovir or foscarnet.

Prognosis

• Most neuropathies persist and require symptomatic management. • Natural course of AIDP and CIDP is similar to that in the HIV-negative population. • Even with treatment, the prognosis for progressive polyradiculopathy with CMV is poor, and most patients die within weeks or months.

CHARCOT–MARIE–TOOTH DISEASE43 (HEREDITARY MOTOR AND SENSORY NEUROPATHY) Definition and epidemiology

These are genetic disorders resulting in peripheral neuropathy where the peripheral neuropathy is either the dominant or only manifestation. CMT is the most common type of hereditary neuropathy. Prevalence is generally said to be 1 in 2500 individuals worldwide, but substantial geographic differences have been reported (approximately 10–80 per 100,000 population).44

Etiology and pathophysiology

Hereditary neuropathies are classified based on electrophysiology (axonal vs. demyelinating vs. intermediate), inheritance pattern (autosomal dominant, autosomal recessive, or X-linked), and specific gene mutations. Demyelinating forms have upper extremity conduction velocities < 38 m/s but typically < 30 m/s, while axonal forms are > 38 m/s, but often near normal. Some mutations cause an intermediate electrophysiologic picture with velocities from 25 to 45 m/s. About 90% of all cases have mutations in one of five genes (PMP22, MPZ, GJB1, MFN2, or GDAP1). However, there are now more than 100 genetically identified causes of CMT.44 As this is a rapidly evolving field, novel genes are still being discovered, and there are many more subtypes than are covered in this chapter.

TIP • Approximately 60–70% of autosomal dominant neuropathies are CMT type 1A.

CMT GENETICS – SELECTED EXAMPLES CMT type 1

Autosomal dominant, demyelinating. The mutations disrupt myelin and Schwann cell function leading to demyelination and secondary axonal loss.

CMT 1A

• 60–70% of type 1 cases. • Duplication of a large region of DNA on chromosome 17 (17p11.2) which includes the peripheral myelin protein-22 (PMP22) gene; this is hypothesized to produces a toxic gain of function of the protein.

The normal function of PMP22 is not known, but it is believed to help maintain myelin structure and is expressed in compact myelin. • Deletion of 1 copy of the same stretch of DNA causes hereditary neuropathy with liability to pressure palsies (HNPP).

CMT 1B

• 5–10% of type 1 cases. • Mutation of the myelin protein zero (MPZ) gene on chromosome 1 (1q22–23). MPZ mutations also cause CMT 2I. • MPZ maintains linkage between myelin layers and accounts for the majority of myelin protein in the peripheral nervous system.

CMT 1C

• Rare. • Mutations in lipopolysaccharide-induced tumor necrosis factor-alpha factor (LITAF) also known as small integral membrane protein of the lysosome/late endosome (SIMPLE) on chromosome 16 (16p13.3–p12). • LITAF is expressed on Schwann cells, and if abnormal, may have altered protein degradation.

CMT 1D

• < 1% of type 1 cases.

Diseases of the Peripheral Nerve and Mononeuropathies • Mutations in the early growth response 2 (EGR2) gene on chromosome 10 (10q21.1–22.1). • ERG2 may play a role in regulating myelin genes in Schwann cells.

CMT 1E

• < 5% of all type 1 cases. • Point mutations in PMP22. • Associated with hearing loss.

CMT 1F

• < 5% of all type 1 cases. • Point mutations in NEFL. NEFL mutations also cause CMT 2E. • Associated with hearing loss.

CMT type 2

Autosomal dominant, axonal; nerve conduction velocity > 38 m/s; much less common than type 1. Disruption of axonal transport is a feature. • Presents later in life. • Patients may not complain of sensory loss, but examination of sensory modalities (vibratory sense, proprioception) reveals marked diminishment. • Less intrinsic hand involvement and less frequent foot deformities compared with type 1. • Anterior and posterior compartments of the distal lower extremities tend to be equally affected. • Generalized areflexia is unusual.

CMT 2A

• Most common of type 2 cases (up to 33% of type 2). • Mutation of the mitofusin-2 (MFN2) gene on chromosome 1 (1p36.2). • MFN2 is presumed to function in the maintenance of the mitochondrial network.45 May have optic atrophy, hearing loss, pyramidal signs, white matter abnormalities.

791 • Approximately 12% of all CMT cases. • Mutation of connexin-32 on chromosome X (Xq13). • Connexin-32 is a gap junction formation in the Schwann cells.

Hereditary neuropathy with liability to pressure palsies

• Autosomal dominant. • Majority of cases are due to deletion of the PMP22 gene on chromosome 17 (17p11.2), as opposed to duplication of the gene in CMT type 1A.

Clinical features CMT type 1

• Usual onset in the first decade to 40s. Patient may experience frequent ankle sprains prior to diagnosis. • Patients may not complain of sensory loss (as opposed to acquired neuropathies), but examination of sensory modalities (vibratory sense, proprioception) reveals marked diminishment. • Anterior compartment of the distal lower extremities is usually affected first resulting in foot drop and ‘inverted champagne bottle’-shaped legs (Figure 25.19). • Relative sparing of the proximal extremities, although, over time, proximal weakness may develop. • Atrophy of the distal upper extremities, formation of clawhand deformities (Figure 25.20). • Generalized areflexia. • Upper limb tremor may be present, and when prominent, it is known as Roussy–Levy syndrome. • Pes cavus and hammer toes are more frequent than in other types (Figure 25.21).

CMT type 2

• Presents later in life. • Patients may not complain of sensory loss, but examination of sensory modalities (vibratory sense, proprioception) reveals marked diminishment.

CMT type 2B

• Due to mutations in RAB7. • RAB7 is a small GTPase controls transport to late endocytic compartments. • Predominant sensory involvement.

CMT type 3

• Outdated term, now called Dejerine–Sottas or congenital hypomyelinating neuropathy (DSN/CHN), severe demyelination or hypomyelination. • Autosomal recessive or de novo autosomal dominant: ERG2, EGR2 periaxin , PMP22, MPZ.

CMT type 4

• Autosomal recessive, axonal or demyelinating. • Type 4A is due to a mutation of ganglioside-induced differentiation-associated protein-1 (GDAP1) on chromosome 8 (8q13–q21). GDAP1 mutations also cause CMT 2K. • GDAP1 helps regulate the mitochondrial network.

CMT type 1X

• X-linked dominant.

FIGURE 25.19  Tapering of the legs to the ankles in a case of CMT type 1A.

Hankey’s Clinical Neurology

792 CMT type 1X

• Affected men have a similar presentation to CMT type 1. • Female carriers may present with a mild neuropathy that is usually asymptomatic. • Rare CNS involvement.

HNPP

FIGURE 25.20  Intrinsic hand muscle atrophy with mild clawing of the fourth and fifth fingers in a case of CMT type 1A. • Less intrinsic hand involvement and less frequent foot deformities compared with type 1. • Anterior and posterior compartments of the distal lower extremities tend to be equally affected. • Generalized areflexia is unusual. • CMT type 2A: can present early in life with a severe course; some cases present later and have a course more typical for CMT 2. May be associated with optic atrophy, hearing loss, pyramidal signs, and white matter abnormalities.

DSN/CHN

• Usually, weakness at birth (hypotonic infant); if severely affected, it may have respiratory distress that may lead to death. • Less severe cases present in early childhood. Children have significant delay in motor milestones, but may eventually ambulate. • All sensory modalities are affected. • Sensorineural hearing loss. • Abnormal pupillary reaction. • Enlarged peripheral nerves. • Pes cavus and kyphoscoliosis.

CMT type 4

• Onset in early infancy with motor developmental delay. • Weakness and muscle atrophy. • Mild sensory loss, areflexia, may have scoliosis.

• Presentation occurs in second or third decade. • Some patients present at an earlier age while others may be asymptomatic for their lifetime. • Painless sensory loss and weakness in a single nerve distribution after light external compression of that nerve (e.g. peroneal neuropathy after briefly crossing the legs). Mononeuropathies usually resolve, but may take weeks or months. • Most commonly affected nerves include median nerve at the wrist, ulnar nerve at the elbow, radial nerve in the spiral groove, peroneal nerve at the fibular head. Cranial nerves with physiologic entrapment sites, such as the facial and acoustic nerves, may also be involved. • On examination, there is diminished sensation to all modalities, depressed or normal reflexes, pes cavus, hammer toes.

Differential diagnosis

• Other hereditary motor and sensory neuropathies (Refsum’s disease, Fabry’s disease, porphyria, familial amyloid polyneuropathy). • Hereditary spastic paraparesis if there is clinical examination evidence of pyramidal tract involvement or white matter disease. • CIDP when proximal weakness is present. • Distal myopathy: E. g. Miyoshi’s myopathy (dysferlinopathy). • For HNPP: other causes of mononeuropathy multiplex such as vasculitic neuropathy or diabetes.

Investigations

The various forms of hereditary neuropathies may be difficult to distinguish from one another based on the clinical phenotype. NCS are helpful to determine whether the neuropathy is demyelinating or axonal. Based on these results, appropriate genetic testing can be obtained. Many genetic tests are available commercially. Nerve biopsies are usually not necessary as the diagnosis is often achieved through less invasive modalities.

CMT type 1 NCS

FIGURE 25.21  High arch and hammer toes in a case of CMT type 1A.

• May be normal at birth, but severe conduction velocity slowing is evident by age 5 and remains relatively unchanged. • In most cases, nerve conduction velocities range from 20 m/s to 25 m/s. • Markedly prolonged distal motor latencies. • CMAP amplitudes may be reduced when recorded from an atrophic muscle or as a manifestation of axonal loss occurring over time. • Delayed or absent F-waves. • Because demyelination is uniform throughout the nerve, most cases do not have conduction blocks or temporal dispersion, which is helpful to distinguish from acquired demyelinating neuropathies.

Diseases of the Peripheral Nerve and Mononeuropathies

793

EMG

• Denervation of the distal lower extremities (i.e. tibialis anterior, gastrocnemius, and intrinsic foot muscles) and distal upper extremities (i.e. forearm and intrinsic hand muscles).

Genetic testing

• In many clinics, free panels for screening multiple CMT mutations is available. • If not, obtain testing for CMT type 1A (PMP22 duplication) first, as this is the most common type of hereditary neuropathy. Consider CMT type 1X second if no male-to-male transmission is documented, since this is the second most common form. If negative, consider a broad CMT screening panel followed by whole exome sequencing if needed.

Nerve biopsy

• Not generally indicated for diagnosis. • May appear normal in early childhood, but as time goes on, the axons become thinly myelinated. • Recurrent demyelination and remyelination causes shortening of the internodal length. • ‘Onion bulbs’, comprising concentrically proliferated Schwann cells surrounding surviving myelinated fibers, are characteristic beyond adolescence (Figure 25.22).

EMG

• Denervation in distal extremity muscles.

CMT type 2 NCS

• Evidence of axonal neuropathy with reduced or absent SNAPs and reduced CMAP amplitudes. • Distal motor latencies are usually normal or mildly prolonged. • Nerve conduction velocities are normal or minimally slow, depending on the amount of axonal loss, and are usually > 38 m/s. • The NCS may be similar to nonhereditary axonal polyneuropathy. However, in CMT type 2, sensory abnormalities are

not a major complaint; patients with axonal polyneuropathy from other etiologies usually present with sensory symptoms.

Nerve biopsy

• Not generally indicated for diagnosis. Reduction in myelinated fibers and regenerative clusters. • Axonal atrophy. • Onion bulbs are not a classic feature.

Genetic testing

Consider screening for mitofusin mutations, especially if phenotype is consistent. If negative, consider a broad CMT screening panel, followed by whole exome sequencing if needed.

DSN/CHN NCS

• Motor nerve conduction velocity is usually 5–10 m/s or less, indicating dysmyelination. • Markedly prolonged distal motor latencies. • Absent SNAPs.

EMG

• Denervation with neurogenic MUPs; severe cases may have less reinnervation resulting in small, myopathic-appearing MUPs.

Nerve biopsy

• Not generally indicated for diagnosis. • Three categories of disease severity: • Most common, occurring in infantile onset: hypomyelination with basal lamina onion bulbs. • Mild form: classic onion bulbs. • Severe form: nerves have virtually no myelin, no onion bulbs; many patients do not survive.

Genetic testing

Consider a broad CMT screening panel, followed by whole exome sequencing if needed.

CMT type 4 NCS

• Reduced CMAP amplitudes. • Absent SNAPs. • Individual variability in nerve conduction velocity from normal to quite slow (axonal or demyelinating) depending on cause. Both Schwann cells and neurons express GDAP1, which may explain the variability seen in patients with GDAP1 mutations.

Nerve biopsy

• Hypomyelination with basal lamina onion bulbs. • Type 4B also has fibers with excessively folded myelin sheaths.

CMT type 1X NCS

• Both axonal and demyelinating features that are more pronounced in men than in women. • Nonuniform slowing of motor conduction velocities and dispersion of CMAPs gives appearance of an acquired demyelinating neuropathy.

FIGURE 25.22  ‘Onion bulb’ formation.

EMG

• Denervation in distal extremity muscles.

Hankey’s Clinical Neurology

794 Nerve biopsy

• Axonal atrophy, loss of myelinated fibers. Regenerating clusters. • Mild grade onion bulb formation surrounding the thinly myelinated fibers.

Genetic testing

Consider a broad CMT screening panel, followed by whole exome sequencing if needed.

HNPP NCS

• Despite focal clinical symptoms, NCS reveal prolonged distal latencies, slightly slowed conduction velocity, and normal/mildly reduced amplitudes. • Slowing of nerve conduction velocities and conduction block occur at common entrapment and compression sites.

Nerve biopsy

• Nerve fiber loss with demyelination and remyelination and axonal atrophy, but not as severe as CMT type 1. • Tomacula: focal, large, sausage-shaped thickening of the myelin sheath (superfluous loops of myelin), which is best viewed on tease fiber preparations.

Genetic testing

HNPP screening is generally included in CMT gene panels. Targeted testing for the PMP22 deletion is also an option.

Treatment of CMT • • • • • • • •

Current treatment is symptomatic. Ankle–foot orthoses for foot drop. Neuropathic pain is usually treated medically. Severe foot deformities can be evaluated by orthopedic surgery for potential intervention. Genetic counseling. HNPP, patients should avoid even mild nerve compression. Careful positioning during anesthesia is important. Trials of exercise, creatine, purified brain gangliosides, Vitamin C, myostatin inhibition and orthoses have not shown significant benefit.46 Potential benefit was noted in a small trial of neurotrophin-3 and a study of PXT3003, a combination of baclofen, narcan and sorbitol. Further trials are underway.46

Prognosis

Depending on the type, CMT has the potential to cause significant disability. However, implementing use of splints and compliance with exercise can help reduce heel cord and finger contractures. If patients are well monitored and aware of their limitations, many can lead active lives. Many do have to modify their activities, such as avoiding jobs involving fine hand movements or constant standing.

SYNDROMIC HEREDITARY PERIPHERAL NEUROPATHIES REFSUM’S DISEASE (HEREDOPATHIA ATACTICA POLYNEURITIFORMIS)

• Autosomal recessive. • Mutation in the phytanoyl-CoA alpha-hydroxylase (PAHX) gene on chromosome 10 (10p13). • Onset in first or second decade.

Etiology

• Defect in alpha-oxidation of branched-chain fatty acids, which elevates the serum phytanic acid level. • Phytanic acid accumulates in central and peripheral nervous systems (particularly the olivocerebellar tracts, anterior horn cells, and peripheral nerves).

Clinical features

• Onset in infancy to early adulthood. • Classic features include retinitis pigmentosa (night blindness, which is often the presenting symptom), peripheral neuropathy causing muscle atrophy and weakness in the distal legs and foot drop, cerebellar ataxia (may be a late manifestation). • Other features include sensorineural hearing loss, cardiac conduction abnormalities, anosmia, and ichthyosis.

Investigations

• NCS: mild to marked conduction velocity slowing; CMAP amplitudes are normal or reduced. • Elevated serum phytanic acid levels. • Elevated CSF protein. • Nerve biopsy: loss of myelinated fibers, onion bulb formation is associated with the remaining axons.

Treatment

• Low phytanic acid diet results in considerable improvement in clinical symptoms as well as the findings on NCS.

FABRY’S DISEASE (ANGIOKERATOMA CORPORIS DIFFUSUM) • • • •

Rare, X-linked. Age of onset: 10–30 years. Primarily affects males. Mutation in the alpha-galactosidase gene located on chromosome X (Xq21–22).

Etiology

• Defective alpha-galactosidase activity results in accumulation of ceramide trihexosidase in the skin, blood vessels, cornea, and the dorsal root ganglia. • Lipid depositions in endothelial cells of the vessel walls. • Axonal degeneration of the small myelinated and unmyelinated fibers.

Clinical features

• Severe paresthesias/burning of hands and feet. • Rashes include angiokeratomas (reddish maculopapular lesion usually located around the umbilicus, scrotum, and inguinal region) and angioectasias of the nailbeds, oral mucosa, and conjunctiva. • Corneal opacities. • Premature atherosclerosis results in hypertension, renal failure, cardiac disease, and strokes. • Women may develop a mild painful small fiber neuropathy.

Investigations

• NCS are usually normal. • Since it affects mainly the small fibers, quantitative sensory testing indicates impaired temperature perception. • Diminished activity of alpha-galactosidase as measured in leukocytes and cultured fibroblasts.

Diseases of the Peripheral Nerve and Mononeuropathies • Nerve biopsy: reduced small myelinated and unmyelinated fibers. • Skin biopsy: reduced epidermal nerve fiber density.

Treatment

• Enzyme replacement therapy with alpha galactosidase, or, for patients with certain mutations, migalastat an oral chaperone. • Early initiation of treatment may help prevent severe axon loss.

PORPHYRIA

• Autosomal dominant with variable degrees of expression. • Higher incidence in females.

Etiology

• Impaired porphyrin metabolism. • Three forms associated with neuropathy: • Acute intermittent porphyria (AIP): porphobilinogen deaminase deficiency. • Hereditary coproporphyria (HCP): defects in coproporphyrin oxidase. • Variegate porphyria (VP): impaired protoporphyrinogen oxidase.

Clinical features

• Attacks are triggered by drugs metabolized by the p450 system and hormonal changes such as pregnancy. • Initial presentation is often acute abdominal pain followed by agitation, hallucinations, and seizures. • 2–3 days later, a progressive proximally predominant subacute motor neuropathy can develop, as well as severe back and leg pain. Weakness is rapid. • The neuropathy may be asymmetric and may involve cranial nerves (facial weakness, dysphagia). • Autonomic dysfunction (dilated pupils, tachycardia, neurogenic bladder). • HCP and VP may develop photosensitive skin rashes. Brown discoloration of urine due to the presence of porphyrin metabolites.

Investigations and diagnosis

• Diagnosis: accumulation of the precursors of heme (δ-aminolevulinic acid, porphobilinogen, uroporphobilinogen, coproporphyrinogen, protoporphyrinogen) in urine or stool. • Specific enzyme activities are reduced in erythrocytes and leukocytes. • NCS: primary abnormality is significantly reduced CMAP amplitude. • EMG: denervation in the proximal muscles about 14 days after symptom onset. • Nerve biopsy: axonal degeneration. • Differential diagnosis: Guillain–Barré syndrome.

Treatment

• Hematin and glucose should be given to reduce accumulation of heme precursors. • Avoid medications that can precipitate an attack (i.e. barbiturates, carbamazepine, phenytoin, and primidone).

Hereditary amyloidosis

• Autosomal dominant. • Variability in age of onset and severity even among family members.

795 • Mutations in the transthyretin (TTR), apolipoprotein A1, or gelsolin genes. • TTR mutations occur in the majority of cases: most common mutation involves a methionine to valine substitution at position 30 (Val30Met).

Etiology

• TTR functions as a transport protein and is synthesized in the liver. • Mutation results in formation of β-pleated sheets of the protein and resistance to protease degradation (amyloidogenic properties). • Amyloid deposits in the endoneurium and blood vessels in autonomic ganglia and peripheral nerves. • Other affected organs include heart, tongue, gastrointestinal tract, skeletal muscles, and kidney.

Clinical features

• Insidious onset of painful paresthesias in the distal lower extremities in the third to fourth decade. • Most common sensory modalities affected are pain and temperature. • Can have severe autonomic involvement (postural hypotension, constipation or diarrhea, erectile dysfunction, impaired sweating). • Amyloid can deposit in the flexor retinaculum resulting in carpal tunnel syndrome. • Death within 7–15 years due to cardiac failure.

Investigations and diagnosis

• Diagnosis: • Genetic testing of the TTR, APOA1 or GSN gene. • Detection of amyloid deposition in abdominal fat pad, rectal, or nerve biopsies. • NCS: • Abnormal sympathetic skin testing. • Predominantly axonal, but occasionally demyelinating sensorimotor polyneuropathy. • Nerve biopsy: • Amyloid deposits within the endoneurium, epineurium, or perineurium, and around blood vessels in autonomic ganglia and peripheral nerves. • Loss of small myelinated and unmyelinated fibers.

Treatment

TTR silencers inotersen and patisiran are antisense oligonucleotide (ASO) inhibitors– novel treatments for transthyretin amyloidosis (ATTR). • Inotersen – ASO inhibitor which binds to TTR mRNA leading to its degradation, which prevents synthesis of misfolded TTR. Subcutaneous once weekly injection results in a mean reduction in serum TTR of 74%.47 • Patisiran – small interfering RNA (siRNA) also belongs to the group of ASOs. This intravenous infusion every 3 weeks results in mean reduction in serum TTR of 81%.48 Other therapies for ATTR include: • Tafamidis – TTR tetramer stabilizer. • Diflunisal – TTR tetramer stabilizer. • Doxycycline – fibril disruptor (off-label).

Hankey’s Clinical Neurology

796 • Liver transplantation, which decreases serum TTR levels and may improve clinical symptoms and electrophysiologic features.

• Although the spinal accessory nerve does not arise from the brachial plexus, it may be involved in IBPN (Figure 25.23).

Examination

Shoulder shrug (trapezius), tilting head toward ipsilateral shoulder and rotating head toward contralateral shoulder (sternocleidomastoid).

MONONEUROPATHIES Definition

Damage to an individual nerve causing weakness and/or sensory changes in that nerve’s specific distribution.

UPPER EXTREMITY NEUROPATHY SPINAL ACCESSORY NEUROPATHY Definition

• Dysfunction of the spinal accessory nerve (cranial nerve XI) supplying the sternocleidomastoid and trapezius muscles.

Anatomy

• The spinal accessory nerve does not arise from the brachial plexus. • It is divided into bulbar (accessory) and spinal components: • Bulbar component arises from the medulla and supplies the soft palate. • Spinal component arises from the anterior horn cells in the cervical cord down to C6. • Spinal component fibers ascend the spinal canal and enter the cranial cavity through the foramen magnum and then exit via the jugular foramen to terminate in the sternocleidomastoid and trapezius muscles.

Etiology

• Common: surgical procedures in the posterior triangle (lymph node biopsy or dissection, carotid endarterectomy). Dorsal scapular nerve to rhomboids Nerve to subclavius Long thoracic nerve to serratus anterior Suprascapular nerve to supraspinatus and infraspinatus

Clinical features

• Drooping of the ipsilateral shoulder and lateral winging of the scapula. • Winging accentuated by shoulder abduction to 90 degrees. • Most lesions are distal to sternocleidomastoid innervation, affecting only the trapezius.

Investigations

• NCS of the spinal accessory nerve recording off of the trapezius and comparing the CMAP from both sides. • EMG of the trapezius and sternocleidomastoid.

Treatment and prognosis

• IBPN: see above. • Surgical injury: recovery depends on degree of nerve injury.

DORSAL SCAPULAR NEUROPATHY Definition and epidemiology

• Dysfunction of the dorsal scapular nerve supplying the rhomboids and levator scapulae. • Uncommon in isolation.

Anatomy

• Course of the dorsal scapular nerve: • Arises from the upper trunk of the brachial plexus, carrying fibers from the C4 and C5 nerve roots. • Pierces the medial scalenus muscle.

C4 C5 C6 C7

Pectoralis minor Musculocutaneous nerve Axillary nerve Short head of biceps Coracobrachialis Radial nerve Median nerve Ulnar nerve Medial cutaneous nerve of forearm Medial cutaneous nerve of arm Thoracodorsal nerve to latissimus dorsi

FIGURE 25.23  Diagram of the brachial plexus.

T1 T2

Scalenus anterior Medial pectoral nerve Lateral pectoral nerve Lateral cord Posterior cord Medial cord Subscapular nerves to subscapularis and teres major

Diseases of the Peripheral Nerve and Mononeuropathies

797

• Innervates the levator scapulae (C4–C5), which elevates the scapula. • Courses along the medial border of the scapula to innervate the rhomboids (C5), which adduct the medial border of the scapula. • Rhomboids and levator scapulae keep the scapula attached to the posterior chest wall during arm motion.

Etiology

• Whiplash injury: stretching of scalene muscles causing trauma to the nerve.49 • Entrapment due to hypertrophy of the middle scalene muscle – occupations involving extended overhead work are at risk. • IBPN may involve the dorsal scapular nerve.

Examination

Stand behind the patient and ask the patient to put their hand behind their back, face the palm of the hand backward, and ask the patient to push backward against the resistance of your hand. The muscle bellies can be felt medial to the medial border of the scapula and occasionally visualized. An alternative method involves placing the hand on the hip and pushing the elbow backward against resistance.

Clinical features

• Scapular winging with the inferior angle rotated laterally. • Elevation of the arm above the head accentuates the scapular winging.

Investigations

EMG abnormalities are restricted to the rhomboids and levator scapulae.

Treatment and prognosis

• Sectioning of the middle scalene muscle to relieve compression of the nerve. • IBPN: see above.

LONG THORACIC NEUROPATHY Definition and epidemiology

• Dysfunction of the long thoracic nerve to the serratus anterior. • Uncommon.

Anatomy

• The long thoracic nerve arises from the motor roots of C5, C6, and C7. • Courses downward through and in front of the medial scalene muscle, descends further dorsal to the brachial plexus along the medial wall of the axilla, and innervates the serratus anterior muscle.

Examination

Inspect for scapular winging (Figure 25.24), which may be present in the resting position. • Ask the patient to push against a wall with both arms slightly flexed at the elbow. Look for winging of the scapula on the affected side, which indicates weakness of the serratus anterior. • If weakness is so severe, the patient may not be able to flex the extended arm at the shoulder and will require assistance from the examiner. Ask the patient to push their fist forward and watch for winging.

FIGURE 25.24  Left scapular winging, accentuated by forward abduction of the arm.

• Elevation of the arm may not be possible. This can be achieved if the examiner presses the patient’s scapula against the chest wall.

Clinical features

• Difficulty with elevating the upper arm during activities such as shaving, combing hair, eating, and drinking. • Dull shoulder ache, mainly because of strain on the shoulder muscles and ligaments in the absence of the serratus anterior muscle tightening the scapula against the rib cage.

Investigations

• NCS: record from the serratus anterior and compare bilateral CMAPs. • EMG: abnormalities noted in the serratus anterior.

Differential diagnosis

• C6 or C7 radiculopathy, but usually there is additional weakness of the extensors of the arms, wrists, or fingers. • Myopathy: weakness is usually bilateral and involves additional muscles of the shoulder and upper arm. • Distinguish scapular winging from that of spinal accessory neuropathy and dorsal scapular neuropathy.

Treatment and prognosis

• Physical therapy and occupational therapy. • Bracing to keep the shoulder abutted against the thorax. • If shoulder function does not improve, surgery to stabilize the scapula is an option. • Most recover spontaneously.

Etiology

• Trauma. • Surgery to the chest wall: radical mastectomy, axillary node dissection, thoracostomy. • IBPN: often involves other nerves in addition to the long thoracic nerve. • Radiation therapy for breast carcinoma. • Rare: Lyme disease, inherited brachial plexus neuropathy.

Hankey’s Clinical Neurology

798

TIPS • Scapular winging may be due to neuropathy of: • The spinal accessory nerve: inferior angle of the scapula is rotated laterally. • The dorsal scapular nerve: inferior angle of the scapula is rotated laterally. • The long thoracic nerve: inferior angle of the scapula is rotated medially.

SUPRASCAPULAR NEUROPATHY Definition and epidemiology

• Dysfunction of the suprascapular nerve. • Uncommon.

Anatomy

• The suprascapular nerve arises from the upper trunk of the brachial plexus, carrying fibers from the C5 and C6 nerve roots. • Passes under the trapezius muscle and courses from the upper border of the scapula beneath the transverse superior scapular ligament. • Innervates supraspinatus and infraspinatus muscles. • Fibers to the infraspinatus pass separately through the spinoglenoid notch, which is covered by the transverse inferior scapular ligament. • Entrapment sites (Figure 25.25): • Suprascapular notch. • Spinoglenoid notch. • Supraspinatus muscle abducts the upper arm up to 30 degrees (deltoid takes over abduction at that point). • Infraspinatus muscle assists in external rotation of the upper arm at the shoulder.

Etiology

• Trauma to shoulder region: • Stab wounds above the scapula. • Improper use of crutches.

• Stretching of the nerve that may occur with serving a volleyball or pitching a baseball. • Ganglion cysts. • IBPN. • Lesion at the spinoglenoid notch: isolated weakness and atrophy of the infraspinatus muscle.

Examination

• Test the supraspinatus muscle with the patient abducting the upper arm from resting position against resistance. • To test the infraspinatus muscle, ask the patient to flex the elbow to 90 degrees. The examiner should stabilize the patient’s elbow against the trunk and ask the patient to rotate the upper arm externally against resistance on the dorsum of the patient’s hand.

Clinical features

• May have pain at the superior margin of the scapula radiating toward the shoulder. • Atrophy of the supraspinatus and infraspinatus muscles.

Differential diagnosis

• Nonneurogenic disorders of the shoulder: • Frozen shoulder: pain, inhibited mobility of the shoulder joint, wasting and weakness of the muscles around the shoulder, especially the supraspinatus, deltoid may also be involved. • Rotator cuff tear. • Tendonitis. • Neurogenic disorders: • C5 or C6 radiculopathy, but usually pain radiates into the arm and the biceps reflex is diminished.

Investigations

• Motor NCS are technically difficult. • EMG is more helpful: • Denervation in both supraspinatus and infraspinatus muscles if the lesion is proximal to the suprascapular notch. • Denervation is limited to the infraspinatus muscle if the lesion occurs at the spinoglenoid notch.

C5 C6

Suprascapular nerve Supraspinatus muscle Infraspinatus muscle

FIGURE 25.25  Course of the suprascapular nerve and sites of compression.

Compression sites

Diseases of the Peripheral Nerve and Mononeuropathies Treatment

• Conservative therapy with pain control is recommended. • Corticosteroid injections to the sites of compression. • Surgical decompression of the entrapment sites is controversial.

AXILLARY NEUROPATHY Definition and epidemiology

• Dysfunction of the axillary nerve. • Uncommon.

Anatomy

• The axillary nerve arises from the posterior cord of the brachial plexus, carrying fibers from the C5 and C6 nerve roots. • Passes just below the shoulder joint, encircles the humerus until it is under the deltoid muscle and then passes through the quadrilateral space (teres minor, teres major, long head of the triceps, neck of the humerus). • Innervates the deltoid muscle and teres minor muscle. • The lateral cutaneous nerve of the upper arm arises from the axillary nerve, follows a short and separate route, and innervates a small area of skin overlying the deltoid muscle.

Etiology

• Trauma: • Fracture or dislocation of the head of the humerus. • Hyperextension of the shoulder (e.g. during sleep or surgery). • Intramuscular injections into the deltoid. • Soft tissue or peripheral nerve tumor. • IBPN. • Ischemia (e.g. vasculitis). • Multifocal motor neuropathy.

Examination

• Ask the patient to keep the arm abducted in the horizontal plane against resistance. The supraspinatus muscle initiates the first 30 degrees of arm abduction. • The teres minor muscle cannot be examined in isolation because it acts together with the infraspinatus muscle in external rotation of the upper arm. • Loss of sensation in a small area of skin overlying the deltoid muscle (Figure 25.26).

799 Clinical features

• Atrophy of the deltoid muscle. • Prominence of the acromion and head of the humerus (due to deltoid wasting).

Differential diagnosis

• Nonneurogenic disorders of the shoulder: frozen shoulder and rotator cuff tear. • Neurogenic: C5 or C6 radiculopathy.

Investigations

• NCS: • Axillary CMAPs recorded from the deltoid muscle with supraclavicular stimulation of the brachial plexus. • Bilateral comparison to identify asymmetric loss of amplitude on the affected side. • Superficial radial SNAP can help distinguish a posterior cord lesion from an upper trunk lesion. • EMG: denervation in deltoid and teres minor muscles (although teres minor is difficult to localize for testing).

Treatment and prognosis

• Conservative treatment with physical therapy and occupational therapy, primarily to prevent a frozen shoulder (the elderly people are particularly vulnerable). • If there is no improvement within 6 months, surgical treatment and nerve grafting should be considered. • Axillary neuropathy due to penetrating injury should be surgically explored. • Partial lesions tend to recover spontaneously. Otherwise, recovery occurs very slowly over many months.

MUSCULOCUTANEOUS NEUROPATHY Definition and epidemiology

• Dysfunction of the musculocutaneous nerve. • Rare in isolation.

Anatomy

Course of the musculocutaneous nerve: • Arises from the lateral cord of the brachial plexus, carrying fibers from the C5 and C6 nerve roots. • Passes through the axilla, pierces the coracobrachialis muscle (giving off branches to it), descends between the biceps and brachialis muscles, giving off branches to both parts of the biceps muscle and the brachialis muscle, and terminates as the lateral antebrachial cutaneous nerve. • The sensory branch (lateral antebrachial cutaneous nerve) innervates the skin of the lateral aspect of the forearm from the elbow to the wrist.

Etiology

FIGURE 25.26  Area of skin innervated by the axillary nerve.

• Trauma: • Fractures or dislocations of the shoulder. • Clavicle fracture. • Axillary node dissection. • Strenuous exercise of the arm (e.g. heavy weight training, repetitive push-ups) resulting in hypertrophy of the biceps muscle compressing the nerve. • Soft tissue or peripheral nerve tumor. • IBPN. • Ischemia (e.g. vasculitis). • Multifocal motor neuropathy.

Hankey’s Clinical Neurology

800 Examination

• With the forearm in full supination, ask the patient to flex the elbow against resistance to test the biceps and brachialis muscles. • Coracobrachialis weakness results in difficulty with arm elevation.

Clinical features • • • •

Axillary nerve Deltoid Teres minor Triceps, long head Triceps, lateral head

Numbness or paresthesias of the lateral forearm. May have pain in the elbow or forearm. Absent biceps stretch reflex. Weakness of elbow flexion with the forearm supinated.

Differential diagnosis

• Nonneurogenic: ruptured biceps tendon, but no sensory loss and on contraction of the biceps muscle, a hardening mass evolves under the insertion of the pectoralis major muscle. • Neurogenic: C6 radiculopathy, although this is usually accompanied by sensory loss in the hand and weakness of other C6-innervated muscles.

Investigations NCS

• Lateral antebrachial cutaneous SNAP should be reduced in axonal lesions of the musculocutaneous nerve and upper trunk or lateral cord lesions, but normal in C6 radiculopathy. • Musculocutaneous CMAP can be obtained with recording from the biceps muscle and stimulating the brachial plexus in the supraclavicular fossa. Comparison of both sides is necessary.

Triceps medial head Brachioradialis Extensor carpi radialis longus Extensor carpi radialis brevis Supinator Extensor carpi ulnaris Extensor digitorum communis Extensor digiti minimi Abductor pollicis longus Extensor pollicis longus Extensor pollicis brevis Extensor indicis

Radial nerve

Posterior inter osseous nerve

EMG

• Denervation in the biceps, brachialis, and coracobrachialis muscles.

Treatment

• Most cases are treated conservatively. • Nerve injury from severe trauma may require surgical treatment.

RADIAL NEUROPATHY Definition and epidemiology

• Dysfunction of the radial nerve. • Reasonably common.

Anatomy

Course of the radial nerve (Figure 25.27): • Arises from the posterior cord of the brachial plexus carrying fibers from the C5, C6, C7, C8, and occasionally T1 nerve roots.

Axilla

• Courses through the axilla, giving off branches to the triceps muscle, goes between the medial and lateral heads of the triceps muscle, then enters the spiral groove, winding around the humerus posteriorly from the medial to the lateral side. • The spiral groove is a common compression site, particularly affecting the motor fibers.

FIGURE 25.27  Diagram of the axillary and radial nerves and the muscles which they supply.

Upper arm

• In the spiral groove, a sensory branch (posterior antebrachial cutaneous nerve) leaves the radial nerve to innervate the skin of the lateral arm and the dorsal forearm. • As the radial nerve emerges from the spiral groove, it supplies the brachioradialis, which is the only flexor muscle innervated by the radial nerve, and more distally the extensor carpi radialis longus and brevis. • Lateral to the biceps at the level of the lateral epicondyle, it enters the forearm between the brachialis and brachioradialis.

Forearm

• The radial nerve divides into a motor branch, the posterior interosseous nerve, and a sensory branch, the superficial radial nerve. • The posterior interosseous nerve innervates the supinator, the abductor pollicis longus, extensor carpi ulnaris,

Diseases of the Peripheral Nerve and Mononeuropathies

801 Biceps Brachialis Brachioradialis

FIGURE 25.28  Area of skin innervated by the superficial radial sensory nerve. extensor digitorum communis, extensor digiti minimi, extensor pollicis longus and brevis, and extensor indicis. • The superficial radial nerve branches off the main trunk about 10 cm (4 in) above the wrist to supply the skin over the lateral dorsum of the hand. The sensory fibers originate from the C6 and C7 nerve roots (Figure 25.28).

Wrist

• The superficial terminal branch of the radial nerve passes superficially on the lateral side of the forearm, over the styloid process just proximal to the wrist (where it can be easily compressed) and toward the dorsum of the thumb. • It ends in five dorsal digital nerves: two supply the dorsum of the thumb, two supply the dorsum of the index finger, and one supplies the first phalanx of the middle finger.

Etiology Axillary lesions

• Rare in isolation. • Compression from crutches, but the median and ulnar nerves as well.

usually

involves

Upper arm lesions

• Fracture of the humerus. • External compression against the spiral groove: • Falling asleep after intoxication, with the arm folded over the back of a chair (Saturday night palsy). • Improper positioning during general anesthesia. • Stretch injury due to hyperabduction of the arm. • HNPP. • Traumatic aneurysm of the radial artery. • Soft tissue or peripheral nerve tumor. • IBPN. • Ischemia (i.e. vasculitis). • Multifocal motor neuropathy.

Forearm lesions (posterior interosseous neuropathy)

• IBPN, usually with other involvement. • Compression by tumors, ganglion cysts, lipoma, Canadian crutch.

Median nerve Supinator

Superficial radial sensory nerve Posterior inter osseous nerve Arcade of Frohse

FIGURE 25.29  Course of the radial nerve through the forearm, showing arcade of Frohse and relationship to the posterior interosseous nerve.

• • • • • • • • • •

Compression by the arcade of Frohse (Figure 25.29). Dislocation of the elbow. Fracture of the ulna with dislocation of the radial head. Rheumatoid arthritis of the elbow joint. Arteriovenous fistula for dialysis. Congenital hemihypertrophy of the supinator muscle. Accessory brachioradialis muscle. Soft tissue or peripheral nerve tumor. Ischemia (e.g. vasculitis). Multifocal motor neuropathy.

Wrist lesions (superficial radial neuropathy) • • • •

External compression (e.g. handcuffs, tight watch bands). De Quervain’s tenosynovitis. Soft tissue or peripheral nerve tumor. Transposition of a flexor tendon toward the thumb.

Examination Axillary lesions

• Weakness of the triceps and all muscles extending the wrist, fingers, and thumb. • Decreased sensation on the back of the upper arm and forearm, in the web between the index finger and the thumb, and lateral dorsum of the hand.

Upper arm lesions

• Hand and finger drop due to weakness of wrist extensors and metacarpophalangeal joints. • Sparing of the triceps muscle and sensation in the upper arm. • May have decreased sensation in the posterior aspect of the forearm and lateral dorsum of the hand. • Weakness of brachioradialis and supinator.

Hankey’s Clinical Neurology

802 Forearm lesions (posterior interosseous neuropathy)

• Dropped fingers without dropped hand. • Despite severe weakness of the extensor carpi ulnaris, wrist extension is possible because the extensor carpi radialis functions normally (the branch to the extensor carpi radialis leaves the radial nerve above the elbow and proximal to innervation of the supinator muscle). • If extensor carpi ulnaris is weak, a distinct lateral deviation of the extended hand occurs when the patient tries to make a fist. • The examiner should be careful to check interossei (ulnar nerve) muscle strength appropriately. The interossei can be assessed with the fingers supported on a flat surface.

Wrist lesions (superficial radial neuropathy)

Reduced sensation over the lateral dorsum of the hand, the dorsum of the thumb (except the nail area), the index finger (proximal to the middle phalanx), and the first phalanx of the middle finger.

Clinical features Axillary lesions

• Pain is not prominent.

Upper arm lesions

• Sudden onset of inability to extend wrist, fingers and thumb, and numbness/paresthesia of the lateral forearm. • May have pain in the elbow or forearm.

Forearm lesions

• Slowly progressive onset of symptoms. • Initially, the little finger gets curled up during tasks such as retrieving something from a trouser pocket. • Later, inability to extend the metacarpophalangeal joint of the little finger and then similar weakness begins in other fingers, one after the other. • May have difficulty playing the piano, but writing and grip strength remain normal. • Pain is uncommon.

Wrist lesions

• Shooting pain in the lateral side of the wrist. • Painful paresthesias in the thumb and index finger evoked by palpating the lateral side of the wrist. • Reduced sensation on the lateral side of the hand.

Differential diagnosis

• Nonneurogenic: • Diseases of extensor tendons. • Compartment syndrome of the deep extensor muscles of the forearm. • Neurogenic: • Upper motor neuron lesion. • Spinal muscular atrophy: often have weakness in intrinsic hand muscles as well. • C7 radiculopathy.

Investigations NCS

• Decreased or absent superficial radial SNAP. • Radial nerve CMAP: • Recorded from the extensor indicis with stimulation at various locations along the nerve.

• Important to stimulate below and above the spiral groove to assess for conduction block or conduction velocity slowing across this site, indicating compression of the nerve at the spiral groove.

EMG

• Localize the site and severity of a radial nerve lesion. • For example, denervation of the extensor carpi ulnaris and not the extensor carpi radialis is consistent with posterior interosseous neuropathy.

Treatment

• Surgical exploration is recommended for mass lesions (i.e. tumor, lipoma, aneurysm of the radial artery) and penetrating trauma with severe axonal injury. • Closed trauma injury, including humerus fracture, usually recovers spontaneously. Thus, conservative therapy is tried prior to surgery. • Conservative therapy: finger and wrist splints, pain control, physical therapy, occupational therapy. • Posterior interosseous neuropathy: • Surgery is recommended if a posterior interosseous neuropathy is related to open trauma. If not, it should be managed conservatively. • Decompressive surgery may be beneficial in selected cases.

MEDIAN NEUROPATHY Definition and epidemiology

• Dysfunction of the median nerve. • Common.

Anatomy

The median nerve (Figure 25.30) arises from the lateral and medial cords of the brachial plexus, carrying fibers from the C6– T1 nerve roots.

Axilla

• Emerges from the axilla with the radial and ulnar nerves and the axillary artery and vein, through the inelastic axillary sheath.

Upper arm

• Descends through the upper arm and bicipital sulcus to the elbow, where it lies medial to the brachial artery. • The median nerve does not innervate any muscles in the upper arm.

Forearm

• Enters the forearm between the two heads of the pronator teres. • Supplies the pronator teres, flexor carpi radialis, palmaris longus, and flexor digitorum superficialis muscles. • Distal to the pronator teres, the anterior interosseous nerve arises: • Purely motor nerve, which descends anterior to the interosseous membrane (which joins the radius and the ulna) and between the flexor digitorum profundus I and II and flexor pollicis longus. • Innervates the flexor digitorum profundus I and II, flexor pollicis longus, and pronator quadratus.

Diseases of the Peripheral Nerve and Mononeuropathies

Median nerve Pronator teres Flexor carpi radialis Palmaris longus Flexor digitorum superficialis

Abductor pollicis brevis Flexor pollicis brevis

Anterior interosseous nerve Flexor digitorum profundus I, II Flexor pollicis longus Pronator quadratus Opponens pollicis First lumbrical Second lumbrical

FIGURE 25.30  Diagram of the median nerve and the muscles which it supplies. Note: the white rectangle signifies that particular muscle receives part of its nerve supply from another nerve.

803 • The digital branches provide sensation to the skin on the palmar aspect of the thumb, index finger, middle finger, and lateral side of the ring finger (Figure 25.31). • Anomalies: • Fibers from the median nerve in the forearm may cross to the ulnar nerve (the Martin–Gruber anastomosis) in 15–30% of the general population and a high frequency in patients with trisomy 21 (Figure 25.32). • The most common variation is that fibers of the anterior interosseous nerve anastomose with the ulnar nerve to innervate muscles normally innervated by the ulnar nerve (usually first dorsal interosseous, adductor pollicis, and abductor digiti minimi). • The number of axons taking the anomalous course varies. • Less common: • Median nerve may innervate the hypothenar muscles via an anomalous branch arising from its course in the carpal tunnel. • The deep motor branch of the ulnar nerve may communicate with the median nerve in the hand (Riche– Cannieu anastomosis). • Any of the intrinsic hand muscles (flexor pollicis brevis in particular) may receive median, ulnar, or dual innervation.

Etiology Proximal lesions

• Compression in the axilla (improper use of crutches). • Trauma: shoulder dislocation, humerus fracture, tourniquet paralysis.

a

Wrist and hand

• A few centimeters proximal to the wrist, the palmar cutaneous branch leaves the main trunk of the median nerve and travels over the transverse carpal ligament to the thenar eminence and innervates the skin on the lateral side of the palm (thenar eminence). • Immediately proximal to the wrist, the median nerve becomes more superficial and enters the carpal tunnel formed by the carpal bones with the transverse ligament serving as the roof (nine flexor tendons to the fingers lie within the carpal tunnel). • Within, or distal to, the carpal tunnel, the recurrent motor branch arises and innervates the abductor pollicis brevis, the opponens pollicis, and the superficial head of the flexor pollicis brevis. • Terminal branches of the median nerve supply the first and second lumbrical muscles.

b

FIGURE 25.31  Illustration of the median nerve sensory distribution. Red and blue areas indicate the sensory changes with lesions of the median nerve in the forearm (a); red areas indicate the sensory changes with lesions of the median nerve at the carpal tunnel (b).

Hankey’s Clinical Neurology

804

First dorsal interosseus Adductor pollicis

Adductor digiti minimi

Anterior interosseus nerve

Martin–Gruber anastomosis

Median nerve

Ulnar nerve

FIGURE 25.32  Martin–Gruber anastomosis. Note: dotted line indicates fibers from the median nerve and anterior interosseous nerve that cross over into the ulnar nerve and ultimately supply the first dorsal interosseous, adductor pollicis, and abductor digiti minimi muscles. • Compression by ligament of Struthers. • Pronator teres syndrome: controversial syndrome as there is usually no objective evidence of weakness in medianinnervated muscles. This is caused by a thickened lacertus fibrosus, fibrous arch of the flexor digitorum superficialis, or tendinous band or hypertrophied pronator teres muscle. • Ischemia (e.g. vasculitis). • IBPN. • Soft tissue or peripheral nerve tumor. • Multifocal motor neuropathy.

Anterior interosseous syndrome

• IBPN. • Compression by a fibrous band between the deep head of the pronator teres muscle and the flexor digitorum superficialis. • Compartment syndrome. • Ischemia (e.g. vasculitis). • Soft tissue or peripheral nerve tumor. • Multifocal motor neuropathy.

Wrist lesions (carpal tunnel syndrome) • • • • • • • • • • •

Idiopathic (45% of cases). Occurring in the setting of a polyneuropathy (e.g. diabetic). Obesity. Pregnancy. Anatomic predisposition: limited longitudinal sliding of the median nerve under the transverse carpal ligament, a smaller cross-sectional area of the tunnel. Degenerative joint disease or rheumatoid arthritis. Sarcoidosis or amyloidosis. Endocrinopathies (i.e. hypothyroidism, acromegaly, diabetes). Structural lesions (i.e. ganglion cysts, lipomas, hemangiomas, osteomas). Trauma: fracture of carpal bones, repetitive movement in the workplace. HNPP.

Examination

• Anterior interosseous nerve: test flexion of the interphalangeal joint of the thumb (flexor pollicis longus) and terminal phalanx of the index finger (flexor digitorum profundus I and II). To test the pronator quadratus, the examiner should give resistance against the patient’s hand as pronation is attempted with the elbow flexed; this muscle is usually less severely affected. No sensory loss. • Carpal tunnel syndrome: sensory loss over the thumb, index finger, middle finger, and lateral side of ring finger. Test thumb abduction at a right angle to the palm (abductor pollicis brevis), thumb flexion at the interphalangeal joint (flexor pollicis brevis), and opposition of the thumb to the little finger (opponens pollicis) (Figure 25.33).

Clinical features

• Proximal lesions should have weakness of median-innervated forearm muscles (pronator teres, flexor carpi radialis, flexor digitorum superficialis) in addition to weakness in hand muscles. Sensory loss of the thumb, index finger, middle finger, and lateral ring finger. • Anterior interosseous syndrome: ask the patient to form a circle by pinching the terminal phalanx of the thumb and index finger together (the ‘OK’ sign) (Figure 25.34).

TIP • Median mononeuropathy at the wrist (carpal tunnel syndrome) is the most common mononeuropathy.

FIGURE 25.33  Action of the abductor pollicis brevis, displaying the muscle belly (arrow).

Diseases of the Peripheral Nerve and Mononeuropathies

805 Investigations NCS Proximal lesions

• Median SNAP and CMAP (usually recorded from the abductor pollicis brevis) have reduced amplitude depending on the amount of axon loss. • Distal latency or conduction velocity of the median SNAP is normal or slightly prolonged compared with the loss of amplitude. • Important to evaluate for conduction velocity slowing, temporal dispersion, or focal conduction block within the upper arm or forearm (i.e. MMN).

Carpal tunnel syndrome FIGURE 25.34  The ‘OK’ sign testing for anterior interosseous neuropathy. The patient is not able to form a circle with the thumb and index finger.

Carpal tunnel syndrome

• Paresthesias/numbness involving the palmar surface of the hand (particularly thumb, index finger, middle finger, and ring finger) and may extend into the forearm and arm. • Pain frequently wakes the patient from sleep. • Pain is relieved by rapid shaking of the hands (the ‘flick’ sign). This may help distinguish from the pain of arthritis and soft tissue injuries, which may be exacerbated by this movement. • Median nerve provocative tests (which are often negative): • Tinel’s sign: percussing over the flexor retinaculum of the carpal tunnel causes paresthesias in the median nerve territory. • Phalen’s sign: forced flexion of the wrist for 60 seconds produces paresthesias in the median nerve territory. • If severe axonal damage, atrophy of the abductor pollicis brevis may create a ‘scalloped’ appearance to the thenar eminence (Figure 25.35).

Differential diagnosis C6, C7, C8 radiculopathy.

FIGURE 25.35  Atrophy of the thenar eminence due to chronic compression of the median nerve at the wrist (severe carpal tunnel syndrome).

• 10% of cases with histories highly suggestive of carpal tunnel syndrome will have normal NCS. • Perform studies on median SNAP and CMAP. Include other upper extremity nerves to exclude a more diffuse process such as polyneuropathy. • Median SNAP is more sensitive than CMAP in detecting carpal tunnel syndrome abnormalities. CMAP amplitude is usually affected much later in the course (as axon loss progresses). • Earliest abnormality: prolonged distal latencies or slowing of the median SNAP. • Compare median SNAP distal latency/conduction velocity following wrist stimulation, with recordings following palmar stimulation. This assesses for more focal slowing or conduction block across the wrist and is valuable in those who have polyneuropathy to check for a superimposed carpal tunnel syndrome.

EMG

• Denervation noted in median-innervated muscles. Performed to assist in further lesion localization.

Treatment and prognosis

• Nonsurgical therapy: • 20–70% improve to some degree. • Wrist splints (particularly while sleeping). • Corticosteroid injections into the carpal tunnel. • Surgical decompression: division of the transverse carpal ligament: • Rationale: to create an environment under which the nerve can recover and the symptoms resolve; it does not aim to improve nerve function itself. The capacity of the nerve to recover also depends on patient age, coexisting disease, and severity of the deficit. • Usually performed after a trial of conservative therapy. • 75% success rate with about 8% worsening. • < 50% success rate in those with marked thenar atrophy, absent responses on NCS, or denervation on EMG. In these cases, surgery can be considered for pain relief rather than improved strength or sensation. • Poor prognosis if there is significant axonal degeneration, particularly with proximal lesions, due to the long distance the nerve must grow to completely reinnervate. • Carpal tunnel syndrome has the best prognosis if there are minimal electrodiagnostic abnormalities and no active denervation on EMG, and conservative therapy is initiated within 3 months.

Hankey’s Clinical Neurology

806 ULNAR NEUROPATHY Definition and epidemiology

• Dysfunction of the ulnar nerve. • Reasonably common.

Anatomy

• The ulnar nerve arises from the lower trunk and medial cord of the brachial plexus, carrying fibers from C8 and T1 (and occasionally C7) nerve roots. • Travels through the axilla in close proximity to the median nerve and axillary artery. • Passes between the biceps and triceps. • Midway down the upper arm, it deviates posteriorly and becomes superficial behind the medial epicondyle (lying in the ulnar groove), where it can be easily injured. • Supplies no muscles in the upper arm.

Forearm

• Enters the forearm and innervates the flexor carpi ulnaris and flexor digitorum profundus III and IV (ring and little fingers). • Gives off the dorsal cutaneous branch of the ulnar nerve, supplies the skin over the medial aspect of the dorsum of the hand. • Just prior to entering Guyon’s canal at the wrist, the palmar branch arises to supply sensation to the hypothenar eminence and innervates the palmaris brevis.

• • • •

Compression by the arcade of Struthers. Arthritis. Ganglion cyst. Rheumatoid synovial cyst.

Wrist and hand lesions

• External compression (e.g. bicyclist, walking cane). • Structural lesion (i.e. ganglion cyst, lipoma, nerve sheath tumor). • Osteoarthritis and rheumatoid arthritis.

Examination Sensation

• Decreased sensation of the little finger and medial side of the ring finger. • Extent of sensory changes depends on level of the lesion (Figure 25.36). • Sensory abnormalities should be distal to the wrist and not extend into the forearm.

Hand

• Passes through Guyon’s canal (formed by hook of hamate, pisiform, pisohamate ligament as the floor, transverse carpal ligament as the roof). • Just distal to Guyon’s canal, the nerve divides into its terminal branches: • Superficial terminal branch: supplies sensation to palmar aspect of the little finger and medial side of the ring finger, and distal portion of these digits dorsally. • Deep motor branch: innervates the hypothenar muscles (abductor, opponens, and flexor digiti minimi) and then deviates laterally, supplying the third and fourth lumbricals and interossei to reach the lateral aspect of the hand to innervate the adductor pollicis and medial half of the flexor pollicis brevis.

Etiology Proximal lesions (axilla to upper elbow) • • • • •

a

b

Trauma: improper crutches, tourniquet paralysis. Compression during sleep. Soft tissue or peripheral nerve tumor. Ischemia (e.g. vasculitis). Multifocal motor neuropathy.

Elbow lesions

• External pressure – compression at the ulnar groove: • Resting the elbow against a hard surface. • Prolonged bed rest. • Malpositioning during general anesthesia. • HNPP. • Polyneuropathy (e.g. diabetic): possibly more susceptible to neuropathy at compression site. • Deformities of the elbow joint: • Tardy ulnar palsy: deformities of the elbow due to previous fractures of the humerus or other trauma to the joint.

c

FIGURE 25.36  Ulnar nerve sensory distribution. Sensory changes with ulnar nerve lesions: above the origin of the dorsal cutaneous branch: green, red, and blue areas (a); below the origin of the dorsal cutaneous branch and above the origin of the palmar branch: green and red areas (b); below the origin of the palmar branch: green areas (c).

Diseases of the Peripheral Nerve and Mononeuropathies Weakness

• Proximal lesions have the same pattern of weakness as compressive lesions at the elbow. • Early stages of proximal lesions show weakness and wasting of the hypothenar eminence and first dorsal interosseous. Flexor carpi ulnaris and flexor digitorum profundus are rarely weak or wasted initially. • To test flexor digitorum profundus III and IV, fix the middle phalanx of the ring finger and little finger and ask the patient to flex the distal interphalangeal joint against resistance. • To test adductor pollicis, ask the patient to squeeze a piece of paper between the base of the thumb and the index finger. If the adductor pollicis is weak, the interphalangeal joint of the thumb flexes due to the use of the medianinnervated flexor pollicis longus to hold onto the paper (Froment’s sign).

Wrist and hand lesions (Figure 25.37)

1. Just proximal to or within Guyon’s canal: a. Affects both the superficial sensory and the deep motor branches. b. Sensory loss of the palmar aspect of the little finger and medial side of the ring finger. c. Weakness in all ulnar-innervated hand muscles. d. Dorsal ulnar cutaneous nerve is spared. 2. Compression distal to Guyon’s canal: a. Only superficial sensory branch is affected. b. Sensation is decreased, but all motor function is spared. 3. Proximal deep motor branch: compression is distal to the take-off of the superficial sensory branch; affects only the deep motor branch including all ulnar-innervated hand muscles. 4. Distal deep motor branch: sensation spared and only the interossei and adductor pollicis muscles are affected.

Clinical features

• Flexor carpi ulnaris often escapes compression at the elbow, but if not, there may be a lateral deviation of the hand on wrist flexion. Wrist flexion is generally not affected due to an intact flexor carpi radialis (median-innervated).

Branch to first dorsal interosseus Branch to adductor pollicis Superficial sensory branch Branch to abductor digiti minimi Guyon’s canal

2 4 3

1

Deep motor branch Ulnar nerve

FIGURE 25.37  Wrist and hand lesions (numbered as in the text) of the ulnar nerve.

807 • Severe ulnar neuropathy gives rise to the ‘ulnar claw hand’ with guttering of the dorsum of the hand from atrophy of the interosseous muscles and the third and fourth lumbricals, hyperextension of the fourth and fifth metacarpophalangeal joints, mild flexion of the interphalangeal joints, and abduction of the little finger.

Differential diagnosis

• C8–T1 radiculopathy (i.e. cervical rib, Pancoast’s tumor). • Motor neuron disease: atrophic intrinsic hand muscles.

Investigations NCS Proximal lesions

• Reduced amplitude of the ulnar CMAP with no conduction block or slowing across the elbow.

Ulnar neuropathy at the elbow

• Ulnar SNAP and dorsal ulnar cutaneous SNAP may be abnormal. • Ulnar CMAP is usually recorded from the abductor digiti minimi. However, recording from the first dorsal interosseous can be performed for comparison. Because of the fascicular arrangement of the fibers within the nerve, one muscle may be more affected than the other. • Compression of the nerve initially creates demyelination at the ulnar groove, which shows slowed conduction velocity between the above-elbow and below-elbow recordings. The segment between the below-elbow and wrist recordings should be normal.

Wrist and hand lesions

• Just proximal to or within Guyon’s canal: • May have abnormal ulnar SNAP. • Normal dorsal ulnar cutaneous SNAP. • May have abnormal CMAP when recorded from either first dorsal interosseous or abductor digiti minimi. • Compression just outside Guyon’s canal: only ulnar SNAP may be abnormal. • Proximal deep motor branch: • Normal ulnar SNAP. • May have abnormal CMAP when recorded from either first dorsal interosseous or abductor digiti minimi. • Distal deep motor branch: • Ulnar SNAP and CMAP recorded from the abductor digiti minimi should be normal. • Only the ulnar CMAP recorded from the first dorsal interosseous would be abnormal.

EMG

Proximal lesions and ulnar neuropathy at the elbow. • Denervation in the flexor carpi ulnaris, flexor digitorum profundus III and IV, and ulnar-innervated hand muscles. • Not able to distinguish proximal lesions from elbow lesions with EMG.

Wrist and hand lesions

• Just proximal to or within Guyon’s canal: denervation in the first dorsal interosseous and abductor digiti minimi with sparing of the flexor carpi ulnaris and flexor digitorum profundus III and IV. • Compression just outside Guyon’s canal: no EMG abnormalities.

Hankey’s Clinical Neurology

808 • Proximal deep motor branch: denervation in the first dorsal interosseous and the abductor digiti minimi. • Distal deep motor branch: denervation in the first dorsal interosseous and adductor pollicis with sparing of the abductor digiti minimi.

• About 12 cm (4.7 in) below the exit from the tunnel, the nerve gives off an anterior branch, which supplies the skin over the lateral and anterior surface of the thigh, and a posterior branch which innervates the lateral and posterior portion of the thigh.

Etiology

Treatment

• Idiopathic: diabetes, obesity, and pregnancy appear to be risk factors. • External compression: • Tight trousers. • Heavy belts as worn by police officers and construction workers. • Seat belt trauma. • Surgeries: retrocecal appendectomy, hip surgery, cesarean section, aortobifemoral bypass grafting. • Trauma: • Avulsion fracture of the anterior superior iliac spine. • Anterolateral thigh injury.

• Prevention: adequate support of the arms of bedridden patients and during surgeries. • Nonsurgical therapy: • Elbow pads, particularly while sleeping. • Splinting the elbow in extension at night. • Avoidance of leaning on the elbows. • Surgical approach: • Options include simple decompression, medial epicondylectomy, and nerve transposition. • Appropriate candidates have failed conservative therapy and have motor signs and symptoms. However, 30% or more patients have persisting symptoms.

Clinical features

Paresthesias, numbness, or burning pain of the anterolateral thigh in a ‘pants pocket’ distribution (Figure 25.39). No weakness.

LOWER EXTREMITY NEUROPATHY

Differential diagnosis

LATERAL FEMORAL CUTANEOUS NEUROPATHY

• L2 or L3 radiculopathy. • Lumbosacral plexopathy.

Definition and epidemiology

Investigations NCS

• Dysfunction of the lateral femoral cutaneous nerve. The syndrome is also known as meralgia paresthetica. • Not uncommon.

• SNAPs should be performed bilaterally to evaluate for asymmetry. • Normal individuals may have absent SNAPs bilaterally. • Some advocate the use of cutaneous somatosensory evoked potentials (SSEP), to distinguish from radiculopathy or plexopathy by comparing to the ilioinguinal SSEP.

Anatomy

The first sensory branch of the lumbar plexus (Figure 25.38): • Arises from the L2 and L3 nerve roots. • Emerges from the lateral border of the psoas major muscle and courses along the brim of the pelvis to the lateral end of the inguinal ligament. • Reaches the upper thigh after passing through a tunnel formed by the lateral attachment of the inguinal ligament and the anterior superior iliac spine.

EMG

• Should be normal and may help distinguish from radiculopathy and plexopathy.

L4 Iliohypogastric nerve

L1 L5 Superior gluteal nerve

Ilioinguinal nerve

L2

Lateral femoral cutaneous nerve

L3

Femoral nerve Genitofemoral nerve

Inferior gluteal nerve

L4

Posterior femoral cutaneous nerve

L5

Common peroneal nerve

Obturator nerve

Tibial nerve

Lumbosacral trunk

Sciatic nerve

S1

S2

S3

S4

Pudendal nerve

FIGURE 25.38  Diagrams of the lumbosacral plexus, with anterior division colored green and posterior divisions colored purple.

Diseases of the Peripheral Nerve and Mononeuropathies

809 Clinical features

Altered sensation in the skin over the lower part of the buttock and the posterior aspect of the thigh. No weakness.

Differential diagnosis Sacral radiculopathy.

Diagnosis

• Requires the presence of isolated sensory loss confined to the distribution of the posterior femoral cutaneous nerve. • No specific electrodiagnostic studies.

Treatment

• Nonsurgical: relieves pressure to the lower buttock and dorsal thigh. • Surgical approach: removal of the responsible mass lesion.

FEMORAL NEUROPATHY Definition and epidemiology

• Dysfunction of the femoral nerve. • Uncommon.

Anatomy

FIGURE 25.39  Area of sensory change resulting from a lateral femoral cutaneous neuropathy (meralgia paresthetica).

Treatment

• Nonsurgical therapy: • Removal of the external compression. • Weight loss. • Steroid injection at the suspected trigger point at the inguinal ligament. • Surgical approach: as a last resort, neurolysis with transposition or sectioning of the nerve.

• The femoral nerve arises from the L2, L3, and L4 nerve roots. • Reaches the front of the leg passing along the lateral edge of the psoas muscle, which it supplies together with the iliacus. • Exits the pelvis under the inguinal ligament just lateral to the femoral artery and vein. • Sensory branches supply the skin of the anterior thigh and medial aspect of the calf (Figure 25.40).

POSTERIOR FEMORAL CUTANEOUS NEUROPATHY Definition and epidemiology

• Dysfunction of the posterior femoral cutaneous nerve. • Uncommon.

Anatomy

• The posterior femoral cutaneous nerve arises from the lower part of the lumbosacral plexus, carrying fibers from the S1, S2, and S3 nerve roots. • Descends together with the inferior gluteal nerve through the greater sciatic notch, below the piriformis muscle. • Enters the thigh at the lower border of the gluteus maximus and close to the sciatic nerve, giving off branches to the skin of the perineum. • Descends superficially over the hamstring muscles to the popliteal fossa, supplying fibers to the skin over the lower part of the buttocks, the dorsal aspect of the thigh, and the proximal third of the calf.

Etiology

• External compression: prolonged sitting, extensive cycling. • Trauma: wounds to the posterior thigh. • Structural lesions: colorectal tumors, hemangiopericytoma, venous malformation.

FIGURE 25.40  Area of skin innervated by the femoral nerve.

Hankey’s Clinical Neurology

810 • Saphenous nerve: largest and longest sensory branch of the femoral nerve: • Supplies the skin over the medial aspect of the thigh, leg, and foot. • Accompanies the femoral artery in the femoral triangle and then descends medially under the sartorius muscle. • Gives off the infrapatellar branch at the lower thigh, supplying the medial portion of the knee. • Accompanying the long saphenous vein, the terminal branch passes just anterior to the medial malleolus to supply the medial portion of the foot. • Muscle branch innervates the pectineus, the sartorius, and the quadriceps femoris (consists of the rectus femoris, vastus lateralis, vastus intermedius, and vastus medialis).

Etiology • • • • • • •

Retroperitoneal hematoma. Lithotomy position. Retractor blades used during abdominal surgery. Hip arthroplasty or dislocation. Femoral artery procedures (e.g. catheterizations). Femoral artery aneurysms or pseudoaneurysms. Radiation to the pelvis for malignancy.

Examination

• Weakness of hip flexion (iliopsoas) and knee extension (quadriceps), which should be tested with the knee flexed to prevent the advantage of a locked knee (subtle weakness could be missed). • Decreased or absent knee jerk. • Loss of sensation over the anterior and medial aspect of the thigh and the medial aspect of the lower leg.

Clinical features

• Sudden falls caused by buckling of the knee, particularly if walking on uneven surfaces, climbing up an incline, or descending a staircase (i.e. when the body weight has to be supported with some knee flexion). • Wasting of the anterior aspect of the thigh can occur. • May have deep, severe nerve trunk pain, with or without paresthesias.

• Only if direct penetrating trauma with severe axonal injury or complete interruption of nerve continuity. • Retroperitoneal hematomas are usually decompressed surgically or aspirated to relieve pain and may not improve nerve recovery. • Femoral neuropathy after surgery, from stretch injury or compression, tends to recover spontaneously, although this may take months.

OBTURATOR NEUROPATHY Definition and epidemiology

• Dysfunction of the obturator nerve. • Rare in isolation.

Anatomy

• The obturator nerve arises from the anterior divisions of the L2, L3, and L4 nerve roots, formed within the psoas muscle. • Enters the pelvis immediately anterior to the sacroiliac joint. • Passes through the obturator canal and gives off an anterior branch supplying the adductor longus and brevis and gracilis, and a posterior branch supplying the obturator externus and half of the adductor magnus muscle. • Sensory fibers supply the skin of the medial upper thigh (Figure 25.41).

Etiology • • • • • •

Pressure during normal labor. Pelvic fracture. Surgical procedures for pelvic cancer. Urological surgery with prolonged hip flexion. Psoas muscle hematoma. Endometriosis.

Differential diagnosis

• Lumbosacral radiculopathy: important to test strength of leg adduction (obturator nerve), as this should be spared in a femoral neuropathy. • Diabetic radiculoplexus neuropathy.

Investigations NCS

• Femoral CMAPs performed bilaterally for comparison. The responses may be difficult to obtain with large body habitus. • Estimated axon loss based on CMAP amplitude is a good measure of prognosis.

EMG

• Denervation noted in quadriceps, and iliopsoas if the lesion is in the pelvis.

Treatment and prognosis

• Conservative treatment with pain management. • Surgical approach:

FIGURE 25.41  Area of skin innervated by the obturator nerve.

Diseases of the Peripheral Nerve and Mononeuropathies Examination

• Weakness in hip adduction. • Normal strength of quadriceps muscle and normal knee jerk. • Pain in the groin is usually the initial symptom. • Reduced sensation on the inner aspect of the thigh. • Broad-based gait may be present.

Differential diagnosis

• Lumbosacral plexopathy or radiculopathy (L2–L4). • Osteitis or other disorders of the symphysis: pain in the groin and medial thigh is similar to the neuralgic pain of an obturator neuropathy.

Investigations

• No NCS technique is described. • EMG: denervation confined to the hip adductors.

Treatment

Conservative treatment with pain management unless surgical treatment is required based on the etiology (e.g. psoas muscle hematoma drainage).

GLUTEAL NEUROPATHY Definition and epidemiology

• Dysfunction of the superior and/or inferior gluteal nerves. • Uncommon.

Anatomy

• Course of the superior gluteal nerve: • Arises from the L4, L5, and S1 nerve roots. • Descends over the piriformis muscle, through the suprapiriform foramen, and then innervates the gluteus medius and minimus muscles. • Course of the inferior gluteal nerve: • Arises from the L5, S1, and S2 nerve roots. • Descends through the infrapiriform foramen, dorsolateral to the sciatic nerve. • Innervates the gluteus maximus muscle.

Etiology

• Superior gluteal nerve: • Fall on the buttocks with entrapment of the nerve between the piriformis muscle and the major sciatic incisure. • Intramuscular injection into the buttocks. • Hip surgery via a posterior approach. • Inferior gluteal nerve: colorectal tumor. • Bilateral gluteal neuropathy: prolonged labor.

Clinical features

• Pain in buttocks. • Difficulty walking: weakness of gluteus medius and minimus leads to weakness of hip abduction, which causes defective tilting of the pelvis and difficulty swinging the contralateral leg forward. • Weakness of hip extension (gluteus maximus) causes difficulty with descending stairs and arising from chairs.

Differential diagnosis

• Proximal myopathy polymyositis). • Hip joint disorder.

(certain

muscular

dystrophies,

811 Investigations

EMG of the glutei. No NCS technique is described.

Treatment

Conservative with pain management.

SCIATIC NEUROPATHY Definition and epidemiology

• Dysfunction of the sciatic nerve. • Not uncommon.

Anatomy

• The sciatic nerve arises from the L4, L5, S1, and S2 nerve roots. • Leaves the pelvis through the greater sciatic foramen. • Consists of a peroneal portion derived from the posterior division of the anterior rami and a tibial portion composed of the anterior divisions. • The peroneal and tibial components separate in the lower part of the thigh to form the common peroneal nerve and tibial nerve.

Etiology

• External compression: prolonged sitting on toilet seat (stupor from alcohol or drugs). • Gluteal compartment syndrome from hematoma. • Misdirected intragluteal injection. • Hip arthroplasty or fracture. • Femur fracture. • Lithotomy positioning. • Intraoperative thigh tourniquet. • Compression from intra-abdominal structural lesion: • Spread of neoplasm from the genitourinary tract or rectum. • Abscess of the pelvic floor. • Pressure from pregnancy. • Neurinoma of the sciatic nerve. • Ischemia from aortic occlusion. • Endometriosis (‘catamenial sciatica’). • Infiltration by lymphoma. • ‘Piriformis syndrome’: • Controversial syndrome. • Theoretically, it is sciatic nerve compression by the piriformis muscle at the level of the sciatic notch. • Symptoms include buttock and posterior thigh pain that is reproduced with maneuvers that stretch the sciatic nerve. • No objective clinical, electrodiagnostic, or imaging evidence of nerve injury.

Clinical features

• Wasting and weakness of the muscles innervated by the sciatic nerve: knee flexion (‘hamstring muscles’ – semitendinosus, semimembranosus, biceps femoris) and all movements of the foot and toes. May be painful. • Within the buttock and proximal thigh, the two components of the sciatic nerve (tibial and peroneal) have anatomically separated. In sciatic nerve injuries, the peroneal component tends to be more affected than the tibial component, which lends toward a misdiagnosis of an isolated peroneal neuropathy. • Absent ankle jerk if the tibial component is involved. • Diminished sensation of the entire foot and the distal lateral leg.

Hankey’s Clinical Neurology

812

TIP • Peroneal nerve fibers within the sciatic nerve have less connective tissue and are positioned laterally and posteriorly. This makes them more susceptible to injury than the tibial nerve fibers.

Differential diagnosis

• L5 or S1 radiculopathy. • Lumbosacral plexopathy.

Investigations NCS

May have abnormal tibial and peroneal CMAPs and/or sural and superficial peroneal SNAPs.

• Enters the leg and gives off a small recurrent nerve supplying sensation to the patella. • Bifurcates into the superficial peroneal and deep peroneal nerves: • Superficial peroneal nerve innervates the peroneus longus and brevis, then divides into the medial and intermediate dorsal cutaneous nerves, which supply the skin to the lateral lower leg and dorsum of the foot and toes. • Deep peroneal nerve supplies the tibialis anterior, extensor digitorum longus and brevis, extensor hallucis longus, peroneus tertius, and an area of skin between the first and second toes (Figure 25.43). • A sural communicating branch joins the medial sural cutaneous branch of the tibial nerve to form the sural nerve, supplying skin over the lateral side of the heel, the sole, and the little toe.

EMG

Denervation noted in peroneal- and tibial-innervated muscles.

Treatment

• Nonsurgical: pain management, may benefit from epidural steroid injection. • Surgical approach: resection of compressive lesion, fasciotomy may be indicated if local pressure has caused rhabdomyolysis of the gluteal compartment.

PERONEAL NEUROPATHY Definition and epidemiology

• Dysfunction of the peroneal nerve. • One of the most common mononeuropathies.

Anatomy

• The common peroneal nerve (Figure 25.42) arises from a division within the sciatic nerve, separating at the level of the popliteal fossa. It carries fibers from the L4, L5, and S1 nerve roots. • Below the knee, it winds around the head of the fibula, becoming quite superficial and prone to compression or stretch injury.

FIGURE 25.42  Area of skin innervated by the common peroneal nerve.

TIP • The short head of the biceps femoris is innervated by peroneal nerve fibers, making it the only peroneal-innervated muscle above the knee.

Etiology Compression at the fibular head • • • • • • • • • • • • • •

Prolonged squatting or kneeling. Lithotomy position. Sitting with legs crossed. Bed rest. Malpositioning during anesthesia. Weight loss from starvation or malignancy. Casts or tight stockings. Fracture of the femur or fibula. Proximal tibia osteotomy. Surgery in the popliteal fossa. Knee surgery. Baker’s cyst. Tumors or cysts of the tibiofibular joint. Underlying polyneuropathy: predisposition to compressive neuropathies. • HNPP. • Pretibial myxedema.

FIGURE 25.43  Area of skin innervated by the deep peroneal nerve.

Diseases of the Peripheral Nerve and Mononeuropathies Lesion between the fibular head and the ankle

• Vasculitis. • Compartment syndrome: swelling of necrotic muscles from injuries such as trauma or excessive exercise: • Anterior compartment syndrome compresses the deep peroneal nerve. • Lateral compartment syndrome compresses the superficial peroneal nerve.

Lesion at the ankle

• Anterior tarsal tunnel syndrome: entrapment of the terminal branch of the deep peroneal nerve at the anterior aspect of the ankle: • Tight footwear. • Ganglion. • Local trauma. • Talotibial exostoses. • Compression of terminal branches of the superficial peroneal nerve: • Epidermoid cysts. • Fascial bands. • Cannulation of foot veins.

Clinical features Lesion above the ankle

• Deep peroneal nerve involvement – motor: • Foot drop or dorsiflexion weakness (tibialis anterior muscle innervated by deep peroneal nerve) producing a steppage gait. Family members often report the sound of the patient’s foot ‘slapping’ on the ground. • Weakness of toe extension (extensor digitorum longus and brevis and extensor hallucis longus innervated by deep peroneal nerve). • Weakness of ankle eversion if the superficial peroneal nerve is involved. • Sensory deficits of the lateral part of the lower leg and dorsum of the foot (superficial peroneal nerve) and/ or the area between the first and second toes (deep peroneal nerve). • Normal ankle jerk, which helps distinguish from a sciatic neuropathy.

Lesion at the ankle (anterior tarsal tunnel syndrome)

• Pain on the dorsum of the foot. • Atrophy of the extensor digitorum brevis. • Sensory abnormalities between the first and second toes.

Differential diagnosis

It is important to assess for the different etiologies of foot drop: • Lower motor neuron: • L5 radiculopathy. • Lumbosacral plexopathy. • Sciatic neuropathy. • Anterior horn cell lesion: – Spinal muscular atrophy. – Motor neuron diseases. – Amyotrophic lateral sclerosis (also look for UMN signs). • Upper motor neuron: • Stroke or tumor.

813 • Distal myopathy: • Dysferlinopathy. • Myotonic dystrophy. • Inclusion body myositis.

TIP • In addition to foot dorsiflexion and eversion weakness, L5 radiculopathy should also have foot inversion weakness.

Investigations NCS

• Usually recorded off of the extensor digitorum brevis. • Lesions at the fibular head: stimulation below the knee and above the knee may show slowing of conduction velocity and/or conduction block at the fibular head. Recording from the tibialis anterior may increase the chance of detecting a conduction block (Figure 25.44). • If conduction block is detected in the segment of the nerve above the ankle and below the knee (between stimulation at the ankle and stimulation below the knee, not a common compression site), consider a demyelinating neuropathy such as CIDP (Figure 25.45). • An accessory deep peroneal nerve (anomalous communicating branch) may be demonstrated if the distal amplitude is smaller than the proximal amplitude.

EMG

• Helpful in distinguishing L5 radiculopathy: L5-innervated muscles that are not supplied by the peroneal nerve are involved (i.e. gluteus medius, tibialis posterior). • Rule out motor neuron disease.

Ankle 100 mA

Below knee 100 mA

Above knee 100 mA 2 mV 5 ms

FIGURE 25.44  Nerve conduction study of the peroneal nerve. Conduction block occurred between the above-knee stimulation and below-knee stimulation, which indicates compression across the fibular head.

Hankey’s Clinical Neurology

814

• Enters the foot, passing between the medial malleolus and the flexor retinaculum (the tarsal tunnel). • Splits into medial and lateral plantar nerves after giving off the calcaneal nerve. • Medial plantar nerve supplies the abductor hallucis and short flexor digitorum muscles and the skin over the medial anterior two-thirds of the sole and the plantar aspect of the first three toes and medial fourth toe. • Lateral plantar nerve supplies the flexor and abductor digiti minimi, abductor hallucis, and the interossei and the skin over the fifth toe, the lateral fourth toe, and the lateral aspect of the sole.

Ankle 100 mA Below knee 100 mA

Etiology Proximal to the ankle

Above knee 100 mA 1 mV 5 ms

FIGURE 25.45  Nerve conduction study of the peroneal nerve. Conduction block and temporal dispersion occurring between the below-knee stimulation and ankle stimulation, which indicates an acquired demyelinating neuropathy. • Poor prognosis if there are no recruitable motor units noted when testing the tibialis anterior.

Treatment

• Most cases that are due to external compression recover spontaneously over weeks to months. • Ankle–foot orthoses to prevent dragging of the toes on the ground and tripping. • Surgical decompression: • Penetrating trauma, which may have disrupted the continuity of the nerve and which necessitates immediate exploration. • Local mass lesions such as nerve tumors, lipomas, or ganglions. • Fasciotomy for compartment syndromes.

TIBIAL NEUROPATHY Definition and epidemiology

• Dysfunction of the tibial nerve. • Not uncommon.

Anatomy

• The tibial nerve arises from a separate trunk within the ventral part of the sciatic nerve at a variable level above the knee. • Carries fibers from the L4, L5, S1, and S2 nerve roots. • Travels deep and well protected through the popliteal fossa and calf. • In the popliteal fossa, the tibial nerve gives off the medial sural cutaneous branch, which then unites in the calf with the sural communicating branch of the common peroneal nerve to form the sural nerve. • In the calf, the tibial nerve innervates the medial and lateral heads of the gastrocnemius, soleus, tibialis posterior, flexor digitorum longus, and flexor hallucis longus muscles.

• • • •

Compression from casts or tourniquets. Penetrating wounds. Tibial plateau fractures or dislocations. Tumor (i.e. neurofibroma, osteochondroma, lymphoma, lipoma). • Ruptured Baker’s cyst. • Popliteal hemorrhage.

Ankle and foot

• Tarsal tunnel syndrome. • Ganglion arising from the flexor hallucis longus tendon sheath. • Fractures of the metatarsals in the foot. • Poorly fitting footwear. • Rheumatoid arthritis.

Clinical features Proximal to the ankle

• Atrophy and weakness of plantar flexion (gastrocnemius), ankle inversion (tibialis posterior), and toe flexion (flexor digitorum longus). If the tibial component of the sciatic nerve is affected, there should be weakness of knee flexion (hamstrings). • To test subtle plantar flexion weakness, the patient should walk on their toes. • Decreased or absent ankle jerk. • Diminished sensation of the heel, sole of the foot, and dorsal aspect of the toes. • Tarsal tunnel syndrome: • Usually unilateral, burning pain in sole of foot. • Symptoms may only be present at night or while exercising. • May have atrophy of intrinsic foot muscles. • Sensory loss in the sole of the foot and toes in the distribution of the medial plantar nerve (most commonly), lateral plantar nerve, or both. • Often, idiopathic tarsal tunnel syndrome occurs in the setting of polyneuropathy.

Differential diagnosis

• S1 radiculopathy. • Lumbosacral plexopathy. • Tibial neuropathy at the ankle (tarsal tunnel syndrome): • Plantar fasciitis. • Stress fractures. • Polyneuropathy.

Diseases of the Peripheral Nerve and Mononeuropathies

815

Investigations NCS Proximal to the ankle

• Reduced amplitude of the tibial CMAP, usually recorded off of the abductor hallucis. • Depending on the location of the lesion, sural SNAP may or may not be abnormal.

Tarsal tunnel syndrome

• Prolonged motor latencies along the medial or lateral plantar nerve with stimulation proximal to the medial malleolus. Affected side should be compared with the unaffected side. • Difficult to demonstrate conduction velocity slowing across the flexor retinaculum, unlike in carpal tunnel syndrome.

L4 L5 S1 S2 S3 S4 S5 Sciatic nerve

EMG

• Denervation noted in the muscles innervated by the tibial nerve; most commonly in the gastrocnemius. • Intrinsic foot muscles may show denervation in the tarsal tunnel syndrome, polyneuropathy, or normal individuals.

Treatment Proximal to the ankle

Tibial nerve

Common peroneal nerve

Medial sural cutaneous branch

Sural communicating branch

• Treat underlying cause.

Tarsal tunnel syndrome

• Conservative therapy includes change in footwear. • Surgical decompression is an option when conservative management fails.

SURAL NEUROPATHY Definition and epidemiology

Sural nerve

• Dysfunction of the sural nerve. • Uncommon.

Anatomy

• The sural nerve arises from the confluence of the medial sural cutaneous branch from the tibial nerve and the sural communicating branch from the common peroneal nerve (Figure 25.46). • Descends the calf more laterally, between the Achilles tendon and the lateral malleolus. • Curves around the lateral malleolus and terminates at the lateral border of the foot. • Innervates the skin of the lateral side of the ankle and the lateral border of the dorsum of the foot up to the base of the fifth toe.

Etiology

• At the popliteal fossa: • Baker’s cyst. • Surgery in the popliteal fossa. • At the level of the calf: • High-topped footwear (e.g. ski boots). • Calf muscle biopsy. • Vasculitis. • At the ankle: • Residual symptoms from a sural nerve biopsy. • Prolonged crossing of the ankles. • Ganglion. • Neuroma. • Fifth metatarsal bone fracture.

FIGURE 25.46  Origin and course of the sural nerve.

Clinical features

Pain and/or paresthesias of the lateral ankle or sole of the foot.

Differential diagnosis • S1 radiculopathy.

Investigations

NCS should be abnormal with sural neuropathy and normal with lesions proximal to the dorsal root ganglion (i.e. S1 radiculopathy).

Treatment

• Avoid external compression if causative factor. • Neurolysis or nerve section for compression by posttraumatic fibrosis or tumors.

PUDENDAL NEUROPATHY Definition and epidemiology

• Dysfunction of the pudendal nerve. • Not uncommon.

Hankey’s Clinical Neurology

816 Anatomy

• The pudendal nerve arises from the S2, S3, and S4 nerve roots and innervates most of the perineum. • Descends from the pelvis below the piriformis muscle, crosses the sacrospinous ligament, and enters the perineum through the lesser sciatic notch. • Courses anteriorly along the intrapelvic wall within a tunnel in the dense obturator fascia and divides into three branches: • The inferior rectal nerve supplies the external anal sphincter, the perianal skin, and the mucosa of the lower anal canal. • The perineal nerve innervates the muscles of the perineum, the erectile tissue of the penis, the external urethral sphincter, the distal part of the mucous membrane of the urethra, and the skin of the perineum and labia/scrotum. • The dorsal nerve of the clitoris/penis supplies the corpus cavernosum then courses forward on the dorsum of the clitoris/penis to innervate the skin, prepuce, and glans.

Etiology • • • •

Pelvic or hip fractures. Childbirth. Invasive tumors. Prolonged bicycle rides.

Clinical features

• Incontinence of urine or feces. • Impotence. • Altered sensation in labia majora/penis and perineum.

Differential diagnosis

• Conus medullaris or cauda equina syndromes. • Structural abnormalities of the pelvic floor and relevant viscera. • Polyneuropathy.

Investigations NCS

• Transrectal or transvaginal stimulation of the terminal parts of the pudendal nerve, recording from the external anal sphincter.

EMG

• Anal sphincter.

Motor and somatosensory evoked potentials

• Can be used to study central as well as peripheral nerve conduction from the perineal region.

Treatment

Depends on the cause.

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817 a clinicopathological study of 22 cases. J Rheumatol 32:853–858. 34. Schaublin GA, Michet CJ, Jr., Dyck PJ, Burns TM (2005). An update on the classification and treatment of vasculitic neuropathy. Lancet Neurol 4:853–865. 35. Niewold TB, Harrison MJ, Paget SA (2007). Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis. QJM 100:193–201. 36. Beghi E, Kurland LT, Mulder DW, Nicolosi A (1985). Brachial plexus neuropathy in the population of Rochester, Minnesota, 1970–1981. Ann Neurol 18:320–323. 37. Jaeckle KA (2004). Neurological manifestations of neoplastic and radiation-induced plexopathies. Semin Neurol 24:385–393. 38. Thyagarajan D, Cascino T, Harms G (1995). Magnetic resonance imaging in brachial plexopathy of cancer. Neurology 45:421–427. 39. Tsairis P, Dyck PJ, Mulder DW (1972). Natural history of brachial plexus neuropathy. Report on 99 patients. Arch Neurol 27:109–117. 40 Robinson-Papp J, Simpson DM (2009). Neuromuscular diseases associated with HIV-1 infection. Muscle Nerve 40:1043–1053. 41 Peltier AC, Russell JW (2006). Advances in understanding drug-induced neuropathies. Drug Saf 29:23–30. 42 Ellis RJ, Marquie-Beck J, Delaney P, et al. (2008). Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Ann Neurol 64:566–572. 43. Bird TD. Charcot-Marie-Tooth (CMT) hereditary neuropathy overview. 1998 Sep 28 [updated 2020 Jan 2]. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http:// www.ncbi.nlm.nih.gov/books/NBK1358/ PubMed PMID: 20301532. 44. Laurá M, Pipis M, Rossor AM, Reilly MM. CharcotMarie-Tooth disease and related disorders: an evolving landscape. Curr Opin Neurol. 2019 Oct;32(5):641–650. doi: 10.1097/WCO.0000000000000735. PubMed PMID: 31343428. 45. Engelfried K, Vorgerd M, Hagedorn M, et al. (2006). Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2). BMC Med Genet 7:53. 46. Young P, De Jonghe P, Stögbauer F, Butterfass-Bahloul T (2008). Treatment for Charcot-Marie-Tooth disease. Cochrane Database Syst Rev 1:CD006052. 47. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379:22–31. 48. Adams D, Geonzalez-Duarte A, O’Riordan W, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379;11–21. Mononeuropathies 49. Akgun K, Aktas I, Terzi Y (2008). Winged scapula caused by a dorsal scapular nerve lesion: a case report. Arch Phys Med Rehabil 89:2017–2020. Further reading Amato A, Russell J (2016). Neuromuscular Disorders, 2nd edn. McGraw-Hill, New York.

818 Bilbao J, Schmidt R (2015). Biopsy Diagnosis of Peripheral Neuropathy, 2nd edn. Springer, New York. Brown W, Aminoff M, Bolton C (2002). Neuromuscular Function and Disease: Basic, Clinical, and Electrodiagnostic Aspects, 1st edn. Elsevier Health Sciences, Philadelphia. Herskovitz S, Scelsa S, Schaumburg H (2010). Peripheral Neuropathies in Clinical Practice (Contemporary Neurology Series), 1st edn. Oxford University Press, Oxford. Kimura J (2013). Electrodiagnosis in Diseases of Nerve and Muscle Principles and Practice, 4th edn. Oxford University Press, Oxford.

Hankey’s Clinical Neurology Preston DC, Shapiro BE (2013). Electromyography and Neuromuscular Disorders, 3rd edn. Elsevier Saunders, Philadelphia. Useful websites www.who.int/topics/leprosy/en/ www.molgen.ua.ac.be/CMTMutations/Home/IPN.cfm http://neuromuscular.wustl.edu

26

NEUROMUSCULAR JUNCTION DISORDERS

Diana Mnatsakanova, Qin Li Jiang

Contents Myasthenia Gravis............................................................................................................................................................................................................ 820 Definition...................................................................................................................................................................................................................... 820 Epidemiology................................................................................................................................................................................................................ 820 Pathophysiology.......................................................................................................................................................................................................... 820 Anatomy of the neuromuscular junction......................................................................................................................................................... 820 Clinical features............................................................................................................................................................................................................821 Ocular muscles.......................................................................................................................................................................................................821 Facial muscles..........................................................................................................................................................................................................821 Bulbar muscles........................................................................................................................................................................................................822 Limb muscles..........................................................................................................................................................................................................822 Respiratory muscles...............................................................................................................................................................................................822 Myasthenic crisis....................................................................................................................................................................................................822 Anti-MuSK antibody-positive MG.....................................................................................................................................................................822 MG associated with thymoma.............................................................................................................................................................................822 Investigations and diagnosis......................................................................................................................................................................................822 Bedside testing........................................................................................................................................................................................................822 Electrophysiologic testing.....................................................................................................................................................................................822 Antibody testing.....................................................................................................................................................................................................824 Chest imaging.........................................................................................................................................................................................................824 Other tests...............................................................................................................................................................................................................824 Differential diagnosis...................................................................................................................................................................................................824 Ocular MG...............................................................................................................................................................................................................824 Generalized MG.....................................................................................................................................................................................................824 Treatment.................................................................................................................................................................................................................824 Short-term immunotherapy.................................................................................................................................................................................827 Treatment of respiratory crisis............................................................................................................................................................................827 Treatment of ocular MG.......................................................................................................................................................................................827 MG in pregnancy....................................................................................................................................................................................................827 Transient neonatal MG.........................................................................................................................................................................................827 Prognosis....................................................................................................................................................................................................................... 828 Congenital Myasthenic Syndromes............................................................................................................................................................................... 828 Definition...................................................................................................................................................................................................................... 828 Lambert–Eaton Myasthenic Syndrome.........................................................................................................................................................................829 Definition and epidemiology.....................................................................................................................................................................................829 Pathophysiology...........................................................................................................................................................................................................829 Clinical features........................................................................................................................................................................................................... 830 Investigations and diagnosis..................................................................................................................................................................................... 830 Electrophysiology.................................................................................................................................................................................................. 830 Antibody testing.................................................................................................................................................................................................... 830 Other tests.............................................................................................................................................................................................................. 830 Differential diagnosis.................................................................................................................................................................................................. 830 Myopathy................................................................................................................................................................................................................ 830 MG........................................................................................................................................................................................................................... 830 ALS............................................................................................................................................................................................................................831 Treatment.................................................................................................................................................................................................................831 Medications that improve acetylcholine release..............................................................................................................................................831 Immunotherapy......................................................................................................................................................................................................831 Botulism...............................................................................................................................................................................................................................831 Definition and epidemiology.....................................................................................................................................................................................831 Major forms.............................................................................................................................................................................................................831

819

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820

Pathophysiology...........................................................................................................................................................................................................832 Differential diagnosis...................................................................................................................................................................................................832 Investigations................................................................................................................................................................................................................832 Electrophysiology...................................................................................................................................................................................................832 Diagnosis........................................................................................................................................................................................................................832 Treatment......................................................................................................................................................................................................................832 Prognosis........................................................................................................................................................................................................................832 References............................................................................................................................................................................................................................832

MYASTHENIA GRAVIS Definition

Myasthenia gravis (MG) is an acquired autoimmune disorder characterized by fatigable and fluctuating muscle weakness preferentially affecting certain muscle groups. In most cases, it results from serum antibodies targeting the acetylcholine receptors (AChRs) on the postsynaptic membrane of the neuromuscular junction (NMJ). Treatment of MG consists of symptomatic control with cholinesterase inhibitors (CIs) and immunotherapies.

of neuromuscular transmission is the difference between the EPP and the potential needed to generate a MFAP. In a normal person, the safety factor is large, i.e. the EPP is much greater than the threshold potential needed for MFAP, but in MG, the safety factor is reduced due to the loss of functional AChRs. Immunoglobulin G (IgG) autoantibodies develop against the nicotinic AChR on skeletal muscles. Failure of neuromuscular transmission results from the loss of functional AChR through:1 • Complement-mediated lysis of muscle endplate leading to disruption of postsynaptic muscle membrane.

Epidemiology

• Estimated prevalence of 20 per 100,000 US population. Prevalence rate has increased in recent decades. • Incidence varies according to studied population groups and ranges from 1.7 to 15 per million. • MG can occur at any age, but peaks at the second decade and sixth to seventh decades. Women are three times more likely to be affected than men before age 40. Incidence is nearly equal before puberty and after age 40. Men have a higher incidence after age 50.

Vesicle Acetylcholine Mitochondrion

Motor nerve terminal Acetylcholine receptor

Pathophysiology Anatomy of the neuromuscular junction

The NMJ (Figure 26.1) consists of the presynaptic motor nerve terminal, postsynaptic muscle membrane, and the synaptic cleft. Acetylcholine, synthesized from acetyl-CoA and choline catalyzed by the rate-limiting enzyme choline acetyltransferase, is stored in the synaptic vesicles in the presynaptic nerve terminal; acetylcholinesterase breaks acetylcholine into choline and acetate, thus terminating the action of acetylcholine. AChRs are clustered and anchored to the muscle membrane through the actions of rapsyn and muscle-specific receptor tyrosine kinase (MuSK). AChR is a transmembrane glycoprotein receptor that has five subunits: two α, one β, one δ, and one ε (γ replaces ε in the fetal form). The α subunit contains the main immunogenic region (MIR) and about one-half of patients with MG generate antibodies against MIR. Acetylcholine is released into the synaptic cleft either spontaneously or triggered by nerve impulse. The release of acetylcholine is dependent on the inward flow of calcium and outflow of potassium ions through voltage-gated ion channels. Binding of acetylcholine to the AChR causes a conformational change of the receptor, which leads to opening of the receptor-operated cation channel and allowing inward flow of ions (mainly sodium ions). The ionic flow eventually leads to the production of an endplate potential (EPP). When the summated EPP reaches a certain threshold, an all-or-none muscle fiber action potential (MFAP) is triggered that propagates around the sarcolemma and T-tubules, causing the release of Ca2+ from the sarcoplasmic reticulum and activation of the muscle contractile mechanism. The safety factor

α

AChR δ β ε

Postsynaptic muscle membrane α

MuSK

Rapsyn

FIGURE 26.1  Diagrammatic representation of the neuromuscular junction, showing release of the neurotransmitter acetylcholine into the synaptic space and its uptake by receptors on the postsynaptic membrane. AChR, acetylcholine receptor; MuSK, muscle-specific receptor tyrosine kinase.

Neuromuscular Junction Disorders • Cross-linking of AChR causing degradation of functional receptors. • Blocking of AChR. MuSK antibodies are present in 40–70% of MG patients who are seronegative for AChR antibody.2 MuSK mediates the clustering of AChRs. The thymus gland has a role in the immunopathogenesis of MG, in that approximately 75% of MG patients have thymic abnormalities; 85% of these patients have thymic hyperplasia and 15% have thymoma. 3,4 Myoid cells in the thymus express AChR on their surface. MuSK antibody-positive patients do not have thymic abnormalities. A small percentages of patients have anti-titin or anti-­ryanodine receptor antibodies (anti-striated muscle antibodies). These are found mainly in thymomatous and late-onset myasthenia. B cells produce anti-AChR antibodies, and CD4+ T cells provide help required for the synthesis of high-affinity antibodies. Regulatory T cells appear to be dysfunctional in MG, and may play an important role in the autoimmune reaction.

821 fluctuating. Almost all patients at some point during the course of their illness develop ocular manifestations. Diplopia results from extraocular muscle weakness which can be subtle. The medial rectus muscle is preferentially affected. Fatiguing maneuvers, such as sustained upgaze or lateral gaze for 30–60 seconds, can aid in demonstrating weakness and fatigability. The cover–uncover test can help bring out subtle extraocular muscle weakness by causing shifting fixation in the direction of the weak muscle.

Facial muscles

• Loss of facial expression. ‘Myasthenic snarl’ results from inability to move the corners of the mouth when the patient attempts to smile (Figures 26.3, 26.4). • Weakness of eye closure can be tested by asking the patient to close the eyelids forcefully while the examiner attempts to manually open the closed eyelids. Bell’s phenomenon (upward movement of the eyeball) can be seen in a partially closed eye. • Other signs: inability to fully puff cheeks or whistle.

Clinical features

• The hallmark of MG is fluctuating and fatigable muscle weakness that improves with rest. • Weakness to varying degrees affects the extraocular, facial, bulbar, limb, and axial muscles. Severe respiratory muscle involvement is seen in myasthenic crisis (see section below). • Common presenting symptoms: ptosis, diplopia or blurred vision, dysphagia, dysarthria, chewing difficulty, and limb weakness. • For those presenting with ocular symptoms, slightly more than half will develop generalized disease within 6 months and three-quarters will develop generalized disease within 1 year. After 3 years, the risk of developing generalized disease drops to 6%. • Only rarely, after decades of disease will a patient with ocular myasthenia develop generalized weakness. • Atypical presentations include neck extensor weakness (head drop), focal limb weakness, limb-girdle phenotype, and selective respiratory muscle weakness.

Ocular muscles

At least one-half of patients present with ocular symptoms including ptosis and diplopia. Ptosis results from weakness in eyelid opening (levator palpebrae superioris). It can be unilateral or bilateral (Figure 26.2), but generally is asymmetric and

FIGURE 26.2  Bilateral ptosis in a patient with myasthenia gravis.

FIGURES 26.3, 26.4  ‘Myasthenic snarl’ as the patient tries to open his eyes, due to facial weakness, before an edrophonium test. Restored muscle power (Figure 26.4) within minutes of injection of edrophonium 5 mg IV. (Courtesy of Dr AM Chancellor, Neurologist, Tauranga, New Zealand.)

Hankey’s Clinical Neurology

822 Bulbar muscles

• Weakness in jaw closure and fatigue with chewing, especially during a prolonged meal or eating large pieces of meat. • Dysarthria and dysphagia result from oropharyngeal muscle weakness: • Nasal regurgitation and nasal quality of speech result from palatal weakness. • Weakness in the tongue results in lingual dysarthria, reduced ability to protrude the tongue, and inability to press the tongue against the inside of the cheek. • ‘Dropped head syndrome’ can result from neck extensor weakness. Neck flexors can also be affected.

Limb muscles

Proximal muscles are typically more involved than distal and more or less symmetrically, but finger extension and foot dorsiflexion can also be affected. Limb fatigue can be exposed by asking the patient to sustain arm abduction for about 1 minute.

Respiratory muscles

• Weak inspiratory sniff, difficulty clearing throat, blowing nose, and weak cough. • Impending respiratory crisis: initial arterial blood gas may show evidence of respiratory alkalosis (hyperventilation). • Severe weakness in respiratory muscles can lead to myasthenic crisis (see below).

TIP • MG patients may have muscle weakness only after exertion; therefore, it is important to perform maneuvers that exercise specific muscle groups to elicit fatigability.

Myasthenic crisis

Myasthenic crisis is respiratory failure as a result of severe respiratory muscle weakness requiring intubation and mechanical ventilation. Infection (pneumonia or viral upper respiratory tract infection) is the most common precipitant. Fifteen to twenty percent of patients will experience at least one episode of myasthenic crisis. Median interval from MG symptom onset to first crisis is 8 months, with 75% of cases occurring in the first 2 years of symptom onset. Myasthenic crisis has a higher prevalence in patients with thymoma. Neck and oropharyngeal muscle weakness is typically associated. Signs of impending respiratory failure include: • • • • • •

Difficulty clearing secretions or swallowing saliva. Severe dysphagia. Head drop. Rapid and shallow breathing. Using accessory muscles for breathing. Low forced vital capacity (FVC) or negative inspiratory pressure (NIF).

Anti-MuSK antibody-positive MG

MuSK is a transmembrane endplate polypeptide involved in a signaling pathway that maintains functional integrity of the NMJ. Patients have predominant involvement of bulbar, facial,

and respiratory muscles and relative sparing of ocular muscles.5 Atypical features may include facial and tongue atrophy, paraspinal, and upper esophageal weakness. • • • •

Marked female predominance, age < 40 years. Respiratory crisis more common. Acetylcholinesterase inhibitors may exacerbate symptoms. Normal thymus pathology.

MG associated with thymoma

Of patients with thymoma, 40–50% have MG, and 15% of patients with MG have thymoma. The mean age of patients with thymoma is 55 years. One-third of patients with thymoma present with MG symptoms.6 MG symptoms in thymoma patients are similar to those in non-thymomatous MG; however, the presentation tends to be more severe. AChR antibodies are present in high titers. Additional antibodies associated with thymomatous MG include anti-striated muscle, AChR-modulating, ryanodine, titin, KCNA4, and other paraneoplastic autoantibodies.

Investigations and diagnosis Bedside testing Edrophonium chloride (Tensilon) test

• An acetylcholinesterase inhibitor with fast onset and short duration that is easy to administer. • Inject an initial dose of edrophonium 1–2 mg, and observe for response. If no response, give an additional 5–6 mg (to a maximum of 10 mg). • A positive response should be observed within 90 seconds (Figure 26.4). • This test is most useful when resolution of eyelid ptosis or objective improvement in a single paretic extraocular muscle is observed. • Side effects result from excessive acetylcholine: abdominal cramps, salivation, bronchial secretions, sweating, nausea, vomiting, and bradycardia. Severe side effects are rare, but caution should be taken in patients with history of cardiac disease and asthma. • Atropine should be available and some would also advocate cardiac monitoring. • Sensitivity ranges from 71.5% to 95% in generalized MG. However, positive tests have been reported in various other disorders. • Tensilon is no longer available; edrophonium chloride is currently distributed as Enlon.

Ice pack test

• A bag of ice is placed on the closed eyelid for 2–5 minutes after which ptosis is assessed for improvement. Low temperature decreases the activity of the acetylcholinesterase increasing the bioavailability of the acetylcholine in the synaptic cleft. • Sensitivity of 80%.7 • May be difficult for patients to tolerate.

Electrophysiologic testing Repetitive nerve stimulation

• Repetitive nerve stimulation (RNS) at slow rates (2–5 Hz) depletes available stores of acetylcholine and causes failure in neuromuscular transmission. A reproducible

Neuromuscular Junction Disorders

823

a

11%

43%

b

5.0 mv

35%

c

2 ms

FIGURE 26.5  Repetitive nerve stimulation (3 Hz) in myasthenia gravis. (a) Baseline; (b) immediately after 10 seconds of exercise (postexercise repair); (c) 3 minutes after 60 seconds of exercise (postexercise exhaustion). Percentages indicate the degree of compound muscle action potential amplitude decrement comparing first and fourth stimulation.

•

• • •

decremental response of compound muscle action potential (CMAP) amplitude of at least 10% is characteristic in MG. Decrement can occur at baseline or 2–4 minutes after prolonged exercise of 60 seconds (postexercise exhaustion). Repair of decrement occurs after brief exercise of 10 seconds (postexercise repair) (Figure 26.5). RNS is more likely to be positive if performed in a weak muscle. Therefore, sensitivity increases when performed in a proximal or facial muscle. Sensitivity ranges from 53% to 100% in generalized MG and is 10–17% in ocular MG. RNS may be abnormal in other neuromuscular disorders. Therefore, results must always be interpreted in the context of standard nerve conduction studies (NCS), needle electromyography (EMG), and clinical presentation.

Single-fiber electromyography

• Single-fiber electromyography (SFEMG) needle electrodes are able to record muscle fiber action potentials from individual muscle fibers. Jitter is produced when there is delayed or failed neuromuscular transmission in a pair of

muscle fibers supplied by branches of a single motor nerve (Figure 26.6). • Advantages of SFEMG are that it has a high sensitivity (82– 99%) and can show abnormally prolonged jitter in clinically unaffected muscles. • Disadvantages are that it is not widely available, secondary to the need for specialized training and equipment. It is also limited by its low specificity. Therefore, SFEMG should only be performed in the appropriate clinical setting by an experienced electromyographer when other electrodiagnostic testing is normal. • SFEMG can also be performed by using conventional disposable electromyography electrodes, and this technique may be comparable.

TIP • Cholinesterase inhibitors diminish the degree of abnormality seen on repetitive nerve stimulation and singlefiber EMG. Therefore, it is recommended to hold this medication prior to performing these tests.

200 µv

Jitter

0.5 ms

FIGURE 26.6  Single-fiber EMG in a patient with myasthenia gravis showing increased jitter due to variable delay in neuromuscular transmission.

Hankey’s Clinical Neurology

824 Antibody testing

Acetylcholine receptor-binding antibody is the most specific serologic test and with current assays is positive in approximately 85% of patients with generalized disease and 50–65% of patients with ocular MG. Serum antibody titer does not correlate with clinical severity. High levels of acetylcholine receptor-modulating antibody may be associated with thymoma. Striated muscle antibody has a high association with thymoma for patients between the ages of 20 and 50 years, but is nonspecific and can be seen in normal elderly. MuSK antibody is present in approximately 40% of patients who are negative for acetylcholine receptor-binding antibody. Low-affinity IgG antibodies to AChRs have been found in 66% of patients with MG who are antibody negative on conventional anti-AChR and anti-MuSK antibody assays.8 Antibodies to lipoprotein-related protein 4 (LRP-4) have been found in 2–50% of patients with MG who are anti-AChR and MuSK negative. LRP-4 is a receptor for agrin which activates MuSK and AChR clustering at the neuromuscular junction.9

Chest imaging

Chest computed tomography (CT) or magnetic resonance imaging (MRI) should be done in every MG patient to evaluate for the presence of thymoma. Intravenous iodine contrast must be used with caution, as it may exacerbate MG symptoms.

Other tests • • • •

Evaluation for associated disease: thyroid dysfunction. Pulmonary function test. Barium swallow. Prior to immunosuppressant therapy initiation: • Tuberculosis screening. • Hepatitis B screening.

Differential diagnosis Ocular MG

• Thyroid ophthalmopathy: • Typical symptoms: proptosis, lid retraction, lid lag. Ptosis is usually not present. • MG and Graves’ disease can coexist. • Chronic progressive external ophthalmoplegia: • Patients generally do not complain of diplopia in the presence of very restricted extraocular movements, which is typically more severe than seen in MG. • Retinal degeneration can coexist, and more generalized muscle weakness can occur later in the disease course. • Cranial neuropathy: • MG never involves the pupil, distinguishing it from Horner’s syndrome or a third nerve palsy. • MG may mimic sixth nerve palsy with isolated lateral rectus weakness, but may be distinguished by fatigability and lack of pain. • MG may produce a pseudointernuclear ophthalmoplegia with isolated medial rectus weakness. Patients with true internuclear ophthalmoplegia usually have spared convergence. • Brainstem pathology: • Tumors, strokes, aneurysms, carcinomatous meningitis, and so on. • Diagnosed with head imaging (CT, MRI) and cerebrospinal fluid (CSF) studies.

Generalized MG

• Lambert–Eaton myasthenic syndrome (LEMS): • LEMS has more prominent lower extremity weakness than MG. Ocular and bulbar symptoms are less prominent in LEMS than in MG and are seldom the presenting symptoms. • Autonomic symptoms are common: dry mouth, impotence, decreased sweating. • Voltage-gated calcium channel (VGCC) antibodies are present in 90% of patients with LEMS. • Low amplitude CMAPs, a decremental response to slow repetitive stimulation studies (2–5 Hz) and postexercise facilitation (10 seconds of exercise) of the CMAP amplitude of more than 100% are characteristic of LEMS (see section on LEMS). • Motor neuron disorders: • Extraocular muscle weakness and ptosis are generally not present. • Upper and lower motor neuron signs coexist: muscle fasciculations, atrophy, hyperreflexia, Babinski’s sign, and hypertonia. • Widespread evidence of motor nerve denervation and reinnervation on needle EMG. • Botulism: • Rapid onset of a descending pattern of weakness including ocular, bulbar, respiratory, and generalized weakness. • May have pupillary and autonomic involvement. • Low CMAP amplitudes and postexercise facilitation of CMAP amplitude to a lesser degree than seen in LEMS are characteristic. • Needle EMG may demonstrate fibrillation potentials and short-duration polyphasic motor unit action potentials (MUPs) as a result of chemodenervation. • Drug-induced MG: • Penicillamine: induces production of acetylcholine antibodies; symptoms resolve within 3–12 months after withdrawal of the medicine. • Congenital MG (see below): • Long history of symptoms (often from infancy or childhood) with gradual progression. • AChR or anti-MuSK antibodies are absent. • May have a positive family history. • May have characteristic findings on NCS (repetitive CMAP in slow channel syndrome or acetylcholinesterase deficiency). • Requires genetic testing or specialized electrophysiologic testing on intercostal or anconeus muscle. • Not responsive to immunotherapies.

Treatment Cholinesterase inhibitors – Pyridostigmine

• Increase the amount of acetylcholine available for binding at the NMJ. • Provide symptomatic relief, but do not affect disease progression. • Rarely provide complete or sustained benefit. • Initial dose of pyridostigmine is 30 mg every 4–6 hours which is increased to maximize benefit and minimize side effects. Dosages exceeding 120 mg every 3–4 hours are rarely beneficial and may place patient at risk for cholinergic overdose.

Neuromuscular Junction Disorders • Dose-limiting side effects include stomach cramps, diarrhea, excessive perspiration, salivation, bradycardia, nausea, vomiting, and increased bronchial secretions. • Cholinergic overdose (dosages exceeding 450 mg daily) can induce worsening muscle weakness and is usually associated with muscarinic symptoms.

TIP • Vigilant monitoring of corticosteroid side effects is indicated with serum glucose and vitamin D levels, bone density test, cataract screening, and so on. Most patients taking prednisone for more than 3 months should also take daily calcium, vitamin D, and a bisphosphonate.

Corticosteroids

• Prednisone is the most commonly used immune-directed therapy: • Induces marked improvement or remission in >70% of patients.10,11 • Typically, started at a high daily dose (0.75–1.0 mg/kg/ day) and gradually tapered off over months or continued at a low daily or alternate-day dose. • One-third to one-half of patients experience a transient worsening of symptoms approximately 1–2 weeks after initiation. Some advocate gradual initiation of prednisone to reduce this risk. • Beneficial effects start in 2–4 weeks and peak after 6–12 months. • Side effects are common (Tables 26.1, 26.2).

Thymectomy

• The only absolute indication for thymectomy is thymoma. Radiation therapy is needed for invasive cases. Patients typically require chronic immunotherapy in addition to thymectomy. The prognosis in MG with thymoma is similar to nonthymomatous MG.

TABLE 26.1  Common Side Effects of Corticosteroid Treatment Weight gain Glucose intolerance Hypertension Osteoporosis Bruising/thinning of the skin Cataracts Fluid retention

TABLE 26.2  Steps to Minimize Side Effects of Corticosteroids Calcium supplementation (1200–1500 mg daily) Vitamin D supplementation (600–800 IU daily) Bisphosphonates Routine DEXA scans Routine ophthalmologic examinations Blood glucose monitoring Blood pressure monitoring Diet modification Abbreviation: DEXA, dual-energy X-ray absorptiometry.

825 • An elective thymectomy is also recommended to patients of 18–65 years of age who have generalized MG with AChR-positive antibodies without thymoma. The beneficial effects of thymectomy have been shown to extend for at least 5 years.12,13 • Optimization of MG treatment should be obtained prior to thymectomy in all cases. • There is no evidence to support thymectomy in MuSK myasthenia.

Chronic immunotherapy (Table 26.3)

• Azathioprine (AZA): • Interferes with B- and T-cell proliferation by inhibiting purine synthesis. • Used for corticosteroid sparing. • Full benefit of treatment may not be reached until >1 year. • Initiated at 50 mg daily or twice daily and increased by 50 mg per week until maintenance dose of 2–3 mg/ kg/day. • Major side effects are hepatotoxicity and leukopenia. Therefore, liver function tests and white blood cell count should be monitored. A flu-like reaction may appear a few weeks after initiation (or in some cases much later), which may be severe and associated with neutropenia. AZA must be promptly discontinued. • Risk for certain malignancies, particularly hematopoietic malignancies, may increase in long-term treatment with AZA. • Mycophenolate mofetil (MMF): • Interferes with B- and T-cell proliferation by inhibiting purine synthesis. • A double-blind, placebo-controlled pilot study showed a promising trend, favoring benefit of MMF compared to placebo.14 However, two double-blind, placebo-­ controlled studies showed that there was no significant benefit of mycophenolate plus corticosteroids over corticosteroid treatment alone.15,16 However, patients were only followed for 12 and 36 weeks in these two studies, and the mechanism of action of mycophenolate as well as experience with AZA and other immunosuppressive drugs suggest that longer treatment may be necessary for peak clinical effect. • Typical starting dose is 1000 mg twice daily. • A potentially serious side effect is myelosuppression, and so complete blood cell count should be monitored.

Eculizumab

• First medication approved by US Food and Drug Administration (FDA) as a treatment for adult patients with generalized MG who are anti-AChR antibody-positive. It is indicated in patients who have had inadequate response to initial immunosuppressive treatments such as corticosteroids, azathioprine, and mycophenolate mofetil.17 • Eculizumab is a complement inhibitor, where it specifically binds to the complement protein C5 and inhibits its cleavage to C5a and C5b, which subsequently inhibits deployment of the terminal complement system. • Eculizumab is given intravenously. Initially it is given 900 mg IV weekly for first 4 weeks, followed by 1200 mg IV for the fifth dose 1 week later, followed by 1200 mg IV every 2 weeks thereafter.

Hankey’s Clinical Neurology

826 TABLE 26.3  Immunotherapy in Myasthenia Gravis Medication

Dosage

Long-Term Immunotherapy First-line Prednisone 0.75–1 mg/kg/day followed by slow wean

Onset

Indication

Mechanism

Major Side Effects

2–4 weeks

• Quick response

• Suppresses migration of leukocytes • Reduces activity of lymphatic system

• • • • • • • • • • • •

Weight gain Hyperglycemia Hypertension Osteoporosis Cataracts Fluid retention Hepatotoxicity Leukopenia Flu-like reaction Hematopoietic malignancy Myelosuppression Flu-like reaction

• • • •

Meningococcal infections Upper respiratory infections Myalgias Arthralgias

Azathioprine

2–3 mg/kg/day

6–12 months

• Steroid-sparing

• Purine inhibition • B- and T-cell suppression

Mycophenolate mofetil

500–1500 mg bid

4–8 months

• Steroid-sparing

Eculizumab

900 mg weekly × 4 1200 mg weekly × 1 122 mg every 2 weeks thereafter

1–12 weeks

• Refractory to other agents

• Purine inhibition • B- and T-cell suppression • Complement C5 inhibitor

3–5 mg/kg divided bid Serum trough goal 75–150 ng/mL

1–2 months

• Initial therapy • Steroid-sparing

Second-line Cyclosporine

Tacrolimus

3–5 mg daily divided bid 1–2 months

• Steroid-sparing • MG with thymoma?

• Disruption of calcineurin pathway • Decreased T-cell proliferation • Disruption of calcineurin pathway

Rituximab

1 g weekly × 3, repeat in 6 months as needed

• Refractory myasthenia • MuSK myasthenia?

• Monoclonal antibody to CD20+ cells

• Respiratory crisis • Severe symptoms • High-dose steroid initiation • Preoperatively • Same as plasmapheresis • Serially in refractory MG

• Removes circulating antibodies

12 weeks

Short-Term/Acute Therapy Plasma exchange 3–4 L exchange QOD × 6 After 3–6 exchanges

Intravenous 1–2 g/kg divided over immunoglobulin 1–5 days

3–4 days

• Common side effects include upper respiratory infections, myalgias, arthralgias, increased bruising, and increased susceptibility to encapsulated bacteria including meningococcal infections. • Patients are required to obtain vaccination for meningococcal disease according to the Advisory Committee on Immunization Practices (ACIP) recommendations at least 2 weeks prior to initial eculizumab dose.

Cyclosporine

• Cyclosporine causes disruption of the calcineurin signaling pathway and blocking of interleukin-2 synthesis leading to disruption of T-cell proliferation. • Generally utilized as a corticosteroid-sparing agent if AZA or MMF fails. It has been demonstrated to be effective in both immunosuppressant-naïve patients and in combination with corticosteroid.

• Competition with autoantibodies • Fc-receptor binding?

• Drug interactions • Nephrotoxicity • Hypertension • • • • •

Hyperglycemia Hypertension Hypercholesterolemia Nephrotoxicity Flu-like reaction

• Hypotension • Hypocalcemia • Reduction in coagulation factors • Risks of vascular access • Aseptic meningitis • Flu-like reactions • Acute tubular necrosis • Thromboembolic events

• The initial dose is 3–5 mg/kg divided to twice-daily regimen. Onset of benefit may take 1–2 months. • Side effects include tremor, excessive hair growth, anemia, nephrotoxicity, and hypertension; renal function should be monitored, and trough cyclosporine levels should be followed regularly with a goal of 75–150 ng/mL. • Cyclosporine may increase the risk of certain malignancies.

Tacrolimus

• Tacrolimus blocks T-cell proliferation by inhibiting the calcineurin signaling pathway. In a pilot study, patients on tacrolimus required less plasma exchange and corticosteroid. • Typical low-dose therapy is 3–5 mg/day divided into bid dosing. • Side effects: tremor, hyperglycemia, hypercholesterolemia, hypertension, nephrotoxicity, and hair loss.

Neuromuscular Junction Disorders Rituximab

• Monoclonal antibody that targets CD20+ B lymphocytes. • Both anti-AChR antibody-positive and anti-MuSK-positive refractory MG patients appear to respond to rituximab without significant adverse effects. • Experience with this drug comes from small case series; a large randomized trial is needed to assess its effectiveness in MG.

Short-term immunotherapy Plasma exchange

Plasma exchange (PE) temporarily removes circulating antibodies. Improvement from PE is generally observed after three to six exchanges; typically, a 3–4 L exchange of plasma is given every other day for six exchanges. It is mainly used in patients who are in crisis, prior to thymectomy or in combination with high-dose corticosteroids to prevent a steroid-induced exacerbation. The effect of PE begins to taper after 2 weeks. Adverse effects include hypotension, hypocalcemia, reduction in coagulation factors, thrombosis, and infection associated with central venous access.

TIP • Most serious adverse effects of PE are associated with the indwelling central venous catheter.

IV immunoglobulin

IV immunoglobulin (IVIG) is used in a similar fashion to PE. It is also used serially in patients who have not obtained an adequate response with typical immunosuppressants. Initial dose is 2 g/kg divided over 1–5 days followed by 1 g/kg every 3–4 weeks as required. The efficacy of IVIG was evaluated in a randomized, placebocontrolled trial in 2007; the IVIG-treated group had clinically significant improvement on the Quantitative Myasthenia Gravis (QMG) Score at 14 and 28 days.18 IVIG and PE were shown to be equally efficacious in MG exacerbation, although IVIG was better tolerated. Arguably, suboptimal regimens of PE were utilized in the studies comparing PE and IVIG, and the onset of effect was also not assessed. Experience would dictate that PE may be more efficacious in situations of crisis. Side effects include flu-like reaction, headache, aseptic meningitis, renal failure, and stroke.

TIP • Side effects from IVIG infusion can be minimized by ample hydration, pretreatment with antihistamines and acetaminophen (paracetamol), and utilizing a slow rate of infusion.

Treatment of respiratory crisis

• MG crisis should be managed in the intensive care unit with close monitoring of pulmonary function. Elective intubation should be done if FVC < 15 mL/kg or NIF > −30 cmH2O. • A precipitating factor can be identified in the majority of patients in crisis and include: bronchopulmonary infection,

827 aspiration, surgical procedure including thymectomy, rapid tapering of immunotherapy, and treatment with drug that can exacerbate myasthenic weakness including corticosteroid-induced worsening. • Acute treatment with PE or IVIG; PE is preferable. • Discontinue CIs as they can contribute to bronchopulmonary secretions and will not protect a patient from respiratory crisis. • Initiation of high-dose daily corticosteroid and immunosuppressant concomitantly with acute therapy.

Treatment of ocular MG

• The majority of patients have ocular symptoms at disease onset. • If symptoms do not generalize within 2 years of the disease onset, then there is 90% likelihood that disease will remain restricted to the ocular muscles. • CIs may be adequate in controlling ocular symptoms in some patients; however, corticosteroids are typically more effective, and in general, ocular MG can be controlled at a relatively low dose of prednisone (5–15 mg/day or the equivalent alternate-day dose).

MG in pregnancy

• Course is unpredictable during pregnancy, but worsening of symptoms, if it occurs, tends to be in the first trimester or postpartum. • Goal is to optimize MG treatment prior to delivery. • CIs, corticosteroids, IVIG, and PE can be used during pregnancy. • Immunosuppressant agents should generally be avoided due to potential teratogenic effects. • Magnesium sulfate should not be used for premature labor due to its negative effect on neuromuscular transmission. • Pregnancy-related changes in intestinal absorption and renal clearance may alter the amount of medication needed. • Risk of pregnancy-related complications may be higher, but overall prognosis for MG is unchanged.

Transient neonatal MG

• Transient neonatal MG is caused by transplacental passage of maternal antibodies. • Severity and duration of MG in the mother does not correlate with risk of development of neonatal MG. • Two-thirds of cases develop within a few hours of birth (after maternal CIs are cleared by the infant). • Signs: poor suck and swallow, generalized hypotonia, respiratory distress, and in rare cases, arthrogryposis multiplex congenita. • Occurs in approximately 5–20% of infants born to mothers with MG. • Mothers with a previously affected child have a higher risk with subsequent births. • These mothers may be treated with PE or IVIG prophylactically. • Symptoms generally last less than 1 month, but may last much longer in some cases. • Treatment: supportive care, such as assisted ventilation or tube feeding, CIs, and in severe cases, PE.

Medications that may exacerbate MG are listed in Table 26.4.

Hankey’s Clinical Neurology

828 TABLE 26.4 Medications That May Exacerbate Myasthenia Gravis CONTRAINDICATED Alpha-interferon, curare, D-penicillamine, botulinum toxin USE WITH CAUTION • Neuromuscular blocking agents: • Succinylcholine, d-tubocurarine • Antibiotics: • Aminoglycosides (gentamicin, kanamycin, neomycin, streptomycin, tobramycin) • Macrolides (erythromycin, azithromycin) • Fluoroquinolones (ciprofloxacin, levofloxacin, norfloxacin) • Quinine, quinidine, procainamide • Magnesium salts • Calcium channel blockers • Beta-blockers • Lithium • Iodinated contrast agents

Prognosis

• Patients who present with ocular complaints have an 80–85% chance of generalizing. • There is some evidence that treatment with corticosteroids may decrease this risk. • The mortality rate from MG was more than 30% before the 1960s, but with the onset of modern critical care and immunosuppressive therapy, life expectancy in MG now approaches normal.

• At least 80% of patients are able to experience significant improvement in their symptoms; however, fixed weakness may develop later in the disease course if muscle weakness is not treated optimally. • Few patients are able to wean off immunotherapy completely.

CONGENITAL MYASTHENIC SYNDROMES Definition

Congenital myasthenic syndrome (CMS) is a heterogeneous group of disorders caused by various genetic mutations resulting in failed neuromuscular transmission. CMS should be considered in the differential diagnosis in seronegative myasthenia especially when there is a positive family history or the onset of symptoms is in infancy or at a young age. Typical symptoms are similar to those seen in autoimmune MG, with fluctuating and fatigable muscle weakness resulting in ptosis, ophthalmoparesis, neck and limb, as well as respiratory muscle weakness. There may be a history of decreased fetal movement in utero, and arthrogryposis is seen in some newborn infants. CMS may be classified according to the site of defect (Table 26.5). Diagnosis is confirmed by genetic testing. To date, more than 30 mutations have been identified. More forms of CMS are being identified due to improved DNA sequencing methods. The most common forms are AChR deficiency, DOK7, and rapsyn CMS.

TABLE 26.5  Congenital Myasthenic Syndromes19 Site of Defect

Mutation (Encoded Protein)

Major Clinical Features

Treatment

MYO9A (myosin-IXA)

Severe neonatal-onset ptosis, hypotonia, respiratory and bulbar weakness

Pyridostigmine and 3,4-DAP

Neonatal onset, apneic crisis Hypotonia and feeding difficulties at birth Neonatal onset, episodic apnea, arthrogryposis, malformations, cognitive delay Episodic apnea, ptosis, ophthalmoplegia, respiratory failure

Pyridostigmine Pyridostigmine Pyridostigmine

Contractures and breathing difficulty at birth

3,4-DAP

Presynaptic Axonal transport

Acetylcholine synthesis and recycling CHAT (choline acetyltransferase) PREPL (prolyl endopeptidase-like) SLC5A7 (choline transporter 1) SLC18A3 (vesicular acetylcholine transporter) Synaptic vesicles exocytosis SNAP25 (synaptosomal-associated protein 25) SYT2 (synaptotagmin 2) VAMP1 (vesicle-associated membrane protein 1) UNC13A1 (mammalian uncoordinated-13 protein)

Nonprogressive motor neuropathy and LEMS-like 3,4-DAP syndrome Severe hypotonia, muscle weakness, and feeding difficulty Pyridostigmine Severe hypotonia and respiratory failure, thin corpus callosum, microcephaly

3,4-DAP

Neonatal or early-onset severe ptosis, ophthalmoparesis, generalized weakness, respiratory difficulty Respiratory and feeding difficulties at birth, ptosis

β2-adrenergic agonists

Synaptic and basal lamina COLQ (collage-like tail subunit of acetylcholinesterase) COL13A1 (collagen XIII α1 chain)

Pyridostigmine

3,4-DAP, salbutamol (Continued)

Neuromuscular Junction Disorders

829

TABLE 26.5  Congenital Myasthenic Syndromes19 (Continued) Site of Defect

Mutation (Encoded Protein)

Major Clinical Features

Treatment

LAMB2 (laminin β2)

Neonatal onset breathing difficulty, ptosis, ophthalmoplegia, and proximal weakness Myopia, facial tics

Ephedrine

Most common symptom is restricted ocular movement, wide spectrum of phenotype

Pyridostigmine, 3,4-DAP, β2-adrenergic agonists

Slow-channel syndrome. Variable age of onset, ptosis, ophthalmoparesis, cervical and distal upper limb muscle weakness Fast-channel syndrome. Severe weakness from birth, ptosis, ophthalmoplegia and respiratory crises

AchR open channel blockers such as fluoxetine or quinidine Pyridostigmine, 3,4-DAP

LAMA5 (laminin α5)

Pyridostigmine 3,4-DAP

Postsynaptic Primary AChR deficiency CHRNE Kinetic abnormalities of the AChR CHRNA1 (α-subunit of AChR) (SCS) CHRNE (ε-subunit of AChR)

a

Defects within the AChR clustering pathway AGRN (agrin) LRP4 (low-density lipoprotein receptor-related protein) MuSK (muscle-specific kinase)

DOK7 (downstream of tyrosine kinase 7) aRAPSN (receptor-associated scaffold protein of the synapse) a

Wide spectrum of phenotypes, spared extraocular muscles β2-adrenergic agonists Variable severity from severe myasthenia to slightly β2-adrenergic agonists delayed motor milestones Limb-girdle weakness sparing eye muscles 3,4-DAP Worsens with pyridostigmine Limb-girdle weakness, ptosis β2-adrenergic agonists Early-onset hypotonia, respiratory weakness and feeding difficulty, mild arthrogryposis, facial dysmorphism, ptosis, and strabismus

Pyridostigmine, 3,4-DAP

Proximal muscle weakness sparing ocular and facial muscles, myopathy coexists Limb-girdle weakness, myopathy coexists, cognitive dysfunction

Pyridostigmine and 3,4-DAP Pyridostigmine, 3,4-DAP, and β2-adrenergic agonists

Limb-girdle weakness, myopathy coexists

Treatment of efficacy not reported

Limb-girdle weakness, significantly increased CK

Pyridostigmine, 3,4-DAP, salbutamol

Abnormal glycosylation GFPT1 (glutamine–fructose-6phosphate transaminase-1) DPAGT1 (dolichyl-phosphate-Nacetylglucosaminephosphotransferase-1) ALG2 (alpha-1,3mannosyltransferase) and ALG14 (UDP-N-acetylglucosaminyl­ transferase subunit) GMPPB (GDP-mannose pyrophosphorylase B)

Most common congenital myasthenic syndrome (CMS). Abbreviations: 3,4-DAP, 3, 4-diaminopyridine; LEMS, Lambert–Eaton myasthenic syndrome; AChR, acetylcholine receptor. a

LAMBERT–EATON MYASTHENIC SYNDROME Definition and epidemiology

LEMS is an autoimmune disorder caused by antibodies directed against the VGCC in the presynaptic motor nerve terminal. It is characterized by proximal limb and facial muscle weakness, fatigability, hyporeflexia, and autonomic dysfunction. LEMS is strongly associated with small-cell lung cancer (SCLC). • LEMS is a rare disease with a reported incidence of 0.48 per million population. • Patients are usually older than 40 years of age, and there is a male predominance.

• LEMS occurs in 3% of patients with SCLC, and 60% of patients with LEMS have SCLC.20 • SCLC can occur years after the onset of LEMS.

Pathophysiology

Antibodies develop against the VGCC on the presynaptic motor nerve terminal and autonomic nerve terminal. The majority of antibodies are against the P/Q-type VGCC while a small number of antibodies are against the N-type VGCC. The antibodies disrupt influx of calcium and release of acetylcholine. Miniature endplate potential amplitude in LEMS is similar to normal muscle. There is an adequate number of vesicles containing acetylcholine. AChR are also normal in number and function.

Hankey’s Clinical Neurology

830 There is a significant reduction in acetylcholine release which can be facilitated by increased calcium concentration. SCLC cells express VGCC on the membrane surface.

Antibody testing

• Antibodies to P/Q-type VGCC are present in 90% of patients with LEMS. • 60% of LEMS patients have cancer, most invariably SCLC; a low antibody titer may be present in those with other paraneoplastic disorders, autoimmune disorders, or amyotrophic lateral sclerosis (ALS). • Studies showed that anti-SOX1 antibody is found in 64–67% of patients with LEMS and SCLC, and only 0–5% LEMS patients without tumor. It is used as a marker for early tumor detection in patients diagnosed with LEMS and is highly specific in distinguishing between LEMS with or without tumor.21,22

Clinical features

• Progressive muscle weakness that preferentially affects the proximal lower extremities. • Patients may report difficulty rising from a chair or climbing stairs; patients may also complain of muscle stiffness or aching. • Facial, ocular, oropharyngeal, and respiratory muscle weakness occur in some patients. • Most patients experience dry mouth. Other autonomic symptoms include: erectile dysfunction, less frequently blurred vision, and constipation. • Absent or depressed deep tendon reflexes that may augment after brief, intense exercise. • Some patients have paraneoplastic cerebellar degeneration occurring with LEMS concomitantly.

TIP • In LEMS patients, the degree of muscle weakness found on examination is often less than expected based on the patient’s complaints.

Investigations and diagnosis Electrophysiology

• Low CMAP amplitude on routine NCS. • Increment of CMAP amplitude immediately after brief, intense exercise or with high-frequency (10–50 Hz) repetitive stimulation. The incremental response is usually > 100%. This is called postexercise or postactivation facilitation (Figure 26.7). • An incremental response may not be present if baseline CMAP amplitude is normal and the disease is mild. An abnormal decrement is present in almost all patients and may be the only abnormal finding early in the disease course. • LEMS patients typically have significant jitter with blocking on SFEMG that may improve with higher firing rates.

The Dutch-English LEMS Tumor Association Prediction (DELTA-P) score is a prediction model with a reliability of more than 94% in predicting the risk of SCLC in each LEMS patient. It is calculated as a sum score from categories including age of onset, smoking at onset, weight loss, Karnofsky’s performance status, bulbar symptoms, and male sexual impotence all within 3 months of disease onset. A score of 0–1 has a risk of SCLC of 0–2.6%; a score of 3–6 has a SCLC probability between 83.9% and 100% and requires a thorough search for SCLC.23 CT chest is superior than X-ray in detecting lung cancer. Positron emission tomography (PET) is able to detect a small tumor and should be considered in those with negative imaging but high risk of cancer.

Differential diagnosis Myopathy

• The most common misdiagnosis in LEMS patients is myopathy because patients frequently present with proximal lower extremity weakness. Therefore, a high index of suspicion is necessary. • Muscle weakness does not fluctuate in myopathy, and deep tendon reflexes are generally preserved.

MG

• Ocular and bulbar symptoms are more common and pronounced in typical MG. • Autonomic symptoms and signs do not occur in MG. • Reflexes are preserved in MG.

b 2.0 mv

a

Other tests

5 ms

FIGURE 26.7  Postexercise facilitation in LEMS. (a) Before exercise; (b) after brief, intense exercise.

Neuromuscular Junction Disorders ALS

• ALS typically presents with asymmetric distal limb weakness, whereas in LEMS, weakness is symmetric and proximal. • Muscle atrophy and fasciculations are not typical in LEMS. • Brisk reflexes are expected in ALS whereas hyporeflexia is seen in LEMS.

Treatment

Treatment of cancer often improves symptoms. In patients who continue to have significant muscle weakness after cancer treatment, medications to improve neuromuscular transmission or immune therapy can be considered.

Medications that improve acetylcholine release

3,4-Diaminopyridine (3,4-DAP) is a potassium channel inhibitor and enhances acetylcholine release by enhancing calcium entry into the presynaptic nerve terminal. 3,4-DAP produces clinical benefit in the majority of patients with LEMS: • Trials of 3,4-DAP in LEMS patients have demonstrated that it is effective in improving muscle strength and CMAP amplitude24–26 • Typical initial dose is 5 mg 3–4 times a day. Dose can be increased by 5 mg a day to a maximum of 80 mg daily. • It is generally well-tolerated. Common side effects are perioral tingling. Caution should be taken in patients who have history of seizure as it may lower seizure threshold. • It is not available in the United States, but may be obtained from certain compounding pharmacies or through a pharmaceutical research protocol. • Coadministration with a CI may potentiate the effect of 3,4-DAP. • Amifampridine phosphate (Firdapse) is the salt form of the 3,4-DAP base; it was approved by FDA in 2018 to treat LEMS in adults. Starting dose is 15–30 mg orally three times a day.27

Immunotherapy

Use of immunomodulating therapies has been studied. IVIG, PE, prednisone, AZA, mycophenolate mofetil, and rituximab have been reported to show benefit in small case series or retrospective reviews. PE and IVIG are generally used when there is severe weakness. Only IVIG was studied in a randomized, double-blind, placebocontrolled study. The patients in the IVIG group were shown to have a significant, but short-term, improvement in muscle strength and a fall in serum VGCC antibody titer.28

BOTULISM Definition and epidemiology

Botulism is caused by neurotoxins released by Clostridium botulinum, a gram-positive, spore-forming anaerobic bacterium. The toxins can be transmitted via ingestion of contaminated food as in food-borne and infantile botulism, or via entry through a wound site. The toxins interfere with fusion of neurotransmitter-containing vesicles in the presynaptic nerve

831 terminal. Disease manifestation and electrophysiologic findings can be variable. • Over 100 cases of botulism are reported in the United States every year. • Infantile botulism is the most common form, followed by food-borne and wound botulism.

Major forms Food-borne botulism

• Caused by ingestion of food contaminated with C. botulinum, its spores, or neurotoxin. • The toxins have accessory proteins that protect them from the proteolytic activity of the stomach acid. • It is usually transmitted through inadequately prepared canned foods. • Gastrointestinal symptoms (nausea, vomiting, diarrhea) may occur prior to onset of neurologic symptoms. • Within 2–36 hours of ingestion, most patients develop cranial nerve dysfunction and autonomic symptoms. Patients typically report blurred vision or diplopia, slurred speech, and difficulty swallowing. On examination, the most common findings are ptosis, ocular paresis or ophthalmoplegia, and nasal speech. This is followed by upper limb and then lower limb and respiratory weakness in severe cases. • Autonomic symptoms include: constipation, dry mouth, postural hypotension, urinary retention, mydriasis, and loss of pupillary reaction to light.

Infantile botulism

• Most frequently reported form of botulism. • Infants ingest toxin-containing spores of C. botulinum, which germinate and colonize the intestinal track. It occurs in infants less than 1 year of age and has been associated with ingestion of honey. • Constipation is typically the initial sign followed by symmetric cranial nerve dysfunction (ptosis, impaired eye movement, poor suck, and gag reflex). Limb weakness occurs next with generalized hypotonia. • Autonomic symptoms also occur and manifest as decreased production of tears and saliva and pupillary abnormalities. Respiratory failure that requires mechanical ventilation can occur. • Implicated as an explanation for some cases of sudden infant death syndrome. However, confirmatory bacteriologic evidence is lacking.

Wound botulism

• Clostridium bacteria, spores, or toxins inoculate wounds and gain access to the peripheral nerve terminal via blood. • Symptoms are similar to those seen in food-borne botulism, except for lack of gastrointestinal symptoms. • Higher incidence in intravenous drug users.

Inadvertent botulism

Clinical botulism, manifesting as generalized weakness, has been reported in patients who have received intramuscular injections of botulinum toxin for treatment of dystonia or spasticity. This is to be distinguished from inadvertent focal weakness, such as dysphagia after sternocleidomastoid injection, which occurs secondary to spread of toxin from the injected muscles into adjacent muscles.

Hankey’s Clinical Neurology

832 Patients develop generalized weakness, likely from circulating botulinum toxin.

Pathophysiology

There are eight types of known botulinum toxin, among which types A, B, E, F, and G cause disease in humans. The toxins spread hematogenously to reach the presynaptic nerve terminal and the autonomic ganglia. The neurotoxins gain access into the nerve terminal via receptor-mediated endocytosis. When inside the nerve terminal, the toxins degrade SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, a superfamily of proteins that mediate the fusion of vesicles with the cell membrane. Acetylcholine release is reduced resulting in decreased EPP.

Differential diagnosis

Guillain–Barré syndrome (GBS) is the most important diagnosis to exclude. GBS patients have prominent sensory symptoms at presentation whereas the sensory nerves are spared in botulism. Late responses are normal in botulism, but they are frequently first to become abnormal in GBS. Other diagnoses to consider include Miller Fisher syndrome, tick paralysis, MG, LEMS, diphtheritic neuropathy, and periodic paralysis.

Investigations Electrophysiology

• CMAP amplitudes are low in 85% of patients with botulism. After brief exercise, the CMAP amplitude may increase. • Nerve stimulation at high rates (50 Hz) or 10 seconds of isometric exercise, which is less painful for the patient, results in an incremental CMAP response (posttetanic facilitation) in about 62% of patients. • Typically, the incremental response is 30–100% in botulism and can persist for several minutes, in contrast to LEMS, where the incremental response is typically over 100% and persists for 30–60 seconds. • Infrequently, there is a decrement to slow rates (3–5 Hz) of stimulation. • Needle EMG may reveal spontaneous activity in the form of fibrillation potentials and positive sharp waves. Motor units may be myopathic in morphology. Significant jitter with blocking is seen on SFEMG.

3,4-DAP and pyridostigmine can also be used for symptomatic control. Wound debridement should be performed in wound botulism.

Prognosis

Mortality rate was 8% in a retrospective review of 706 patients with food-borne botulism. Although recovery is expected, it could take months to years in patients with severe disease, because recovery is dependent on sprouting of new nerve terminals leading to the regeneration of new endplates.

REFERENCES





Diagnosis

• Diagnosis is confirmed by testing for toxin in serum, stool, wound culture, or contaminated food. • C. botulinum is found in the stool of 60% of patients with food-born botulism, if collected within 2 days of ingesting the toxin. C. botulinum is also found in the wound in approximately 60% of patients with wound botulism.

Treatment

The mainstay of treatment for severe botulism is intensive care unit monitoring with close observation of respiratory and cardiac functions. The use of antitoxin is controversial due to its lack of benefit in many cases and high risk of side effects. It must be given within 24 hours of symptom onset when toxins are still in the circulation. Equine serum antitoxin is used in babies older than 1 year of age and adults. There is a 2% risk of anaphylaxis with equine serum antitoxin. A human-derived antitoxin is used in babies less than 1 year of age. Antitoxin can only be obtained from the Center for Disease Control, Department of Public Health in Alaska and California.29







1. Meriggioli MN, Sanders DB (2009). Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol 8:475–490. 2. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A (2001). Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nature Med 7(3):365–368. 3. Castleman B (1966). The pathology of the thymus gland in myasthenia gravis. Ann NY Acad Sci 135:496–505. 4. Drachman DB (1994). Myasthenia gravis. N Engl J Med 330:1797–1810. 5. Evoli A, Tonali PA, Padua L, et al. (2003). Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 126(Pt 10):2304–2311. 6. Vernino S (2009). Paraneoplastic disorders affecting the neuromuscular junction or anterior horn cell. Contin Life Learn Neurol 15(1):132–146. 7. Golnik KC, Pena R, Lee AG, Eggenberger ER (1999). An ice test for the diagnosis of myasthenia gravis. Ophthalmology 106(7):1282–1286. 8. Leite MI, Jacob S, Viegas S, et al. (2008). IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 131(7):1940–1952. 9. Zhang B, Tzartos JS, Belimezi M, et al. (2012). Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol 69(4):445–451. 10. Pascuzzi RM, Coslett HB, Johns TR (1984). Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol 15(3):291–298. 11. Schneider-Gold C, Gajdos P, Toyka KV, Hohlfeld RR (2005). Corticosteroids for myasthenia gravis. Cochrane Dat Syst Rev 2:CD002828. 12. Wolfe GI, Kaminski HJ, Aban IB, et al. (2016). Randomized trial of thymectomy in myasthenia gravis. N Engl J Med 376:511–22. 13. Wolfe GI, Kaminski HJ, Aban IB, et al. (2019). Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia-­ gravis: 2-year extension of the MGTX randomized trial. Lancet Neurol 18:259–268. 14. Meriggioli MN, Rowin J, Richman JG, Leurgans S (2003). Mycophenolate mofetil for myasthenia gravis: a doubleblind, placebo-controlled pilot study. Ann NY Acad Sci 998:494–499. 15. The Muscle Study Group (2008). A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 71(6):394–399.

Neuromuscular Junction Disorders 16. Sanders DB, Hart IK, Mantegazza R, et al. (2008). An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 71(6):400–406. 17. Howard JF, Utsugisawa K, Benatar M, et al. (2017). Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (REGAIN): a phase 3, radomised, double-blind, placebocontrolled, multicentre study. Lancet Neurol 16:976–86. 18. Zinman L, Ng E, Bril V (2007). IV immunoglobulin in patients with myasthenia gravis. Neurology 68:837–841. 19. Beeson D, Palace J, Rodriguez Cruz PM (2018). The neuromuscular junction and wide heterogeneity of congenital myasthenic syndromes. Int J Mol Sci 19(6):1677. 20. O’Neill JH, Murray NMF, Newsom-Davis J (1988). The Lambert-Eaton myasthenic syndrome: a review of 50 cases. Brain 111(Pt3):577–596. 21. Sabater L, Titulaer M, Saiz A, Verschuuren J, Güre AO, Graus F (2008). SOX1 antibodies are markers of paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology 70(12):924–928. 22. Titulaer MJR, Klooster M, Potman M, et al. (2009). SOX antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome; frequency and relation with survival. J Clin Oncol 27:4260–4267.

833 23. Titulaer MJ, Maddison P, Sont JK, et al. (2011). Clinical Dutch-English Lambert-Eaton myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS. J Clin Oncol 29:902–908. 24. McEvoy KM, Windebank AJ, Daube JR, Low PA (1989). 3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med 321(23):1567–1571. 25. Sanders DB, Massey JM, Sanders LL, Edwards LJ (2000). A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology 54(3):603–607. 26. Oh SJ, Claussen GG, Hatanaka Y, Morgan MB (2009). 3,4-Diaminopyridine is more effective than placebo in a randomized, double-blind, cross-over drug study in LEMS. Muscle Nerve 40:795–800. 27. Oh SJ, Schcherbakova N, Kostera-pruszczyk A, et al. (2016) Amifampridine phosphate (Firdapse) is effective and safe in a phase 3 clinical trial in LEMS. Muscle Nerve 53:717–725. 28. Bain PG, Motomura M, Newsom-Davis J, et al. (1996). Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the LambertEaton myasthenic syndrome. Neurology 47:678–683. 29. Carrillo-Marquez MA (2016). Botulism. Pediatr Rev 37(5):183–192.

27

MUSCLE DISORDERS

Kourosh Rezania, Peter Pytel, Betty Soliven

Contents Introduction........................................................................................................................................................................................................................839 Myopathy............................................................................................................................................................................................................................ 841 Definition...................................................................................................................................................................................................................... 841 Clinical features........................................................................................................................................................................................................... 841 Diagnosis....................................................................................................................................................................................................................... 841 Idiopathic Inflammatory Myopathy.............................................................................................................................................................................. 842 Definition...................................................................................................................................................................................................................... 842 Polymyositis....................................................................................................................................................................................................................... 842 Definition and epidemiology.................................................................................................................................................................................... 842 Clinical features........................................................................................................................................................................................................... 842 Differential diagnosis.................................................................................................................................................................................................. 842 Investigations............................................................................................................................................................................................................... 843 Diagnosis....................................................................................................................................................................................................................... 843 Pathology...................................................................................................................................................................................................................... 843 Treatment..................................................................................................................................................................................................................... 843 Prognosis....................................................................................................................................................................................................................... 843 Dermatomyositis............................................................................................................................................................................................................... 844 Definition and epidemiology.................................................................................................................................................................................... 844 Etiology.......................................................................................................................................................................................................................... 844 Pathophysiology.......................................................................................................................................................................................................... 844 Clinical features........................................................................................................................................................................................................... 844 Muscle disease....................................................................................................................................................................................................... 844 Cutaneous manifestations................................................................................................................................................................................... 844 Systemic features................................................................................................................................................................................................... 844 Malignancy............................................................................................................................................................................................................. 845 Childhood dermatomyositis............................................................................................................................................................................... 845 Differential diagnosis.................................................................................................................................................................................................. 845 Investigations............................................................................................................................................................................................................... 845 Diagnosis....................................................................................................................................................................................................................... 845 Pathology...................................................................................................................................................................................................................... 845 Immune-Mediated Necrotizing Myopathy................................................................................................................................................................. 845 Antisynthetase Syndrome............................................................................................................................................................................................... 846 Treatment..................................................................................................................................................................................................................... 846 General.................................................................................................................................................................................................................... 846 Immunomodulatory treatment of myositis..................................................................................................................................................... 846 Prognosis....................................................................................................................................................................................................................... 847 Sporadic Inclusion Body Myositis................................................................................................................................................................................. 847 Definition and epidemiology.................................................................................................................................................................................... 847 Etiology and pathophysiology................................................................................................................................................................................... 847 Clinical features........................................................................................................................................................................................................... 847 Differential diagnosis.................................................................................................................................................................................................. 847 Investigations............................................................................................................................................................................................................... 847 Diagnosis....................................................................................................................................................................................................................... 848 Pathology...................................................................................................................................................................................................................... 848 Treatment..................................................................................................................................................................................................................... 848 Prognosis....................................................................................................................................................................................................................... 849 Critical Illness Myopathy................................................................................................................................................................................................. 849 Definition and epidemiology.................................................................................................................................................................................... 849

835

836

Hankey’s Clinical Neurology

Etiology and pathophysiology................................................................................................................................................................................... 849 Clinical features........................................................................................................................................................................................................... 849 Differential diagnosis.................................................................................................................................................................................................. 849 Investigations............................................................................................................................................................................................................... 849 Pathology...................................................................................................................................................................................................................... 849 Prevention and treatment.......................................................................................................................................................................................... 849 Prognosis....................................................................................................................................................................................................................... 849 Endocrine and Metabolic Myopathies.......................................................................................................................................................................... 850 Definition...................................................................................................................................................................................................................... 850 Endocrine Myopathies............................................................................................................................................................................................... 850 Thyrotoxic myopathy.................................................................................................................................................................................................. 850 Clinical features..................................................................................................................................................................................................... 850 Diagnosis................................................................................................................................................................................................................. 850 Treatment................................................................................................................................................................................................................ 850 Dysthyroid eye disease (exophthalmic ophthalmoplegia).................................................................................................................................. 850 Clinical features..................................................................................................................................................................................................... 850 Diagnosis................................................................................................................................................................................................................. 850 Treatment................................................................................................................................................................................................................ 850 Hypothyroid myopathy...............................................................................................................................................................................................851 Clinical features......................................................................................................................................................................................................851 Diagnosis..................................................................................................................................................................................................................851 Treatment.................................................................................................................................................................................................................851 Chronic steroid myopathy..........................................................................................................................................................................................851 Definition.................................................................................................................................................................................................................851 Clinical features......................................................................................................................................................................................................851 Investigations and diagnosis................................................................................................................................................................................851 Treatment.................................................................................................................................................................................................................851 Weakness due to Addison’s disease and other forms of hypoadrenalism.........................................................................................................851 Definition.................................................................................................................................................................................................................851 Clinical features......................................................................................................................................................................................................851 Diagnosis..................................................................................................................................................................................................................851 Treatment.................................................................................................................................................................................................................851 Acromegaly....................................................................................................................................................................................................................851 Clinical features......................................................................................................................................................................................................851 Diagnosis..................................................................................................................................................................................................................851 Treatment.................................................................................................................................................................................................................851 Hyperparathyroidism..................................................................................................................................................................................................851 Definition.................................................................................................................................................................................................................851 Clinical features......................................................................................................................................................................................................852 Investigations and diagnosis................................................................................................................................................................................852 Treatment.................................................................................................................................................................................................................852 Disorders of Glycogen Metabolism................................................................................................................................................................................852 Acid maltase deficiency (Pompe’s disease, glycogen storage disease type II)..................................................................................................852 Definition and epidemiology................................................................................................................................................................................852 Clinical features......................................................................................................................................................................................................852 Differential diagnosis.............................................................................................................................................................................................852 Investigations..........................................................................................................................................................................................................853 Diagnosis..................................................................................................................................................................................................................853 Pathology (adult form)..........................................................................................................................................................................................853 Treatment.................................................................................................................................................................................................................853 McArdle’s disease (type V glycogenosis).................................................................................................................................................................853 Definition and epidemiology................................................................................................................................................................................853 Pathophysiology......................................................................................................................................................................................................853 Clinical features......................................................................................................................................................................................................853 Differential diagnosis of cramps +/− weakness............................................................................................................................................... 854 Investigations......................................................................................................................................................................................................... 854 Diagnosis................................................................................................................................................................................................................. 854 Pathology................................................................................................................................................................................................................. 854 Treatment................................................................................................................................................................................................................ 854

Muscle Disorders

837

Phosphofructokinase deficiency (Tarui’s disease, glycogenosis type VII)....................................................................................................... 854 Definition and epidemiology............................................................................................................................................................................... 854 Clinical features......................................................................................................................................................................................................855 Investigations and diagnosis................................................................................................................................................................................855 Debranching enzyme deficiency (type III glycogenosis, Cori–Forbes disease)..............................................................................................855 Definition.................................................................................................................................................................................................................855 Clinical features......................................................................................................................................................................................................855 Investigations and diagnosis................................................................................................................................................................................855 Polyglucosan body disease (glycogenosis type IV, Andersen’s disease, or amylopectinosis)........................................................................855 Definition.................................................................................................................................................................................................................855 Clinical features......................................................................................................................................................................................................855 Investigations and diagnosis................................................................................................................................................................................855 Disorders of Lipid Metabolism.......................................................................................................................................................................................855 Muscle carnitine deficiency.......................................................................................................................................................................................855 Definition.................................................................................................................................................................................................................855 Clinical features......................................................................................................................................................................................................855 Diagnosis..................................................................................................................................................................................................................855 Treatment.................................................................................................................................................................................................................855 Carnitine palmitoyltransferase II deficiency..........................................................................................................................................................855 Definition.................................................................................................................................................................................................................855 Clinical features..................................................................................................................................................................................................... 856 Investigations and diagnosis............................................................................................................................................................................... 856 Treatment................................................................................................................................................................................................................ 856 Mitochondrial Myopathy................................................................................................................................................................................................ 856 Definition...................................................................................................................................................................................................................... 856 Etiology and pathophysiology................................................................................................................................................................................... 856 Clinical features........................................................................................................................................................................................................... 856 Investigations............................................................................................................................................................................................................... 856 Pathology...................................................................................................................................................................................................................... 857 Treatment..................................................................................................................................................................................................................... 857 Muscular Dystrophies...................................................................................................................................................................................................... 857 Definition...................................................................................................................................................................................................................... 857 Dystrophinopathies.......................................................................................................................................................................................................... 857 Definition...................................................................................................................................................................................................................... 857 Etiology and pathophysiology................................................................................................................................................................................... 857 Clinical features........................................................................................................................................................................................................... 860 General.................................................................................................................................................................................................................... 860 Duchenne’s muscular dystrophy........................................................................................................................................................................ 860 Becker’s muscular dystrophy.............................................................................................................................................................................. 860 Other dystrophinopathies....................................................................................................................................................................................861 Differential diagnosis...................................................................................................................................................................................................861 Investigations and diagnosis......................................................................................................................................................................................861 Pathology.......................................................................................................................................................................................................................861 Treatment......................................................................................................................................................................................................................861 Current management............................................................................................................................................................................................861 Other therapeutic strategies.................................................................................................................................................................................862 Facioscapulohumeral Muscular Dystrophy..................................................................................................................................................................862 Definition.......................................................................................................................................................................................................................862 Etiology and pathophysiology....................................................................................................................................................................................862 Clinical features......................................................................................................................................................................................................862 Differential diagnosis.................................................................................................................................................................................................. 863 Investigations and diagnosis..................................................................................................................................................................................... 863 Pathology...................................................................................................................................................................................................................... 863 Treatment..................................................................................................................................................................................................................... 863 Emery–Dreifuss Muscular Dystrophy.......................................................................................................................................................................... 863 Definition...................................................................................................................................................................................................................... 863 Etiology and pathophysiology................................................................................................................................................................................... 863 Clinical features........................................................................................................................................................................................................... 864 Investigations and diagnosis..................................................................................................................................................................................... 864

838

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Pathology...................................................................................................................................................................................................................... 864 Treatment..................................................................................................................................................................................................................... 864 Limb-Girdle Muscular Dystrophy................................................................................................................................................................................. 864 Definition...................................................................................................................................................................................................................... 864 Etiology and pathophysiology................................................................................................................................................................................... 864 Protein types........................................................................................................................................................................................................... 864 Clinical features........................................................................................................................................................................................................... 864 Differential diagnosis.................................................................................................................................................................................................. 865 Investigations and diagnosis..................................................................................................................................................................................... 866 Pathology...................................................................................................................................................................................................................... 866 Treatment..................................................................................................................................................................................................................... 867 Myotonic Dystrophy......................................................................................................................................................................................................... 867 Definition and epidemiology.................................................................................................................................................................................... 867 Etiology and pathophysiology................................................................................................................................................................................... 867 Clinical features........................................................................................................................................................................................................... 867 Systemic symptoms............................................................................................................................................................................................... 867 Neuromuscular symptoms and signs................................................................................................................................................................ 867 CNS manifestations.............................................................................................................................................................................................. 867 Special forms.......................................................................................................................................................................................................... 868 Differential diagnosis of myotonia........................................................................................................................................................................... 868 Investigations and diagnosis..................................................................................................................................................................................... 868 Pathology...................................................................................................................................................................................................................... 868 Treatment..................................................................................................................................................................................................................... 868 Medications for myotonia................................................................................................................................................................................... 868 Treatment of excessive daytime sleepiness.......................................................................................................................................................869 Future therapeutic strategies................................................................................................................................................................................869 Prognosis..................................................................................................................................................................................................................869 Muscle Channelopathies (Disorders of Membrane Excitability).............................................................................................................................869 Myotonia Congenita..........................................................................................................................................................................................................869 Definition and epidemiology.....................................................................................................................................................................................869 Etiology and pathophysiology....................................................................................................................................................................................869 Clinical features............................................................................................................................................................................................................869 Differential diagnosis...................................................................................................................................................................................................869 Investigations and diagnosis......................................................................................................................................................................................869 Treatment......................................................................................................................................................................................................................869 Paramyotonia Congenita (Eulenburg’s Disease) and Potassium-Aggravated Myotonias...................................................................................869 Definition.......................................................................................................................................................................................................................869 Etiology and pathophysiology....................................................................................................................................................................................870 Clinical features............................................................................................................................................................................................................870 Differential diagnosis...................................................................................................................................................................................................870 Investigations and diagnosis......................................................................................................................................................................................870 Treatment......................................................................................................................................................................................................................870 Hyperkalemic Periodic Paralysis.....................................................................................................................................................................................870 Definition.......................................................................................................................................................................................................................870 Etiology and pathophysiology....................................................................................................................................................................................870 Clinical features............................................................................................................................................................................................................870 Differential diagnosis...................................................................................................................................................................................................870 Investigations................................................................................................................................................................................................................870 Diagnosis........................................................................................................................................................................................................................870 Treatment......................................................................................................................................................................................................................870 Hypokalemic Periodic Paralysis......................................................................................................................................................................................870 Definition and epidemiology.....................................................................................................................................................................................870 Etiology and pathophysiology....................................................................................................................................................................................870 Clinical features............................................................................................................................................................................................................871 Differential diagnosis...................................................................................................................................................................................................871 Investigations and diagnosis......................................................................................................................................................................................871 Pathology..................................................................................................................................................................................................................871 Treatment......................................................................................................................................................................................................................871 Malignant Hyperthermia..................................................................................................................................................................................................871 Definition.......................................................................................................................................................................................................................871

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839

Etiology and pathophysiology....................................................................................................................................................................................871 Clinical features............................................................................................................................................................................................................871 Differential diagnosis...................................................................................................................................................................................................871 Investigations................................................................................................................................................................................................................871 Diagnosis........................................................................................................................................................................................................................871 Pathology..................................................................................................................................................................................................................871 Treatment......................................................................................................................................................................................................................871 Prevention and prognosis...........................................................................................................................................................................................872 References............................................................................................................................................................................................................................872

INTRODUCTION Skeletal muscle tissue is unique in several regards. It comprises individual, large, multinucleated, tube-shaped syncytial structures called myofibers. These develop through fusion of mononucleated precursors. Myofibers are grouped into fascicles that, in turn, are arranged into individual muscles (Figures 27.1, 27.2). The basic contractile units of myofibers are sarcomeres, composed of actin and myosin filaments, which give muscles their striated appearance (Figures 27.3, 27.4). Organelles are arranged around the sarcomeres (Figures 27.4, 27.5). Different functional types of myofiber can be distinguished based on the expression of myosin isoforms and metabolic activity. The main distinction is between anaerobic fast-twitch type II fibers and aerobic slow-twitch type I fibers (Figure 27.6). There are other proteins besides sarcomeric ones that are essential for muscle function, including ion channels, metabolic enzymes, and the dystrophin–glycoprotein complex. FIGURE 27.1  Diagram of myofiber architecture. In normal skeletal muscle, individual myofibers are tightly packed into fascicles. Within individual fascicles, only minimal delicate endomysial connective tissue separates myofibers. The perimysial connective tissue between fascicles contains larger blood vessels and nerve branches. Myofiber nuclei normally show a peripheral localization. Most of the cytoplasm is filled with the sarcomeres that make up the contractile apparatus. The dystrophin–­g lycoprotein complex includes dystrophin, sarcoglycans, and dystroglycans. It creates a link between the inside actin cytoskeleton and the basement membrane.

FIGURE 27.2  Normal muscle hematoxylin and eosin (H&E) histology. On cross sections, myofibers show polygonal profiles of relatively uniform size. Nuclei are peripherally placed. There is very little connective tissue between tightly packed myofibers within a fascicle. The lower half of the image shows a connective tissue septum separating fascicles.

Basal lamina α

Laminin Sarcoglycans

α β γ δ β

Dystroglycan Syntrophins Dystrobrevin Dystrophin Actin cytoskeleton Myofiber with peripheral nuclei and sarcomeres Epimysium Perimysial connective tissue with nerves and blood vessels Fascicles with endomysial connective tissue

Hankey’s Clinical Neurology

840 A band I band

M line H zone

I band

H zone

FIGURE 27.3  Major regions and proteins of a sarcomere. Muscle contraction is the result of interaction of actin and myosin heads. Z line contains actin, α actinin, and a number of other proteins. Mutations of α actinin are associated with nemaline rod disease. Titin is the largest known protein; it stretches from the Z line to the M line. Mutations in titin are associated with limb-girdle muscular dystrophy (LGMD) R10. Desmin is present in the peripheral part of the Z line and connects different sarcomeres. Desmin and myotilin mutations are associated with myofibrillar myopathy. Telethonin/TCAP is another protein of Z line and has been linked to LGMD R7.

Z line

Actin–tropomyosin– troponin complex

Myosin Actin Titin Telethonin Myotilin Desmin

FIGURE 27.4  Normal histology, electron microscopy. A sarcomere is contractile unit. It is outlined by two Z bands (red arrows) that anchor the thin actin filaments. These overlap with the thick myosin filaments that extend outward from the M band (yellow arrow). Mitochondria (blue arrow) are found between sarcomeres.

FIGURE 27.5  Normal histology, modified Gomori’s trichrome stain. Mitochondria and organelles stain in a delicate dark reticular pattern that outlines individual sarcomeres. Aggregates of mitochondria, lipids, or disease-related inclusions can be visualized with this stain. FIGURE 27.6  Normal histology, ATPase. The ATPase reaction distinguishes fiber types. At pH 9.4, type I fibers are light and type II fibers are dark. Normally myofibers show the illustrated checkerboard type of admixture.

Muscle Disorders

841 Diagnosis

TIP • Histologically, type I fibers react strongly to stains for oxidative enzymes such as nicotinamide dinucleotide dehydrogenase (NADH), and weakly to ATPase and phosphorylase. Type II fibers exhibit the reverse reactivity, and can be further classified into types IIA, IIB, and IIC based on their ATPase reactions at different pH values. Type IIC fibers are fetal precursors and rarely seen in adult muscles. Type I fibers are innervated by small motor units, and type II fibers by large motor units.

MYOPATHY Definition

Weakness, fatigue, and/or myalgia secondary to pathologic processes that primarily affect sarcolemma, contractile element, organelles, connective tissue, vasculature, and/or basement membrane.

Clinical features

• Symptoms: • Negative: weakness, fatigue, and contractures. • Positive: pain (myalgia), cramps, myotonia (inability to relax), and urine discoloration (due to myoglobinuria). • Signs: • Weakness on manual strength testing. • Muscle atrophy, hypertrophy, or pseudohypertrophy. • Normal or reduced deep tendon reflexes. • Grip myotonia or percussion myotonia.

• Pattern of weakness: usually proximal > distal with or without facial or bulbar involvement, but other patterns of weakness are also observed (Table 27.1). • Muscle enzyme levels – creatine kinase (CK), aldolase: • Normal CK and aldolase do not exclude a myopathy. • Mild to moderately high CK is not specific for myopathy and can be seen in neurogenic disorders such as motor neuron diseases such as Kennedy’s disease or amyotrophic lateral sclerosis. • Certain myopathies are associated with very high CK (Table 27.2). • Electromyography (EMG) findings: • Spontaneous activity (fibrillation potentials and positive waves) is seen in myopathies with vacuolization, segmental myofiber necrosis, and fiber splitting. Examples are polymyositis, dermatomyositis, inclusion body myositis, necrotizing myopathy (toxic, medications), intensive care unit (ICU) myopathy (some cases), muscular dystrophy, and acid maltase deficiency. • Absence of spontaneous activity does not exclude a myopathy. Examples are steroid myopathy, other endocrine myopathies, and some cases of ICU myopathy. • Activation of the muscle recruits short duration, sometimes polyphasic motor units. Early recruitment of motor units is usually seen. • Muscle biopsy: • Selection of the muscles should be based on the distribution of muscle weakness, electromyography (EMG) findings, and sometimes magnetic resonance imaging (MRI). • It is important to select a mild to moderately affected muscle (not severely affected or completely unaffected muscle). • Muscle biopsy should be processed in a specialized laboratory setup to snap freeze tissue.

TABLE 27.1  Patterns of Weakness in Myopathies Pattern

Type of Myopathy

Limb girdle (proximal > distal)

Inflammatory myopathies, Polymyositis, Dermatomyositis, Endocrine, Hypothyroidism and hyperthyroidism,, Steroid myopathy, Hyperparathyroidism, Acromegaly, Toxic, Metabolic, Glycogenoses, Lipid storage, Muscular dystrophy, Dystrophinopathies, Limb-girdle muscular dystrophies, Myotonic dystrophy type 2 Myotonic dystrophy type 1 Some congenital myopathies Distal muscular dystrophies Hereditary inclusion body myopathy (hIBM) Scapuloperoneal dystrophy Facioscapulohumeral dystrophy hIBM Emery–Dreifuss muscular dystrophy, Lamin A/C deficient myopathy Sporadic inclusion body myopathy (sIBM) Mitochondrial myopathy Myotonic dystrophy type 1 (only ptosis) Oculopharyngeal muscular dystrophy Nemaline rod myopathy (only ptosis)

Distal > proximal

Proximal arm/distal leg (scapuloperoneal) Distal arm/proximal leg Ptosis and/or ophthalmoparesis

Head drop (neck extension weakness)

Isolated neck extension myopathy sIBM, hIBM Polymyositis Myotonic dystrophy type 2, carnitine deficiency, nemaline rod myopathy, hyperparathyroidism

Prominent axial/respiratory muscle weakness

Acid maltase deficiency (adult onset), critical illness myopathy, myotonic dystrophy, nemaline myopathy, centronuclear myopathy, myopathy with cytoplasmic bodies, hIBM

Hankey’s Clinical Neurology

842 TABLE 27.2 Differential Diagnosis of Myopathy Based on Creatine Kinase (CK) Levels CK Level

Type of Myopathy

Very high (>10×)

Necrotizing myopathy Metabolic myopathy (during rhabdomyolysis) Severe trauma Muscular dystrophy Duchenne’s Dysferlinopathy Calpain deficiency Polymyositis Hypothyroidism (some patients) ICU myopathy (acute stage) Inclusion body myositis Metabolic myopathy (between episodes of rhabdomyolysis) Hypothyroidism Other (except hyperthyroidism) Idiopathic hyper-CKemia Steroid myopathy Iatrogenic Cushing’s syndrome Myopathy of disuse Alcoholism Hyperthyroidism End-stage muscle Multiorgan failure ICU myopathy (chronic stage)

Mild to moderate

Normal or low

Abbreviation:

ICU, intensive care unit.

• Routine stains include hematoxylin/eosin (H&E), modified Gomori’s trichrome stain, and ATPase reaction (Figures 27.2, 27.5, and 27.6). • Enzyme histochemical studies, immunocytochemical tests, and electron microscopy can be helpful. • Frozen muscle tissue can be utilized for biochemical testing and immunoblot (Western). • Biopsy allows distinction between neurogenic and myopathic processes, and often provides a specific diagnosis of the type of myopathy (Figure 27.7). • Genetic testing. Specific genetic tests and biochemical studies are discussed in disorder-specific sections below. • Others (e.g. biochemical studies)

IDIOPATHIC INFLAMMATORY MYOPATHY Definition

Polymyositis, dermatomyositis, and inclusion body myositis (IBM) were the three major traditional categories of idiopathic inflammatory myopathy (IIM).1 This classification had its caveats, and updates have been proposed. Immune-mediated necrotizing myopathy (IMNM) and antisynthetase syndrome (ASS) are now often regarded as distinct subsets of inflammatory myopathies, and have partly replaced what was considered ‘idiopathic polymyositis’ a decade ago. IBM usually does not respond or is minimally responsive to immunosuppressive

a

b

c

d

FIGURE 27.7  Myopathic changes (H&E). A key feature of many myopathic processes is the presence of myofibers with morphologic changes of individual fiber degeneration and regeneration. Necrotic amorphous cytoplasm (a) becomes progressively infiltrated and organized by inflammatory cells (b, c). The cytoplasm of regenerative myofibers (d) has a blue hue because of high RNA content. Their nuclei are large, reflective of activation. treatments. Inflammation plays a role in the pathogenesis of IBM, but it could be secondary to a primarily degenerative process.

POLYMYOSITIS Definition and epidemiology

An acquired inflammatory myopathy characterized by progressive muscle weakness and the presence of inflammatory infiltrates and degenerating or regenerating fibers in the muscle. • Incidence and prevalence of polymyositis were estimated at 3.8 and 9.7 per 100,000 people, respectively, in a recent study.1 However, this could be an overestimation, as many cases of polymyositis with older criteria turned out to have another type of myopathy (e.g. IMNM, IBM, and muscular dystrophy) when newer techniques such as immunohistochemistry were used. • Age at onset: > 18 years of age. • Gender: F ≥ M.

Clinical features

• Slow onset (weeks to months). • Usually, symmetric weakness of proximal limb muscles, including the neck flexors; pelvic girdle muscles are involved more severely than the shoulder girdle. • Occasionally, pain and muscle tenderness. • Weight loss, dysphagia, and hoarseness are common. • No skin rash. • Underlying cancer is less frequently associated with polymyositis (in contrast to dermatomyositis).

Differential diagnosis • Dermatomyositis. • IBM.

Muscle Disorders • IMNM. • ASS. • Myositis associated with systemic autoimmune or connective tissue diseases. • Muscular dystrophies: • Endomysial inflammatory infiltrate is often seen in facioscapulohumeral dystrophy, dysferlinopathy, calpainopathy, and some congenital myopathies. • Myotonic dystrophy type 2 typically presents with proximal > distal weakness. • Viral myositis: human immunodeficiency virus (HIV), human T-cell lymphotropic virus type 1, influenza A, parainfluenza, adenovirus 2. • Acute rhabdomyolysis: influenza A and B, Echo 9, adenovirus 21, herpes simplex, Epstein–Barr virus, coxsackie B5 (also B1, B3, and B4). • Bacterial myositis: acute suppurative myositis (Staphylococcus aureus, Streptococcus spp., Yersinia spp., anaerobic organisms). • Fungal myositis. • Parasitic myositis (e.g. toxoplasmosis, cysticercosis, trichinosis). • Toxic myopathy: • Mitochondrial (zidovudine, germanium). • Lysosomal (colchicine, chloroquine, hydroxychloro­ quine). • Myofibrillar (emetine). • Myosin deficiency (steroids, vecuronium, atracurium). • Rhabdomyolysis (statins, fibrates, cyclosporine, alcohol, cocaine, snake venoms). • Eosinophilia–myalgia syndrome (L-tryptophan). • Vacuolar (drugs that cause hypokalemia). • Inflammatory (D-penicillamine, α-interferon, statins). • Others (ε-amino caproic acid, amiodarone, valproic acid). • Polymyalgia rheumatica: • Pain with limitation of movement. • CK is normal, and muscle biopsy shows only minimal abnormalities, but erythrocyte sedimentation rate (ESR) is elevated. • Endocrine myopathy. • Other neuromuscular diseases (e.g. myasthenia gravis [MG]).

843

• • • •

other conditions in which myositis may occur, such as systemic sclerosis and systemic lupus erythematosus (SLE). Electrocardiography (ECG): occasionally shows heart block. EMG (myopathic pattern) (see Introduction). Muscle MRI is often useful to differentiate active myositis from steroid myopathy, and to help choose an appropriate muscle for biopsy.5 Muscle biopsy: a muscle biopsy can help to confirm the diagnosis and exclude some other disease processes.

Diagnosis

Based on clinical features, supported by laboratory investigations (CK, myositis antibody panel, EMG, and biopsy).

Pathology

• Predominantly endomysial inflammatory cell infiltrates, mainly of cytotoxic T-cell (CD8+) type, surrounding or partially invading individual muscle fibers (Figure 27.8). Inflammatory cells may appear to invade morphologically normal myofibers. • B cells are infrequent. Dendritic cells are frequently present, sometimes in contact with T cells. • Fairly widespread increase in major histocompatibility complex class I (MHCI) expression on the surface of myofibers. • Absence of rimmed vacuoles, perifascicular atrophy, and perifascicular necrosis. • Myopathic changes in muscle morphology with degenerating/necrotic myofibers, regenerating myofibers, as well as variation in myofiber size, and internalized nuclei (Figure 27.8).

Treatment

See subsequent sections for treatment of polymyositis and dermatomyositis.

Prognosis

The response is less favorable than in dermatomyositis, particularly in those with a long duration of illness at

Investigations

• Blood tests: • Serum CK level: usually elevated (5–50 times normal). CK level often does not correlate with the severity of weakness; however, along with the clinical assessment of weakness, CK level is used in monitoring the response to therapy. • ESR: usually, though not invariably, elevated. • Autoantibodies. Myositis-specific antibodies (MSAs) are positive in the majority of IIM patients, and are useful to identify patients at risk of interstitial lung disease (ILD), which adversely affects the prognosis.2–4 MSA seropositivity in an individual patient is limited to one autoantibody, and generally categorizes the patients as IMNM or ASS. 2 Myositisassociated antibodies (MAAs), on the other hand, refer to those autoantibodies that are also found in

FIGURE 27.8  Polymyositis (H&E). Myopathic changes with myofiber necrosis/regeneration and variation in myofiber size are associated with focal mononuclear cell infiltrates. These tend to be most prominent in the endomysium.

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844 presentation. Immunosuppressive therapy usually prevents further progression, but significant improvement may not occur. Antibody to signal recognition peptide, found in 5% of cases, is associated with a fulminant course and resistance to treatment.

DERMATOMYOSITIS Definition and epidemiology

An inflammatory myopathy with characteristic cutaneous manifestations. • Incidence and prevalence of dermatomyositis were estimated at 1.4 and 5.8 cases per 100,000, respectively; more common in females and among older people.1 • Age at onset: any age, affects children and adults. Comprises 95% of childhood myositis. • Gender: F > M (2:1).

Etiology

• Unknown in most cases. • Caused or exacerbated by drugs in a few patients: • Hydroxyurea (predominantly skin manifestations). • Quinidine. • Nonsteroidal anti-inflammatory drugs. • Penicillamine. • 3-Hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (‘statins’).

Pathophysiology

• A humorally mediated microangiopathy (e.g. antibodies against capillary endothelial cells with complement activation). • Overexpression of type 1 interferons and their related proteins may play an important role in the pathogenesis of dermatomyositis.6, 8

Clinical features Muscle disease

• Initial symptoms include subacute onset of myalgias, fatigue, and symmetric proximal weakness, manifested as difficulty climbing stairs and raising the arms for actions such as shaving or brushing hair. • Pain and tenderness on palpation of the muscles is variable. • The course is slowly progressive during a period of weeks to months. • Difficulty swallowing (dysphagia) or symptoms of aspiration may reflect involvement of striated muscle in the pharynx or upper esophagus. • Dysphonia.

Cutaneous manifestations

• Heliotrope rash (Figure 27.9): a violaceous to dusky erythematous rash, with or without edema, in a symmetric distribution involving the periorbital skin. • Gottron’s papules: slightly raised violaceous papules and plaques, with or without a slight scale and rarely a thick psoriasiform scale, over bony prominences, particularly the metacarpophalangeal joints, proximal interphalangeal joints, and distal interphalangeal joints. Papules may also be found overlying the elbows, knees, and feet.

FIGURE 27.9  Heliotrope rash. Violaceous discoloration of the eyelids, cheeks, and nose in a patient with dermatomyositis.

• An erythematous to violaceous psoriasiform dermatitis involving the scalp. • Malar erythema. • Poikiloderma (which is the combination of atrophy, dyspigmentation, and telangiectasia) on sun-exposed skin such as the extensor surfaces of the arms, the ‘V’ of the neck, and the upper back (shawl sign). • Nailfold changes: periungual telangiectases and/or hypertrophy of the cuticle, and small hemorrhagic infarcts in the hypertrophic area.

Systemic features

• Raynaud’s phenomenon. • Generalized arthralgias, sometimes arthritis. • Esophageal disease, manifested by dysphagia, occurs in about 15–50% of patients. There are two main forms: • Proximal dysphagia is caused by involvement of striated muscle of the pharynx or proximal esophagus, correlates with severity of the muscle disease, and responds to steroid treatment. • Distal dysphagia is due to involvement of nonstriated muscle and is more common in patients who have an overlap with scleroderma or another collagen–vascular disorder. • Pulmonary disease: occurs in about 15–30% of patients, particularly those with esophageal disease, and is usually due to an interstitial pneumonitis. Less common causes include the muscle disease itself (causing hypoventilation or aspiration), and treatments for the muscle disease (causing opportunistic infections or drug-induced hypersensitivity pneumonitis). It is associated with a poor prognosis. • Cardiac disease: present in up to 50% of patients but uncommonly symptomatic. Disorders include conduction defects and primary end-rhythm disturbances, and even less commonly congestive heart failure, pericarditis, and valvular disease. It is associated with a poor prognosis. • Calcinosis of the skin (firm, yellow- or flesh-colored nodules, usually over bony prominences, and occasionally extruding through the surface of the skin) or muscle

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845

(generally asymptomatic) is unusual in adults, but may occur in up to 40% of children and adolescents with dermatomyositis.

Malignancy

• About 20–25% patients have associated malignancy, before the onset of myositis, concurrently with myositis, or after the onset of dermatomyositis. • Malignancy is more common in older patients (> 50 years) but may even occur in children. • The site of malignancy can be predicted by the patient’s age (e.g. testicular cancer in young men, colon and prostate cancer in elderly men). • Gynecological malignancy, particularly ovarian carcinoma, is common. • Nasopharyngeal carcinoma is common among Asians with dermatomyositis.

Childhood dermatomyositis

Childhood dermatomyositis is more common than childhood and adolescent polymyositis. Onset is usually subacute (over weeks), although it can be insidious (over months) or acute (over days and mistaken for a viral-type illness or dermatitis). Proximal weakness and neck flexion weakness occur, dysphagia in 30%, and sometimes chewing problems, or dysarthria. It is commonly characterized as a vasculitis and has greater potential for calcinosis than adult disease.

Differential diagnosis

• Muscle weakness (see the differential diagnosis of polymyositis). • Heliotrope rash (Figure 27.9) and photosensitive poikilodermatous eruption: • SLE: a heliotrope rash is rarely seen. • Scleroderma: a heliotrope rash is rarely seen. • Gottron’s papules: • SLE. • Psoriasis: distinct histopathology. • Lichen planus: distinct histopathology. • Scalp erythematous to violaceous psoriasiform dermatitis: • Psoriasis. • Seborrheic dermatitis. • Facial erythema: • SLE. • Rosacea. • Seborrheic dermatitis. • Atopic dermatitis.

Investigations

• Blood tests: • ESR is usually elevated. • Elevated serum muscle enzymes: CK, aldolase, lactate dehydrogenase, alanine aminotransferase (ALT). • CK levels may be raised up to 20 times normal, particularly in acute cases. CK levels can be normal. • High antinuclear antibody titers; antibodies to Ro (SSA) are found in rare cases. • Antibodies to Jo-1 are associated with ASS, but also occur in patients who have typical dermatomyositis, and are predictive of ILD, Raynaud’s phenomenon, mechanic’s hand.

• •

• •

• Anti-Mi2 antibody, on the other hand, a classic marker of dermatomyositis and is associated with a good response to steroids, presence of classical skin involvement and low risk of ILD and cancer.9 • Other dermatomyositis-specific antibodies include antinuclear matrix protein 2 (NXP 2) and antismall ubiquitin like modifier 1 activating enzyme (SAE).9 EMG (myopathic pattern) (see Introduction). Muscle MRI often shows signal abnormalities secondary to inflammation and edema. It may be useful in differentiating active myositis from steroid myopathy, and in helping to choose an appropriate muscle for biopsy.1 Skin biopsy and/or muscle biopsy. Work-up for malignancy: • Depending on the patient’s age and gender, appropriate work-up is necessary to assess for malignant disease. • Repeat each year for the first 3 years after diagnosis or whenever new symptoms arise.

Diagnosis

Based on clinical features, supported by laboratory investigations.

Pathology

• Infiltration of muscle by macrophages and T helper (CD4 +) and B lymphocytes. • The inflammatory infiltrates are predominantly perivascular, around the interfascicular septa, rather than endomysial (in contrast to polymyositis). • Expression of MHCI is typically increased. This stain often highlights a perifascicular accentuation of staining. • No invasion of inflammatory cells into nonnecrotic myofibers. • Microangiopathy: intramuscular blood vessels show endothelial hyperplasia with tubuloreticular inclusions, fibrin thrombi (particularly in children), and obliteration of capillaries. There is often capillary labeling for membrane attack complex/C5b-9 that tends to follow a perifascicular distribution. • Capillary numbers are reduced; there are immunoglobulin deposits on vessel walls, and blood vessel endothelial cells. The capillary loss and consequent ischemia cause microinfarcts and may be responsible for the striking perifascicular atrophy that is seen sometimes. • Perifascicular atrophy (Figure 27.10) is found in about 90% of children and at least 50% of adults with dermatomyositis and is diagnostic of dermatomyositis, even in the absence of inflammation.

IMMUNE-MEDIATED NECROTIZING MYOPATHY

• IMNM is a subtype of IIM that causes rapidly progressive proximal > distal weakness sometimes with myalgia and dysphagia, very high CK levels, and might be resistant to conventional immunosuppressive therapy.10 The muscle biopsy shows significant myofiber necrosis with minimal or no inflammatory infiltrates. • IMNM can be paraneoplastic and is also strongly associated with antibodies to signal recognition particle (SRP) and to 3-hydroxy 3-methylglutaryl CoA reductase (HMGCR).

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846

• Attention to swallowing, adequacy of ventilation, and precautions against deep venous thrombosis must be considered.

Immunomodulatory treatment of myositis Corticosteroids

FIGURE 27.10  Dermatomyositis (H&E). Atrophic and myopathic changes show preferential involvement of periseptal/perifascicular myofibers.

• Patients with SRP antibody-associated IMNM may have cardiomyopathy, and the condition is treatment refractory, often mimicking a muscular dystrophy.2 • Only 40–60% of patients with positive HMGCR antibodies have history of exposure to statins; and statin-naive patients appear to be younger and less responsive to immunomodulatory treatments.11

ANTISYNTHETASE SYNDROME

• ASS is the most common phenotype of IIM, is characterized by antibodies to aminoacyl-tRNA synthetase (ARS; aka antisynthetase autoantibodies). • Anti Jo-1 (histidyl-tRNA synthetase) antibody is the common anti-ARS antibody, detected in 15–25% of adult patients with IIM.9 • Anti Jo-1 antibody is usually associated with a polymyositis phenotype but may also occur in patients with a skin rash typical of dermatomyositis; it is also associated with ILD and greater risk of cardiomyopathy. • Other less common anti-ARS antibodies, detected in 1–5% of IIM patients, include anti-PL7 (anti-threonyl-tRNA synthetase), anti-PL12 (anti-alanyl-tRNA synthetase), anti-EJ (anti-glycyl tRNA synthetase), anti-OJ (anti-isoleucyl-tRNA synthetase), anti-Ha (anti-tyrosyl-tRNA synthetase), anti-KS (anti-asparaginyl-tRNA synthetase), and anti-Zo (anti-phenylalanyl-tRNA synthetase).12 • ASS clinical features consist of myositis, fever, ILD, ‘mechanic’s hands’, arthritis, and Raynaud’s phenomenon, but the presentation could be with one of these features such as idiopathic ILD or an inflammatory arthritis.

Treatment5, 13 General

• Encouragement of mobility (particularly in the elderly). • Physiotherapy to prevent contractures is essential. • Range-of-motion exercise program if patients have advanced weakness. • Raise the head of the bed and avoid meals before bedtime in patients with dysphagia. • A high-protein diet is advisable.

• First line of treatment in polymyositis and dermatomyositis. Patients with dermatomyositis generally respond better than those with polymyositis to steroids. • In more severe cases, an initial course of IV methylprednisolone (1 g/day for 3 days) can be considered. • In severe cases, oral prednisone 1.5 mg/kg/day up to 100 mg/day has been used. • Tapering to alternate-day regimen (up to 100 mg every other day) should be attempted over 1–3 months depending on the severity of the disease. • In milder cases, oral prednisolone 0.5–1 mg/kg/day for at least 1 month after myositis has become clinically and enzymatically inactive. The dose is then gradually reduced over a period lasting 1.5–2 times the period of active intense treatment, depending on clinical progress and, to some extent, serum CK levels. • Noticeable improvement is usually seen in 3–6 months. Diagnosis should be reassessed if there is no response to high-dose steroids (looking for IBM or muscular dystrophy for example). • Complete response to steroids is seen in 30–60% of dermatomyositis and only 10–30% of polymyositis. A higher percentage of patients respond partially.

Second-line agents

• Consider starting a second-line agent with the steroids in cases with severe disease, underlying diabetes, osteoporosis, or postmenopausal state. • Intravenous immunoglobulin (IVIG):14 starting dose is 2 g/kg divided over 4–5 days, every month for the first 2–3 months. This can be tapered to 0.5–1 g/kg every month depending on the individual response. IVIG is generally reserved for more severe and refractory cases and patients with significant adverse effects to steroids and other immunosuppressants. • Methotrexate: can be given as a single weekly oral dose, but not recommended in patients with underlying interstitial lung disease or those positive for anti-Jo antibodies. • Azathioprine 2.5 mg/kg/day. Bone marrow suppression and hepatotoxicity are the most important side effects. • Mycophenolate: starting dose is 0.5 g twice a day, which is gradually increased (up to 3 g/day). The most common side effect is diarrhea; patients should be monitored for leukopenia.

Third-line agents

• Cyclosporine: at a dose of 3–5 mg/kg/day in two divided doses, trough levels of 100–150 µg/mL are usually achieved. Common side effects include nephrotoxicity, hypertension, headache, hirsutism, neurotoxicity, tremors, and hepatotoxicity. • Tacrolimus: 3–5 mg/day in two divided doses to achieve a plasma trough level of 6–8 ng/mL. Side effects are similar to cyclosporine but less frequent.

Muscle Disorders • Cyclophosphamide should be considered in cases refractory to immunosuppressants and IVIG. It can be given in monthly intravenous pulses (0.5–1 g/m2 for 6–12 months) or oral (starting dose: 1 mg/kg/day). Side effects include bone marrow suppression, infection, infertility, alopecia, and hemorrhagic cystitis. • Tumor necrosis factor-α inhibitors such as etanercept and infliximab have been used with mixed results.2, 5 • Rituximab has shown efficacy in some refractory cases, including patients with ASS and ILD.5, 15, 16

Other ‘last resort’ forms of treatment

• Plasmapheresis has been tried in treatment refractory cases in small number of cases.17 • Autologous stem cell transplant has been successfully used in treatment refractory SRP-related IMNM and juvenile dermatomyositis (JDM).18, 19

Treatment of skin disease

• Patients should avoid sunlight or use a broad-spectrum sunscreen with a high sun-protective factor, if they are photosensitive. • Hydroxychloroquine hydrochloric acid 200–400 mg/day is effective in about 80% of patients when used as a steroidsparing agent. • Chloroquine phosphate 250–500 mg/day can be used if patients are not responsive to hydroxychloroquine. • Periodic ophthalmologic examinations and blood counts are required for patients on continuous antimalarial therapy. • Methotrexate 15–35 mg/week can also be used.

Prognosis

If treated early, most patients will respond well, with many showing full recovery of muscle function. Prognosis is adversely affected by: • • • • • •

Increasing age. Severity of myositis. Dysphagia or dysphonia. Cardiopulmonary involvement. Malignant disease. Poor response to corticosteroid therapy.

SPORADIC INCLUSION BODY MYOSITIS Definition and epidemiology

Sporadic inclusion body myositis (sIBM) is a slowly progressive, often asymmetric myopathy. Degenerative and inflammatory factors may play a role in its pathogenesis. • Prevalence: there is a global variability in the prevalence of IBM ranging from 4 to 70 per million.20 • The most common cause of acquired myositis in patients over 50 years of age. • Age at onset: after 50 years of age. • Gender: M > F (3:1). • Race: more common in whites than blacks.

Etiology and pathophysiology

• Although inflammatory and degenerative processes both contribute to the disease progression, it is uncertain which process comes first. • Cytotoxic (CD8+) T cells infiltrate myofibers, which express MHCI antigens.

847 • Deposition of amyloid precursor protein and amyloid β could play a role in vacuolar degeneration and myofiber atrophy. • Many other proteins are also overexpressed, including prion protein, phosphorylated tau, ubiquitin, apolipoprotein E, and α-synuclein. • Multiple mitochondrial deoxyribonucleic acid (DNA) deletions are present in 75% of patients.

Clinical features

• Gradual onset with slow progression. • Painless weakness starting in the proximal thigh and distal hand muscles, including long finger flexors, wrist flexors, and quadriceps, which may be asymmetric. • Muscle wasting can be marked. • Dysphagia in up to 30% of cases. • Mild facial weakness, but extraocular muscles are spared. • Early loss of deep tendon reflexes.

TIP • Most myopathies manifest as symmetric proximal weakness with some exceptions, such as sIBM where there is a combination of proximal and distal weakness. sIBM should be suspected when there is prominent involvement of quadriceps, wrist flexors, and finger flexors.

Differential diagnosis • • • • • •

Polymyositis. Diabetic amyotrophy. Motor neuron disease. Myofibrillar myopathy. Nemaline rod myopathy. Hereditary IBM: the hereditary forms have rimmed vacuoles and filamentous inclusions, but usually lack inflammatory response and myofiber MHCI expression: • IBM–Paget’s disease – frontotemporal dementia (mutations in valosin-containing protein).8 Onset of weakness at 25–40 years. – Paget’s disease is present in more than half the affected patients. – Dementia is present in more than one-third of patients usually manifesting as frontal lobe dysfunction in mid-50s. • IBM2: autosomal recessive, due to mutations in GNE (encoding UDP-acetylglucosamine 2-epimerase). – Predominantly in Middle Eastern Jewish population. – Onset in late teens or early adult life with distal weakness and foot drop. – Weakness extends to the hands and thighs, but usually spares the quadriceps, even in advanced stages. • Other forms of vacuolar myopathy, such as Welander’s distal myopathy.

Investigations

• Blood tests: • Serum CK level: often normal or mildly raised.21 • ESR: normal in 80% of cases.

Hankey’s Clinical Neurology

848 • Antibodies to cytosolic 5’-nucleosidase 1A (anticN1A, aka NT5C1A antibody) is positive in about one-third of IBM patients, whereas their prevalence in dermatomyositis and polymyositis was < 5%.22, 23 Patients with SLE and Sjögren’s disease may also be seropositive to NT5C1A antibody.24 Antibody to NT5C1A is a good serological biomarker for sIBM, but its specificity is not 100%, hence its presence does not obviate the need for a muscle biopsy. In an appropriate clinical setting, it is often useful to make the diagnosis of IBM.20 • EMG: • Fibrillations and positive waves are usually seen. • Although myopathic units and recruitment are seen, the presence of large, neurogenic units can be misleading and suggests a primarily neurogenic disease such as neuropathy or motor neuron disease. • 30% of patients have EMG signs of axonal neuropathy. • Muscle MRI: may reveal changes in the T2-weighted image in a characteristic pattern early in the disease: involvement of quadriceps, medial gastrocnemius, and flexor forearm muscles. • Muscle biopsy: rimmed vacuoles and congophilic inclusions are probably late changes and may be not seen in early stages of the disease. If the clinical phenotype is present, diagnosis of IBM is not excluded in the absence of these findings.

Diagnosis

Highly likely if there is asymmetric muscle weakness with prominent wrist flexor, finger flexor, and quadriceps involvement. The diagnosis should be confirmed with a muscle biopsy.

Pathology

• Inflammatory infiltrates may vary in extent (Figure 27.11). They are most often endomysial and predominantly CD8+ T cells. They often surround or invade individual morphologically normal-appearing muscle fibers.

FIGURE 27.12  Inclusion body myositis (modified Gomori’s trichrome stain). Vacuoles with dense, somewhat red rimming are characteristic of inclusion body myositis but can also be found in some familial ‘inclusion body myopathies’ that typically lack inflammatory changes.

• MHCI usually shows widespread extensive sarcolemmal staining. • Myopathic changes with some individual fiber degeneration/regeneration. • Rimmed vacuoles are the hallmark of this disease (Figure 27.12). Ultrastructurally, these correspond to myeloid membranous debris and are often associated with aggregates of 15–21 nm filaments. The inclusions are congophilic and contain proteins associated with neurodegenerative diseases including tau and ubiquitin. • Chronic changes in the form of endomysial fibrosis and fatty replacement (Figure 27.11). • Sometimes clusters of atrophic angulated fibers may mimic neuropathic disease. • Cytochrome oxidase (COX) negative and ragged red fibers are sometimes seen. • Other immunohistochemical markers that have been used to improve the diagnostic yield of the muscle biopsy include amyloid β, ubiquitin, TAR DNA-binding protein-43 (TDP-43), and p62 protein; the latter two are thought to be more sensitive, but not specific for sIBM. 20

Treatment

FIGURE 27.11  Inclusion body myositis (H&E). Myopathic changes in the form of myofiber degeneration/regeneration and increased variation in myofiber size are often associated with some chronic changes in the form of endomysial fibrosis and fatty replacement. Mononuclear inflammatory infiltrates tend to be endomysial.

• sIBM is generally resistant to immunomodulatory treatment. • In some younger patients, the condition may stabilize with a 3–6-month trial of prednisolone combined with methotrexate (or azathioprine). • IVIG is often used in sIBM patients with dysphagia.25 • Immunosuppression directed against T cells (anti-thymocyte globulin and alemtuzumab) has shown promise in some preliminary studies, but larger studies have to be conducted.26 • β-Agonist clenbuterol, which has anabolic effects, is used in some centers.

Muscle Disorders • A physiotherapy/strength training program and aerobic conditioning are advised. • Besides IVIG treatment, patients with dysphagia may benefit from esophageal dilation or cricopharyngeal myotomy.

Prognosis

Gradual deterioration with increasing weakness is typical. The prognosis partly depends on the age of onset. The average time to need a walker is about 10 years in patients with age of onset of less than 60 years, and 5.7 years in those with onset of the disease later than 60. After 15–20 years into the disease, most of the patients are wheelchair-bound.

CRITICAL ILLNESS MYOPATHY Definition and epidemiology27

• Critical illness myopathy (CIM) is a major cause of severe and diffuse muscle weakness in the critically ill patients in the ICU. • A concomitant critical illness polyneuropathy (CIP) is usually also present. • 50% of ICU patients with a stay of more than 3 days have electrophysiologic evidence of CIM +/− CIP. • 50–70% of patients with an ICU stay of more than 1 week develop clinical CIM +/− CIP; this figure may reach 100% in patients with long ICU stays with sepsis and end-organ damage.

Etiology and pathophysiology

Use of high doses of corticosteroids and neuromuscular blocking drugs (both typically used in severe asthma and chronic obstructive pulmonary disease) predisposes to CIM, but CIM can occur in the absence of these factors. Other predisposing factors include: • • • • •

Long ICU stay. Sepsis. Multiorgan dysfunction. Vasopressor support. Central nervous system (CNS) disease (encephalopathy).

849 Investigations

• CK: elevated in at least 50%. It may peak in 2–5 days and then gradually normalize. • Nerve conduction studies (NCS): sensory responses are normal (unless CIP is also present); motor response amplitudes can be normal or decreased; motor conduction velocity is normal (could be slow if a concomitant CIP is present). • EMG: abnormal spontaneous activity (positive waves and fibrillations) is seen in some cases. Short duration and polyphasic motor units with early recruitment are sometimes noted. • Direct muscle stimulation has been used to differentiate CIM from CIP. • Muscle biopsy: the gold standard for the diagnosis, but is often not needed.

Pathology27

Three subtypes exist: • Myosin-deficient myopathy (Figures 27.13, 27.14). • Cachectic myopathy (atrophic fibers, internalized nuclei, increased endomysial collagen tissue, and fat cells). • Necrotizing myopathy (myofiber vacuolization and phagocytosis).

Prevention and treatment

• Minimize the use of high doses of steroids and neuromuscular blocking agents. • Some investigators suggest that sedation should be intermittent, and not continuous or prolonged to decrease the duration of immobility. • Aggressive rehabilitation treatment may hasten recovery. • Aggressive insulin treatment, keeping the blood sugar at 80–110 mg/dL, has been suggested to reduce the incidence of CIM and CIP.

Prognosis

• CIM +/− CIP increase the length of ICU and hospital stay, and the overall mortality rate.

The pathophysiology is not completely elucidated. Increased levels of proinflammatory cytokines such as tumor necrosis factor-α, interleukins-1 and -6, and interferon-γ cause increased activity of proteolytic enzymes including calpain and lysosomal enzymes. There is increased catabolism and breakdown of muscle proteins, with myosin heavy chains predominantly targeted for unknown reasons. Membrane depolarization and changes in the voltage dependence of fast inactivation of Na+ channels are observed in a rat model of CIM.

Clinical features

• Inability to wean from the ventilator in the absence of a pulmonary or cardiac explanation. • Generalized muscle weakness and flaccidity. • Reflexes are lost early. • Facial weakness and ophthalmoparesis are rare. • Muscle atrophy in chronic cases.

Differential diagnosis

• CIP (often coexists with CIM). • Acquired inflammatory polyneuropathy. • Prolonged neuromuscular block.

FIGURE 27.13  Critical illness myopathy/myosin-deficient myopathy (ATPase reaction, pH 9.4). There is relatively selective loss of the myosin heavy chain. The ATPase activity of myosin is responsible for the color reaction in this stain. Critical illness/ ICU myopathy is often associated with the washed-out–appearing loss of reactivity and central clearing of staining in type II fibers illustrated here.

Hankey’s Clinical Neurology

850

In most cases, the weakness reverses when the metabolic defect is corrected, but improvement may take weeks to months. Typically, EMG shows a myopathic pattern, but only nonspecific findings of type II fiber atrophy are found on muscle biopsy.

Thyrotoxic myopathy Clinical features

FIGURE 27.14 Critical illness myopathy/myosin-deficient myopathy (electron microscopy). Ultrastructurally, the basic framework of sarcomeres may appear relatively preserved, but thick myosin filaments are lacking (Figure 27.4). No M line is seen between Z bands (arrows).

• Spontaneous recovery can occur within weeks in mild cases and within months in moderate cases. Severe cases may result in chronic disability and lack of ambulation. • Undetectable compound muscle action potential (CMAP) amplitude heralds a less favorable prognosis. CIM probably has a better prognosis than CIP.

ENDOCRINE AND METABOLIC MYOPATHIES Definition

Metabolic and endocrine myopathies are a large, heterogeneous group of inherited and acquired disorders of muscle due to a disturbance of metabolism. Hormones such as thyroid triiodothyronine (T3) and thyroxine (T4) and steroids regulate many aspects of muscle biology. For example, thyroid hormone has a regulatory role on the transcription of numerous muscle genes encoding both myofibrillar and calcium-regulatory proteins. Carbohydrates, lipids, and amino acids are the main fuels used by the muscle during rest and exercise. The relative contribution of each depends on the length and the intensity of exercise, sex, diet, and training status. Lipids (free fatty acids, intracellular lipid stores, and lipoprotein-derived triglycerol) contribute maximally during low- and moderate-intensity exercise, i.e. up to 60% maximal O2 consumption. In higher levels of endurance exercise, carbohydrates (blood glucose and intracellular glycogen deposits) become the more important source. Endurance exercise training results in a switch from carbohydrate to fat consumption during a certain level of exercise.

ENDOCRINE MYOPATHIES

Myopathy can be part of the clinical manifestations, and sometimes the presenting symptom of a variety of endocrine diseases, including different diseases affecting the thyroid, adrenal, pituitary, and parathyroid glands.

• Proximal muscle weakness and some wasting occurs. • Occasionally, only the bulbar and respiratory muscles are affected. • Fatigue. • Heat intolerance. • Normal or augmented reflexes. • Fasciculations, cramps. • Rarely associated with hypokalemic periodic paralysis and MG.

Diagnosis

• Serum CK: normal or slightly elevated. • EMG: myopathic units and recruitment, usually without positive waves, fibrillations, or fasciculations. • Abnormal thyroid function tests.

Treatment

• Correct the hyperthyroidism. • Symptomatic therapy with beta-blockers. • Glucocorticoids can be used in thyroid storm to block the peripheral conversion of T4 to T3.

Dysthyroid eye disease (exophthalmic ophthalmoplegia) Clinical features

• Can be quite asymmetric. • Difficulty of upgaze initially (inferior rectus infiltrated early). • Diplopia, ptosis often. • Lid retraction. • Exophthalmos. • Conjunctival and lid edema. • Exposure keratopathy. • Often mild pain (grittiness or fullness). • Eventually raised intraocular pressure and blindness may occur.

Diagnosis

• The patient is usually, but not necessarily, thyrotoxic. • Thyroid antibodies: often positive. • Computed tomography (CT) scan of the orbits: enlarged extraocular muscles.

Treatment • • • •

Restore the euthyroid state. Tarsorrhaphy to protect the cornea. Surgical correction of diplopia if necessary. Severe cases: high doses of corticosteroids, cyclosporine, and even orbital decompression have been used to save sight.

Muscle Disorders Hypothyroid myopathy Clinical features • • • • • •

More common in women. Myalgia and muscle cramps. Muscle hypertrophy. Muscle weakness (rare). Myoedema (ridging of muscle on percussion). Slow-recovery reflexes.

Diagnosis

• Serum CK: may be grossly elevated. • Thyroid function tests: low thyroxine. Thyroid-stimulating hormone (TSH) may be elevated if primary hypothyroidism is present. • Urine myoglobin: rhabdomyolysis may be present.

Treatment

Restore the euthyroid state.

Chronic steroid myopathy Definition

Proximal weakness due to prolonged treatment with corticosteroids or less frequently, endogenous corticosteroid secretion (Cushing’s syndrome). About 70% of patients with Cushing’s syndrome have myopathy. Fluorinated corticosteroids, such as dexamethasone and triamcinolone, have more myopathic potential. The dose required to cause myopathy varies among individuals.

Clinical features

• Proximal muscle weakness, earlier and worse in the lower limbs than upper limbs, and sometimes painful. Wasting is late. • Cushingoid features may be present. • Myalgia may or may not be present.

Investigations and diagnosis

• Serum CK: normal. • EMG: normal insertional activity and no spontaneous activity. Myopathic units could be present. • Muscle biopsy: type II myofiber atrophy (Figure 27.15).

851 Treatment • • • •

Change to a nonfluorinated steroid. Reduce steroid dose to the lowest possible therapeutic level. Try to administer the steroid on an alternate-day basis. Adequate diet and exercise may assist recovery.

Weakness due to Addison’s disease and other forms of hypoadrenalism Definition

Weakness due to diseases of adrenal gland or panhypopituitarism.

Clinical features

• Myalgia and muscle cramps. • Although the patients may be generally weak, real myopathy generally does not occur. • Fatigue and lassitude. • Orthostatic hypotension. • More severe cases may have confusional state, stupor, and coma. • Skin hyperpigmentation may be present.

Diagnosis • • • •

Serum electrolytes: hyponatremia and hyperkalemia. Panhypopituitarism may be present. CK may be mildly elevated. Low serum cortisol.

Treatment

• Cortisone (20–37.5 mg/day). • Fludrocortisone. • Increased salt intake.

Acromegaly Clinical features

• Increased muscle bulk. • Improved strength initially, but later muscle wasting and weakness occur. • Nonspecific headache. • Associated entrapment neuropathy (e.g. carpal tunnel syndrome). • Sensorimotor peripheral neuropathy (sometimes with enlarged nerves). • Visual field defects. • Obstructive sleep apnea. • Complications of diabetes and hypertension.

Diagnosis

• Hypopituitarism. • Serum CK: sometimes elevated.

Treatment

• Resection of pituitary adenoma. • Octreotide.

FIGURE 27.15  Type II fiber atrophy. The ATPase reaction at pH 9.4 shows a preferential atrophy of type II fibers (dark). This pattern of type II fiber atrophy is found with chronic steroid use as well as disuse or cachexia.

Hyperparathyroidism Definition

Weakness associated with primary hyperparathyroidism (e.g. adenoma) or secondary hyperparathyroidism (e.g. renal disease).

Hankey’s Clinical Neurology

852 Clinical features

Proximal and often painful muscle weakness, mainly affecting the legs and associated with mild wasting.

AM

GBE

IV

Acid maltase deficiency (Pompe’s disease, glycogen storage disease type II) Definition and epidemiology

An autosomal recessive glycogen storage disorder caused by a deficiency of lysosomal α-glucosidase (acid maltase) which results in impaired lysosomal conversion of glycogen to glucose so that glycogen accumulates in various organs depending on the disease form. • Incidence (of all forms combined) is estimated to be 1/40,000. • M = F.

Clinical features

• Infantile form: a generalized glycogenosis with severe cardiomyopathy, hypotonia, macroglossia, cardiomegaly, and hepatomegaly. Death occurs in infancy. • Juvenile form: onset in teenage years, proximal > distal weakness: • Gower’s sign, waddling gait. • Sometimes calf hypertrophy. • Hepatic and cardiac involvement uncommon, death occurs, usually because of respiratory muscle weakness, in the third decade. • Adult form: a slowly progressive myopathy that often predominantly affects the diaphragm and other respiratory muscles (hence respiratory failure): • Other muscles commonly involved are biceps, shoulder girdle, and thigh adductor muscles. • Scapuloperoneal pattern is rarely seen.

Glycogen

VIII V

GPa

PLD Glucose-1-P

III I

GDE

Glucose-6-P

PFK

VII

Fructose-6-P Fructose-1,6-P

DISORDERS OF GLYCOGEN METABOLISM

Glycogen is the main source of carbohydrates in the muscle; it is formed by a core protein called glycogenin and multiple branches of glucose chains. The concerted action of multiple enzymes is required for the synthesis, maturation, and degradation of the glycogen molecule. Several inherited disorders of glycogen metabolism (also called glycogenoses or glycogen storage diseases) have been described (Figure 27.16). Acid maltase deficiency and McArdle’s disease are typical examples that present predominantly with weakness and exercise intolerance, respectively. The most common forms of glycogenoses associated with muscle involvement will be discussed in the next sections.

PhK

UDPG

Treatment

• Primary hyperparathyroidism: remove the adenoma. • Secondary hyperparathyroidism (typically to renal disease): • Partial parathyroidectomy. • 1, 25-dihydroxycholecalciferol. • 1-alpha tocopherol. • Osteomalacia: vitamin D therapy.

GPb Lysosomal degradation

Investigations and diagnosis

• Serum CK: usually normal. • Serum calcium, parathyroid hormone.

Glucose

II

Glyceraldehyde-3-P

PGK

IX

PGAM

X

3-P glycerol phosphate 3-Phosphoglycerate 2-Phosphoglycerate Phosphoenol pyruvate

LDH

XI

Pyruvate Lactate

FIGURE 27.16  Schematic view of the glycogen metabolism pathway. Different types of glycogenosis (glycogen storage diseases) are caused by deficiency of different enzymes of the pathway. To date, 11 types of glycogenosis have been identified. Types II, III, IV, V, and VII are discussed in the text. Types I and VI do not cause myopathy. PLD, phosphorylase limit dextrin; UDPG, uridine diphosphoglucose; AM, acid maltase; PhK, phosphorylase kinase; GPb, GPa, glycogen phosphorylase a, b; GBE, glycogen branching enzyme; GDE, glycogen debranching enzyme; PFK, phosphofructokinase; PGK, phosphoglycerate kinase; PGAM, phosphoglycerate mutase; LDH, lactate dehydrogenase. • Symptoms typically begin in the third or fourth decades. • There is generally no hepatomegaly or cardiac involvement. • Sometime associated with intracerebral aneurysm.

Differential diagnosis

• Polymyositis. • Other glycogen storage disease. • Limb-girdle muscular dystrophies (LGMDs).

Muscle Disorders

853

• Congenital myopathies for the infant form. • Neuromuscular junction disease.

Investigations

• Serum CK: slightly to moderately elevated (1.5–15 times normal). • EMG: myopathic motor units and recruitment. Myotonic discharges may be seen, but the patients do not have clinical myotonia. • Blood leukocyte or urine α-glucosidase activity is reduced. Blood enzyme activity is simple, noninvasive, with high sensitivity and specificity. • Muscle biopsy: a targeted truncal/paraspinal biopsy may be required for diagnosis; more distal muscles may lack diagnostic changes. • Chorionic villi biopsy can be used for prenatal diagnosis. • Genetic testing.

Diagnosis

The diagnosis of acid maltase deficiency is usually established by finding of an abnormal activity of acid α-glucosidase (GAA) enzyme, which is generally used as a screening test, followed by confirmation of a disease-causing mutations using DNA analysis of the GAA gene. Finding of homozygous pathologic mutations confirms the diagnosis without testing the enzymatic activity. On the other hand, if genetic testing shows one or two variants of unclear significance, proving abnormal enzyme activity on dried blood spot, skin fibroblast culture, and blood lymphocyte culture will become necessary to conform the diagnosis. A muscle biopsy is usually not necessary to make the diagnosis of acid maltase deficiency.28, 29

Pathology (adult form)

• Affected muscles show features of a vacuolar myopathy (Figure 27.17). Vacuoles correspond to diastase-sensitive periodic acid–Schiff (PAS)-positive deposits of glycogen.

FIGURE 27.18  Acid maltase deficiency. Electron microscopy confirms that the vacuoles correspond to accumulations of glycogen in the cytoplasm of the myofibers and within membranebound structures that correspond to lysosomes. Additionally, there are deposits of membranous, partly lamellated myeloid lysosomal debris. • There is increased activity of the lysosomal enzyme acid phosphatase. • Electron microscopy typically shows glycogen accumulation that is partly located in membrane-bound lysosomal structures and associated with myeloid lysosomal debris (Figure 27.18).

Treatment30, 31

• Enzyme replacement therapy (intravenous recombinant human α-glucosidase). Two brands of recombinant human α-glucosidase (Myozyme and Lumizyme) are approved by the US Food and Drug Administration, for infantile- and adult-onset acid maltase deficiency, respectively. • Inspiratory exercises are useful.

McArdle’s disease (type V glycogenosis) Definition and epidemiology

Autosomal recessive disorder characterized by postexertional cramps or weakness. The gene for myophosphorylase (PYGM) maps to chromosome 11q13. It is caused by a myophosphorylase (α-1, 4-glucan orthophosphate glycosyltransferase) deficiency, which results in impaired conversion of glycogen to glucose1-phosphate in muscle. • Males are affected more than females (4:1). • The prevalence of McArdle’s disease is about 1 in 100,000.

Pathophysiology

FIGURE 27.17  Adult acid maltase deficiency. The H&E stained section of a paraspinal muscle biopsy shows the pattern of a vacuolar myopathy. The vacuoles show no prominent rimming. A deltoid biopsy showed no significant morphologic changes illustrating the selective pattern of muscle involvement often seen in adult acid maltase deficiency.

Glycogen breakdown is impaired during a sudden burst of muscle activity, causing elevation in intracellular calcium and adenosine diphosphate, and lower inorganic phosphate; muscle cell pH is shown not to become acidotic, which increases the sensitivity of the contractile apparatus to calcium.

Clinical features

• Usually onset is in childhood or adolescence. • Attacks of exercise intolerance with muscle pain (myalgia) and stiffness, often precipitated by brief, strong exercises.

Hankey’s Clinical Neurology

854 • Muscle contractures and dark urine (myoglobinuria) usually do not develop until the second or third decades. • Exercise which causes myalgia can be resumed at the same level after a brief period of exercise (second wind phenomenon). • Often nonprogressive, but some patients develop fixed weakness after recurrent rhabdomyolysis.

Differential diagnosis of cramps +/− weakness • • • • • • • •

Glycogen storage disease. Mitochondrial disease. Hypothyroid myopathy. Tetany secondary to hypocalcemia. Myotonia and neuromyotonia. Motor neuron disease. Medication-induced cramps. Electrolyte imbalance.

Investigations

• Serum CK: usually elevated even between periods of rhabdomyolysis. • Urine: myoglobinuria occasionally. • Routine NCS is normal, but repetitive nerve stimulation or stimulation following a short period of exercise may demonstrate decremental amplitude of the motor responses. • EMG: can be normal, or show fibrillations, positive waves, myotonic discharges, or myopathic motor units. If needle study is done during a muscle contracture, it shows electrical silence. • Forearm ischemic exercise: physiologic response to strenuous hand exercise is a three- to fivefold increase in serum lactate and ammonia, drawn from a vein in the forearm. In McArdle’s disease, there is flat response (no increase) in venous lactate while the physiologic rise in serum ammonia is present. • Muscle biopsy: histochemical and biochemical studies. • Genetic testing: sequence analysis or assessment for targeted mutations of PYGM.

FIGURE 27.19  Myophosphorylase deficiency. The H&E stained section from a patient with McArdle’s disease shows no significant morphologic changes. In particular, there is no significant abnormal accumulation of glycogen. The enzyme histochemical studies (Figure 27.18) establish the diagnosis. • Oral sucrose supplementation before exercise increases exercise tolerance. • Oral creatine supplementation may improve skeletal muscle function.

Phosphofructokinase deficiency (Tarui’s disease, glycogenosis type VII) Definition and epidemiology

Autosomal recessive disorder due to phosphofructokinase (PFK) deficiency. PFK gene is mapped to chromosome 12. PFK catalyzes the conversion of fructose-6-phosphate to fructose-1, 6-diphosphate in muscle, which is the rate-limiting step in the glycolytic pathway. • Prevalent in Ashkenazi Jews and some Italian families.

Diagnosis

Based on sequence analysis of PYGM, which detects small deletions, insertions, and missense or nonsense changes. PYGM sequencing can be ordered individually if clinical presentation is highly suggestive, or can be part of a panel of genetic causes of rhabdomyolysis or metabolic myopathy in general. 32

Pathology

• A muscle may be morphologically normal (Figure 27.19) or show subsarcolemmal and intermyofibrillar deposits of glycogen. • Sometimes, there is evidence of individual fiber degeneration/regeneration. • Enzyme histochemical staining shows significantly reduced or absent myophosphorylase (Figure 27.20). Staining for phosphorylase could be falsely positive soon after an episode of rhabdomyolysis, probably because of upregulation of a fetal isoenzyme.

Treatment

• Endurance exercise training: it has been shown that after a period of endurance training exercise, there is less reliance on glucose (and more on lipids) for a moderate-intensity exercise.

FIGURE 27.20  Myophosphorylase deficiency. This enzyme histochemical reaction on the biopsy illustrated in Figure 27.19 shows lack of normal enzyme reactivity. The insert illustrates normal staining. Type II fibers are darker than type I fibers, but both show brown reaction product.

Muscle Disorders Clinical features

• Onset: second to fourth decades. • Exercise intolerance, muscle aches, contractures, myoglobinuria, and renal failure less frequent than McArdle’s disease. • Second wind phenomenon less prominent than that of McArdle’s disease. • A subgroup of PFK deficiency is present with late-onset progressive proximal (or less commonly scapuloperoneal) weakness without myoglobinuria or cramps. • A mild hemolytic tendency is sometimes present, causing gout or jaundice.

Investigations and diagnosis

• Serum CK is usually elevated. • Forearm ischemic exercise produces no increase in venous lactate levels (similar to McArdle’s disease). • In most patients, PFK activity is absent in the muscle and 50% reduced in the red blood cells. • Muscle biopsy may be morphologically normal or show accumulation of normal glycogen and, less likely, accumulation of a diastase-resistant, PAS-positive material. Enzyme histochemical staining can confirm the lack of enzyme activity. Frozen tissue can be used for biochemical testing.

855 Clinical features

• The most common presentation is in childhood with liver involvement and cirrhosis. • It can also present with neuronal involvement and hypotonia in infancy. • Myopathy and cardiac involvement may occur in the childhood type. • Myopathy is a rare manifestation of adult-onset polyglucosan body disease. • More common manifestations of polyglucosan body disease include upper and lower motor neuron disease, sensory neuropathy, extrapyramidal findings, dementia, and bladder involvement.

Investigations and diagnosis

• CK may be normal or mildly elevated. • NCS: may be normal or show a neuropathy. • Needle EMG may show spontaneous activity, neurogenic changes or myopathic units and early (myopathic) recruitment when myopathy is also present. • Muscle biopsy shows polyglucosan bodies which are PASpositive diastase-resistant inclusions. • Polyglucosan bodies are also found in skin apocrine glands, peripheral nerves, and cardiac muscle, although mild accumulation of these structures can be seen with aging. • Decreased or absent branching enzyme in skin fibroblasts.

Debranching enzyme deficiency (type III glycogenosis, Cori–Forbes disease) Definition

DISORDERS OF LIPID METABOLISM

Clinical features

Muscle carnitine deficiency Definition

Investigations and diagnosis

Clinical features

Autosomal recessive; the gene is localized to chromosome 1. Debranching enzyme catalyzes the hydrolysis of glycogen to glucose-1-phosphate.

• Infantile type: • Growth retardation, hepatomegaly, mild myopathy, and seizures which tend to improve after puberty. • Fasting hypoglycemia and ketonuria. • Adult type: mild weakness of hands and legs. Cardiomyopathy is a late complication.

• Serum CK: elevated 2–20 times. • NCS: normal, or may show a sensorimotor polyneuropathy. • Needle EMG: may show myopathic units, spontaneous activity and myotonic discharges. • Forearm ischemic exercise produces no increase in venous lactate levels (similar to McArdle’s disease). • Muscle biopsy: cytoplasmic (not lysosomal) glycogen, which is PAS-positive and digestible by diastase. Glycogen deposits may be seen in nerve biopsy. • Debranching enzyme deficiency can be proven by biochemical assessment of fibroblasts or lymphocytes.

Polyglucosan body disease (glycogenosis type IV, Andersen’s disease, or amylopectinosis) Definition

Autosomal recessive disorder caused by the deficiency of glycogen branching enzyme. This enzyme catalyzes the transfer of a glucose string from one glycogen chain to another while creating a new branch. The gene is localized to chromosome 3.

Long-chain fatty acids are a major source of muscle energy and are consumed during muscular activity. Carnitine is involved in the transport of free fatty acids into mitochondria.

• Myopathy secondary to lipid accumulation due to deficiency of carnitine, which may be primary or secondary. • Secondary carnitine deficiency is seen in systemic diseases such as sepsis, malnutrition, hemodialysis, HIV infection (especially associated with zidovudine treatment), mitochondrial diseases, and treatment with valproic acid.

• • • •

Myopathy develops in infants, children, or early adulthood. Limb-girdle pattern of weakness. Facial muscles or tongue may be affected. No pain or rhabdomyolysis.

Diagnosis

• CK moderately elevated. Normal blood level of carnitine. • Muscle biopsy: accumulation of lipid which is deficient in carnitine. • Biochemical testing on muscle tissue.

Treatment

Carnitine 2–4 g/day.

Carnitine palmitoyltransferase II deficiency Definition

Autosomal recessive disorder caused by impaired transport of free fatty acids into mitochondria. The abnormal gene maps

Hankey’s Clinical Neurology

856 to chromosome 1. Carnitine palmitoyltransferase II (CPT2) deficiency is the most common inherited cause of recurrent myoglobinuria.

Clinical features

• Most patients are male. • Onset in adolescence or early adulthood. • Intermittent attacks occur without warning; precipitated by prolonged exertion, fasting, or a high-fat diet. • Muscle cramps, muscle pain, and dark urine (myoglobinuria) are present, with normal muscle strength between attacks. • Exposure to cold, viral infections, general anesthesia, and valproic acid can also precipitate rhabdomyolysis. • Renal failure (due to myoglobinuria) and respiratory failure may occur. • Patients have a normal capacity to perform short, demanding exercise. • Muscle weakness may occur later in life.

Investigations and diagnosis

• Urine: myoglobinuria. • CK normal or mildly elevated between attacks and markedly elevated during attacks. • High ratio of serum palmitoylcarnitine (C16:0) and oleoylcarnitine (C18:1) to acetylcarnitine (C2). • Normal serum carnitine. • During an acute episode, the muscle shows myofiber degeneration and regeneration. • Between attacks it shows normal morphology. Biochemical testing on frozen muscle tissue can confirm the diagnosis.

Treatment

• High-carbohydrate (70%) and low-fat (< 20%) diet. • Frequent meals; avoiding extended fasting and prolonged exercise. • Oral carnitine. • Infusion of glucose during periods of infection to prevent catabolism. • Aggressive hydration during attacks of rhabdomyolysis to prevent renal failure. • Caution should be exercised in the use of valproic acid, general anesthesia, ibuprofen, and diazepam in high doses.

• Common mtDNA mutations include large deletions as well point as mutations disrupting individual tRNAs or rRNAs. • A single cell may contain thousands of copies of mtDNA. In most cases, a certain threshold of mutated mtDNA copies has to be exceeded to cause disease. • The load of mutated mtDNA copies may vary between different tissues; this can explain differences in disease phenotypes. Some mutations are not detected unless diseased tissue is tested. • Some mutations in nuclear DNA may lead to defects in individual components of the respiratory chain. Other mutations may disrupt mitochondrial function by disrupting the import of proteins into mitochondria, by changing the lipid composition of the inner mitochondrial membrane, or by changing intergenomic signaling to cause mtDNA depletion or multiple mtDNA mutations. • Some mitochondrial mutations cause defects in individual proteins while others affect general function, for example, by interfering with translation of mitochondrial genes. Toxin exposure, treatment with zidovudine (azidothymidine [AZT]), and normal aging can result in acquired defects in mitochondrial function.

Clinical features

• The onset can vary from birth to adulthood. • Clinically, skeletal muscle involvement can result in fixed weakness, exercise intolerance, premature fatigue, or myoglobulinuria. • The disease course and presentation are extremely variable. The course can be rapidly progressive or static. The presentation can include generalized weakness, proximal weakness, extraocular eye muscle weakness, or rhabdomyolysis. • Other features include cardiomyopathy, cataract, neurosensory hearing loss, and CNS involvement.

Investigations

The mitochondrial DNA (mtDNA) encodes 13 structural proteins that are part of the respiratory chain, 2 rRNAs, and 22 tRNAs. The genetics of mitochondrial disease vary in several aspects from those of other disease:

• Serum CK: CK levels are often normal or mildly elevated. • ECG and echocardiogram: cardiologic evaluation is important and helpful in deciding on the timing for interventions including pacemaker placement. • EMG: can vary from normal to nonspecific, to typically myopathic features. • MRI: CNS imaging can be helpful in establishing the diagnosis of mitochondrial diseases associated with typical CNS involvement including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and Leigh’s disease. • Muscle biopsy: a muscle biopsy can be helpful in establishing the diagnosis if the typical features discussed above are present. Some mitochondrial diseases are not associated with morphologic changes in the muscle. • Genetic testing: can detect mtDNA mutations. Deciding on the most applicable mutations to screen and the appropriate tissue to use is important – in some cases with negative peripheral blood testing frozen muscle biopsy tissue may turn out to be informative.

• mtDNA mutations are always inherited maternally, nuclear mutations follow Mendelian inheritance patterns.

A negative genetic study does not rule out a mitochondrial disease.

MITOCHONDRIAL MYOPATHY Definition

Mitochondrial diseases are systemic conditions resulting from mutations in nuclear or mitochondrial genes and present with very variable clinical features that may include myopathy. This section focuses primarily on muscle involvement.33–36

Etiology and pathophysiology

Muscle Disorders

857 • Electron microscopy can confirm the presence of abnormal mitochondrial aggregates as well as the presence of abnormal mitochondrial forms and mitochondria with paracrystalline inclusions (Figure 27.22).

Treatment

There are no specific therapies. Supportive therapy should address the presentation of the disease including seizure control, surgery for cataracts, management of endocrine disorders, and monitoring and treating cardiac involvement. In specific cases, supplementation with metabolites can be helpful including folic acid in Kearns–Sayre syndrome (KSS). CoQ10 has been used in KSS, myoclonic epilepsy with ragged red fibers, MELAS, or CoQ10 deficiency.

FIGURE 27.21  Mitochondrial myopathy (modified Gomori’s trichrome stain). Mitochondria cluster together in a preferentially subsarcolemmal distribution (arrow) instead of the normal fine stippled uniform distribution found on this stain (Figure 27.5). Myofibers with this morphology are referred to as ragged red fibers.

Pathology

Some mitochondrial diseases are associated with normal skeletal muscle morphology. There may be nonspecific changes including variation in myofiber size as well as evidence of individual myofiber degeneration and regeneration: • The COX reaction may identify degeneration and regeneration. More specific features include myofibers lacking normal enzyme activity. • The modified Gomori’s trichrome stain (Figure 27.21) and enzyme histochemical reactions for NADH and succinate dehydrogenase may identify myofibers with abnormal aggregates of mitochondria visible under light microscopy (‘ragged red fibers’).

MUSCULAR DYSTROPHIES Definition

Defects in many of the proteins important for normal muscle function have been linked to disease. Some of these result in skeletal muscle-specific phenotypes, while others additionally lead to cardiomyopathy or involvement of other organ systems. Clinical features such as age of onset, muscle groups affected, rate of disease progression, and involvement of other organs can vary widely depending on the type of mutation, environmental factors, and genetic modifiers. In some instances, family members who carry the same mutation present with distinctly different clinical phenotypes. Important groups discussed below are dystrophinopathies, facioscapulohumeral dystrophy, Emery–Dreifuss muscular dystrophy (EMD), LGMDs, and myotonic dystrophies. Other primarily pediatric diseases such as congenital myopathies (CMs) and congenital muscular dystrophies (CMDs) (summarized in Tables 27.3 and 27.4) are not discussed in detail, but may sometimes be considered in the differential diagnosis. In practice, the distinction of these two entities is not always clear, but in principle, the following features apply: CMs are typically characterized by: (1) childhood onset; (2) static or slowly progressive course; (3) association with specific structural abnormalities; (4) relative lack of ongoing degeneration/regeneration. 37 CMDs are characterized by: (1) childhood onset; (2) ongoing myofiber degeneration/regeneration and higher CK levels; (3) frequent CNS involvement. 38 In general, patients with muscular dystrophies are best cared for in a multidisciplinary setting that addresses the complex nature of their care.

DYSTROPHINOPATHIES Definition

Dystrophinopathies include diseases of skeletal and cardiac muscle that are characterized by an X-linked inheritance pattern and mutations in the dystrophin (DMD) gene on Xp21. 39 The spectrum of clinical presentations includes Duchenne’s muscular dystrophy (DMD, incidence 1:3500) and Becker’s muscular dystrophy (BMD, incidence 1:35,000).

Etiology and pathophysiology FIGURE 27.22  Mitochondrial myopathy (electron microscopy). Some of the abnormally aggregated mitochondria contain paracrystalline inclusions that show as electron dense geometric structures within mitochondria.

Dystrophin is a large filamentous protein that is integral part of the dystrophin–glycoprotein complex (DGC) (Figure 27.1). The DGC is thought to provide structural integrity to individual myofibers during contraction by spanning the cell membrane and linking the actin cytoskeleton on the inside to the basement membrane

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TABLE 27.3  Congenital Myopathies, Protein Aggregate Myopathies, and Autophagic Vacuolar Myopathies Disease Group/Disease Subgroup CONGENITAL MYOPATHIES Nemaline NEM1* myopathies

Central core disease*

NEM2* NEM3* NEM4* NEM5* NEM6* NEM7*

Locus

Tropomyosin-3 (TPM3)

1q21.3

Nebulin (NEB) Alpha-actin-1 (ACTA1) Tropomyosin-2 (TPM2) Troponin T1 (TNNT1) KBTBD13 Cofilin-2 (CFL2) Ryanodine receptor 1 (RYR1)

2q23.3 lq42.13 9p13.3 19q13.42 15q22.31 14q13.1 19q13.2 Weakness, joint contractures, delayed motor development; allelic with malignant hyperthermia; biopsy: central areas of disorganized sarcomeres and disrupted myofiber architecture (‘cores’) 19q13.2 Axial myopathy, respiratory failure, scoliosis; biopsy: multiple short cores in most myofibers; mutations in RYR1 are also associated with central core disease and malignant hyperthermia Xq28 Severe hypotonia requiring ventilation, normal cognition; biopsy: atrophic myofibers with central nuclei (geometric center) mimicking myotubes in development 19p13.2 Weakness and wasting most prominent in neck and proximal muscles; DNM2 and RYR1 are linked to dominant inheritance, BIN1 to recessive; biopsy: central nuclei; DNM2 mutations also linked to CMT; mutations in RYR1 are also associated with multiminicore disease and central core disease 19q13.2

Multiminicore disease*

Ryanodine receptor 1 (RYR1)

Centronuclear X-linked, myotubular myopathy* myopathy

Myotubularin (MTM1)

Centronuclear AD myopathy*

Dynamin-2 (DNM2)

AD AR Congenital AR/AD fiber type disproportion (CFTD) *

PROTEIN AGGREGATE MYOPATHIES (PAM)

AR/AD AR/AD Actin aggregate myopathy*

Clinical Features/Allelic Diseases/Characteristic Pathologic Features

Protein (gene)

Ryanodine receptor 1 (RYR1) Amphyphysin 2 (BIN1) Selenoprotein N (SELENON)

Alpha-actin-1 (ACTA1) Tropomyosin 3 (TPM3) Alpha-actin-1 (ACTA1)

Facial, bulbar, respiratory, and proximal muscle weakness; wide range in clinical severity and presentation; cardiac involvement is rare but described; ACTA1 mutations are also linked to CFTD and PAM; TPM3 mutations are also linked to CFTD/biopsy: nemaline rod type inclusions and variable degrees of chronic remodeling Other genes linked to nemaline myopathy include KLHL40, KLHL41, LMOD3, and MYPN

2q14.3 1p36.11 Hypotonia, weakness, failure to thrive, facial and respiratory weakness, contractures; wide phenotypic spectrum; biopsy: predominance and atrophy of type I fibers (not specific); mutations in SEPN1 are associated with a spectrum that includes desmin-related myopathy with Mallory’s bodies, CFTD, and RSMDl; mutations in ACTA1 are also associated with nemaline myopathy and PAM; mutations in TPM3 are also associated with nemaline myopathy lq42.13 1q21.3 lq42.13 ACTA1 mutations are also associated with nemaline myopathy and CFTD

Mallory’s body Selenoprotein N lp36.11 Mutations in SEPN1 are associated with a spectrum that includes myopathy* (SELENON) desmin-related myopathy with Mallory’s bodies, CFTD, and RSMD1 Myosin storage/hyaline Slow-skeletal beta cardiac 14q11.2 Allelic with familial hypertrophic cardiomyopathy, dilated body myopathy* myosin (MYH7) cardiomyopathy, Laing’s distal myopathy, left ventricular noncompaction Desmin-related Desmin (DES) 2q35 Also associated with cardiomyopathy and cardiac conduction defects myopathy* Spheroid body Myotilin (MYOT) 5q31.2 Also associated with cardiomyopathy myopathy* (Continued)

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TABLE 27.3  Congenital Myopathies, Protein Aggregate Myopathies, and Autophagic Vacuolar Myopathies (Continued) Disease Group/Disease Subgroup AUTOPHAGIC Danon’s disease* VACUOLAR MYOPATHIES (AMV) X-linked autophagic vacuolar myopathy (XMEA or MEAX)*

Clinical Features/Allelic Diseases/Characteristic Pathologic Features

Protein (gene)

Locus

Lysosome-associated protein 2 (LAMP2)

Xq24

Triad of hypertrophic cardiomyopathy, myopathy, and mental retardation; biopsy: vacuolar myopathy associated with lack of LAMP2 expression

VMA21

Xq28

Slowly progressive atrophy and weakness of proximal muscles; sparing of cardiac and respiratory muscles; biopsy: morphology similar to Danon’s disease; LAMP2 expression normal; deposition of complement C5b-9

*Nomenclature in Online Mendelian Inheritance in Man (OMIM). Abbreviations: CFTD, congenital fiber type disproportion; CMT, Charcot–Marie–Tooth disease; LGMD, limb-girdle muscular dystrophy; PAM, protein aggregate myopathy; RSMD1, rigid spine muscular dystrophy.1

TABLE 27.4  Congenital Muscular Dystrophies Disease Group/ Disease

Subgroup

Protein (gene)

Congenital muscular Ullrich’s congenital Collagen VI chains (COL6A1, dystrophy with muscular dystrophy COL6A2, and COL6A3) defects in (UCMD) extracellular matrix Congenital muscular Merosin (LAMA2) dystrophy 1A (MDCIA) Congenital muscular Fukuyama’s Fukutin (FKTN) dystrophies with congenital the abnormalities muscular dystrophy in the receptors for extracellular matrix Fukutin-related protein (FKRP)

Locus 2q37.3 21q22.3 21q22.3 6q22.33

9q31.2

Clinical Features/Allelic Diseases/Characteristic Pathologic Features Hypotonia, proximal contractures, distal hyperextensibility, scoliosis, proximal weakness; Bethlem is a milder allelic disease; biopsy: mismatched expression of perlecan and collagen VI by immunofluorescent microscopy Congenital muscular dystrophy; some LGMD-like; some with mostly subclinical cardiac disease; some have seizures or mental retardation Hypotonia; defects in CNS development, seizures, mental retardation

19q13.32 Some with congenital muscular dystrophy; some with LGMD, some with cardiac disease, some with changes on brain MRI 22q12.3 Congenital muscular dystrophy; mental retardation; structural brain changes

Acetylglucosaminyltransferase-like protein (LARGE1) Protein O-mannose betalp34.1 Congenital muscular dystrophy; congenital myopia, 1,2-Nglaucoma, retinal hypoplasia; mental retardation acetylglucosaminyltransferase (POMGNT1) Protein O-mannosyl9q34.13 Congenital muscular dystrophy; structural brain changes transferase-1 and 2 (POMT1 and and hydrocephalus; POMT also linked to LGMD2K and POMT2) 14q24.3 Integrin alpha-7 Integrin alpha-7 (ITGA7) 12q13.2 Delayed psychomotor milestones associated with deficiency dystrophic changes on biopsy Congenital muscular Rigid spine with Selenoprotein N (SELENON) 1p36.11 Hypotonia, neck weakness, early scoliosis, respiratory dystrophy with muscular dystrophy insufficiency; mutations in SEPN1: spectrum that includes abnormal 1 (RSMD1) desmin-related myopathy with Mallory’s bodies, endoplasmic congenital fiber type disproportion and RSMD1 reticulum protein Abbreviations: CMT, Charcot–Marie–Tooth disease; CNS, central nervous system; LGMD, limb-girdle muscular dystrophy; MRI, magnetic resonance imaging.

on the outside. The DGC is also thought to play an important role in cell signaling. Both functions can be disrupted by mutations in dystrophin or other DGC components, including sarcoglycans and dystroglycans which are discussed below. Important components of dystrophin include the actin binding N-terminus, a long helical rod domain, and a highly conserved C-terminal domain

that interacts with other proteins. Tears in the cell membrane can lead to calcium influx, complement activation, and degeneration/ necrosis of myofiber segments. Repeated episodes of degeneration and regeneration lead to chronic remodeling of muscle tissue with endomysial fibrosis and fatty replacement. The dystrophin gene spans 2.5 million base pairs and is composed of 79 exons.

Hankey’s Clinical Neurology

860 The clinical disease severity depends on the underlying genetic defect and the amount of residual mutant protein made: • BMD is a milder phenotype that typically shows expression of some residual dystrophin and is often linked to in-frame mutations in the rod domain that preserve the N- and C-terminal domains. • DMD is more severe and typically linked to mutations that result in the virtually complete absence of any dystrophin protein. Often the underlying mutation disrupts the normal reading frame. Many mutations result in an early stop codon.

Clinical features General

• Cognitive impairment and mental retardation occur in a subset of DMD and BMD patients.40 Typically, these are nonprogressive and not related to the severity of the underlying muscle disease. Disruption of brain-specific splice variants may explain this part of the phenotype. • Cardiac involvement with conduction defects as well as cardiomyopathy is common in BMD and DMD. The incidence in DMD patients is up to 90% at 18 years and nearly 100% in their 30s. • Some patients have symptoms attributed to smooth muscle involvement including intestinal pseudo-obstruction, delayed gastric emptying, as well as acute gastric dilation, causing sudden episodes of vomiting and abdominal pain.

Duchenne’s muscular dystrophy

CK elevations of 10–100 times normal are present at birth even though infants usually show no clinical disease manifestation. Typically, delay in motor development is not noted until the age of 2–5 years. The skeletal muscle disease is relentlessly progressive.

Early (ages 2–6) • • • • • • • • •

Onset of walking delayed beyond 18 months. Abnormal gait with toe walking or waddling. Difficulty running. Frequent falls, difficulty rising from the floor (Gower’s sign, Figures 27.23, 27.24). Prominent calf muscle bulge (‘pseudohypertrophy’). Hyperlordosis resulting in a protruding abdomen. Weakness in the lower extremities, pelvis, and lower trunk is clinically most apparent. In some patients, there is global developmental delay, severe learning disabilities, and failure to thrive. In some instances, patients come to attention because of elevated ALT/aspartate aminotransferase (AST) during routine work-up, myoglobulinuria, or malignant hyperthermia-like episode with anesthesia.

Ages 7–10

• Progressive leg weakness leading to loss of walking and wheelchair dependence by mean age of 9.5 years. • Joint contractures, especially of the iliotibial bands, hip flexors, and heel cords. • Progressive scoliosis and thoracic deformities after loss of mobility.

Teenage years

• Development of more apparent upper extremity weakness. • Worsening respiratory reserve and sleep hypoventilation, rapid eye movement sleep–related hypoxemic dips, and obstructive apnea.

FIGURES 27.23, 27.24  A boy with Duchenne’s muscular dystrophy rising from the floor, climbing up his legs, and pushing up against the legs to assist with straightening the trunk (Gower’s sign). (Courtesy of Professor BA Kakulas, Neuropathology Department, Royal Perth Hospital, Australia). • Scoliosis progresses rapidly with the pubertal growth spurt, with adverse effects on respiration, feeding, sitting, and comfort. • In the past, most patients died in the late teens and early twenties. Improved therapy and supportive care have increased the mean survival over historical controls and will change the clinical problems facing these patients. Mean survival in the United Kingdom is now 27 years.

Becker’s muscular dystrophy

• BMD is characterized by a later onset of symptoms and a slower rate of progression than that of DMD. The onset of disease is variable, but often not until teenage years, with the mean at 12 years and 90% before age 20. The patients

Muscle Disorders often show similar but milder features than those found in DMD. The mean age at loss of ambulation is in the fourth decade, but patients may live for many decades. For some, cardiomyopathy dominates the clinical presentation.

Other dystrophinopathies

• Exercise intolerance with myalgias, muscle cramps, or myoglobulinuria. • Asymptomatic elevation of CK levels. • (Fatal) X-linked dilated cardiomyopathy without muscle weakness. • Carriers may develop with mild-to-moderate muscle weakness (about 8%), cardiomyopathy, or asymptomatic CK elevation.

Differential diagnosis

• Spinal muscular atrophy. • Congenital myopathies such as nemaline myopathy or central core disease (Table 27.3). • Congenital dystrophies such as fukutin or fukutin-related protein (FKRP) deficiency (Table 27.4) may have to be considered. • X-linked or autosomal EMD can mimic DMD or BMD by also causing a presentation characterized by features of muscular dystrophy and cardiomyopathy. These patients typically show selective early involvement of distal leg muscles, triceps, and biceps, as well as contractures of elbows and neck. • LGMD. • Childhood-onset acid maltase deficiency may result in proximal muscle weakness and calf enlargement by age 5 years.

Investigations and diagnosis

• CK: elevated CK levels in the thousands or tens of thousands IU/L precede clinical manifestation in DMD: • CK elevation is less prominent in older patients with loss of muscle mass. • BMD patients and female carriers also show variable CK elevation. • ECG and echocardiogram: to assess cardiac involvement. • EMG: myopathic changes early in the disease course. Muscle tissue may become unexcitable as the number of activated muscle fibers decreases with disease progression. • MRI: provides data on the degree of involvement of different muscle groups and establishes the presence of a typical pattern of involvement. • Muscle biopsy with immunohistochemical studies and sometimes immunoblot analysis can be helpful in confirming the diagnosis. In current practice, the use of muscle biopsies is usually reserved for patients in whom genetic testing identified variants of uncertain significance, genetic testing is negative despite a strong clinical suspicion, or patients on clinical trials. • Genetic testing is the most efficient way to confirm the diagnosis in typical cases of DMD with a positive family history. • Genetic testing is usually performed as part of panelbased/next-generation sequencing (NGS)-based testing or whole-genome/whole-exome sequencing.41 • In some cases, mRNA analysis performed on cDNA obtained through reverse transcriptase (RT)polymerase chain reaction (PCR) can help to confirm unusual mutations or duplications.

861 • 30–40% of dystrophin mutations are new spontaneous mutations. • Pedigree analysis and CK analysis may help to identify possible carriers; however, CK levels are only elevated in 45–70% of definite carriers. In many cases, a carrier state can be confirmed by available genetic tests. • Up to 20% of new DMD cases may result from gonadal mosaicism that would be missed by genetic testing on somatic cells of the mother, but could be confirmed by carrier detection analysis on the mother’s daughters and sisters. • Prenatal diagnosis can be achieved through chorionic villous sampling at 8 weeks of gestation or through preimplantation DNA testing on embryos.

Pathology

• Muscle biopsies show myopathic changes with evidence of individual fiber degeneration and regeneration (Figure 27.25). • With progression, there is increasing variation in myofiber size with atrophy, hypertrophy, and fiber splitting. Endomysial fibrosis and fatty replacement cause disruption of normal fascicular architecture. • Beyond macrophages in degenerating myofibers, inflammatory infiltrates are usually absent. • BMD patients may show changes that are similar in principle but much milder than those in DMD patients of comparable age. • DMD immunocytochemical studies typically show absence of staining with antibodies specific for all main domains of dystrophin (Figure 27.26). BMD patients often show less severe disruption of dystrophin expression with patchy staining or complete absence of only one of the domains.

Treatment Current management

• Corticosteroids or the prednisolone-derivative deflazacort are effective in delaying loss of mobility by 6 months to 2 years. Patients are typically started on 0.75–1.5 mg/kg/day

FIGURE 27.25  Duchenne’s muscular dystrophy (H&E). There are myopathic changes with necrotic myofibers and variation in fiber size. Some fibers are hypercontracted and appear bright dark red. Individual myofibers are no longer tightly packed together but separated by endomysial fibrosis: a sign of disease chronicity.

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FIGURE 27.26  Duchenne’s muscular dystrophy (immunohistochemistry for dystrophin). In normal muscle (insert), this stain uniformly outlines individual myofibers. This patient’s sample lacks dystrophin expression that would show up as brown rimming of myofibers. in the early ambulatory phase (4–6 years). Some regimens include intermittent courses. Weight gain and vertebral body fractures are common complications. Calcium and vitamin D supplementation are therefore also given. • Rehabilitation with knee–ankle–foot orthoses can prolong walking for some 18–24 months. Passive exercise, stretching of joints, and night-time splints can help to prevent or reduce joint contractures. Surgery may be considered for management of scoliosis and release of contractures of the ankle and hip. • Respiratory therapy includes inspiratory resistive exercises that may increase the endurance of respiratory muscles. Cough assist devices may aid respiratory function. Noninvasive ventilation at night may help to improve respiration during sleep. Long-term assisted ventilation in advanced muscular dystrophy raises ethical questions and is controversial. • Angiotensin-converting enzyme (ACE) inhibitors and/or beta-adrenergic blockers may be beneficial in treating and potentially preventing/delaying cardiomyopathy.

Other therapeutic strategies

• Correction of genetic alterations: these are specific for certain types of mutations. • Antisense oligonucleotides can restore a disrupted reading frame and lead to the expression of a shortened but functional dystrophin protein.42 Eteplirsen (Exondys 51) is the first approved antisense therapy for Duchenne’s dystrophy in United States designed to skip exon 51 and provides treatment option for 14% of all DMD patients.43 It is given as 30 mg/kg intravenously once a week. Other exon-skipping therapies targeting exons 53 and 45 are in early phase of clinical trials. • Aminoglycosides and newer drugs like PTC124 cause preferential stop-codon read-through in premature stop codons.42 • Gene replacement:

• Use of viral vectors to replace a mutated dystrophin gene. Currently, there are clinical trials utilizing adeno-associated virus (AAV) microdystrophins (truncated but functional dystrophins). • Muscle tissue is unique because fusion of stem cells or stem cell–like cells to existing myofibers is a process of normal muscle repair. Bone marrow–derived stem cells as well as engineered muscle tissue–derived stem cells may therefore offer possible ways to replace a mutated dystrophin gene. • Others: • Utrophin is a protein that is expressed at neuromuscular and musculotendinous junctions. It shows homology to dystrophin. Upregulation of utrophin may be able to compensate for some of the effects of dystrophin loss. • Inducing muscle hypertrophy by upregulating genes involved in muscle growth, such as insulin-like growth factor 1 (IGF-1) or L-arginine, may help to fight muscle wasting. • Blocking the effect of myostatin as a negative regulator of muscle mass could have a similar beneficial effect.

FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY Definition

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common muscular dystrophy after DMD and myotonic dystrophy, with an incidence of about 1/20,000. It is an autosomal dominant disease characterized by weakness and atrophy of facial, scapulohumeral, as well as anterior tibial muscles.

Etiology and pathophysiology

FSHD has been linked to genetic alterations in the subtelomeric portion of chromosome 4q35. This region normally contains 11 to over 100 so-called D4Z4 repeat elements.44 FSHD patients show a contraction in the number of these D4Z4 repeats to fewer than 11. This results in inefficient repression of a retrogene DUX4 and inappropriate DUX4 protein expression in muscle cells. The mechanisms underlying DUX4-induced muscle toxicity remain unclear. Patients with one to three repeats remaining may show most severe disease, but in contrast to nucleotide repeat diseases, there is no clear anticipation and no strong correlation between the number of repeats and the clinical phenotype. The change in D4Z4 repeats is thought to result in complex changes in gene expression rather than simply alteration of a single gene.

Clinical features

• Asymmetry in weakness and muscle atrophy. • Stepwise progression that may include long periods of stable disease. Often the disease shows a downward progression with early involvement of facial muscles and late effects on pelvic girdle and leg muscles (Figures 27.27, 27.28). • Facial weakness affecting the orbicularis oculi and orbicularis oris but sparing the masseter, temporalis, extraocular eye muscles, and oropharyngeal muscles. • The muscles that fix the scapula to the chest, including the latissimus dorsi, lower trapezius, rhomboid, and serratus anterior, are prominently affected, leading to scapular elevation when raising the arms.

Muscle Disorders

863 Differential diagnosis

The diagnosis of facial weakness in the patient or in family members is very helpful. A number of conditions may present with scapuloperoneal weakness: • • • • • • • •

EMD (typically associated with contractures). Dysferlin deficiency. Reducing body myopathy. Hyaline body myopathy. Acid maltase deficiency. Mitochondrial disease. Inflammatory myopathy. Scapuloperoneal syndrome.

Investigations and diagnosis

• Serum CK: normal or mild elevation (two to seven times normal). • EMG: myopathic pattern. • Muscle biopsy: as discussed below, the muscle biopsy may show myopathic changes with or without inflammation, but lacks specific features. • Genetic testing: typically done by EcoRI/BlnI double digest. With a cutoff of 35 kb of DNA for the lower limit of normal, this test is 100% specific and 95% sensitive.

Pathology

FIGURES 27.27, 27.28  Facioscapulohumeral muscular dystrophy. Wasting and weakness of the muscles of the face, upper arms, and shoulders with prominent atrophy of the pectoral muscles and winging of the scapulae. • Sternocleidomastoid, biceps, brachioradialis, and pectoralis muscles are typically weak and atrophic, while the deltoids and other distal arm muscles are relatively spared. • Abdominal muscle weakness may lead to marked lumbar lordosis. If asymmetric, it can lead to lateral positioning of the umbilicus when sitting up from a supine position (Beevor’s sign). • The tibialis anterior is often affected early, even when other pelvic and leg muscles are spared. This leads to foot drop in some patients. Only about 25% of all patients develop lower extremity weakness severe enough to require a wheelchair. • Respiratory muscle involvement is uncommon. • Clinically significant cardiac involvement is unusual. Some patients show evidence of cardiac arrhythmia. • Pain is a frequent finding in FSHD patients. • Subclinical retinal vasculopathy is relatively common but only rarely associated with clinically significant visual impairment. • High-tone hearing loss is found in 25–65% of patients.

• Morphologic findings vary widely, depending on the severity of the patient’s phenotype and the site of the muscle biopsy. • Muscle biopsies may show nonspecific myopathic changes with degeneration and regeneration of individual myofibers. • There may be evidence of chronic remodeling in the form of endomysial fibrosis and fatty replacement. • Biopsies on FSHD patients may show significant perimysial or endomysial inflammatory infiltrates. This feature is shared with dysferlin deficiency and merosin deficiency, but is unusual in other muscular dystrophies.

Treatment

• Mild aerobic exercise may help to improve muscle tone. • Ankle–foot orthoses are helpful in the management of foot drop. • The use of steroids during time of disease progression and the utility of scapular fixation surgery are debatable. • For many FSHD patients, neck and back pain is the most limiting factor to their quality of life. Nonsteroidal antiinflammatory agents are often helpful. Some patients require long-acting narcotic analgesics.

EMERY–DREIFUSS MUSCULAR DYSTROPHY Definition

Emery–Dreifuss muscular dystrophy (EMD) is a condition that historically was characterized by the triad of: (1) slowly progressive muscle weakness and atrophy in a humeroperoneal distribution; (2) cardiomyopathy with conduction defects; (3) early contractures in Achilles’ tendon, spine muscles, and elbows.

Etiology and pathophysiology

• X-linked EMD (EMD1) is linked to mutations in the STA gene encoding emerin.

Hankey’s Clinical Neurology

864 • Autosomal dominant (EMD2) and autosomal recessive (EMD3) presentations are linked to mutations in the LMNA gene encoding lamin A/C. Mutations in lamin A/C can also result in other clinical phenotypes that include dilated cardiomyopathy with conduction defects, familial partial lipodystrophy, autosomal recessive axonal neuropathy (CMT2B1), and Hutchinson–Gilford progeria syndrome. • Lamin A/C and emerin are part of the inner nuclear envelope. They are thought to have a role in maintaining nuclear shape and to be important for scaffolding DNA in the nucleus. Through DNA binding, these proteins may influence gene expression. • Mutations in four other genes (FHL1, SYNE1, SYNE2, and TMEM43) can result in EMD phenotype.

Clinical features

• Muscle weakness and contractures precede the development of cardiac manifestations in most but not all cases. • The degree of muscle involvement can vary from asymptomatic to debilitating between and even within families. • Muscle weakness typically has humeroperoneal (EMD1) or scapulohumeroperoneal (EMD2) pattern. With progression, patients may develop some weakness of facial, thigh, and hand muscles. Loss of ambulation is more common with EMD2. • Affected patients invariably develop cardiac disease manifestations during their adult life. Cardiac conduction defects typically progress from prolonged PR interval and sinus bradycardia to complete heart block and atrial paralysis. There is a risk of sudden cardiac death. • Female carriers of EMD1 typically do not show evidence of skeletal muscle disease, but are at risk of cardiac involvement including sudden cardiac death.

Investigations and diagnosis

• Serum CK levels vary from normal to 10 times normal. • ECG and echocardiogram: ECG can identify early cardiac involvement in younger patients. Arrhythmias are more severe during sleep; 24-hour monitoring may therefore be helpful. Annual Holter’s monitoring is advised for all patients with ECG abnormalities or those older than 17 years. • EMG: myopathy pattern or normal. • Genetic testing: can confirm the presence of an STA gene or LMNA gene mutation.

Pathology

The skeletal muscle may show nonspecific myopathic changes including an increase in myofiber size, an increased number of myofibers with internalized nuclei, and mild features of myofiber degeneration/regeneration. EMD1 cases usually indicate a loss of emerin expression on immunocytochemical analysis. LMNA gene mutations, however, typically show preserved expression of lamin A/C. Some studies have described irregularities of the nuclear membrane and the peripheral arrangement of heterochromatin by electron microscopy.

Treatment

• Pacemaker insertion is recommended for patients with a ventricular heart rate below 50 beats/min. Implantation of an implantable cardioverter defibrillator helps to reduce the risk of sudden cardiac death.

• Prophylactic anticoagulation can reduce the risk of embolization. • ACE inhibitors and diuretics are helpful in patients with symptomatic ventricular involvement. • Cardiac transplantation may be considered in patients with dilated cardiomyopathy. • Orthopedic surgery may help to alleviate symptoms from foot deformities and marked neck hyperextension.

LIMB-GIRDLE MUSCULAR DYSTROPHY Definition

The LGMDs are a group of clinically as well as genetically heterogeneous diseases that share an autosomal inheritance pattern and predominant weakness of the proximal limb-girdle muscles. Some of the associated genes have been linked to other allelic diseases. The overall incidence is around 1:25,000–1:50,000. Cases with mutations in calpain3, dysferlin, FKRP, or one of the sarcoglycans are the most common forms.

Etiology and pathophysiology

LGMDs are inherited as autosomal dominant (LGMD D) or autosomal recessive (LGMD R) traits and are linked to a growing number of some 19 individual loci or genes as summarized in Table 27.5. The proteins encoded by these genes fall into several functional categories: (1) proteins of the cell membrane important for function of the dystrophin–glycoprotein complex; (2) other cell membrane proteins; (3) proteins associated with the contractile apparatus; (4) proteins with enzymatic functions; (5) proteins of the inner nuclear membrane.45

Protein types

1. The dystrophin–glycoprotein complex includes the sarcoglycans and dystroglycans. It is discussed above under dystrophinopathies. Defects in sarcoglycans present as LGMD R3–R6. Mutations in FKRP, POMT1, and Fukutin disrupt the function of glycosyl transferases that are important for the posttranslational modification of alpha-dystroglycan in the DGC (Figure 27.1). 2. Dysferlin (LGMD R2) is a transmembrane protein that is thought to mediate the fusion of vesicles to the cell membrane to repair sites of injury and the fusion of vesicles during cell trafficking. 3. Mutations in sarcomeric (Figure 27.2) thin filaments are linked to nemaline myopathy (Table 27.3), and mutations in thick filaments are linked to hypertrophic cardiomyopathy. LGMD has been linked to mutations of Z-disk proteins telethonin and myotilin as well as to mutations in titin. Beyond a pure mechanical role, these proteins may also play important signaling functions. 4. Calpain 3 (LGMD D4/R1) is a muscle-specific protease that has an important role in regulating other proteases as well as signaling pathways. It also interacts with dysferlin and may have a role in membrane resealing. TRIM32 (LGMD R8) is thought to play a role in the ubiquitin–proteasome pathway that is important for protein degradation.

Clinical features

Table 27.5 summarizes some of the important specifics about individual LGMDs. The phenotype of different LGMDs is

Muscle Disorders

865

TABLE 27.5  Summary of Limb-Girdle Dystrophies Locus

Gene

D1 7q36.3

DNAJB6

Allelic Diseases

R2 2p13.2

+/− Cardiac

5–39 y (mean 17 y)

DYSF

30–55 y

+/– Distal LE; +/− resp.

Transient early Distal calf hypertrophy contractures

Late

Resp.

Calf hypertrophy; macroglossia Calf hypertrophy; macroglossia Calf hypertrophy; macroglossia Calf hypertrophy, macroglossia

Miyoshi’s myopathy; 15–26 (mean distal myopathy 18 y) with tibial onset 2–15 y

Calf hypertrophy

2–15 y

15–25 y

Resp.

R5 13q12.12 SGCC

2–10 y

< 15 y

Resp.

R6 5q32.2– q33.3 R7 17q12 R8 9q33.1

1–10 y

15 y

Resp.

10–15 y Sarcotubular 6–40 y myopathy Congenital muscular 1–40 y dystrophy 1C CMD 1G 2–25 y 1–6 y

30–35 y 60 y

Distal LE Distal LE; resp.; facial +/− Resp.

11–50 y

20–60 y

SGCD

TCAP TRIM32

R9 19q13.32 FKRP R10 2q31.2 TTN R11 9q34.13 POMT1

R12 11p14.3 ANO5

FKTN

30–l0 y 20–50 y

F. Associated with hypokalemia (< 3.5 mEq/L). Thyrotoxic periodic paralysis is most common in Asians, Latin Americans, and native Americans.

Etiology and pathophysiology

• Mutations in the voltage sensor (S4) of the CACNA1S channel impair the transduction of the depolarization

Muscle Disorders signal to the ryanodine receptors and, as a result, there is a defect in excitation–contraction coupling. • Mutations in the voltage sensor of SCN4A result in enhanced channel inactivation and lead to slow and small action potentials. • In thyrotoxic periodic paralysis, KCNJ18 is transcriptionally regulated by thyroid hormones.

Clinical features

• Onset: early childhood to 30s. • Attacks begin in early morning hours, and triggered by physical activity, carbohydrate-rich meal, and alcohol in the preceding day. • Truncal musculature is weak; cranial nerves are spared except in thyrotoxic periodic paralysis where bulbar muscles and respiratory muscles may be involved. • Duration of attack: hours to days (longer than hyperPP). • Myotonia: focal in eyelids, usually not in limbs. • Older patients may have proximal myopathy. • In hypoPP2, myalgias are prominent. • Rhabdomyolysis may occur in some patients. • Attacks are aggravated by acetazolamide in hypoPP2 and thyrotoxic PP.

Differential diagnosis

Same as listed for hyperPP.

Investigations and diagnosis

• Serum K level, TSH. • CMAP is small during attacks, but similar results with exercise test as in hyperPP. • Provocative tests: glucose plus insulin. • Genetic testing for mutations in CACNA1S, SCN4A, and KCNJ18.

Diagnosis is based on clinical presentation and laboratory investigations, including genetic testing.

Pathology

Muscle biopsy may show predominance of vacuolar changes in hypoPP1 and tubular aggregates in hypoPP2. Other changes include internal nuclei and vacuolar dilation of sarcoplasmic reticulum.

Treatment • • • •

Oral potassium supplement. Correct thyrotoxicosis if present. Acetazolamide except in hypoPP2 and thyrotoxic PP. Dichlorphenamide.

MALIGNANT HYPERTHERMIA Definition

An autosomal dominant disorder characterized by susceptibility to a number of drugs, particularly anesthetics such as halothane and succinylcholine. Other drugs, including tricyclic antidepressants, monoamine oxidase inhibitors, methoxyflurane, ketamine, enflurane, diethyl ether, and cyclopropane, can cause malignant hyperthermia.

Etiology and pathophysiology

• Due to a malfunction of the calcium channel of the sarcoplasmic reticulum (the ryanodine receptor). The abnormal ryanodine receptor may accentuate calcium release.

871 • The gene for the ryanodine receptor (RYR1) maps to chromosome 19 (13–1). Some mutations in RYR1 cause malignant hyperthermia, some central core disease, and some both. • Fast, uncontrolled increase in skeletal muscle metabolism associated with rhabdomyolysis may also occur in association with dystrophinopathies.

Clinical features

• Rapid elevation of temperature which may rise to 43°C (109°F). • Tachycardia. • Muscle rigidity (e.g. begins with trismus). • Areflexia. • Coma.

Differential diagnosis

• Neuroleptic malignant syndrome: also presents with high fever, rigidity, tachycardia, and rhabdomyolysis, but it is of slower onset over days to weeks, not familial, and usually triggered by drugs that block central dopaminergic pathways, such as phenothiazines, lithium, and haloperidol, or can occur after discontinuation of L-dopa for Parkinson’s disease. • Sepsis. • Hyperthyroid crisis. • Heat stroke. • Pheochromocytoma crisis.

Investigations

• Arterial blood gases: metabolic acidosis. • Serum CK: precipitous rise, sometimes to 10,000 times the normal values. • Blood coagulation profile: may show evidence for disseminated intravascular coagulation. • Urine: myoglobinuria.

Diagnosis

RYR1 gene mutations are identified in up to 80% of individuals with confirmed malignant hyperthermia.56, 57 • Halothane and caffeine contracture tests. • Contracture of muscle (obtained from a fresh muscle biopsy) when exposed to 3% halothane or increasing concentrations of caffeine. • This test may be considered to diagnose MH when genetic testing is not available or comes back negative in clinically suspected cases.

Pathology

• There are no specific morphologic changes. • In vitro contracture testing with halothane, caffeine, and ryanodine on fresh muscle has been used to confirm the diagnosis. • Central core disease and malignant hyperthermia are both linked to mutations in the ryanodine receptor. Some patients with central core disease have malignant hyperthermia, and some patients with malignant hyperthermia show central cores on muscle biopsy (Table 27.3).

Treatment

• Mild cases: discontinue the anesthetic (succinylcholine and inhalational anesthetic). • More severe cases: • Dantrolene 2 mg/kg IV q 5 min, up to 10 mg/kg: inhibits calcium release from the sarcoplasmic reticulum. • Treat associated hyperkalemia.

Hankey’s Clinical Neurology

872 • Increase ventilation. • Correct the acid–base disturbance: give IV sodium bicarbonate 2–4 mg/kg. • Cool the patient: cooling blankets and cold IV fluids until temperature reaches 38°C (100°F). • Intravenous hydration with or without diuretics if myoglobinuria is present. • Give steroids for the acute stress reaction.

Prevention and prognosis

• If the disease-related mutation is known, the relatives of affected patients should be tested for that mutation. • Barbiturate, nitrous oxide, and opiate nondepolarizing relaxant anesthesia should not induce malignant hyperthermia. • There is a high mortality rate unless the patient is immediately diagnosed and treated. • The patients may also have complications such as myoglobinuria, renal failure, and disseminated intravascular coagulation. • With immediate diagnosis and treatment, the rate of mortality and morbidity is less than 5%.

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Further reading

General Dubowitz V, Sewry CA (2007). Muscle biopsy: a practical approach, 3rd edn. Saunders/Elsevier, Philadelphia. Engel A, Franzini-Armstrong C (2004). Myology, 3rd edn. McGraw-Hill Medical Pub Div, New York. van Adel BA, Tarnopolsky MA (2009). Metabolic myopathies: update 2009. J Clin Neuromuscul Dis 10(3):97–121.

Inflammatory myopathies

Amato AA, Griggs RC (2003). Treatment of idiopathic inflammatory myopathies. Curr Opin Neurol 16(5):569–575. Dalakas MC (1998). Controlled studies with high-dose intravenous immunoglobulin in the treatment of dermatomyositis, inclusion body myositis, and polymyositis. Neurology 51(6 Suppl 5):S37–S45. Gordon PA, Winer JB, Hoogendijk JE, Choy EH (2012). Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis. Cochrane Database Syst Rev 8:CD003643. Needham M, Mastaglia FL (2007). Inclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches. Lancet Neurol 6(7):620–631. Peng A, Koffman BM, Malley JD, Dalakas MC (2000). Disease progression in sporadic inclusion body myositis: observations in 78 patients. Neurology 55(2):296–298.

Hankey’s Clinical Neurology

874 Selva-O’Callaghan A, Pinal-Fernandez I, Trallero-Araguás E, Milisenda JC, Grau-Junyent JM, Mammen AL (2018). Classification and management of adult inflammatory myopathies. Lancet Neurol 17(9):816–828. Van Der Meulen MF, Bronner IM, Hoogendijk JE, et al. (2003). Polymyositis: an overdiagnosed entity. Neurology 61(3):316–321.

Khan J, Harrison TB, Rich MM (2008). Mechanisms of neuromuscular dysfunction in critical illness. Crit Care Clin 24(1):165–177. Lacomis D, Zochodne DW, Bird SJ (2000). Critical illness myopathy. Muscle Nerve 23(12):1785–1788. Kramer CL (2017). Intensive care unit-acquired weakness. Neurol Clin 35(4):723–736.

preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50(3):509–517. Meola G, Moxley RT IIIrd (2004). Myotonic dystrophy type 2 and related myotonic disorders. J Neurol 251(10):1173–1182. Mercuri E, Jungbluth H, Muntoni F (2005). Muscle imaging in clinical practice: diagnostic value of muscle magnetic resonance imaging in inherited neuromuscular disorders. Curr Opin Neurol 18(5):526–537. Nishino I (2006). Autophagic vacuolar myopathy. Semin Pediatr Neurol 13(2):90–95. Norwood F, De Visser M, Eymard B, Lochmuller H, Bushby K (2007). EFNS guideline on diagnosis and management of limb girdle muscular dystrophies. Eur J Neurol 14(12):1305–1312. Ranum LP, Day JW (2004). Myotonic dystrophy: RNA pathogenesis comes into focus. Am J Hum Genet 74(5):793–804. Ranum LP, Rasmussen PF, Benzow KA, Koob MD, Day JW (1998). Genetic mapping of a second myotonic dystrophy locus. Nat Genet 19(2):196–198. Roux K, Burke B (2007). Nuclear envelope defects in muscular dystrophy. Biochim Biophys Acta 1772(2):118–127. Schoser BG, Ricker K, Schneider-Gold C, et al. (2004). Sudden cardiac death in myotonic dystrophy type 2. Neurology 63(12):2402–2404. Tawil R (2008). Facioscapulohumeral muscular dystrophy. Neurotherapeutics 5(4):601–606. Tubridy N, Fontaine B, Eymard B (2001). Congenital myopathies and congenital muscular dystrophies. Curr Opin Neurol 14(5):575–582. Wheeler TM, Thornton CA (2007). Myotonic dystrophy: RNAmediated muscle disease. Curr Opin Neurol 20(5):572–576. Udd B, Krahe R (2012). The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurol 11(10):891–905.

Muscular dystrophies and congenital myopathies

Toxic myopathies

Metabolic, endocrine, and mitochondrial myopathies

Amato A (2000). Acid maltase deficiency and related myopathies. Neurol Clin 18(1):151–165. Andersen ST, Haller RG, Vissing J (2008). Effect of oral sucrose shortly before exercise on work capacity in McArdle disease. Arch Neurol 65(6):786–789. Devries MC, Tarnopolsky MA (2008). Muscle physiology in healthy men and women and those with metabolic myopathies. Neurol Clin 26(1):115–148. Klein I, Ojamaa K (2000). Thyroid (neuro) myopathy. Lancet 356(9230):614. Rosenow EC IIIrd, Engel AG (1978). Acid maltase deficiency in adults presenting as respiratory failure. Am J Med 64(3): 485–491. Vorgerd M, Grehl T, Jager M, et al. (2000). Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebocontrolled crossover trial. Arch Neurol 57(7):956–963.

Critical illness myopathy

Brook JD, Mccurrach ME, Harley HG, et al. (1992). Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3’ end of a transcript encoding a protein kinase family member. Cell 68(4):799–808. Den Dunnen J, Grootscholten P, Bakker E, et al. (1989). Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications. Am J Hum Genet 45(6):835–847. Dubowitz V (1975). Neuromuscular disorders in childhood. Old dogmas, new concepts. Arch Dis Child 50(5):335–346. Goebel H (2003). Congenital myopathies at their molecular dawning. Muscle Nerve 27(5):527–548. Groh WJ, Groh MR, Saha C, et al. (2008). Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med 358(25):2688–2697. Guglieri M, Straub V, Bushby K, Lochmuller H (2008). Limb-girdle muscular dystrophies. Curr Opin Neurol 21(5):576–584. Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA (2004). Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet 13(24):3079–3088. Koenig M, Hoffman E, Bertelson C, et al. (1987). Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and

Kuncl RW (2009). Agents and mechanisms of toxic myopathy. Curr Opin Neurol 22(5):506–515. Sieb JP, Gillessen T (2003). Iatrogenic and toxic myopathies. Muscle Nerve 27(2):142–156.

Skeletal muscle channelopathies

Colding-Jorgensen E (2005). Phenotypic variability in myotonia congenita. Muscle Nerve 32(1):19–34. Matthews E, Labrum R, Sweeney MG, et al. (2009). Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 72(18):1544–1547. Miller TM (2008). Differential diagnosis of myotonic disorders. Muscle Nerve 37(3):293–299. Ptacek LJ, Tawil R, Griggs RC, et al. (1994). Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77(6):863–868. Ptacek LJ, Tawil R, Griggs RC, et al. (1994). Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Neurology 44(8):1500–1503. Statland JM, Fontaine B, Hanna MG, et al. (2018). Review of the diagnosis and treatment of periodic paralysis. Muscle Nerve 57(4):522–530.

28

SLEEP–WAKE DISORDERS

Margaret Kay-Stacey, Eunice Torres-Rivera, Phyllis C. Zee

Contents Introduction....................................................................................................................................................................................................................... 877 Normal Sleep..................................................................................................................................................................................................................... 877 Definition...................................................................................................................................................................................................................... 877 Sleep stages................................................................................................................................................................................................................... 877 Wake........................................................................................................................................................................................................................ 877 N1 (formerly S1 or Stage 1)..................................................................................................................................................................................878 N2 (formerly S2 or Stage 2)..................................................................................................................................................................................878 N3 (replaced S3 and S4)........................................................................................................................................................................................878 R (REM sleep).........................................................................................................................................................................................................878 Sleep–wake cycles........................................................................................................................................................................................................879 Total sleep requirement changes with age........................................................................................................................................................879 Effect of aging......................................................................................................................................................................................................... 880 Sleep–wake regulation............................................................................................................................................................................................... 880 Homeostatic mechanism..................................................................................................................................................................................... 880 Circadian mechanism........................................................................................................................................................................................... 880 Neural networks.....................................................................................................................................................................................................881 Commonly Performed Sleep Tests................................................................................................................................................................................ 882 Polysomnography........................................................................................................................................................................................................ 882 Definitions of terms used in standard polysomnogram reports.................................................................................................................. 883 Respiratory events (adult).................................................................................................................................................................................... 883 Periodic leg movements....................................................................................................................................................................................... 885 Portable polysomnography....................................................................................................................................................................................... 885 Multiple sleep latency test......................................................................................................................................................................................... 888 Maintenance of wakefulness test............................................................................................................................................................................. 889 Insomnia Disorder............................................................................................................................................................................................................ 889 Definition...................................................................................................................................................................................................................... 889 Epidemiology................................................................................................................................................................................................................ 889 Etiology and pathophysiology................................................................................................................................................................................... 889 Clinical features........................................................................................................................................................................................................... 890 Diagnosis....................................................................................................................................................................................................................... 890 Pathology...................................................................................................................................................................................................................... 890 Treatment..................................................................................................................................................................................................................... 890 Hypersomnias of Central Origin....................................................................................................................................................................................892 Narcolepsy type 1.........................................................................................................................................................................................................892 Definition.................................................................................................................................................................................................................892 Epidemiology...........................................................................................................................................................................................................892 Pathophysiology......................................................................................................................................................................................................892 Clinical features......................................................................................................................................................................................................892 Narcolepsy type 2.........................................................................................................................................................................................................893 Diagnosis of narcolepsy types 1 and 2................................................................................................................................................................893 Treatment of narcolepsy types 1 and 2............................................................................................................................................................. 894 Idiopathic hypersomnia............................................................................................................................................................................................. 894 Pathophysiology......................................................................................................................................................................................................895 Diagnosis..................................................................................................................................................................................................................895 Treatment of idiopathic hypersomnia................................................................................................................................................................895 Kleine–Levin syndrome..............................................................................................................................................................................................895 Clinical features......................................................................................................................................................................................................895 Diagnosis..................................................................................................................................................................................................................895

875

876

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Treatment.................................................................................................................................................................................................................895 Insufficient sleep syndrome.......................................................................................................................................................................................895 Treatment................................................................................................................................................................................................................ 896 Sleep-Related Movement Disorders.............................................................................................................................................................................. 896 Introduction................................................................................................................................................................................................................. 896 Restless leg syndrome................................................................................................................................................................................................. 896 Epidemiology.......................................................................................................................................................................................................... 896 Pathophysiology..................................................................................................................................................................................................... 896 Differential Diagnosis........................................................................................................................................................................................... 896 Diagnosis................................................................................................................................................................................................................. 896 Treatment.................................................................................................................................................................................................................897 Periodic leg movement disorder...............................................................................................................................................................................897 Epidemiology...........................................................................................................................................................................................................897 Pathophysiology......................................................................................................................................................................................................898 Differential Diagnosis............................................................................................................................................................................................898 Diagnosis..................................................................................................................................................................................................................898 Treatment.................................................................................................................................................................................................................898 Sleep-related bruxism.................................................................................................................................................................................................898 Epidemiology...........................................................................................................................................................................................................898 Pathophysiology......................................................................................................................................................................................................898 Differential diagnosis.............................................................................................................................................................................................898 Diagnosis..................................................................................................................................................................................................................898 Treatment.................................................................................................................................................................................................................898 Other sleep-related movement disorders............................................................................................................................................................... 899 Sleep-Related Breathing Disorders................................................................................................................................................................................ 899 Introduction................................................................................................................................................................................................................. 899 Obstructive sleep apnea............................................................................................................................................................................................. 899 Definition and clinical features........................................................................................................................................................................... 899 Epidemiology and risk factors............................................................................................................................................................................. 900 Pathophysiology..................................................................................................................................................................................................... 900 Diagnosis..................................................................................................................................................................................................................901 Treatment.................................................................................................................................................................................................................901 Central sleep apnea..................................................................................................................................................................................................... 902 Circadian Rhythm Sleep–Wake Disorders.................................................................................................................................................................. 902 Introduction................................................................................................................................................................................................................. 902 General diagnostic approach.................................................................................................................................................................................... 902 General treatment approaches................................................................................................................................................................................. 903 Melatonin................................................................................................................................................................................................................ 903 Light therapy.......................................................................................................................................................................................................... 903 Chronotherapy....................................................................................................................................................................................................... 903 Behavioral and environmental modifications.................................................................................................................................................. 903 Delayed sleep–wake phase disorder........................................................................................................................................................................ 903 Advanced sleep–wake phase disorder.................................................................................................................................................................... 904 Irregular sleep–wake rhythm disorder................................................................................................................................................................... 904 Non–24-hour sleep–wake rhythm disorder.......................................................................................................................................................... 905 Jet lag disorder............................................................................................................................................................................................................. 907 Shift work disorder..................................................................................................................................................................................................... 907 Parasomnias....................................................................................................................................................................................................................... 908 Introduction................................................................................................................................................................................................................. 908 NREM Parasomnias......................................................................................................................................................................................................... 908 Definition................................................................................................................................................................................................................ 908 Epidemiology................................................................................................................................................................................................................ 908 Pathophysiology.......................................................................................................................................................................................................... 908 Clinical features of NREM parasomnias................................................................................................................................................................ 908 Disorders of arousal.............................................................................................................................................................................................. 908 Differential diagnosis.................................................................................................................................................................................................. 908 Diagnosis................................................................................................................................................................................................................. 909 Treatment of disorders of arousals.......................................................................................................................................................................... 909 Sleep-related eating disorder.............................................................................................................................................................................. 909 Treatment................................................................................................................................................................................................................ 909 REM parasomnia..........................................................................................................................................................................................................910 Nightmares..............................................................................................................................................................................................................910

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877

REM sleep behavior disorder.....................................................................................................................................................................................910 Epidemiology...........................................................................................................................................................................................................910 Pathophysiology......................................................................................................................................................................................................911 Differential diagnosis.............................................................................................................................................................................................911 Diagnosis..................................................................................................................................................................................................................911 Treatment.................................................................................................................................................................................................................911 Conclusion...........................................................................................................................................................................................................................911 References............................................................................................................................................................................................................................911

INTRODUCTION Sleep disturbances are common in primary care and neurology. It is estimated that 50–70 million Americans are affected by chronic sleep disorders and intermittent sleep problems.1 Additionally, approximately one in three adults do not get the recommended amount of sleep. Sleep disorders often result in impaired daytime functioning, affecting work performance and increasing the likelihood of motor vehicle accidents. These disorders may increase the risk for or exacerbate medical and psychiatric disorders. Most notably, there is mounting evidence of a bidirectional relationship between sleep deficiency and circadian dysfunction with cardiovascular and metabolic disease and neurologic disorders. Therefore, diagnosis and treatment of sleep and circadian rhythm disorders are highly important for general medicine, as well as neurology. Six major categories of sleep disorders in the International Classification of Sleep Disorders, Third Edition (ICSD-3)2 are discussed in this chapter: • • • • • •

Insomnia. Sleep-related breathing disorders. Central disorders of hypersomnolence. Circadian rhythm sleep–wake disorders. Parasomnias. Sleep-related movement disorders.

A comprehensive review of all sleep–wake disorders is beyond the scope of this chapter. The focus will be on the most common sleep disorders and those of greater interest to the neurologist.

NORMAL SLEEP Definition

Sleep can be defined by behavior and physiology, as cycling reversible states of decreased responsiveness to the environment and motor activity. Sleep is not a static brain state, but a dynamic F3–A2 C3–A2 O1–A2 F4–A1 C4–A1 O2–A1 LOC ROC Chin EKG Legs Snore NPT Therm Chest Abdmn SAO2(%)

state that cycles through stages of physiologic distinction divided broadly into rapid eye movement (REM) and non-REM (NREM) sleep. More specific characteristics of sleep include: • When deprived, there is a need for recovery. • Dynamic state that cycles through stages of physiologic distinction consists of REM and NREM sleep. • Regulated by physiologic cycles of neuronal activity involving brainstem, cortex, and spinal cord. Sleep is thereby distinguishable from encephalopathy, coma, or anesthesia, as none of these represents normal physiology, and encephalopathy or coma may or may not be reversible.

Sleep stages

Rules for staging of sleep and wakefulness were established by Rechtschaffen and Kales and were widely used for many years. 3 A stage is assigned to each 30-second epoch of a polysomnogram. The rules were modified in a manual published by the American Academy of Sleep Medicine in 2007,4, 5 as a result of reviews of the literature and the need for standards of digital recording and for new rules for scoring arousals, respiratory events, cardiac events, and movements. The main difference in terminology for sleep staging in the modified system of 2007 concerns NREM stages. Stages S1, S2, S3, and S4 were replaced by N1, N2, and N3, as explained below, in the descriptions of the stages. Stages S3 and S4 were collapsed into a single stage, N3, because there was no need to divide slow-wave sleep into two separate stages.

Wake (Figure 28.1)

• Electroencephalogram (EEG): alpha (8–13 Hz) in quiet wakefulness with eyes closed. • High muscle tone. • REMs. • Irregular respirations and heart rate. FIGURE 28.1  30-second epoch of wakefulness. Note prominent alpha activity, rapid eye movements, high chin EMG tone, and irregular respirations. LOC, L outer canthus; ROC, R outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

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878 F3–A2 C3–A2 O1–A2 F4–A1 C4–A1 O2–A1 LOC ROC Chin EKG Legs Snore NPT Therm Chest Abdmn SAO2(%)

*

FIGURE 28.2  30-second epoch of stage N1 sleep. Note vertex sharp wave near center of epoch (asterisk), dropout of alpha activity, and slow rolling eye movements. LOC, L outer canthus; ROC, R outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

N1 (formerly S1 or Stage 1)

• No or a few slow eye movements. • Regular respirations and heart rate.

NREM light sleep; defines sleep onset (Figure 28.2). • EEG: low-voltage, mixed-frequency pattern (mostly 4–7 Hz) for more than 50% of the 30-second epoch; vertex waves (sharply contoured waves over the central region lasting < 0.5 seconds). • Muscle tone intermediate. • Slow rolling eye movements. • Regular respirations and heart rate.

N3 (replaced S3 and S4)

Deep NREM sleep: slow-wave sleep (Figure 28.4). • EEG: 20% or more of a 30-second epoch consists of 0.5–2 Hz waves, of amplitude > 75 μV, predominant over the frontal regions. • Muscle tone intermediate. • Mostly no eye movements. • Regular respirations and heart rate.

N2 (formerly S2 or Stage 2)

The major stage of NREM sleep in adults (Figure 28.3). • EEG: K-complexes (negative sharp wave followed immediately by a positive component) and/or sleep spindles (11–16 Hz activity lasting > 0.5 seconds). • Muscle tone intermediate.

F3–A2 C3–A2 O1–A2 F4–A1 C4–A1 O2–A1 LOC ROC Chin EKG Legs Snore NPT Therm Chest Abdmn SAO2(%)

*

*

*

R (REM sleep) (Figure 28.5)

• EEG: low-amplitude, mixed-frequency EEG. • Muscle tone low (tonic electromyography [EMG]), except for short bursts of EMG activity lasting < 0.25 seconds (phasic EMG).

*

FIGURE 28.3  30-second epoch of stage N2 sleep. Note K complexes (arrows), sleep spindles (asterisks), and regular respirations. LOC, L outer canthus; ROC, R outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

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879

F3–A2 C3–A2 O1–A2 F4–A1 C4–A1 O2–A1 LOC ROC Chin EKG Legs Snore NPT Therm Chest Abdmn SAO2(%)

FIGURE 28.4  30-second epoch of stage N3 sleep. Note high-amplitude delta waves and very regular respirations. LOC, L outer canthus; ROC, R outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

• REMs, resembling those observed in wakefulness (phasic REM) or no eye movements (tonic REM). • Irregular respirations and heart rate. • Penile or clitoral tumescence. • Poikilothermia.

Sleep–wake cycles6

A typical night in an adult or adolescent begins with 90–110 minutes of NREM sleep followed by a brief, several-minute REM period and then cycling between REM and NREM every 90–120 minutes. There is a rapid descent from stage N1 to stage N2. After 10–25 minutes of N2, there may be deepening into stage N3, slowwave sleep, for a number of minutes, particularly during the first third of the night in younger subjects. A complete night usually

contains four or five sleep cycles. Slow-wave sleep tends to occur during the first third of the night, and REM period duration tends to lengthen as the night progresses (Figure 28.6).

Total sleep requirement changes with age

Infants require 16–18 hours of sleep per 24 hours, young children 11–13 hours, teens 9–10 hours, and adults 7–8 hours. Insufficient sleep now is present in growing numbers of preadolescents and adults and is the most common sleep problem today.7 One in three adults is getting inadequate sleep and the Centers for Disease Control and Prevention (CDC) has reported an increase in multiple health conditions due to insufficient sleep, including coronary artery disease, stroke, asthma, chronic obstructive pulmonary disease (COPD), depression, and diabetes.8

F3–A2 C3–A2 O1–A2 F4–A1 C4–A1 O2–A1 LOC ROC Chin EKG Legs Snore NPT Therm Chest Abdmn SAO2(%)

FIGURE 28.5  30-second epoch of stage REM. Note low-amplitude EEG, rapid eye movements at beginning of epoch, phasic EMG twitch in chin at end of epoch, and irregular respirations. LOC, L outer canthus; ROC, R outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

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880 Sleep Stages Time 22:32

23:33

00:33

01:33

02:33

03:33

04:33

1

2

3

4

5

6

05:33 06:00

W R N1 N2 N3 Hours

7

FIGURE 28.6  Typical hypnogram of a normal young adult. W, wake; R, REM.

Effect of aging

A full-term infant spends about one-half of the total sleep time in REM sleep. By age 5, the amount of REM sleep has decreased to 20–25%, and remains remarkably constant through life, with only very limited decline with aging (Figure 28.7). Slow-wave sleep, in contrast, declines markedly with age.6, 9 This decline is most marked in males, who may exhibit only a few percent or less slow-wave sleep at ages over 50 years.

Sleep–wake regulation

According to a proposed two-process model,10 the propensity for sleep and wakefulness is controlled by a homeostatic mechanism (process S, sometimes also referred to as process H) and a circadian mechanism (process C). Although these two mechanisms exist independently, it is the strength and timing of their relative contributions that under typical conditions regulate both the timing and duration of sleep and alertness (Figure 28.8).

• Following sleep deprivation, there is a need for recovery of the S process, even at adverse circadian times. • Although metabolic and inflammatory substrates may mediate the S process, adenosine has been proposed as a prime candidate. Caffeine, an agent well known to enhance wakefulness, is an adenosine receptor antagonist.

Circadian mechanism (Figure 28.9)

• Circadian rhythms are present in all organisms and in humans, exhibit an average period that is slightly longer than 24 hours. • Circadian clock genes through a complex transcription– translation feedback loop generate this near 24-hour rhythm, and are found in virtually all cells of the body.11 • The mammalian ‘master clock’ is located within the suprachiasmatic nucleus (SCN) in the anterior hypothalamus.12

Homeostatic mechanism

• Sleepiness increases in proportion to prior awake time and reaches a peak after 14–16 hours of wakefulness. • The accumulated S process during wakefulness needs to be dissipated during sleep for the ability to maintain alertness during the day.

Sleep Drive Wake

Melatonin

600

Minutes

500

Sleep latency

400

WASO

300

REM SWS (N3)

200 N2

100 0

N1 5

10

15

25

35

45 Age

55

65

75

85

FIGURE 28.7  Changes in proportions of sleep stages with aging. SWS, slow-wave sleep; REM, rapid eye movement sleep; WASO, wake after sleep onset.

Circadian Alerting Signal

Sleep Awake

Asleep

FIGURE 28.8  Sleep–wake regulation during a 24-hour cycle. Schematic of the relationship of homeostatic sleep process (S) (top) and circadian process (bottom) that promotes wakefulness during the day and promotes sleep at night when accumulation of sleep homeostasis is high. In addition, melatonin is secreted by the pineal gland in the evening, helping to promote sleep. (Adapted with permission from Kilduff TS, Kushida CA. Circadian regulation of sleep. In: Chokroverty S, ed. Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects. 2nd ed. Boston, Mass: Butterworth-Heineman; 1999. Kennaway DJ, Voultsios A. J Clin Endocrinol Metab. 1998;83:1013–1015.)

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881

Melatonin Pineal gland

Inh

ibit

ion

Suprachiasmatic nucleus Retinohypothalamic tract

ion

lat timu

S

Superior cervical ganglion

FIGURE 28.9  Circadian system synchronizing agents. Light signals are transmitted from the retina via specialized retinal ganglion cells to the suprachiasmatic nucleus (SCN) via the direct retinohypothalamic tract (RHT). The SCN in turn sends output signals to regulate the secretion of pineal melatonin and numerous other hormonal, physiologic, and behavioral rhythms. The SCN receives environmental and endogenous cues (or zeitgebers) to synchronize the endogenous rhythm with the external light–dark cycle and behavior. Zeitgebers include melatonin, physical and social activities, meal timing, and light. • The SCN coordinates these signals and sends information to other regions of the hypothalamus that regulate physiology and behavior, such as sleep–wake, temperature, feeding, and hormone release. • Light is the strongest zeitgeber, and photic signals are relayed to the SCN from the intrinsically photosensitive retinal ganglion cells, mainly through the retinohypothalamic tract.13 • Melatonin secretion from the pineal glans is regulated by the SCN, and once secreted, it can also adjust the timing of SCN activity and promote sleep.13

Neural networks

• Ascending reticular activating system: wakefulness (Figure 28.10; Table 28.1). • Location: brainstem, lateral/posterior hypothalamus, basal forebrain. • The orexin- (also known as hypocretin) secreting neurons are key to maintenance of wakefulness. (Figure 28.11) These neurons have wide-ranging activating projections to the wake promoting brain, and inhibitory to sleep promoting regions, such as the ventrolateral preoptic (VLPO) nucleus (see below). • Descending inhibitory system: sleep-promoting (Figure 28.12): • Inhibitory projections arise from the VLPO area and associated neuronal groups, such as the median preoptic nucleus, to initiate and maintain sleep.

Orexogenic neurons SN/VTA TMN BF

Thalamus SN/VTA TMN BF PPT/LDT Raphe LC Reticular formation

   

Cortex

PPT/LDT Raphe LC

FIGURES 28.10, 28.11  Ascending reticular activating system (Figure 28.10) and connections of the wake-promoting orexin/ hypocretin-secreting neurons (Figure 28.11). BF, basal forebrain; LC, locus ceruleus; LDT, lateral dorsal tegmental area; PPT, pedunculopontine tegmental area; Raphe, dorsal and medial raphe nuclei; SN/VTA, substantia nigra and ventral tegmental area; TMN, tuberomammillary nucleus.

Hankey’s Clinical Neurology

882 TABLE 28.1  Wake-Promoting System Location

Nucleus/Cell Structure

Transmitter

Brainstem

Pedunculopontine nucleus Lateral dorsal tegmental nucleus Locus ceruleus Raphe nuclei Substantia nigra Ventral tegmental area Tuberomammillary nucleus Orexigenic neurons Basal forebrain nuclei

Acetylcholine

Brainstem Brainstem Brainstem Brainstem Posterior hypothalamus Lateral hypothalamus Basal forebrain

• Inhibitory projections synapse on multiple nuclei of the reticular activating system. • Neurotransmitters are gamma-aminobutyric acid (GABA) and galanin. Relative activation of the ascending, wake-promoting system versus the descending, sleep-promoting system is thought to be under the control of the interaction between circadian and homeostatic processes. The ascending and descending systems are mutually inhibitory, creating a ‘flip-flop’ switch that enables sudden transitions from wakefulness to sleep and vice versa (Figure 28.13).

Acetylcholine Norepinephrine Serotonin Dopamine Histamine Orexin (hypocretin) Acetylcholine

COMMONLY PERFORMED SLEEP TESTS Polysomnography4

Recommended channels include:

VLPO TMN SN/VTA PPT/LDT Raphe LC

FIGURE 28.12  Descending sleep-promoting inhibitory system. LC, locus ceruleus; LDT, lateral dorsal tegmental area; PPT, pedunculopontine tegmental area; Raphe, dorsal and medial raphe nuclei; SN/VTA, substantia nigra and ventral tegmental area; TMN, tuberomammillary nucleus; VLPO, ventrolateral preoptic area.

The Sleep/Wake Switch GABA

Hypocretin Orexin

GABA

Sleep

GABA (Ventrolateral preoptic area)

–

–

+

Norepinephrine Histamine Dopamine Serolotin Acetylcholine

Wake

Norepinephrine Serotonic

Adapted with permission from Saper et al. Trends neurosci. 2001.24.726.

• EEG: minimum three-channel derivations include either frontal, central, and occipital scalp regions referred to the contralateral mastoid (F4–M1, C4–M1, and O2–M1 according to the International 10–20 System), or C4–M1 and two midline bipolar derivations (Fz–Cz and Cz–Oz). Expanded EEG montages are frequently used when nocturnal seizures are suspected (Figure 28.14). • Electro-oculogram (EOG). • Chin EMG. • Leg EMG. • Airflow monitoring: thermal sensor and nasal pressure transducer. End-tidal carbon dioxide monitoring is often added in pediatric studies or when neuromuscular conditions or obesity–hypoventilation syndromes are a consideration. • Respiratory effort: inductance plethysmography is currently recommended. Less commonly, esophageal manometry is used. • Pulse oximetry. • Microphone for recording of snoring sounds. • Electrocardiogram (ECG). • Body position: recorded by the sleep technologist or by position sensors. • Video recording: most state-of-the-art laboratories now use time-locked audiovisual recording to correlate behaviors FIGURE 28.13  Model of sleep and wake regulation. The putative ‘flip–flop’ or sleep– wake switch allows sudden transitions between wakefulness and sleep and vice versa. During the waking state, monoaminergic neurons inhibit the sleep-promoting ventrolateral preoptic (VLPO) neurons. Maintenance of wakefulness is reinforced by stimulation of the monoaminergic neurons by orexin neurons (ORX). During sleep, the VLPO neurons inhibit both orexin and monoaminergic neurons. (Adapted with permission from Saper et al. Trends Neurosci. 2001; 24:726.)

Sleep–Wake Disorders

883 FIGURE 28.14 Example of an expanded EEG montage, 30-second epoch. Note multifocal sharp waves at the beginning of the epoch.

FP1–F7 F7–T3 T3–T5 F5–O1 FP1–F3 F3–C3 C3–P3 P3–O3 FP2–F8 F8–T4 T4–T6 T6–O2 FP2–F4 F4–C4 C4–P4 P4–O2 LEOG REOG Chin Legs Snore EKG NPT Therm Chest Abdmn SAO2 (%)

and body position with polygraphic findings. This information is most useful for evaluation of sleep-related movement disorders, parasomnias (including REM behavior disorder), and suspected seizures. • Other monitors are occasionally employed: • Intraesophageal pH probe: in suspected gastroesophageal reflux disease (GERD). • Intraesophageal balloon: for pressure measurement, as an aid to distinguish obstructive from central respiratory events. • EMG of the upper extremities: in cases where upper body movements are reported. • Nocturnal penile tumescence: monitoring with strain gauges, in cases of suspected erectile dysfunction – now rarely used.

Definitions of terms used in standard polysomnogram reports Arousal events

An arousal event is defined as an abrupt shift of EEG from any sleep stage to theta (4 Hz) or higher frequencies, not including

F3–A2 C3–A2 O1–A2 F4–A1 C4–A1 O2–A1 LOC ROC Chin Legs Snore NPT Therm Chest Abdmn Sum EKG SAO2 (%)

sleep spindles, lasting at least 3 seconds, with at least 10 seconds of stable sleep preceding (Figure 28.15). An arousal during REM requires a concurrent increase in submental EMG lasting at least 1 second.

TIP • The reason for the extra requirement of increased EMG activity in order to score an arousal in REM sleep is that faster frequencies, including alpha frequencies, are frequently observed in the EEG in normal REM sleep. Do not score an arousal in REM sleep if only a shift to faster EEG frequencies is observed. In non-REM sleep, a shift to faster frequencies alone is sufficient.

Respiratory events (adult)

• Apnea is defined as a drop in peak thermal sensor airflow > 90% of baseline, lasting at least 10 seconds, with 90% of the event’s duration meeting the amplitude reduction criteria. FIGURE 28.15  An arousal event (1-minute epoch). LOC, left outer canthus; ROC, right outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

Hankey’s Clinical Neurology

884 F3–A2 C3–A2 O1–A2 F4–A2 C4–A1 O2–A1 LOC ROC Chin Legs Snore NPT Therm Chest Abdmn Sum EKG SAO2 (%)

FIGURE 28.16  Obstructive apneas (1-minute epoch). Note cessation of airflow as measured by both NPT and thermistor, with continuing respiratory effort. Arousals and oxygen desaturations occur at the end of the events. LOC, left outer canthus; ROC, right outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2 , oxygen saturation. Obstructive apneas are respiratory events associated with continued or increased inspiratory effort (Figure 28.16). • Central apneas are apneas without inspiratory effort (Figure 28.17). • Mixed apneas have absent inspiratory effort in the initial portion of the event, followed by resumption of respiratory effort but continued absence of detectable airflow (Figure 28.18). • Hypopneas are defined as a drop in peak nasal pressure transducer airflow > 30% of baseline, lasting at least 10 seconds, with > 4% oxygen desaturation from the pre-event baseline, and at least 90% of the event’s duration meeting the airflow amplitude reduction criteria.

There is an alternative definition, which defines a hypopnea as a drop in peak nasal pressure transducer airflow ≥ 50% of baseline, lasting at least 10 seconds, with ≥ 3% oxygen desaturation from the pre-event baseline, or an arousal, and at least 90% of the event’s duration meeting the airflow amplitude reduction criteria (Figure 28.19). Which of the two definitions for hypopnea is used should be mentioned in the report of the polysomnogram. • A respiratory effort-related arousal (RERA) is defined as a sequence of breaths lasting at least 10 seconds, with increasing respiratory effort or flattening of the nasal pressure transducer waveform (suggesting airflow limitation)

F3–A2 C3–A2 O1–A2 F4–A2 C4–A1 O2–A1 LOC ROC Chin Legs Snore NPT Therm Chest Abdmn EKG SAO2 (%)

FIGURE 28.17  Central apnea (30-second epoch). LOC, left outer canthus; ROC, right outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

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F4–M1 F3–M2 C3–M2 C4–M1 O1–M2 O2–M1 LOC– M1 ROC–M2 L. Leg R. Leg Snore NPT Therm CPAP Chest Abdmn SAO2 (%) EKG

FIGURE 28.18  Mixed apneas (2-minute epoch). LOC, left outer canthus; ROC, right outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation. leading to an arousal from sleep, when criteria for an apnea or hypopnea are not met (Figure 28.20).

TIP • Differing criteria for scoring of hypopneas are a source of much confusion in the literature. Close scrutiny of these criteria is necessary in any attempt to compare different studies.

Periodic leg movements

A leg movement is defined as a ≥ 8 μV increase in leg EMG voltage above resting EMG, lasting > 0.5 seconds but not more than 10 seconds. A periodic leg movement (PLM) is defined as a leg

movement in a series of at least four leg movements, having intervals of at least 5 seconds and not longer than 90 seconds between them (Figure 28.21). A typical PLM consists of an extension of the great toe with dorsiflexion of the ankle and occasional flexion of the knee and hip. Typical data mentioned in reports of polysomnograms are listed in Table 28.2. The American Association of Sleep Medicine (AASM) manual contains additional rules for staging sleep and scoring events for the pediatric population.

Portable polysomnography

‘Portable monitoring’ refers to polysomnography (PSG) that can be performed outside of the sleep laboratory, usually in the patient’s home. However, it is unclear which patient populations are most appropriate for these studies.14 In 1994, the AASM

F3–A2 C3–A2 O1–A2 F4–A1 C4–A1 O2–A1 LOC ROC Chin Legs Snore NPT Therm Chest Abdmn EKG SAO2 (%)

FIGURE 28.19  Obstructive hypopnea with an arousal (1-minute epoch of REM sleep). LOC, left outer canthus; ROC, right outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

Hankey’s Clinical Neurology

886 F3–A2 C3–A2 O1–A2 F4–A2 C4–A1 O2–A1 LOC ROC Chin Legs Snore NPT Therm Chest Abdmn Sum EKG SAO2 (%)

FIGURE 28.20  Respiratory event-related arousal (1-minute epoch). LOC, left outer canthus; ROC, right outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

reviewed a number of portable monitoring devices and classified them broadly into four categories (Table 28.3).15 Level I approximates what occurs during a polysomnogram in a sleep center, with continuous attendance of a technician, whereas Level IV incorporates only oximetry plus one or two other channels. Advocates of portable monitoring indicate: • Portable monitoring is more readily available than inhouse sleep laboratory studies (although the situation may change with the ongoing proliferation of sleep centers). • It is more cost-effective (although this has yet to be proven). • It can be effectively used to diagnose and rule out severe forms of obstructive sleep apnea (OSA). • Several limited studies and a multisite randomized trial16 have shown outcomes comparable with in-laboratory studies in terms of continuous positive airway pressure (CPAP) treatment with an autotitrating device after diagnosis of sleep apnea by portable monitoring.

Other issues to consider include: • Many portable systems are now available, and comparisons among the systems will be difficult or impossible. • Because most home studies are unattended after the initial setup, data loss is bound to occur, leading to complexity in interpretation of some studies, and in some cases, repeat studies. • Because EEG is not closely analyzed in most systems, total sleep time is not measured, instead total time in bed is measured. As a result, there may be underestimation of the apnea/hypopnea index (AHI) if there are significant periods of wakefulness while in bed. • Portable monitoring cannot diagnose other sleep-related disorders, such as upper airway resistance syndrome, central sleep apnea, complex sleep apnea, PLMs, or nocturnal epilepsy. • Portable monitoring has not yet been validated for: • Mild-to-moderate OSA. • Patients with comorbidities, such as cardiac or pulmonary disease, and neuromuscular conditions.

F3–A2 C3–A2 O1–A2 F4–A2 C4–A1 O2–A1 LOC ROC Chin Legs Snore NPT Therm Chest Abdmn Sum EKG SAO2 (%)

FIGURE 28.21  Periodic leg movements. Note arousals in association with these leg movements. LOC, left outer canthus; ROC, right outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

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TABLE 28.2  Typical Data Included in Polysomnography Reports Category

Parameter

Staging

Lights out (h:min) Lights on (h:min) Total sleep time (TST) (min) Time in bed (min) Sleep latency (SL) (min) Rapid eye movement (REM) latency (min) Wake after sleep onset (WASO) (min) Sleep efficiency (%) Time in each stage (min) % of TST in each stage Number of arousals Arousal index Number of obstructive, mixed, and central apneas Number of hypopneas Number of apneas + hypopneas

Arousal events Respiratory events

Additional Details

Time in bed = lights on minus lights out (min) Lights out to first epoch of any stage Sleep onset to first epoch of REM Wake during time in bed, minus SL TST/time in bed

Number of arousals/hour of sleep Number of all types of apneas/hour of sleep Total number of all apneas and hypopneas/hour of sleep

Apnea index (AI) Apnea + hypopnea index (AHI) Mean oxygen saturation (%) Minimum oxygen saturation during sleep (%) Occurrence of Cheyne–Stokes breathing, if present Number of RERAs Respiratory disturbance index

Respiratory effort-related arousals (RERAs) Total number of apneas, hypopneas, and RERAs/hour of sleep

Number of oxygen desaturations (could be defined as 3% or 4%) Oxygen desaturation index (ODI) Hypoventilation, if present Average heart rate during sleep (beats/min) Tachycardia, bradycardia, or other arrhythmias, if present Number of PLMs PLM index Number of PLMs accompanied by arousals PLM arousal index

Cardiac events Periodic leg movements (PLMs)

Total number of desaturations/hour of sleep

Number of PLMs/hour of sleep Number of PLMs with arousal/hour of sleep

TABLE 28.3  Levels of Portable Polysomnography Level

I

II

Number of channels Specific channels

>7 EEG, EOG, chin EMG, ECG, airflow, respiratory effort, oxygen saturation

>7 EEG, EOG, chin EMG, ECG or heart rate, airflow, respiratory effort, oxygen saturation

Body position Leg movements

Documented or objective EMG or motion sensor desirable but optional Yes

Possibly EMG or motion sensor desirable but optional No

Possible

No

Technician in constant attendance Interventions

III

IV*

2 channels of respiratory movement (or 1 channel of respiratory movement + 1 channel of airflow), ECG or heart rate, oxygen saturation Possibly Possibly

Minimum of oxygen saturation, ± airflow or chest movement

No

No

No

No

No No

*For covered services, the USA Centers for Medicare and Medicaid Services in 2007 broadened the definition of Level IV to a monitor that uses three channels, but did not further specify the channels. Coverage Decision Memorandum for Sleep Testing for Obstructive Sleep Apnea (OSA) (CAG-00405N), 3/2009. https://www.cms.gov/medicarecoverage-database/details/nca-decision-memo.aspx?NCAId=227&ver=11&NcaName=Sleep+Testing+for+Obstructive+Sleep+Apnea+(OSA)&CoverageSelection=National &KeyWord=sleep+testing&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAACAAEAAA&ECG, electrocardiogram; EEG, electroencephalogram; EMG, electromyogram; EOG, electro-oculogram.

Hankey’s Clinical Neurology

888 The AASM has issued guidelines for performance of portable monitoring.17 Some of the more salient recommendations included: • OSA must be diagnosed clinically with a face-to-face or telemedicine visit to assess the patient, his/her symptoms, examination and past medical history, as well as any limitations to having portable studies. • Patients should have a high pretest probability of moderate-to-severe obstructive sleep apnea. It should not be done for routine screening of sleep apnea in patients who are asymptomatic. • Diagnosis, assessment of treatment efficacy, and treatment decisions must not be based solely on automatically scored home sleep apnea test (HSAT) data, which could lead to suboptimal care that jeopardizes patient health and safety. • The raw data from the HSAT device must be reviewed and interpreted by a physician who is either board certified in sleep medicine or overseen by a board-certified sleep medicine physician. • An HSAT is a medical assessment that must be ordered by a physician to diagnose OSA or evaluate treatment efficacy.

Multiple sleep latency test

The multiple sleep latency test (MSLT) is useful in assessment of disorders of excessive somnolence, and in measurement of somnolence in research experiments, such as studying the effect of various drugs on wakefulness or quantifying the effects of sleep restriction. It is also useful in identifying the premature appearance of REM sleep after sleep onset, as may occur in narcolepsy. The procedure consists of a series of opportunities to nap at 2-hour intervals across the day. The montage used is a modification from standard PSG, with employment of only EEG, EOG, mental/submental EMG, ECG, respiratory flow, and snore channels. The patient is encouraged to sleep while resting in a comfortable position. A minimum of four naps is recommended, but the test is often continued for a fifth nap, particularly when narcolepsy is suspected and REM sleep has occurred in one or fewer previous naps. During each nap opportunity, if definite sleep has not occurred after 20 minutes, the test is terminated, and the patient is instructed to remain awake until the next nap. If, on the other hand, sleep onset does occur in the first 20 minutes, the test is continued for another 15 minutes of clock time (not necessarily sleep time) before termination of the nap. Sleep-onset latencies and occurrence of REM sleep (sleep-onset REM periods [SOREMPs]) or lack thereof during each nap are recorded (Figure 28.22).

Time 07:33

The results of the MSLT may be confounded by a number of factors, and every effort must be made to prevent these influences. Prior sleep habits, sleep duration the night before the MSLT, and sleep quality the night before may significantly alter the results. A sleep diary for 1–2 weeks prior to the test is recommended, as well as full-night PSG on the night immediately preceding the MSLT. Documentation of at least 6 hours of sleep on the prior polysomnogram is recommended before proceeding with the MSLT. Sleep disruption, as may occur in the setting of sleep-disordered breathing, movement disorders, and in other conditions, may shorten the mean sleep latency in the MSLT and may even result in SOREMPs. In the event that confounding factors such as these are discovered on the prior polysomnogram, the MSLT may be deferred until the disrupting conditions are adequately treated. Multiple drugs such as hypnotics, sedatives, stimulants, and antidepressants, or withdrawal from these agents, may affect sleep latency and/or REM latency. Ideally, these drugs should be discontinued at least 2 weeks prior to the MSLT, although the situation can be complicated due to factors such as risk of exacerbation of depression during withdrawal from antidepressant medication. Urine drug screening may be useful if the medication history is unclear. In general, a mean sleep latency ≤ 8 minutes is considered pathologic, indicating excessive daytime sleepiness, and can be found in patients with disorders of excessive sleepiness, such as narcolepsy, as well as sleep-deprived normal control subjects. SOREMPs occurring during two out of five naps is considered highly unusual, suggestive of narcolepsy. This pattern has also been observed in sudden withdrawal from REM-suppressant medication, or in association with sleep deprivation, or with sleep disruption as may occur in OSA. If the MSLT is performed during usual hours on a subject with sleep phase delay syndrome (described in the section on circadian rhythm disorders), appearance of REM sleep during the first or second nap may merely reflect physiologic REM cycles during a sleep period that has been prematurely terminated at the end of the prior night’s polysomnogram. As with any guideline, the sensitivity and specificity of these cutoff points relating to mean sleep latency and number of SOREMPs are limited, and the findings of the MSLT must be correlated with the overall clinical picture. The clinician should bear in mind that the mean sleep latency in healthy control subjects has been reported as 10.5 ± 4.6 minutes, and that as many as 25% of narcolepsy/cataplexy patients over 36 years old may have a normal or borderline MSLT (either a mean sleep latency of ≥ 8 minutes, or only one sleep-onset REM period), so there may be considerable overlap between patients with pathologic disorders and normal subjects.

08:33

09:33

10:33

11:33

12:33

13:49

1

2

3

4

5

6

W R N1 N2 N3 Hours

FIGURE 28.22  Hypnogram of a multiple sleep latency test, demonstrating sleep-onset REM periods.

7

Sleep–Wake Disorders Maintenance of wakefulness test

The maintenance of wakefulness test (MWT).18 is the opposite of the MSLT, in that the subject is asked to remain awake and resist sleep, in the circumstance of a sleep-promoting environment. Whereas the MSLT is intended to measure a subject’s ability to fall asleep, the MWT is intended to measure a subject’s ability to stay awake. Most of the concerns regarding sleep habits, conditions causing sleep disruption, and medication use that may affect the results of the MSLT also apply to the MWT. The test is often used to assess the effectiveness of interventions to improve daytime alertness (e.g. CPAP therapy for OSA, or stimulant therapy for narcolepsy). Patients are usually highly motivated to demonstrate daytime alertness, because such demonstration may support continued employment. Sleep logs are generally not required prior to the MWT, and routine PSG on the prior night is not essential, though it may be employed depending on clinical circumstances. A variety of protocols for performance of the MWT have been used. Currently, the AASM practice parameters recommend four trials consisting of 40 minutes for each trial, with 2 hours between each trial. The patient is asked to lie in a comfortable bed in a darkened room, with the head supported by a pillow. A light breakfast is recommended 1 hour before the first trial, and smoking cessation 30 minutes prior. A light lunch is recommended after the second trial. The recording setup is the same as for the MSLT. Sleep latencies, sleep stages, and total sleep time are recorded. Each trial ends after 40 minutes if no sleep has occurred, or after unequivocal sleep, defined as three consecutive epochs of N1 or one epoch of any other stage of sleep. There is a relative lack of normative data for the MWT. Currently, a mean sleep latency of ≤ 8 minutes is considered ‘abnormal’, whereas values between 8 and 40 minutes are regarded to have uncertain significance. Staying awake for the entire duration of all four trials is considered to be an appropriate expectation for individuals engaged in employment requiring ‘the highest level of safety’. However, it is important to realize that regardless of the result of the MWT, there is no way to guarantee maintenance of alertness in the work environment, due to influence of multiple factors that may not be present in the laboratory environment. The MWT is neither necessary nor recommended for commercial truck drivers, because of the poor correlation between the laboratory environment and real-life driving situations. A USA Task Force comprises members of several organizations, including the National Sleep Foundation, recommended clearance for work for truck drivers with OSA, based on demonstrated compliance with positive airway pressure (PAP) and/or a documented AHI of ≤ 10.18

INSOMNIA DISORDER Definition

Insomnia disorder is defined as a difficulty with sleep initiation, sleep duration, sleep consolidation, or sleep quality. 2 The persistent sleep difficulties occur despite having adequate time to sleep with the appropriate environmental circumstances and have negative daytime consequences. Daytime symptoms from insomnia can include symptoms such as fatigue, sleepiness, impaired attention, concentration, or memory, as well as mood disturbances, irritability, aggression, and decreased motivation.

889 Epidemiology

Insomnia is a common complaint. Episodic, short-term insomnia affects 30–50% of the population, and chronic insomnia occurs in approximately 10% of the population.19 Women and older adults are populations at increased risk for insomnia. Insomnia is often comorbid with medical, neurologic, and psychiatric disorders. Patients with a range of neurologic conditions, including multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, traumatic brain injury (TBI), epilepsy, and stroke have a high prevalence of insomnia, ranging anywhere from 25% to 60%.20 Insomnia is also associated with depression, anxiety, substance use disorders, suicidality, hypertension, and diabetes.21 Furthermore, insomnia has a high economic burden on health care as it leads to increased utilization of emergency rooms and provider visits. Indirectly, insomnia also causes an economic burden due to increased rates of absenteeism, decreased productivity, as well as insomnia-related accidents.19

Etiology and pathophysiology

Numerous models of insomnia have been proposed, including a physiologic state of hyperarousal, cognitive models, behavioral models, and an integrated neurocognitive model.22 Several lines of evidence support the concept of a hyperarousal state in insomnia. For example, EEG spectral analysis reveals increased high-frequency activity in patients with primary insomnia.23 In a positron emission tomography (PET) study, seven patients with chronic insomnia exhibited increased global glucose metabolism during wakefulness and NREM sleep when compared to 20 goodsleeper controls.24 Increased heart rate and body temperature as well as elevated levels of cortisol, adrenocorticotropic hormone (ACTH), and corticotropin-releasing factor (CRF) have been reported in patients with insomnia. A cognitive model25 posits that insomnia is a result of interaction of: • Dysfunctional cognition (ruminative thinking or worry). • Concern about the consequences of sleep loss (cognitive, emotional, physical). • Arousal (emotional, cognitive, physiologic). A behavioral model26 (the 3-P model) introduces a behavioral component to explain how acute insomnia becomes chronic: • A person may be disposed toward insomnia due to innate traits (predisposing factors). • Subsequent life stressors (precipitating factors) bring on acute insomnia. • Then maladaptive coping strategies (perpetuating factors) convert acute insomnia to the chronic form. Perpetuating factors include: • Staying in bed while awake. • Extending the time for sleep opportunity, either by going to bed earlier or by staying in bed later, in an attempt to ‘recover’ what has been lost. This maladaptive behavior actually results in more time spent lying awake in bed. Genetic studies to identify genes or receptor polymorphisms related to insomnia have not yet been undertaken. Higher concordance rates of insomnia in monozygotic twin pairs than for dizygotic twins have been reported.27

Hankey’s Clinical Neurology

890 Clinical features

The ICSD-3 classifies insomnia into three types: • Chronic insomnia: > 3+ months; at least 3+ days/week. • Short-term insomnia: < 3 months. Other insomnia disorder: nonspecific, patients have difficulty falling or staying asleep, but do not meet criteria of the other two types of insomnia. Clinical assessment of insomnia should include the following:21 • Evaluation of specific insomnia complaints: difficulty falling asleep, staying asleep, or both. • Sleep–wake schedule: bedtime, waketime. • Nocturnal behavior: what patient does when they cannot sleep. • Daytime symptoms: tiredness, fatigue, trouble concentrating, etc. • Daytime behaviors: asking about naps, exercise, activity level. • Evaluating the three Ps: predisposing, precipitating, and perpetuating factors. • Medications: asking about sleep aids or alerting medications as well as assessing for medications that might contribute to poor sleep. • Sleep review of symptoms: assessing for other sleep disorders causing symptom, such as sleep apnea, restless leg syndrome (RLS), etc. • Obtain bed partner history. • Social history to assess for EtOH, tobacco, and/or drugs that are contributing. • Evaluation for dysfunctional beliefs and attitudes about sleep and insomnia. Some subjective measurement of sleepiness, such as the Epworth Sleepiness Scale (an eight-item questionnaire to assess subjective sleepiness, score range 0–24, normal < 10)28 should be obtained. Some other potentially useful questionnaires include the Pittsburgh Sleep Quality Index, Insomnia Severity Index (ISI), the Beck Depression Inventory, Short Form Health Survey (SF-36), and Dysfunctional Beliefs and Attitudes about Sleep Questionnaire.29 One or more of these tools can be applied during treatment to assess outcomes. Sleep log and/or diary for at least 7 days is recommended prior to and during the course of active treatment. PSG and MSLT testing are not routinely indicated in the evaluation of chronic insomnia. PSG may be useful when there is a question of interrupted sleep due to sleep-disordered breathing, a movement disorder, parasomnia, nocturnal epilepsy, or in cases of treatment failure. Actigraphy, a device that is typically worn on the wrist to estimate sleep and wake activity by recording movements can be used in patients with unreliable sleep log or when a circadian disorder is suspected.21 Personal wearable monitoring devices are also increasingly available, however, the data to support their use in sleep assessments are limited at this time.

Diagnosis

The diagnosis of insomnia relies primarily on a detailed sleep history, and symptoms should be differentiated from the following conditions, all of which are discussed elsewhere in the chapter: 1. Circadian rhythm sleep–wake disorders. 2. Behaviorally induced insufficient sleep/chronic volitional sleep restriction.

3. RLS: can lead to difficulties with initiating and maintaining sleep. 4. Sleep-disordered breathing: predominantly issues with sleep maintenance.

Pathology

The common insomnias do not have any major central nervous system (CNS) pathology that has been identified to date. An important exception is fatal insomnia, a prion disease, which can occur in both sporadic and familial forms. It was first recognized in the familial form,30 which is caused by a missense GAC to AAC mutation at codon 178 of the prion protein gene, in association with a methionine polymorphism at codon 129 on the mutant allele. Interestingly, if codon 129 on the mutant allele codes for valine instead of methionine, the phenotype of familial Creutzfeldt– Jakob disease (CJD) results, rather than fatal familial insomnia.31 Sporadic fatal insomnia does not have a known mutation, but does have a homozygous methionine polymorphism at codon 129. Clinical presentation of both forms of fatal insomnia is similar, with initially insidious onset of difficulties with vigilance and initiating and maintaining sleep, followed by hypertension, evening hyperpyrexia, autonomic dysfunction, ataxia, myoclonus, and worsening dream-like stupor and hallucinations. Patients die usually in 8–72 months, either suddenly or from concomitant respiratory failure or infection. No effective therapy has been found. The hallmark of prion diseases is the deposition of abnormally folded, protease-resistant prion protein. Compared with CJD, the deposition in fatal insomnia is 5–10 times less. The most common neuropathologic feature of fatal insomnia is in the thalamus, where > 50% loss of neurons is observed in the anterior, ventral, and mediodorsal nuclei (Figures 28.23, 28.24).

Treatment29, 32, 33

Treatment of insomnia can be categorized into two types of interventions: • Pharmacologic. • Nonpharmacologic. Cognitive behavioral therapy for insomnia (CBT-I) is recommended as first-line therapy. It is the most widely used among nonpharmacologic interventions. CBT-I has been found to be effective in a wide variety of clinical populations and is considered as the first-line treatment for insomnia.21 In conjunction with CBT-I, hypnotic medications can be beneficial for short-term treatment. 32 The choice of hypnotic medication will depend on the specific symptoms of difficulty falling asleep or staying asleep or both.19 In comorbid insomnias, it is appropriate to direct therapy toward the comorbidity as well. The basic elements of CBT are as follows: • Stimulus control therapy: • Go to bed only when sleepy. • Do not engage in other activities such as watching television, eating, or reading while in bed. • If you are unable to sleep after 20 minutes, leave the bed and engage in a relaxing activity until drowsy, then return to bed – repeat as necessary. • Leave the bed when you have a subjective impression that 20 minutes of wakefulness have elapsed. Do not watch the clock. • Sleep restriction therapy: • Limit time in bed to the estimated total sleep time (but not < 5 hours).

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    FIGURES 28.23, 28.24  Thalamic neuronal loss in fatal insomnia. (Figure 28.23) H&E-stained paraffin section of medial thalamus, region of mediodorsal nucleus, demonstrating loss of neurons and proliferation of astrocytes; (Figure 28.24) H&E-stained paraffin section of lateral thalamus at same coronal level as Figure 28.23, region of reticular nuclei, demonstrating preservation of neurons and background. • Establish a consistent wake-up time. • Increase bedtime by 15 minutes when estimated sleep efficiency has reached 90% by sleep log. • Sleep hygiene therapy: • Keep a regular schedule. • Remove environmental noise, television, and other disturbances from the bedroom. • Avoid napping. • Avoid caffeine, alcohol, nicotine, excessive fluids, exercise, or other stimulating activities before bedtime. Relaxation training: utilize progressive muscle relaxation training, guided imagery, or abdominal breathing to reduce elevated levels of arousal. • Paradoxical intention: aimed to reduce performance anxiety: • Lie quietly awake. • Avoid conscious efforts to fall asleep. • Cognitive therapy:

• Correct faulty beliefs about insomnia. • Reduce catastrophic thinking about consequences of sleep loss. • For pharmacotherapy, over-the-counter antihistamines remain popular with the public, but evidence for their efficacy is lacking, and they are not recommended due to substantial side effects. Sedating antidepressants, especially trazodone, have been widely prescribed for the treatment of insomnia in patients without depression, but due to the lack of evidence for its efficacy and its poor side effect profile, they are only recommended for patients with comorbid depression. Drugs recommended for pharmacotherapy of insomnia are presented in Table 28.4. • Ramelteon, a melatonin MT1 and MT2 receptor agonist, has shown only a modest decrease in sleep latency, occasionally relieves sleep-initiation insomnias, but may have limited benefits for treatment of most insomnias.

TABLE 28.4  FDA-Approved Medications for Insomnia Drug Class

Medication

Benzodiazepines

Nonbenzodiazepines

Melatonin receptor agonist H1 receptor antagonist Dual orexin receptor antagonist

Sleep Onset

Sleep Maintenance

Early Morning Awakening

Estazolam Flurazepam2 Quazepam3 Temazepam4 Triazolam5 Eszopiclone6 Zaleplon7 Zolpidem8 Zolpidem ER9 Zolpidem spray10 Zolpidem sublingual11 Zolpidem sublingual-MOTN11 Ramelteon12 Doxepin13

X X X

X X X

X X X

X X X X X X

X

Suvorexant14 Lemborexant15

X X

1

X

X

X X X X

Abbreviation: MOTN, middle-of-the-night awakening. 1, estazolam US Prescribing Information 2016; 2, flurazepam US Prescribing Information 2007; 3, quazepam US Prescribing Information 2016; 4, temazepam US Prescribing Information 2017; 5, triazolam US Prescribing Information 2016; 6, eszopiclone US Prescribing Information 2009; 7, zaleplon US Prescribing Information 2016; 8, zolpidem US Prescribing Information 2016; 9, zolpidem ER US Prescribing Information 2016; 10, zolpidem spray US Prescribing Information 2016; 11, zolpidem sublingual US Prescribing Information 2016; 12, ramelteon US Prescribing Information 2010; 13, doxepin US Prescribing Information 2010; 14, suvorexant US Prescribing Information 2016; 15, lemborexant US Prescribing Information 2019.

Hankey’s Clinical Neurology

892 • Melatonin is available over-the-counter as a hypnotic, but its manufacture is not regulated, and conclusive studies of its efficacy are lacking. • Zaleplon is a very short-acting nonbenzodiazepine receptor agonist that may be used on nocturnal awakening if at least 4 more hours of subsequent sleep are anticipated. • Doxepin is a selective histamine receptor antagonist. Lowdose doxepin improves sleep-maintenance insomnia by improving wake after sleep onset (WASO), latency to persistent sleep, and total sleep time. 34 • Suvorexant is a reversible dual orexin receptor antagonist, which at doses of 10 mg and 15 mg has been shown to improve sleep efficiency and total sleep time. • Another dual orexin receptor antagonist, lemborexant, was Food and Drug Administration (FDA) approved for sleep-onset and sleep-maintenance insomnia in December of 2019. • Two other benzodiazepines, flurazepam and quazepam, are older benzodiazepines approved by the U.S. FDA as hypnotics, but these are rarely used today, due to their elimination half-lives of over 48 hours. • The benzodiazepine and nonbenzodiazepine agonists have all been approved for short-term use of 7–10 days. No clear limitations on length of treatment have been applied to eszopiclone or zolpidem. • All these agents except ramelteon have distinct sedative properties and should not be combined with other sedatives, such as alcohol, or used with drugs that may inhibit their metabolism. Relatively low doses are appropriate for the elderly.

HYPERSOMNIAS OF CENTRAL ORIGIN These disorders all have a primary complaint of daytime somnolence, which cannot primarily be attributed to disruption of nocturnal sleep or misaligned circadian rhythms.

Narcolepsy type 1 Definition

The term narcolepsy was coined by Gelineau in 1880 from the Greek narcosis (drowsiness) and lambanein (to seize or take).35 Westphal had described a syndrome consistent with narcolepsy with cataplexy earlier in 1877, but did not use those specific terms, and in fact the term cataplexy was not used to describe attacks of loss of muscle tone without loss of consciousness until the 20th century by Henneberg. 36 Multiple factors are thought to contribute to the developed of narcolepsy, including:37 • A genetic predisposition. • Environmental factors. • Triggering events that lead to selective, immune-mediated destruction, and/or dysfunction of the orexin-producing neurons in the lateral hypothalamus.

Epidemiology37

The prevalence of narcolepsy in North America and Europe is estimated to be around 200–500 per million people. Japanese populations have the highest prevalence of narcolepsy, and the lowest prevalence is in Arabic and Jewish populations. Narcolepsy often

begins during adolescence with second small peak around the age of 35. Narcolepsy occurs before the age of 10 in around 10–15% of patients. Males are slightly more affected than females. Narcolepsy does occur in families, but less than 2% of individuals with narcolepsy have more than one affected family member, and families with more than two members with cataplexy are quite rare.

Pathophysiology

Associations between several human leukocyte antigen (HLA) types and narcolepsy have been reported since 1984, prompting speculation that the pathophysiology of narcolepsy may be immune-mediated. HLA-DQB1*0602 occurs between 86% and 98% of patients with narcolepsy type 1 (NT1) and in around 40–50% of those patients with type 2. However, this antigen occurs in up to 38% of the general population, depending on ethnicity, which limits the diagnostic usefulness of HLA testing. The discovery of the hypocretin/orexin in neurons in the lateral hypothalamus was crucial to the understanding of the pathogenesis of narcolepsy. In particular, ‘NT1 is caused by deficiencies in hypocretin signaling, which is most likely due to a selective loss of hypothalamic hypocretin-producing neurons’.2 Orexin neurons innervate tuberomammillary nucleus (TMN), basal forebrain, periaqueductal gray (PAG), dorsal raphe, and locus ceruleus (LC), which are areas that promote arousal and suppress REM. 38 Orexin neurons also suppress REM sleep. Narcoleptics have dysregulated REM sleep which leads to poor circadian timing of REM sleep, rapid transitions into REM sleep, and disruption of REM sleep physiology. 38 The etiology of the loss of the orexin neurons is not totally clear, but it is thought to be a T-cell– mediated autoimmune disease. In 2009–2010, there was a striking increase in the number of patients who developed NT1 after flu vaccination, Pandemrix. There was an 8- to 12-fold increase in NTI in children and adolescents as well as a 3- to 5-fold increase in adults.38, 39 A narcolepsy phenotype (‘secondary narcolepsy’) may occasionally emerge in association with other disorders, such as certain inherited disorders, tumors, encephalitis, and head trauma resulting in hypothalamic dysfunction.

Clinical features Excessive daytime sleepiness

Excessive daytime sleepiness (EDS) is the most common and typically the most disabling symptom in the majority of patients with narcolepsy. The symptom of excessive sleepiness is often the first to occur. In cases of severe sleepiness, episodes of ‘automatic behavior’ may occur, during which the patient performs an activity (such as taking notes or driving), in a semiautomatic fashion, without full consciousness or memory of the event. Patients not only have irresistible urges to sleep and difficulty maintaining wakefulness, but also experience problems with memory and attention. 37 Sleep attacks may occur during unusual circumstances such as while talking, eating, or driving. Naps tend to be of short duration (10–30 minutes or less) and are usually refreshing.

Cataplexy

This phenomenon is thought to be caused by intrusion of the atonia of REM sleep into the wakeful state. Extraocular muscles and muscles of respiration are not affected. Attacks are often triggered by positive emotions, such as amusement, surprise, and elation, but may also occur with negative emotions such as anger or

Sleep–Wake Disorders fear, though this is less common. The distribution of weakness from the atonia is variable, ranging from total postural collapse to minor forms involving focal muscle groups: buckling of the knees, dropping of the head, sagging of the face or jaw, or merely slurred speech. Consciousness is preserved and the duration is short, ranging from a few seconds to a few minutes. Recovery is rapid and complete. Cataplexy can be quite severe around the onset of the disease. Sometimes, attacks are followed by sleep, and patients report dreams immediately after cataplectic episodes. The most severe form of cataplexy involves attacks in rapid succession (termed status cataplecticus) that are usually triggered by very strong emotion, or by withdrawal from medication used to treat cataplexy (see section on treatment below).

TIP • The manifestations of cataplexy may be subtle. Questions such as ‘Do you ever fall down when someone tells a joke?’ are, in isolation, inadequate for a proper history. In-depth questioning regarding jaw sagging, head nodding, slurred speech, a feeling of weakness in the knees, and similar subtle symptoms occurring during periods of strong emotion is necessary.

Sleep paralysis

This event occurs at sleep onset or on awakening and is also thought to be due to an intrusion of REM sleep atonia into wakefulness. It is characterized by a terrifying feeling of being unable to move or speak despite being awake, and there is often a feeling of suffocation. Sleep paralysis rarely lasts more than a few seconds or minutes. About 40–80% of narcoleptic patients experience sleep paralysis, but in order to be considered a significant symptom, it must occur repeatedly, as it is also commonly reported as a rare event in the general population. Hypnagogic or hypnopompic hallucinations may occur along with the episode of sleep paralysis, thereby enhancing the frightening aspect of these spells.

TIP • Patients with isolated sleep paralysis, without any other underlying sleep disorder, occasionally present to a sleep clinic, as the experience can be terrifying.

Hallucinations

During transitions from wakefulness to sleep (hypnagogic events) or from sleep to wakefulness (hypnopompic events), vivid dream-like hallucinations that are thought to be related to sleep-onset REM sleep occur repeatedly in 40–80% of patients with narcolepsy with cataplexy. These are distinguished from hallucinations in other psychotic states by their exclusive association with sleep–wake transitions. Similar to sleep paralysis, hypnagogic hallucinations also occur sporadically in the normal population.

Disturbed nocturnal sleep

Although this feature is not a part of the classical tetrad (sleep attacks, cataplexy, sleep paralysis, and hallucinations) of narcolepsy, patients often complain of fragmented nocturnal sleep.

893 Total sleep time in a 24-hour period, however, is similar for narcoleptic patients and normal subjects.

TIP • Patients with narcolepsy with cataplexy will occasionally present with the most prominent complaint of insomnia and fragmented sleep, rather than sleep attacks or cataplexy, although these other features should also be present to support the diagnosis.

Other associated conditions40

• Periodic limb movements of sleep (25–50% of patients). • REM behavior disorder (25–70% of patients). • Increased body mass index (BMI), occasional obesity (BMI is 10–20% higher in narcoleptics than in the general population. • OSA. Because OSA is relatively common, and because narcoleptic patients are often overweight, OSA may coexist with narcolepsy.

Narcolepsy type 2

Major features are similar to type 1, except for the absence of cataplexy. The exact prevalence is unknown, but type 2 likely accounts for about 15–25% of patients with narcolepsy.2 • Onset is usually in adolescence. • In order to diagnose type 2, there must be EDS for at least 3 months. On an MSLT, there must be a mean sleep latency less than 8 minutes, and there must be at least 2 SOREMPs on the MSLT or the overnight polysomnogram. 37 • The severity of EDS and of REM-related symptoms (sleep paralysis, REM sleep behavior disorder [RBD], and hallucinations). • Narcolepsy type 2 (NT2) is most likely a heterogeneous disorder, and pathogenesis and pathophysiology are largely unknown. Loss of orexigenic neurons in the hypothalamus has been demonstrated in only a minority of cases. NT2 in many ways is really a diagnosis of exclusion, since other diagnoses must be excluded before the diagnosis can be made (e.g., sleep apnea, circadian disorders, insufficient sleep, and medications/substance abuse must be ruled out). 37

Diagnosis of narcolepsy types 1 and 2

Diagnosis is based on a careful history and physical, and the results of nocturnal PSG and a MSLT performed the following day. HLA typing and cerebrospinal fluid (CSF) analysis for low hypocretin-1 (< 110 pg/mL) are not routinely performed, but may be useful to aid in diagnosis of atypical cases. About 90–95% of patients with narcolepsy with cataplexy have low or undetectable levels of hypocretin-1 in the CSF (< 110 pg/mL). Another useful way to screen for type NT1 is through the use of the Swiss Narcolepsy Scale (SNS),41 which was recently shown to be 89% sensitive and 88% specific for NT1 and superior to the Epworth Sleepiness Scale for predicting narcolepsy. The SNS includes the following five items: • Inability to fall asleep. • Being unrefreshed in the morning.

Hankey’s Clinical Neurology

894 • Taking a nap at noon. • Knee buckling during cataplexy. • Sagging of the jaw during cataplexy.

TIP

For NT2, the MSLT results will be the same or similar. However, by clinical history, the patient will not have cataplexy. Additionally, the CSF hypocretin level would not be low.

Treatment of narcolepsy types 1 and 2

• Behavioral adaptations: • Encouragement of good sleep hygiene (avoid sleep deprivation). • Daytime structured naps, if permissible in the work environment. • Avoiding Sedentary activities. • Pharmacologic stimulants for excessive daytime sleepiness. Dopamine enhancement is the mechanism of action of most of these agents, though the exact mechanism for modafinil and armodafinil remains unclear. • Agents for suppression of cataplexy. These drugs act as REM suppressants and enhance mostly the norepinephrine and serotonin systems. One exception is sodium oxybate, whose exact mechanism of action is unknown. Sodium oxybate appears to consolidate the fragmented sleep of narcoleptics and can treat both cataplexy and EDS in these patients.

Examples of commonly used agents are given in Table 28.5.42

• Addition of sodium oxybate to a regimen of pharmacologic stimulants given to a narcolepsy patient will often allow reduction of dosage (occasionally even elimination) of the stimulant medications.

Idiopathic hypersomnia2, 43

• The exact prevalence is unknown, but it is thought to be rare, perhaps between 1 and 2 affected persons per 10,000.43 • Mean age of onset ∼16–21 years and is more common in women than men. • Mainly distinguished from narcolepsy by: • Tendency for naps to be long and unrefreshing. • Absence of REM-associated phenomena, such as cataplexy, hypnagogic hallucinations, or sleep paralysis. • Absence of SOREMPs on the MSLT. • Pathogenesis/pathology is not known. There is no known HLA association or any abnormality in the hypocretin/ orexin system.

Symptoms in idiopathic hypersomnia (IH) include the following:43 • EDS. • Significant sleep inertia or ‘sleep drunkenness’ in the morning, making it very difficult to wake up. • Naps may be short and restorative or long and unrefreshing. Majority of IH patients report the latter (87% report

TABLE 28.5  Medications Used to Treat Narcolepsy Target

Medications

MOA

Excessive daytime sleepiness

Modafinil

Exact MOA unknown, but inhibits Headache, nausea Dopa reuptake

Armodafinil

Same as modafinil

Methylphenidate

Exact MOA unknown, blocks Irritability, mood changes, reuptake and increases release of anorexia hypertension, NE and Dopa insomnia Same as methylphenidate Same as for methylphenidate, above but potentially more intense NE and dopamine reuptake Headache, nausea, insomnia, inhibitor decreased appetite, and anxiety Monoamine oxidase inhibitor Hypertension, palpitations at higher doses Norepinephrine and serotonin Anticholinergic Norepinephrine and serotonin Anticholinergic Norepinephrine and serotonin Anticholinergic Serotonin Nausea, insomnia, headache, and sexual dysfunction Serotonin, norepinephrine, and Nausea, dizziness, dry mouth, dopamine constipation, and sedation Gamma-hydroxybutyrate Nausea, headaches, sedation, respiratory depression, and salt load

Amphetamines Solriamfetol

Selegiline Cataplexy

Imipramine Clomipramine Protriptyline Fluoxetine Venlafaxine

Cataplexy and excessive daytime sleepiness

Sodium oxybate

Abbreviations: MOA, mechanism of action; NE, norepinephrine.

Common Adverse Events

Same as for modafinil

Starting Maximum Dose/24 h 100–400 mg; may be given in divided doses, on awakening and at midday 150–250 mg, once on awakening 10–60 mg; short-acting forms may be given in divided doses 5–60 mg 75–150 mg/day

5–40 mg (not commonly used) 10–150 mg at bedtime 25–50 mg at bedtime 5–20 mg at bedtime 10–40 mg in the morning 37.5–300 mg; may be given in divided doses 4.5–9 g nightly in two divided doses

Sleep–Wake Disorders long naps > 60 minutes; 52–78% consider their naps unrefreshing; may have associated postnap sleep inertia). • Nighttime sleep is normal or long (> 10 hours). • May have associated symptoms such as trouble focusing, headaches, orthostatic hypotension, etc.

Pathophysiology44

• IH is a heterogenous disorder, so exact etiology is unknown. • Homeostatic or circadian dysregulation or dysfunction in the brain arousal systems is suspected to be a possible cause of IH. • One study also showed abnormalities in the GABA signaling pathway, but these were not replicated in a subsequent study.

Diagnosis

For IH, the diagnosis is made when the overnight PSG followed by an MSLT shows a mean sleep latency less than 8 minutes with no more than one SOREM on the MSLT or overnight PSG. Alternatively, if the mean sleep latency is more than 8 minutes, then either a 24-hour PSG with ≥ 660 minutes of sleep or 7-day wrist actigraphy can be used to make the diagnosis.2 IH is a diagnosis of exclusion, after narcolepsy and other causes of fatigue and EDS (especially depression) have been ruled out. When considering causes of hypersomnia, the possibility of hypersomnia secondary to a medical condition should be considered. In particular, in patients with a prior TBI, patients are at risk of developing hypersomnia. If excessive sleepiness persists for at least 3 months and the patient has an MSLT with an MSL< 8 minutes, then the patient would be classified as ‘hypersomnia due to a medical condition’.2, 45 If, in addition to the short MLS, there were also two or more SOREMPs on the MSLT, then the patient would be classified as NL1 or NL2 secondary to a medical condition.

Treatment of idiopathic hypersomnia

Although there are no specific FDA-approved medications for IH, stimulants and wake-promoting agents are treatment options, and modafinil is considered as the first-line therapy.44 Methylphenidate is the second-line option and medications such as amphetamines and pitolisant, which are also used to treat narcolepsy, can also be considered if other options fail. Planned naps are not typically helpful in treating IH because they tend to make patients feel worse, as they tend to be unrefreshing and long.

Kleine–Levin syndrome2, 46

This is a rare disorder of recurrent hypersomnia with at least two recurrent episodes of excessive sleepiness and sleep duration, each persisting 2–5 weeks. Episodes occur annually or at least once every 18 months. • Prevalence is estimated at 1–1.8:1000,000. • Male > Female: 3:1 ratio; median age of onset ∼15 years, but case reports have included ages 4–82 years. Hypersomnia is the essential feature of Kleine–Levin syndrome (KLS). • During the periods of hypersomnia, sleep duration can range from 15 to 24 h/day for many days to weeks. • No consistent pathology has been demonstrated in the few autopsy cases. Brain MRI is normal.

895 • Etiology and pathophysiology are unknown. Single-photon emission computed tomography (SPECT) analysis has demonstrated hypoperfusion in the right thalamus, occipital cortex, and orbitofrontal cortex in a cohort of KLS patients during the symptomatic period.46 EEG is normal in about 30% of patients with KLS, while the remainder have some background slowing, and during wakefulness have some low-frequency, high-amplitude waves in the frontal or frontotemporal areas bilaterally. Prevalence in Ashkenazi Jews and reports of a few familial cases suggest a genetic predisposition. Frequent association with a prodromal febrile illness, particularly upper respiratory infection, suggests a possible immune-mediated etiology.

Clinical features

• Episodes are often preceded by an overwhelming tiredness and irresistible urge to sleep. Patients will have no regard for circadian timing and will sleep at any time, day or night. • Must demonstrate at least one of the following: • Cognitive dysfunction. • Altered perception • Eating disorder: either hyperphagia or anorexia. • Disinhibited behavior (e.g. hypersexuality). • Between episodes, the patient has normal alertness, cognitive function, behavior, and mood.

Diagnosis

• Diagnosis is based on the above clinical features. In the differential diagnosis, it is particularly important to rule out primary psychiatric disease (especially bipolar disorder). An infectious or postinfectious etiology may be considered if the first episode occurs shortly after a febrile illness. Additionally, the use of medications or drugs of abuse must also be considered. Polysomnography is not required and is often impractical due to agitated behavior. • Very rarely, TBI has been reported to precede KLS.45

Treatment

There have been no randomized, controlled trials for KLS. Stimulants have been used during symptomatic periods, which do seem to help with reducing the duration of the episodes, but not with recurrence.46 Lithium has been reported to help reducing the frequency of relapses, and there have been some reports of carbamazepine helping with remission of KLS.

Insufficient sleep syndrome

• Exact prevalence is unknown, but this condition is relatively common in adolescence, when sleep requirement is high, but social and cultural pressures to curtail sleep and a normal age-dependent shifting of sleep phase, delaying sleep onset, combine to produce insufficient sleep. • ICSD-3 diagnostic criteria are as follows:2 • Daily periods of irrepressible need to sleep or daytime lapses into sleep. • Patient’s sleep time is shorter than expected for his or her age. • Sleep is curtailed on most days for at least 3 months (determined by history, sleep logs, and/or actigraphy). • Increasing total sleep time leads to symptom amelioration.

Hankey’s Clinical Neurology

896 • The symptoms are not better explained by another condition. • Polysomnography is not necessary, but if done, should demonstrate a short sleep latency and a high (> 90%) sleep efficiency.

Treatment

The treatment for insufficient sleep is to increase total sleep time.

SLEEP-RELATED MOVEMENT DISORDERS Introduction2

Sleep-related movement disorders are typically characterized by simple motor symptoms that are stereotyped and interfere with sleep or sleep onset. The movements result in disrupted sleep and daytime symptoms, such as fatigue or sleepiness. Notably, the movement itself should not be considered as the hallmark of the disorder as some movements, such as hypnic jerks, are typical of normal physiologic sleep. Although these conditions are typically thought of as benign, the associated sleep disturbance and concomitant insomnia can significantly impact quality of life.

Restless leg syndrome

• RLS, also known as Willis–Ekbom disease, is a sensorimotor disorder during wake and often sleep. It is a clinical diagnosis based on five diagnostic criteria:47 • Urge to move the legs which may be associated with an uncomfortable, unpleasant sensations in the legs. • Symptoms begin or worsen during periods of rest or inactivity. • Symptoms are partially or totally relieved by movement, at least as long as the activity continues. • Symptoms only occur or worsen in the evening or night. • Symptoms are not connected to another medical or behavioral condition.

TIP • Although not required for the diagnosis, in cases of equivocal symptom description or diagnostic uncertainty, certain features such as response to dopaminergic therapy, family history among first-degree relatives, and presence of periodic leg movements in sleep can be supportive of this diagnosis.

Epidemiology

• RLS affects 5–10% of the general population and is thought to be higher in North America and Europe with most estimates ranging from 5.5% to 11.6% and lower in Asia with most estimates ranging from 1.0% to 7.5%.47 Prevalence in women is 1.5–2 times higher than men. This is in part associated with parity, as nulliparous women have disease prevalence similar to men. Age of onset of the disease ranges from childhood to late adulthood, and prevalence increases with age.48 Late-onset disease (> 45 years old) tends to progress more rapidly than early-onset RLS. Strongly associated conditions include chronic kidney disease, pregnancy, and iron deficiency anemia.

Pathophysiology

• Although the pathophysiology of RLS remains poorly understood, we now know that there is a significant genetic contribution. A total of six genes for which allelic variants are thought to confer risk for RLS49 have been identified in genome-wide association studies involving Northern European and North American populations. Overall, the estimated hereditably of RLS is estimated to be between 40% and 50%. • Besides genetic factors, brain iron deficiency and CNS dopamine regulation have also been implicated in the pathophysiology of RLS. Disease models, CSF analysis, brain imaging, and postmortem studies support the interplay of these three factors in the disease development. • RLS can also occur in association with other conditions such as chronic kidney disease and pregnancy. Notably, RLS symptoms significantly improve after delivery and after renal transplantation as compared to dialysis.50 • Several classes of medications, particularly antipsychotics, antidepressants, and antiepileptics, have been linked to RLS development and should be considered as potential causes of RLS. • Other conditions that have been associated with RLS include: • Parkinson’s disease. • Essential tremor. • Multiple sclerosis. • Hereditary ataxias. • Rheumatologic diseases. • Cardiovascular disease. • Spinal cord injury. • Repeated blood donations (causing iron deficiency). • If a patient has at least three or more medical comorbidities present, such as cardiovascular disease, diabetes, hypertension, or depression, the frequency of RLS increases.51 • Although pathology in other organ systems is not classically described with RLS, there is accumulating evidence that autonomic activation associated with it may contribute to risk of cardiovascular disease and stroke.

Differential Diagnosis • • • • • • • •

Positional discomfort. Peripheral neuropathy. Venous stasis/leg edema. Arthritis of the lower limbs. Drug-induced akathisia. Myopathy/myalgia. Nocturnal (sleep-related) leg cramps. Habitual foot tapping.

Diagnosis

As previously mentioned, RLS is a clinical diagnosis and polysomnography is not required, unless there is suspicion of a superimposed disorder, such as sleep-disordered breathing or epilepsy, or if the diagnosis is questionable. Careful evaluation of the patient’s medications, medical comorbidities, and iron studies are necessary. EMG/nerve conduction studies and screening for common causes of neuropathy are recommended if peripheral neuropathy or radiculopathy are suspected. Skin biopsy may be considered if small-fiber neuropathy is suspected, and further investigations may be needed if neuropathy is confirmed.

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897

Treatment

• Initial management of RLS should include discontinuation of potential causative agents and sleep hygiene. • Iron replacement therapy is recommended for all patients with RLS who have iron deficiency or with a serum ferritin level ≤ 75 ng/mL.51 • For non–iron-deficient patients with mild symptoms, nonpharmacologic interventions can be considered as first line of treatment. • Both non-ergot dopamine agonists and α2δ ligands are first-line pharmacologic treatment for patients who are refractory to above interventions. See Table 28.6 for the common pharmacologic options used in RLS. • Non-ergot dopamine agonists include oral ropinirole, oral pramipexole, and transdermal rotigotine. This should be taken 2 hours prior to symptom onset. • Side effects for this class of medication include compulsive behaviors, augmentation, and somnolence. The risk for augmentation increases with duration of treatment and is characterized by symptom onset earlier in the day with involvement of an additional body part. Management of augmentation includes rechecking iron stores, switching to a different dopamine agonist, or changing to different class of medication. • α2δ ligands commonly prescribed for the management of RLS are gabapentin, pregabalin, and gabapentin enacarbil. Common side effects of α2δ ligands include sedation, peripheral edema, and dizziness. • In cases of severe, refractory RLS, benzodiazepines or low-dose opioids are commonly the next line of therapy.

Periodic leg movement disorder

Periodic limb movements in sleep (PLMS) are defined as periodic episodes of repetitive and highly stereotyped limb movements that occur during sleep, which may be accompanied by an arousal or sleep fragmentation.2, 52 The finding of PLMS on polysomnography, in the absence of symptoms of nocturnal sleep disruption or daytime dysfunction, is often regarded as incidental, not warranting treatment. In order to be classified as having periodic limb movement disorder (PLMD), there must be a clinical sleep disturbance or complaints of daytime fatigue. There are three criteria for PLMD diagnosis: • Demonstration of PLMs on polysomnography. • Elevated PLM index (> 15 for adults and > 5 for children is recommended), though emphasis is placed on clinical context rather than absolute numbers. • Clinical sleep disturbance or daytime fatigue/sleepiness must be present.

TIP • Disruption of a bed partner’s sleep by PLMS is not a sole criterion for diagnosis.

Epidemiology

The prevalence of PLMD is unknown, but it is thought to be rare. PLMS, by themselves, are uncommon in patients under the age of 40, but then increase with age. While older studies have suggested that the prevalence of PLMS is somewhere between 4% and 11%, more recent studies have found the prevalence to be almost 30%.52, 53

TABLE 28.6  Medications Used to Treat RLS Medication Class

Drug

Dose

Common Side Effects

Comments

Iron (indicated if serum ferritin is < 75 μg/L)

Ferrous sulfate (oral) Iron dextran

325 mg + 100–200 mg vitamin C, twice a day 1000 mg

Nausea

Pramipexole

0.125–1.0 mg

Follow ferritin levels; goal > 75 μg/L Infrequently used; some reports of response in patients with ‘normal’ ferritin Longer duration than levodopa

Ropinirole Rotigotine Carbidopa/levodopa

0.25–4.0 mg 0.5–6.0 mg 25/100–50/200 mg

Anticonvulsants

Gabapentin

300–1200 mg

Opiates

Gabapentin enacarbil Hydrocodone

600–12,000 mg 5–10 mg

Benzodiazepines

Methadone Clonazepam

2–15 mg 0.5–2.0 mg

Temazepam

15–30 mg

Dopaminergic drugs

Anaphylaxis; long-term safety unknown; usually not repeated before 3 months Nausea, orthostatic hypotension, insomnia, sleep attacks, compulsive behavior; augmentation Same as for pramipexole Slow-release preparations available Same as for pramipexole Transdermal delivery by patch Same as for pramipexole Augmentation more likely than with agonists Weight gain, somnolence, Helpful if painful paresthesias are pedal edema present Same as for gabapentin Gabapentin prodrug Constipation, sedation, abuse potential, central sleep apnea Same as for hydrocodone Latency to benefit Sedation, dizziness, balance Tolerance issues Same as for clonazepam Tolerance

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898 Pathophysiology

The pathophysiology of PLMS remains unknown. One common hypothesis is that PLMs are related to dopaminergic dysfunction. This comes from the overlap between RLS and PLMS.

Differential diagnosis

• Hypnic jerks. • Leg movements associated with arousal from sleep-disordered breathing. • Spinal cord dysfunction (myelopathy) causing flexor spasms in the lower extremities. • Nocturnal epilepsy or myoclonic epilepsy. • Fragmentary myoclonus.

Diagnosis

In order to diagnose PLMD, exclusion of other causes of sleep disruption and PSG are necessary. If epilepsy is being considered as a differential diagnosis, an extended EEG montage should be used during the PSG.

Treatment

Pharmacologic treatment should be considered when PLMS causes significant sleep disturbance or daytime fatigue. Treatment options have been extrapolated from treatment guidelines for RLS and include non-ergot dopamine, benzodiazepines, and opioids. Efficacy data for these remain limited.

Sleep-related bruxism2, 54

Sleep-related bruxism is a repetitive jaw muscle activity in which clenching or grinding of the teeth and/or bracing or thrusting of the mandible during sleep are the hallmark features. It may come to a patient’s attention due to jaw pain, dental wear, buccal lacerations, headaches, orofacial pain, or noise that can be bothersome to bed partners. The diagnosis of sleep bruxism is usually clinical, based on reports of tooth-grinding sounds or jaw clenching during sleep along with one or more of the following: • Abnormal wear on the teeth: surface loss, hypersensitive/ painful teeth. • Jaw muscle discomfort, fatigue, or pain and difficulty opening jaw on awakening. • Masseter muscle hypertrophy. • No better explanation by another sleep disorder, neurologic disorder, medication, or substance abuse.

Epidemiology

The prevalence of sleep-related bruxism is thought to be around 8–13% of the general population. It is more common in children estimated at 14–18%, and lower in the elderly at about 3%. There are no reported sex differences. A high concordance rate in dizygotic twins and an even higher concordance rate in monozygotic twins (based on questionnaires or estimation of tooth wear), as well as reports of dominance of the condition in a familial distribution, suggest a possible genetic component. Patients with OSA and GERD are at increased risk for bruxism. Interestingly, patients with temporomandibular disorder (TMD) have been shown to self-report bruxism, but on PSG, the rates of bruxism are much lower than self-report.

Pathophysiology

The exact etiology of sleep-related bruxism remains controversial. No clear CNS pathology has been demonstrated in sleep-related bruxism. It seems to be a reaction to microarousals during sleep. It may occur concomitantly with other sleep disorders that are associated with an arousal, such as NREM parasomnias. Factors that have been proposed include:55 • Problems with dental occlusion (‘occlusal interferences’). • Stress and anxiety. • Presence of excess systemic catecholamines/sympathetic activation. • Conditions associated with increased arousals, such as smoking, caffeine use, and sleep-disordered breathing.

TIP • In cases of coexisting daytime bruxism, stress and anxiety as etiology should be considered, and management of these may improve bruxism.

Differential diagnosis

• Facio-mandibular myoclonus: myoclonic jerks of the jaw resulting in brief dental occlusion without tooth grinding (usually a benign condition). • Daytime dyskinesias persisting in sleep. • Sleep-related epilepsy (rarely results in bruxism). • Parasomnias: REM or NREM. • GERD.

Diagnosis

As mentioned above, bruxism is a clinical diagnosis, PSG is not required for diagnosis, but it can be used to definitively make the diagnosis. PSG will show masseter and temporalis muscle activity, and the grinding sounds may also be audible. The majority of the episodes will occur during stages N1 or N2, but they can occur during all stages of sleep. PSG can be used when other diagnoses need to be ruled out (Figure 28.25). A clinical examination can also assist in the diagnosis of bruxism, as the patient may have some of the following characteristics: masseter hypertrophy, tenderness on muscle palpation, changes to dentition (i.e. tooth fracture, shiny spots on restorations), scalloping of the tongue, and ridging of the mucosa of the cheek.54 Other less commonly used methods to assist with diagnosis of bruxism include intraoral appliances and EMG.

Treatment54

Only limited effectiveness data are available for the treatment of bruxism. At present, occlusal splints are the treatment of choice. Behavioral interventions can also be considered, which include relaxation techniques, biofeedback, and sleep hygiene measures. Pharmacologic options, such as benzodiazepines, muscle relaxants, beta-blockers, and antidepressants can be considered when conservative measures are unsuccessful. However, there is limited evidence for their use. Botulinum toxin (Botox) has been shown to have equal effectiveness to oral devices, 56 but there are some concerns about potential bony changes where the muscles attach to the bone.

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899

F3–A2 F4–A1 C3–A2 O1–A2 C4–A1 O2–A1 LOC ROC Chin Legs Snore CPAP Chest Abdmn EKG SAO2 (%)

FIGURE 28.25  Bruxism (30-second epoch). LOC, left outer canthus; ROC, right outer canthus; Chin, chin EMG; Legs, leg EMG; NPT, nasal pressure transducer; Therm, thermistor; SAO2, oxygen saturation.

Other sleep-related movement disorders

The ICSD-3 recognizes three additional sleep-related movement disorders: sleep-related leg cramps, sleep-related rhythmic movement disorder, and propriospinal myoclonus. Sleep-related cramps are characterized by: • Painful leg muscle cramp arising from either sleep or wakefulness during periods of rest. • When associated with muscle wasting, weakness, or profound symptoms during wakefulness, neuromuscular disease should be ruled out. Treatment remains controversial and based on expert opinion. Nonpharmacologic options include magnesium, massage, stretching, and tonic water. Benzodiazepines, gabapentin, and sodium channel-blocking antiepileptic drug are some of the pharmacologic alternatives. Sleep-related movement disorder is characterized by: • Repetitive, stereotyped, large-amplitude body movements that take place shortly before sleep onset and may persist into sleep. • Common examples of these movements include body rocking, head rolling, or head banging. In order to qualify as a disorder, the movement has to be associated with a clinical sleep disturbance, lead to injury or cause daytime symptoms such as fatigue. It is typically a disease of infancy although it may persist or emerge at any stage of life. Environmental modification such as bed padding or head gear may be effective in minimizing injury in refractory cases. Clonazepam has been reported as an effective pharmacologic treatment. Propriospinal myoclonus is a rare diagnosis characterized by: • Axial, stereotyped, flexor movement typically occur during sleep–wake transitions. • Diagnosis can be confirmed with EEG–EMG polysomnography which should demonstrate involuntary, nonepileptic, myoclonic jerks over axial muscles at times spreading to limbs. • Work-up should include spine imaging to rule out structural causes. • Clonazepam may be effective reducing frequency of myoclonic jerks.

Hypnic (physiologic) myoclonus is a: • Benign, involuntary jerk that typically occurs during transition to sleep. • Stimulants, such as caffeine, anxiety, or stress can aggravate or increase its frequency. • In such cases, dealing with the underlying precipitant is recommended.

SLEEP-RELATED BREATHING DISORDERS Introduction

Sleep-related breathing disorders (SBDs) are the common group of sleep disorders treated today, which are characterized by abnormal respiration during sleep. The categories of SBDs include OSA, central sleep apnea (CSA), sleep-related hypoventilation, and sleep-related hypoxemia disorder. In this chapter, we will focus on OSA (Figure 28.16) and CSA (Figure 28.17). As the general population ages and the prevalence of obesity continues to rise, these disorders, especially OSA, will continue to increase in frequency and severity.57 Airway anatomy and neural control of pharyngeal and tongue activity can affect both dilation and narrowing of the upper airway58 (Figure 28.26).

Obstructive sleep apnea Definition and clinical features

The hallmark of OSA is airway obstruction causing apneas and/ or hypopneas. In addition, multiple medical consequences result in the symptom complex identified as OSA syndrome.59 The primary effects of obstructive apnea are on the cardiovascular, pulmonary, endocrine, and CNS. Patients with OSA may complain of a variety of symptoms including but not limited to: • • • • • •

Snoring. Apnea witnessed by caregivers or bed partner. Nocturnal choking episodes. Daytime hypersomnolence. Difficulty maintaining sleep. Morning headache.

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Promotion of airway collapse Negative pressure on inspiration Extraluminal positive pressure; fat deposition; small mandible

Promotion of airway patency Pharyngeal dilator muscle contraction (genioglossus) Lung volume (longitudinal traction)

FIGURE 28.26  Airway anatomy affects both dilation and collapse of the airway. The sum of these factors affects the critical pressure.

Epidemiology and risk factors

OSA is common among middle-aged adults and is more common in males than females. In a recent review, the prevalence of OSA in the general adult population ranged from 9% to 38% and was significantly higher in the elderly population.60 Risk factors for OSA include: • Obesity: over 70% of patients with OSA are overweight or obese.61 Patients with mild OSA who gain 10% of their bodyweight are at six times greater risk for progression of symptoms. The loss of 10% of body weight decreases OSA severity by 20%. • Age: there is a two- to threefold increased incidence of OSA above age 60. • Race: risk for severe apnea in African Americans is 2.33 times of the risk in Caucasians. Higher prevalence at lower body mass indices is observed for East Asian populations. • Genetic: first-degree relatives of patients with OSA are twice as likely to have OSA compared to those without affected relatives. • Craniofacial morphology.

Pathophysiology58, 62

Airway patency is affected by: • Pharyngeal dilator muscle constriction. • Lung volume producing longitudinal retraction of the neck. Airway collapse occurs in association with: • • • • •

Negative pressure of inspiration. Extraluminal positive pressure. Extraluminal fat deposition. Small mandible. Muscle and bone factors affecting generation of negative pressure: • Diaphragm and intercostal muscles. • Stability of rib cage.

The airway can be modeled as a Starling resistor, a tube having infinite compliance (totally collapsed) at one transmural pressure and low compliance (not collapsed) at other pressures. The pressure at which the tube closes due to external pressure equaling the intralumenal pressure is called the critical pressure (Pcrit): • Pharyngeal dilator muscle activity (tensor palatine, genioglossus) is diminished during sleep, increasing airway compliance. • As airway collapse increases, increased negative inspiratory pressure is necessary to maintain airflow and results in additional collapse. Eventually, Pcrit is reached, and the airway occludes. • Interaction between pharyngeal structural properties and neuromuscular regulation determines pharyngeal airway collapsibility. Obesity impacts on this balance by reducing lung volume and narrowing the pharyngeal airway, with neural compensation for these abnormalities being lost during sleep (Figure 28.27). Intrinsic airway obstruction increases airway resistance, and increased negative inspiratory pressure is required to maintain airflow: • Anatomic abnormalities: micrognathia or macroglossia. • Adenotonsillar hypertrophy is the most common cause of OSA in young children. Airway obstruction may also result from extrinsic factors: • Para-airway adipose tissue: neck size correlates with increased risk of apnea. • Decreased airway dilator muscle activity, as may occur in the setting of neuromuscular disease.

Common comorbid disorder with OSA63

• Hypertension: globally, 30% of hypertensive patients have OSA, and this increases to 80% in treatment-resistant hypertension.64 Approximately 50% of patients with

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FIGURE 28.27  Illustration relating obesity, body fat distribution, upper airway collapsibility critical pressure (Pcrit), and sleep apnea pathogenesis. Mechanical loads and neuromuscular responses sum (Σ) to increase (+) and decrease (−) Pcrit, respectively. Mechanical and humoral effects of regional adipose depots can affect these components, which can mediate differences in sleep apnea susceptibility between men and women.

•

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OSA are hypertensive. Patients with an AHI > 15 have a risk of hypertension 2.89 times that of normal controls. Stroke: Poststroke, 60–80% of patients have OSA with a respiratory disturbance index (RDI) > 10. Risk of stroke in patients with OSA increases with increasing AHI, rising from 1.75 relative risk if AHI is < 12 to 3.30 if the AHI is > 36. About 54% of strokes occur at night in OSA patients, whereas stroke incidence is greatest in the first few hours after awakening in the general population.65 Congestive heart failure: sleep apnea is seen in over 50% of patients with heart failure. OSA increases the risk of heart failure by an odds ratio of 2.38. Treatment with CPAP increases left ventricular ejection fraction by 25–33%.66 Coronary artery disease: 30–58% of patients with coronary artery disease have OSA. Neurocognitive effects: neurocognitive dysfunction correlates with sleep disruption/deprivation, and especially if intermittent hypoxia occurs in association with respiratory events.67 More recently, it has been suggested that OSA potentiates the neuropathologic and clinical progression of Alzheimer’s disease, which is likely due to multiple factors related to OSA, including sleep architecture disruption, intermittent hypoxia, and hemodynamic changes.64 Patients with hypersomnolence have poorer cognitive functioning than those who do not have daytime sleepiness. OSA has been shown to have negative effects on: • Cognitive processing. • Working memory. • Executive function. • Vigilance.

syndrome, sleep-related hypoventilation due to a medical or neuromuscular condition, and CSA syndromes.

Treatment

• Treatment for sleep apnea includes: • Weight loss. • Positive airway pressure: • Positive pressure is delivered by a mask or similar device (Figure 28.28). Pressure provides a physiologic stent to the airway to relieve obstruction. • CPAP: provides a constant inspiratory and expiratory pressure to stent the airway. Another option is

a

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Diagnosis

• Polysomnography demonstrates an AHI > 5. Current US Medicare criteria for diagnosis and reimbursement of therapy for OSA require that events scored as apneas and hypopneas are accompanied by > 4% oxygen desaturation. Differential diagnosis in a patient observed to snore and have possible observed apneas includes primary snoring (without clinically significant OSA), Cheyne–Stokes respiration, obstructive hypoventilation, obesity hypoventilation

FIGURE 28.28  Positive airway pressure. (a) Demonstrates the anatomy of airway collapse. Note negative pressure in airway and extrinsic forces on airway causing collapse. (b) Effect of positive airway pressure opening the airway and restoring patency.

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•

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an autotitrating machine, which automatically adjusts pressure within a range of pressures set by the physician, as needed throughout the night. Bilevel positive airway pressure (BiPAP): BiPAP delivers increased inspiratory pressure and a decreased expiratory pressure. The goal of decreased expiratory pressure is to preserve the stenting effect while making expiration easier, and allowing therapy to be better tolerated, especially at high inspiratory pressures. This mode may also provide better ventilation for patients with neuromuscular conditions that cause difficulty with expiration against a continuous pressure. Oral appliance: mandibular advancement to enlarge the airway space and decrease upper airway collapsibility.68 Upper airway stimulation: hypoglossal nerve stimulation of protrusor muscles of the tongue, which leads to increased airflow and decreased pharyngeal collapse.69 Positional therapy: sleep apnea is frequently worse in the supine position. There are positional devices to help with side sleeping.

Central sleep apnea70

• Central apneas are due to temporary cessation of respiratory rhythmogenesis in the medulla and its associated breathing networks. CSA is rare in the general population. It most commonly occurs in individuals with cerebrovascular disorders, such as congestive heart failure (CHF), atrial fibrillation, and stroke. It can also occur in chronic opioid use. CSA can be classified as hypocapnic or nonhypocapnic, based on the daytime pCO2 level. • Pathophysiology: in primary CSA, there is a high ventilatory response to rising pCO2, resulting in an increased respiratory rate and excessive lowering of pCO2, which in turn causes apnea. These apneas produce little oxygen desaturation. • Diagnosis: excessive daytime sleepiness and arousals, awakenings, or insomnia complaints are the presenting symptoms. Diagnosis is confirmed by polysomnography demonstrating five or more central apneas per hour greater than 10 seconds in duration. • Treatment for central apnea and hypoventilation syndromes: • Assisted ventilation is the most effective and safest treatment for primary CSA. • Noninvasive BiPAP with a backup rate or adaptive servoventilation (ASV), with proprietary software designed to maintain a tidal volume and rate, may be options for some patients. However, ASV cannot be used in patients with heart failure and reduced ejection fractions (EF ≤ 45%) due to increased mortality in patients with low EF on ASV.

CIRCADIAN RHYTHM SLEEP– WAKE DISORDERS Introduction

Circadian rhythm sleep–wake disorders (CRSWDs) are characterized by a mismatch between the timing of the endogenous circadian rhythm with the 24-hour physical environment and/

or imposed social and work schedules. Although the focus is on sleep and wake disturbances, the consequences of circadian dysregulation or misalignment has been shown to have broad implications, including risk for cognitive impairment, mood disorders, cardiometabolic disease, and accidents. The CRSWDs include advanced sleep–wake phase disorder (ASWPD), delayed sleep–wake phase disorder (DSWPD), non–24-hour sleep–wake rhythm disorder (N24SWD), irregular sleep–wake rhythm disorder (ISWRD), shift work disorder (SWD), and jet lag disorder (JLD).2 Before we describe the diagnosis and management of these disorders, we will briefly review the role of the most important synchronizing agents or zeitgebers, such as light, activity, and melatonin on circadian regulation. Similar to adjusting the hands on a mechanical clock, the central circadian clock located in the suprachiasmatic nucleus (SCN) can be adjusted with timed exposure to zeitgebers. In humans, light is the strongest signal, followed by the nonphotic signals such as melatonin. As seen in Figure 28.29, presentation of light in the early biological evening delays circadian timing, while light in the late biological evening advances circadian timing.71–73 In contrast, administration of melatonin in the early evening advances circadian rhythms, and in the early morning delays.74, 75 In addition to the above factors, multiple other time signals can also influence circadian timing, including feeding, social interactions, and activity.76, 77 Timed exposure of these synchronizing agents is the key clinical strategy used in the management of CRSWDs.

General diagnostic approach

The diagnosis of CRSWDs relies primarily on the clinical history and awareness of these disorders in the differential diagnosis of insomnia and hypersomnia. Sleep logs (diaries) and/or actigraphy monitoring for at least 7 days, but preferably for 14 days are necessary to demonstrate the timing of sleep–wake cycles, and also the overall patterns.78 An example of the actigraphy results from a normal individual is shown in Figure 28.30. Many actigraphy devices have built in light sensors which can provide information

Phase advance

Sleep

Nadir

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17 20 23 02 05 08 11 14 17 20 23 Time of day

FIGURE 28.29  Melatonin phase response curve (orange line) demonstrating delayed and advanced sleep phase shifts, depending on the timing of melatonin administration. For bright-light exposure (red line), the most significant phase delay shift occurs with exposure in the late evening, and the most significant phase advance shift occurs with exposure in the early morning, after the nadir of core body temperature.

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FIGURE 28.30  Normal sleep pattern demonstrated with actigraphy. Note the lack of high-amplitude movements during the sleep periods (shaded blue) recorded by the actigraph. to help personalize light treatment recommendations. Other optional testing elements that can help improve diagnostic accuracy and enhance treatment include: • Questionnaires to assess circadian chronotype, such as the Horne–Ostberg questionnaire and the Munich Chronotype questionnaire, and circadian biomarkers. • Circadian biomarkers, such as the timing of salivary dim light melatonin onset which can effectively be assessed in the home environment, but not yet routinely available in most sleep clinics.

General treatment approaches79, 80 Melatonin

Melatonin has phase shift effects and hypnotic effects. Early evening dosing causes sleep phase advance. Late night or early morning dosing causes sleep phase delay. • It has a half-life of 45 minutes. • Timing of administration is dependent on desired effect on circadian timing, so will differ by the specific CRSWD. • 0.5–1 mg is a typical dose to affect a change in the timing of circadian rhythms, whereas higher doses may have a hypnotic effect.

Light therapy

• Exposure to bright light during the evening causes sleep phase delay. • Exposure to bright light during the morning causes sleep phase advance.

Chronotherapy

• Chronotherapy can be used to resynchronize the circadian clock. • The patient gradually shifts the sleep time over a period of weeks until the desired sleep–wake times are achieved.

• The patient must adhere to the new sleep–wake schedule and light–dark exposure daily. • Although this approach has been shown in small samples to be effective, the strict sleep and light exposure patterns makes adherence difficult in the real world.

Behavioral and environmental modifications

Patients with CRWSDs often develop maladaptive behaviors and live in environments that can contribute to the circadian dysregulation or misalignment. • Intensity and timing of exposure to ambient light at school, work, and home. • Timing of exercise and meals. • Timing of exposure to light-emitting devices.

Delayed sleep–wake phase disorder

• DSWPD is characterized by a delay in sleep–wake timing with respect to the time that the individual is required to be asleep and awake. Symptoms include chronic difficulty falling asleep and awakening in the morning, coupled with daytime sleepiness and mood disturbance. 81 This disorder is more common in adolescents and young adults. • Diagnosis is established by a detailed history, supplemented by a sleep diary and/or actigraphy, preferably with light sensor and questionnaires to assess for evening or late chronotype. The patient should exhibit a stable delay in sleep–wake timing (Figure 28.31) that is associated with impairment in functioning or distress. In addition, if available, salivary measurement of the timing of endogenous melatonin secretion or dim light melatonin onset (DLMO) is preferred as the most accurate marker of circadian timing. The differential diagnosis includes N24SWD and ISWRD. In particular, DSWPD often precedes the development of N24SWD.

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FIGURE 28.31  Actigraphy recording in patient with DSWPD. Note, nightly late onset (delay) of the major sleep phase (range of 2–3 am to 10–11 am) with normal duration. • Treatment is aimed to advance the timing of circadian rhythms, so that the desired or required sleep and wake times are in alignment with social and work schedules. In all patients, behavioral and environmental factors, such as exposure to ambient light or use of light-emitting devices in the evening and poor sleep hygiene should be addressed. Treatment of DSWPD focuses on the use of timed exposure to bright light and melatonin, and in clinical practice, the two are typically used in combination. • Bright light: broad spectrum or short wave length (blue) enriched light exposure immediately after awakening (biological morning) has been demonstrated to produce phase advances in circadian timing.73 • Melatonin (0.3–5.0 mg) between 19:00 and 21:0082 or low dose (0.5 mg) of melatonin 1 hour prior to the desired bedtime, combined with behavioral instructions for scheduling sleep–wake timing to the earlier desired or required sleep time.82, 83

TIP • Delayed sleep–wake timing is common among adolescents and young adults Emphasis on behavioral and environmental interventions, consideration of comorbid mood disorders, and family counseling are often useful, in addition to the approaches mentioned above.

• Diagnosis is established by a detailed history and a sleep diary and/or actigraphy and questionnaires to assess for morning or early chronotype. The patient should exhibit an advance in sleep–wake timing (Figure 28.32) associated with daytime impairments or distress. When allowed to sleep during their preferred time, sleep quality and duration are normal. The differential diagnosis includes early morning awakening associated with depression or sleep maintenance insomnia. • Treatment is aimed to delay the timing of circadian rhythms, so that sleep and wake times are aligned to the desired or required social and work schedules. • Evening bright light exposure for 2 hours between 7 and 9 pm. However, based on the patient’s lifestyle and desired bedtime, the exact time of exposure should be individually adjusted, and light exposure may start later in the evening.85 • Sleep scheduling consisting of a progressive delay of sleep– wake schedule and adherence to the regular desired schedule once it is achieved and practice good sleep hygiene (Figure 28.33).

TIP • ASWPD is more common among older adults, but it should be noted that while many individuals may exhibit an advanced circadian phase and early morning awakening, many people may not consider this pattern to be a disorder. Emphasis on behavioral and environmental interventions, consideration of comorbid mood disorders, and reassurance may be useful.

Advanced sleep–wake phase disorder82, 84

• ASWPD is characterized by an advance in sleep–wake timing, typically presenting with symptoms of early morning awakening (typically before 6 am) and early evening sleepiness (typically before 9 pm). The disorder is more common in older adults, but familial cases may present at any age.

Irregular sleep–wake rhythm disorder2, 82

• ISWRD is characterized by multiple irregular bouts of sleep and wake, without a clear primary consolidated sleep period. Patients or caregivers will report frequent

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FIGURE 28.32  Actigraphy demonstrates nightly early onset (advance) of the major sleep phase with normal duration. The yellow lines indicate light information obtained from some actigraphy devices. Note generally low levels of light exposure in this example. short sleep periods (1–3 hours) during the day and night, resulting in symptoms of insomnia or excessive sleepiness at irregular intervals throughout the 24 hours. This disorder is frequently seen in patients with neurologic disorders, such as children with neurodevelopmental delay, and adults with neurodegenerative disorders.86 Multiple factors, such as degeneration at the level of the SCN, loss of circadian synchronizing agents, such as light input (level of the retina or optic nerve or decreased environmental exposure), and decreased structured social and physical activity may all contribute to the fragmentation of sleep and wake pattern. • Diagnosis of this disorder requires either the patient or caregiver to complete a sleep log and/or the use of actigraphy for at least 7 days, preferably 14 days, to document an irregular rest activity (sleep–wake) pattern (Figure 28.34). • Treatment of the disorder aims to enhance circadian synchronizing agents to help consolidate sleep during the night and wakefulness during the day.

• A multimodal approach consisting of increasing exposure to light during the day, limiting naps during the day, structuring social and physical activity, and providing a healthy sleep environment is recommended. • In children administering melatonin (2–10 mg) around bedtime has been demonstrated to be beneficial, however, consistent results have not been shown in elderly patients with dementia. It should be noted that hypnotics are not recommended for the treatment of this disorder.

Non–24-hour sleep–wake rhythm disorder2

• N24SWD is characterized by a sleep–wake pattern that is not stably entrained to a 24-hour cycle, and in most cases, because the intrinsic human circadian period is typically longer than 24 hours, sleep–wake cycles progressively move later each day, resulting in symptoms of insomnia or excessive sleepiness, depending on the relationship

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Noon

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FIGURE 28.33  Summary of role of light and melatonin in the treatment of DSWPD and ASWPD. Note that light before the onset of melatonin secretion (DLMO) will delay, whereas light after DLMO and after the minimum of the core temperature rhythm, will advance circadian rhythms.

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FIGURE 28.34  Actigraph recording demonstrates fragmented sleep unrelated to external cues, without circadian organization. Note the difficulty initiating and maintaining sleep and frequent daytime naps. between the timing of their intrinsic rhythm with their environment. As a result, patients will have time periods where they are asymptomatic, when they are aligned with the external schedule or environment, but sleep and wake times continue to drift so that they are again misaligned, resulting in insomnia symptoms or excessive sleepiness. N24SWD is more common in blind persons without light perception.87 However, it has also been identified among sighted individuals. Although the etiology is less clear, these sighted individuals may have a very long circadian period (beyond limits of entrainment to 24 hours), or due to alterations in light input (environmental or visual pathways).

• Diagnosis of this disorder relies on the clinical history and documentation with sleep logs or actigraphy of a sleep– wake pattern that progressively drifts (usually delays, but rarely can advance) resulting in a pattern that is no longer entrained to 24 hours. Because the rate of drift may vary considerably among patients, sleep logs and/or actigraphy should be monitored for at least 14 days, preferably longer (Figure 28.35). A screening questionnaire developed to identify blind patients who may be likely to have N24SWD may also be useful.88 • Treatment is aimed to entrain the circadian rhythm to a 24-hour cycle. For both blind and sighted persons, a

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FIGURE 28.35  Actigraphy of an example of a non–24-hour SWD, demonstrating a daily delaying drift of the major sleep and wake times. This delay is caused by the intrinsic circadian rhythm, which is typically longer than the external 24-hour clock. This pattern demonstrates the impact of the loss of entrainment or weakened entrainment of the clock with external cues.

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multimodal approach using timed structured nonphotic cues, such as social and physical activity, meal timing, and melatonin agonists can strengthen circadian entrainment. Studies with melatonin have used 0.5 mg up to 10 mg at a fixed time at desired sleep onset can entrain circadian rhythms, with low doses possibly being more effective than higher doses. Tasimelteon is a melatonin receptor agonist and the only FDA-approved medication for the treatment of N24SWD. When administered 1 hour prior to the desired bedtime, tasimelteon demonstrated entrainment after 1 month of taking the medication, and 90% were able to maintain entrainment.89 For sighted individuals with N24SWD, there have been a handful of case reports that demonstrated the efficacy of timed light exposure in the morning shortly after awakening, timed melatonin, or combination therapy.90

TIP • Many individuals diagnosed with N24SWD have a prior history of DSWPD. In addition, attention deficit disorder and psychiatric disorder, such as anxiety, depression, and bipolar disorder are frequently comorbid with N24SWD.

Jet lag disorder2, 84

• JLD results from a misalignment between the individual’s intrinsic circadian time and the environment due to rapid travel across multiple time zones. Depending on the direction of travel, patients report symptoms of difficulty sleeping and/or daytime sleepiness. In addition, symptoms, such as malaise, gastrointestinal disturbance, and mood disturbance are common. In-flight use of hypnotics, caffeine, or alcohol may exacerbate symptoms. Although typically temporary, some individuals experience prolonged symptoms for more than a week. • Diagnosis is established by a clinical history of symptoms of insomnia or excessive daytime sleepiness after travel across two or more time zones. As with other CRSWDs, it is important to consider other sleep disorders or medical and psychiatric comorbidities.

• Treatment is aimed to decrease the circadian misalignment. However, specific recommendations need to be individualized based on the number of time zones crossed, duration of stay, and the desired sleep–wake times. • Gradual shift of the sleep–wake schedule to that of the destination prior to travel, if possible. • For eastward travel, the aim is to advance circadian rhythms. Administration of evening melatonin, avoiding bright light in the morning (immediately after awakening), and seeking bright light in the afternoon can accelerate realignment. • For westward travel, the aim is to delay circadian rhythms. Exposure to late morning and afternoon bright light to delay circadian timing. However, all of these strategies need to be individualized based on the number of time zones crossed and the desired sleep–wake times. • For short trips of a few days, a short-acting hypnotic at the desired sleep-onset time may also be indicated.

Shift work disorder2

• SWD is a result of a misalignment between an individual’s internal circadian timing of sleep and wake with their required work schedules. Patients present with symptoms of insomnia, excessive sleepiness, or both. Shift work can be broadly defined as work occurring outside of the time of a typical day shift, and may include early morning work schedules. Although shift work is common in modern society, it should be noted that not all shift workers suffer from SWD. Susceptibility to SWD likely depends on factors such as circadian chronotype, ability to recover sleep, social and family support, and comorbid medical and psychiatric disorders. There is substantial evidence that shift work increases the risk for cardiometabolic, stroke, mood disorders, and cancer. • Diagnosis is established by a clinical history of insomnia or excessive daytime sleepiness associated with a recurring work schedule that overlaps the habitual sleep time. Sleep logs and/or actigraphy should be obtained over at least 14 days, and should include both work days and non-work days to confirm the sleep–wake disturbance during work day (Figure 28.36). FIGURE 28.36  Actigraphy demonstrates effects of shift work on the sleep pattern. The night shift occurs between days 4 and 7, with recovery sleep on days 8 and 9.

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908 • Treatment strategies for SWD should be individualized depending on the type of shift and severity of symptoms. Generally, a multimodal approach using behavioral interventions and when necessary, pharmacologic agents to enhance and maintain circadian alignment between sleep–wake behavior and performance on both work- and non-work days is recommended. • Optimizing the sleep environment (cool, dark, and quiet) and allow sufficient time for sleep (prescribed major sleep episode) and a nap prior to work may help improve sleep quality and duration, as well as alertness while at work. • Hypnotics or melatonin may aid in inducing sleep at the desired time. • Bright light exposure during the shift may improve alertness and performance. • Pharmacologic agents, including caffeine and wake-promoting medications such as modafinil and armodafinil (approved by the FDA for the treatment of excessive sleepiness associated with SWD).91

PARASOMNIAS Introduction

Parasomnias are defined by the ICSD-3 as disorders characterized by complex motor or behavioral events that occur during entry into sleep, within sleep, or during arousal from sleep. These events may have undesirable or unpleasant effects such as sleep disruption or injury of the patient or bed partner. They can be classified into REM and NREM parasomnias depending on the stage in which they occur. A third term, parasomnia overlap syndrome, is used to describe cases in which an NREM parasomnia is seen in combination with REM parasomnia.

NREM Parasomnias Definition

NREM parasomnias are a group disorders that occur from incomplete arousal from NREM sleep, most commonly slow-wave sleep (N3), and during the first one-third of the night. Typically, there is partial or total amnesia after the event and associated impaired judgement may lead to behaviors patient would otherwise not engage in. A key feature of NREM parasomnias is the dissociation between self-awareness and behavior, as well as between wakefulness and sleep in different areas of the brain.92 • ICSD-3 categorizes NREM parasomnias into two categories as follows: • Disorders of arousal (DOA): – Confusional arousals: – Sleep-related abnormal sexual behaviors (subtype). • Sleep walking (somnambulism). • Sleep terrors. • Sleep-related eating disorder (SRED).

Epidemiology

Lifetime prevalence of NREM parasomnias is estimated to be as high as 30%.93 Although they are more common in children and adolescents, they may persist through adulthood or arise in adulthood. To date, no ethnicity or sex differences have been reported.

Pathophysiology

The majority of individuals with disorders of arousal do not have an underlying pathology. However, the underlying mechanism is thought to be an interplay between genetic factors and

environmental triggers. Genetics are important in all disorders of arousal. Somnambulism has a strong familial pattern in first-degree relatives. Environmental triggers can lead to microarousals, sleep fragmentation, or changes in NREM sleep architecture. Some examples are alcohol, stress, medications, illegal drugs, external stimuli (e.g. noise), or internal stimuli (e.g. sleep disorder of breathing).

Clinical features of NREM parasomnias Disorders of arousal Confusional arousals2, 92 • • • • • • • •

Occur while the patient is in bed; no associated ambulation. No associated terror or autonomic symptoms. Brief; usual 5 minutes or less. Individual sits up in bed and looks around; seems confused. Slow, blunted speech in response to questions. Easily consoled. Amnestic to the event. Common in children under the age of 8 years old. • Sleep study is indicated in older children to rule out other conditions.

Sleepwalking (somnambulism)2, 92

• May begin as confusional arousal or start abruptly. • Ambulates and may perform other complex behaviors out of bed, including risky behaviors that could result in injury, such as unlocking doors or windows and exiting one’s residence. • May wake up in an unexpected location or return to bed and go back to sleep. • Does not reach conscious awareness at any point. • Peaks in children between ages 10 and 12. • EEG shows that occurs out of slow-wave sleep, with faster rhythms superimposed on slow waves during the arousal (Figure 28.37).

Sleep terrors2, 92

• Arousals are characterized by abrupt terror/fear, often with a vocalization, such as frightened, piercing scream. • Eyes are typically open. • Intense fear and associated autonomic symptoms, such as tachycardia, tachypnea, flushing, increased muscular tone, mydriasis, and diaphoresis. • Unresponsive to external stimuli. • May have aggressive behaviors toward others as well as self-injurious ones. • Usually brief, but can last up to 30–40 minutes. • Amnestic for the episode.

Differential diagnosis

• Alcohol- or drug-related behavioral manifestations during sleep. • Dissociative disorders. • Manifestation of sleep disorder of breathing or PLMD. • Sleep-related epilepsy:94 • Frequency of sleep-related epilepsy occurring exclusively or predominantly at night is up to 12%. • Focal nocturnal seizures are predominantly frontal. • Predominantly hypermotor seizures.

TIP • Episodes that have atypical presentation, occurring at sleep onset, associated with complex movements and vocalizations that appear purposeless or occur more than once per week, raise the question of seizure disorder.

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A1–T3 T3–C3 C3–CZ CZ–C4 C4–T4 T4–A2 CZ–O2 LEOG REOG Chin Legs Snore EtCO2 (mmHg) NPT Therm Chest EKG Abdmn SAO2

FIGURE 28.37  Arousal from slow-wave sleep. This is the typical finding associated with confusional arousal, night terrors, and sleepwalking.

Diagnosis

Diagnostic work begins with obtaining a thorough clinical history, review of home medication list, screening sleep habits, and for sleep-disordered breathing. A video PSG along with extended EMG and/or EEG is not required, unless trying to differentiate REM parasomnia, sleeprelated epilepsy, sleep-related dissociative disorder, or if there is concern for comorbid OSA.

TIP • The exception to the general rule that polysomnography is unnecessary for diagnosis of parasomnias occurs when frontal lobe epilepsy is part of the differential diagnosis. This is particularly true when episodes involve hypermotor behavior and/or dramatic vocalizations. Diagnosis may be impossible from observation of a single episode (even by video-EEG monitoring), as epileptiform activity may not be evident on the scalp EEG because the focus may be deep, and the recording is often obscured by muscle artifact. Video-EEG monitoring over multiple nights may be necessary, and the monitoring should be interpreted in light of the overall clinical features of the episodes.

Treatment of disorders of arousals2, 92

The primary goal of managing a parasomnia disorder is preventing the patient or bed partner from injury. The secondary goal of treatment is to improve sleep quality and decrease sleep disruption for the patient, bed partner, and family. For all disorders, trigger avoidance and safety precautions to prevent injury or inappropriate outcomes are recommended. When the parasomnia is determined to be secondary to another condition, treating the primary diagnosis often leads to its resolution. In cases of refractory NREM parasomnias, benzodiazepines, particularly low-dose clonazepam may be used. The evidence for its use is low, but in chart review studies, they have been shown to be effective for reducing events.

Sleep-related eating disorder2, 92

• Episodes of dysfunctional, involuntary eating that occur during sleep. • Commonly associated with other sleep disorders that cause arousal or disrupt sleep, including sleepwalking. • Partial or complete absence of awareness: • Not required to be amnestic for the diagnosis. • Recurrent episodes must include one or more of the following: • Consumption of unusual goods or combinations of foods/inedible/toxic substances. • Potential injury while in pursuit of food or cooking food. • Negative health consequences from night eating, such as weight gain and its associated adverse events, dental caries, daytime food restriction, etc. • Occurs in 8–16% of patients with eating disorders. • Also associated with use of sedating and hypnotic medications, particularly in the setting of patient escalation of hypnotic medication dosing. • Differential diagnosis includes: • Hypoglycemia. • Peptic ulcer disease. • Reflux esophagitis. • Kluver–Bucy syndrome.

Treatment

Pharmacologic treatment options (mechanisms of efficacy are poorly understood): • Dopaminergic agents. • Topiramate. • Selective serotonin reuptake inhibitors.

TIP • Screening for possible primary sleep disorders associated with arousals should be performed.

Hankey’s Clinical Neurology

910 REM parasomnia Nightmares95

• Definition and clinical features: • Nightmares are dreams that awaken the individual, associated with frightening or disturbing content. • Typical of dream recall, there is vivid memory of events, colors, movement, and passage of time. • Like pleasant dreams, they may recur and continue along a similar theme over a single night or recur across multiple nights without apparent pattern. • Like all dreams, nightmares are one of the REM-sleep related phenomena. • Epidemiology: • Like dreams, nightmares are essentially universal events. • Nightmares can begin in infancy, but confirmation may not be possible without the child being able to describe the dream. • 50% of children will have nightmares between ages 3 and 6. • The incidence decreases with age. • Frequent nightmares occur in 1% of adults. • Differential diagnosis: • Night terrors. • Confusional arousals. • REM behavior disorder. • Investigations; polysomnographic findings: • REM sleep is associated with dreaming. • Typical nightmares are preceded by a REM period and followed by an arousal. • Diagnosis: • Diagnosis is usually obtained by the history of a frightening dream awakening the individual from sleep in the early morning hours. • There is usually vivid recall of the frightening dream. • Nightmares associated with movements that increase with intensity over time raise the question of REM behavior disorder, and in these cases, a polysomnogram is required for diagnosis.

• Treatment: • Typically, nightmares require only reassurance to the patient. • If insomnia develops, then occasional hypnotic use may be helpful. • Use of relaxation techniques prior to sleep onset and ‘worry time’ reviewing stressors in the early evening, a number of hours prior to sleep onset, may also help limit nightmares.

REM sleep behavior disorder96

REM parasomnias arise from stage REM sleep. REM is characterized by rapid eye movements, desynchronized electroencephalographic rhythms, and muscle atonia. Individuals with RBD have increased muscle tone during REM sleep and abnormal behaviors during REM (Figure 28.38). Commonly described dream enactment behaviors include talking, laughing, singing, punching, and kicking. Such behaviors can lead to patient or bed partner injury. Unlike sleep terrors, RBD is associated with vivid dream recall. There are three criteria to diagnose RBD according to the ICSD-3: • Repeated dream enactment with complex motor behaviors, upon clinical history-taking or observed during video polysomnogram (vPSG). • Evidence of REM sleep without atonia (RSWA) on vPSG. • Symptoms should not be due to another cause such as medication, alcohol, or a sleep-disordered breathing.

Epidemiology96

Age of onset is typically between the fifth and sixth decade of life. Mean age of onset is 61 years. Patients with secondary RBD have been reported to have a younger age of onset, especially those with narcolepsy type I and autoimmune disorders. Additionally, patients with anxiety and depression may be more likely to have RBD at a younger age, which in part may relate to RBD secondary to antidepressants. RBD is typically thought to be more common in men, though more recent epidemiologic data did not find a gender difference. It has been theorized that the gender difference

F3–A2 C3–A2 O1–A2 F4–A2 C4–A1 O2–A1 LOC ROC CHIN Legs Snore EKG NPT Therm CPAP Chest Abdmn Sum SAO2 (%)

FIGURE 28.38  Period of REM sleep during which muscle activity persists. This lack of REM atonia is a hallmark of REM sleep behavior disorder.

Sleep–Wake Disorders seen in some prior studies may be related to men being less likely to sleep alone and more likely to present with violent behaviors, such as kicking, punching, and screaming.

911

TIP • The exception to the general rule that polysomnography is unnecessary for diagnosis of parasomnias occurs when frontal lobe epilepsy is part of the differential diagnosis. This is particularly true when episodes involve hypermotor behavior and/or dramatic vocalizations. Diagnosis may be impossible from observation of a single episode (even by video-EEG monitoring), as epileptiform activity may not be evident on the scalp EEG because the focus may be deep, and the recording is often obscured by muscle artifact. Video-EEG monitoring over multiple nights may be necessary, and the monitoring should be interpreted in light of the overall clinical features of the episodes.

Pathophysiology

Idiopathic RBD (iRBD) is a strong predictor of future development of α-synucleopathies neurodegenerative disorders. On longitudinal follow-up, 80–90% of patients with iRBD develop dementia with Lewy bodies (DLB), multisystem atrophy (MSA), or Parkinson’s disease after 14 or more years.97, 98 Moreover, in one retrospective study of patients with RBD and α-synucleinopathies, RBD symptoms may been present for as many as 50 years prior to the onset of overt neurodegeneration, suggesting that RBD may be a harbinger of future neurodegeneration. Although the pathophysiology of this disorder remains poorly understood, its association with parkinsonism is possibly related to deficits in dopamine transporter activity in the striatum. Deficits in glutaminergic pathways have also been described.

Differential diagnosis

• NREM parasomnia. • RLS. • Alcohol- or drug-related behavioral manifestations during sleep. • Sleep-disordered breathing. • Nocturnal seizures.

TIP • Early morning episodes raise the question of REM behavior disorder as compared to early in the night behaviors, which are more likely to be NREM parasomnias.

Diagnosis

Polysomnography that demonstrates epochs of REM sleep with excessive amounts of phasic or tonic EMG tone is required. One of the following must also be present: • A history of sleep-related injurious, potentially injurious, or disruptive behavior. • Abnormal REM sleep behaviors documented during the polysomnogram. Absence of associated EEG epileptiform behavior is required, and better explanation for the sleep disturbance should be ruled out.

Treatment

Underlying causes should be addressed. Safety precautions to limit risk of injury, such as placing the mattress on the floor are also recommended. Medications effective in suppressing dream enactment behaviors include clonazepam 0.25–2.0 mg or melatonin 3–12 mg.

TIP • If REM behavior disorder is suspected, a careful neurologic examination for signs of parkinsonism is advised. For the patient with established idiopathic REM behavior disorder, serial follow-up neurologic examinations over time are appropriate.

CONCLUSION Sleep and circadian rhythm disorders are common, and can increase the risk, as well as contribute to the expression and severity of common medical, neurologic, and psychiatric disorders. Given the frequent overlap of sleep disturbance with many neurologic conditions, neurologists are well positioned to identify and provide treatment of sleep–wake disorders. A basic sleep history, including questions about snoring, sleep habits, sleep initiation and continuity, daytime fatigue or sleepiness, leg symptoms, and bed partner complaints, should become a part of every neurologic evaluation. Addressing sleep disorders will not only help improve sleep quality, but also optimize treatment of comorbid disorders.

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INDEX Page numbers italics represent figures and bold indicate tables in the text. A ABCD1 gene, 77, 269, 736 ABCD2 score, 305, 378 Abdominal reflexes, superficial, 22 Abducens nerve (CN VI), 16–17 Abductor pollicis brevis, 804 Abstraction, 10 Accessory nerve (CN XI), 19–20 Accommodation reflex, 13, 751–752 Acephalgic migraine, 151 Aceruloplasminemia, 185 Acetylcholine, 44, 820 Acetylcholinesterase inhibitors, 539–540, 575 Acid maltase deficiency, 852–853 Acoustic neuroma, 49 Acromegaly, 851 Acrylamide, 774 Actigraphy, 890 Acute and subacute autonomic neuropathy, 751 Acute bacterial meningitis, 412–416 clinical features, 414, 414 definition, 412 diagnosis, 415, 415 differential diagnosis, 414 epidemiology, 412–413, 413 etiology and pathophysiology, 414 investigations, 415 pathology, 413, 413 prognosis, 415–416 treatment, 415–416 Acute disseminated encephalomyelitis clinical features, 475–476 definition, 475 diagnosis, 476–477 differential diagnosis, 476 epidemiology, 475 etiology, 475 investigations, 476 pathology, 475 pathophysiology, 475 prognosis, 477 treatment, 477 Acute encephalopathy, 254, 254–256, 256–257 Acute hemorrhagic leukoencephalitis, 477 Acute inflammatory demyelinating polyradiculoneuropathy (AIDP/Guillain-Barré syndrome), 778–780, 789 Acute inflammatory polyradiculopathy, 751 Acute intermittent porphyria, 751 clinical features, 272–273 definition and etiology, 272 diagnosis and investigations, 273 treatment, 273 Acute ischemic stroke, 379 acute hemorrhagic stroke, 387, 387 anticoagulation, 397 acute, 397 long term, 397 therapy, starting or restarting, 402

antiplatelet therapy, 395 acute, 395, 395 long term, 396–397, 396 starting or restarting, 402 antithrombotic therapy, 403 blood glucose, 390 blood pressure, 390 carotid revascularization carotid endarterectomy, 397 carotid stenting, 397 intracranial stenting, 398 vertebral artery stenting, 398 cytoprotection, 390 direct (non-VKA) oral anticoagulation antiplatelet medications, 388 recombinant factor VIIa, 389 tranexamic acid, 389 early supported discharge, 405 endovascular mechanical thrombectomy efficacy, 385–386 safety, 386 uncertainties, 386 endovascular therapy, 403 extracranial to intracranial bypass surgery, 397 fluids, 390 guidelines, 379 hemorrhagic stroke patients, preventing stroke in, 402 left atrial appendage closure, 401 nimodipine after aneurysmal subarachnoid hemorrhage, 402 oral anticoagulation acute ischemic stroke, 400 anticoagulant-associated hemorrhage, 401 atrial fibrillation, 400 mechanical heart valves, 401 patent foramen ovale, 401 patent foramen ovale closure, 401 pathophysiology collateral circulation, 379 cytotoxic edema, 379 ionic edema, 379 ischemic cascade, 379 ischemic core, 380 ischemic penumbra, 380 perfusion lesion, 380 systemic effects, 380 vasogenic edema, 380 preventing and managing complications cerebral edema, 391, 391–392, 392 epileptic seizures, 392 pneumonia, 391 venous thromboembolism, 390–391 preventing recurrent ischemic stroke of arterial origin, 392, 393 of cardiac origin, 400 recovery, 403

recurrent embolic ischemic stroke of undetermined source, preventing, 402 recurrent hemorrhagic stroke, preventing, 402–403 reducing hematoma growth blood pressure reduction, 387–388 clotting factor deficiencies, 388 hemostasis, 388 vitamin K antagonist anticoagulation, 388 rehabilitation assessment and treatment, timing of, 404 cognition, 404 neurotrophic drugs, 404 physical, 402 spasticity, 404 speech and language, 404 stem cells, 404–405 swallowing, 404 risk factor control, 400–401 blood pressure lowering, 397 glucose (hemoglobin A1c) lowering, 398 homocysteine lowering, 398 hormone replacement therapy, 398 insulin resistance, 398 lifestyle and diet, 398–399 lipid lowering, 397 stroke systems of care, 386–387 stroke unit, 390, 390 support, 405 surgery arteriovenous malformations, 401–402 infratentorial ICH, 389 intracranial aneurysms, 402, 394–395 intraventricular ICH, 389 Moyamoya disease, 403 supratentorial ICH, 389 swallowing and feeding, 390 thrombolysis administration of, 383 alteplase, 380–381, 381–383 elevated blood pressure, management of, 383–384 indications for, 383–384, 384 intracranial hemorrhage, management of, 384 perioral angioedema, management of, 385 tenecteplase, 381–383 treatment, 389 aneurysm, 389 arteriovenous malformation, 389 cerebral cavernous malformations, 389 dural arteriovenous fistulae, 389 Acute necrotizing encephalopathy/ acute hemorrhagic necrotizing encephalopathy, 477 Acute thiamine depletion (Wernicke’s encephalopathy), 94 AD, see Alzheimer’s disease

915

Index

916 ADCY5-related dystonia, 182 Addenbrooke’s Cognitive Examination version 111 (ACE111), 8 Addison’s disease, 851 Adenotonsillar hypertrophy, 900 Adrenomyeloneuropathy, 735–736, 736 Adult neuronal ceroid lipofuscinoses, 277 Advanced Parkinson’s disease, 751; see also Parkinson’s disease Advanced sleep–wake phase disorder (ASWPD), 902, 904 AED, see Antiepileptic drugs Agenesis of the corpus callosum clinical features, 222 etiology and pathophysiology, 222 Ageusia and anosmia, 469 AION, see Arteritic ischemic optic neuropathy Airway dilator muscle activity, 900 Airway patency, 900 Alcohol consumption, 771 Alpha antagonists, 755 Alteplase, 380–381, 381–383 Alzheimer’s disease (AD) chemical pathology, 538–539 clinical features, 535 definition, 534 diagnosis, 537–538 epidemiology, 534 etiology, 534 genetic classification, 537 investigations cognitive evaluation, 536 genetic testing, 537 imaging, 536 informant interview, 536 lumbar puncture, 536–537 serum tests, 536 pathology, 538 pathophysiology, 534–535 prevention, 540 prognosis, 540 senile plaques, 538 treatment, 539–540 weaknesses, 535 Amantadine, 572 American Association of Sleep Medicine (AASM) manual, 885, 888 Amiodarone, 772–773 Amnestic shellfish poisoning (ASP), 649 Amyloid angiopathy, 346, 346–347 Amyloidosis, 752, 755 Amyloid polyneuropathies, familial, 792 Amyotrophic lateral sclerosis, 739–744, 742–743 Amyotrophy, hereditary neuralgic, 787 Anal sphincter, 816 Anaplastic oligodendroglioma and oligoastrocytoma clinical features, 506 definition, 506 diagnosis, 506 investigations, 506 prognosis, 507 treatment, 506–507 Anencephaly, 215 Aneuploidy, 68 Aneurysm, 389

Anisocoria, 14 Anterior closure defects anencephaly, 215 cranial encephalocele, 215 prognosis, 217 Anterior horn cell syndrome, 720 Anterior interosseous nerve, 804 Anterior spinal artery syndrome, 721 Antibody testing, 824 Anticholinergics, 572 Anticoagulant-associated hemorrhage, 399 Anticoagulation therapy, 401 acute, 397 long term, 397 starting or restarting, 402 Antidepressants, 771 Antiepileptic drugs (AEDs), 121, 121–122, 643, 643 Anti-MuSK antibody-positive MG, 822 Antiphospholipid syndrome (APS), 340–341, 341 Antiplatelet therapy, 388, 401 acute, 395, 395 long term, 396–397, 396 starting or restarting, 402 Anti-striated muscle antibodies, 821 Antisynthetase syndrome, 846–847 Antithrombotic therapy, 401 Apnea, 883 Apnea/hypopnea index (AHI), 886 Apolipoprotein E (ApoE) gene, 534 Apraxia, gait, 24 Aqueductal stenosis, 655, 655–656, 656 Arnold–Chiari malformations, 218–221 clinical features, 219 etiology and pathogenesis, 218, 218–219 investigations, 220 prognosis, 220–221 treatment, 220 Arousal event, 883 Arsenic, 774 Arterial hypercoagulable state, 376 Arteriolosclerosis, 335, 335 Arteriovenous fistulae, 349 Arteriovenous malformation (AVM), 389, 401–402, 566 Arteritic ischemic optic neuropathy (AION), 699–700 Arteritis Behcet’s disease, 332, 333 giant cell arteritis, 331, 331–332 isolated arteritis/vasculitis, 332 Takayasu’s arteritis, 331 ARX spectrum disorders clinical features, 225 definition, 224 epidemiology, 224 etiology and pathophysiology, 225 Aseptic meningitis, 432–435 clinical features, 432 definition, 432 differential diagnosis, 433 enteroviruses, 433 etiology and pathophysiology, 432 herpesviruses, 433–434, 434 HIV, 434 investigations, 433 lymphocytic choriomeningitis virus, 435

Mollaret’s meningitis, 435 mumps virus, 434 Ataxia, 24, 552 cerebellar, 24, 109, 425, 594, 610 autosomal dominant, 597–605 autosomal recessive, 605–609 congenital, 594 Joubert’s syndrome, 594–597 hereditary, 591–613 spinocerebellar, 15, 178 telangiectasia, see Louis–Bar syndrome X-linked causes, 611–613 Atherosclerosis, 323–325, 324–325 ATP1A3-related dystonia (DYT12), 182 Atrial fibrillation, 399 Attention, assessment, 9 Auditory nerve, 19 Autoimmune autonomic neuropathy, 525–526, 755 Autoimmune encephalitis (AE), 94–95, 95, 751 Autonomic disorders, 751 Autonomic dysfunction, 752 diabetes mellitus, 770 paraneoplastic, 778 Autonomic neuropathies, 753 accommodation reflex, 752–753 anatomy, 749–750 blood pressure and heart rate, 751 clinical features, 752 definition, 749 diagnosis, 753 etiology and pathophysiology, 751–752 investigations, 753–755 medications, 755 physiology, 751 treatment, 755 Autophagic vacuolar myopathies, 858–859 Autosomal dominant cerebellar ataxias (ADCA) brainstem, 602 classification, 597 clinical features, 600, 600 definition, 597 diagnosis, 601 differential diagnosis, 600 disorders of trinucleotide, 597 epidemiology, 597 etiology, 597, 598–599 investigations, 600–601, 601 pathology, 601 pathophysiology, 597, 598–599 prognosis, 602 SCA1, 602–603 SCA2, 603 SCA3, 603–604 SCA6, 604–605 treatment, 601–602 ventral surface, 602 Autosomal recessive cerebellar ataxias, see Friedreich’s ataxia Axillary neuropathy, 799 Axonal degeneration, 42 Axonotmesis, 765–766 Azaspiracid shellfish poisoning (AZP), 649 Azathioprine, 783, 825

Index B Babinski sign, 23 Bacterial neurotoxins botulism, 648 tetanus, 648 Bardet–Biedl syndrome (BBS), 597 Baroreceptors, 751 Basilar-type migraine, 774–775 BBS, see Bardet–Biedl syndrome BDNF, see Brain-derived nerve growth factor Becker’s muscular dystrophy (BMD), 857, 860–861 Beevor’s sign, 21 Behavioral variant of FTD (bvFTD), 541 Behcet’s disease, 332, 333 Bell’s palsy, 680 clinical features, 681 myositis, 846 prognosis, 681 steroid myopathy, 851 treatment, 681 Benign essential tremor (BET), 566 Benign intracranial hypertension, see Idiopathic intracranial hypertension Benign paroxysmal positional vertigo (BPPV), 169 Benzodiazepine and nonbenzodiazepine agonists, 892 Benzodiazepines (BZD), 642, 899 Bereitschaftspotential, 51, 51 Beta-propeller protein-associated neurodegeneration, 185 Bickerstaff’s brainstem encephalitis, 778 Bilateral facial neuropathy, 679, 680 Bilevel positive airway pressure (BiPAP), 902 Bladder and bowel afferent, 751 efferent, 751 dysfunction, 755 Bleeding diatheses and antithrombotic therapy, 350 Blood ammonia levels, 633 coagulation disorders, 340–351 glucose, 390 glucose levels, 770 pressure, 387–388, 390, 397 tests, 316 arterial hypercoagulable state, 376 vascular dementia (VaD), 550 venous hypercoagulable state, 376 Blood coagulation disorders amyloid angiopathy, 346, 346–347 antiphospholipid syndrome (APS), 340–341, 341 arteriovenous fistulae, 349 bleeding diatheses and antithrombotic therapy, 350 cavernous malformations, 349–350 cerebral arteriovenous malformations, 346–349, 347–349 cerebral microbleeds, 351 cerebral venous thrombosis (CVT), 350

917 cryptogenic (of unknown cause) ischemic strokes, 341 deep perforating vasculopathy, 345, 346 embolic stroke of undetermined source, 341–342 etiologic classification of ischemic stroke, 342, 342–343 hemorrhagic transformation of acute brain infarction, 350 infective endocarditis, 350 intracerebral hemorrhage, 343, 343–345, 345 Moyamoya syndrome, 350 multiple intracerebral hemorrhages, 350, 350 primary intraventricular hemorrhage, 351 saccular aneurysms, 350 Borrelia burgdorferi, 788–789 Bortezomib, 771 Botulinum toxin (BTX), 648 Botulism, 428–430, 648, 751, 831–832 clinical features, 429 definition, 428 definition and epidemiology, 831 diagnosis, 429–430, 832 differential diagnosis, 429, 832 electrophysiology, 832 epidemiology, 428 etiology and pathophysiology, 429 food-borne botulism, 831 inadvertent botulism, 831–832 infantile botulism, 831 investigations, 429 pathology, 428 pathophysiology, 832 prognosis, 832 treatment, 430, 832 wound botulism, 831 Bovine spongiform encephalopathy (BSE), 551 Brachial plexopathy, immune-mediated, 786–787 Brain abscess clinical features, 417 definition, 416 diagnosis, 417–418 differential diagnosis, 417 epidemiology, 416 etiology and pathophysiology, 416–417 investigations, 417 pathology, 416 treatment, 418, 419 biopsy, 556 death, 34 ancillary tests for brain death confirmation, 100 communication with family, 100 definition, 99–100 diagnosis, 100 etiology and pathophysiology, 100 intoxication, 649–650 organ procurement organization, 100 imaging scan, 55–56 Brain-derived nerve growth factor (BDNF), 538 Brain iron accumulation syndromes aceruloplasminemia, 185

beta-propeller protein-associated neurodegeneration, 185 fatty acid hydroxylase-associated neurodegeneration, 185 mitochondrial protein-associated neurodegeneration, 185 neuroferritinopathy, 185 pantothenate kinase–associated neurodegeneration, 184–185 PLA2G6-associated neurodegeneration, 185 treatment, 185–186 Woodhouse–Sakati syndrome, 185 Brainstem auditory evoked potentials (BAEPs), 49 Brightness comparison test, 14 Brown–Sequard syndrome, 720 Bulbar muscles, 822 BZD, see Benzodiazepines

C Calculations, mental/written, 12 Calf muscles, 21 California encephalitis viruses, 439 Capsaicin, 771 Carbamazepine, 771 Carbon disulfide, 774 Carbon monoxide poisoning, 109, 109, 645 Cardiac arrhythmias, 107 Cardiac pacing, 755 Carnitine deficiency, 855–856 Carnitine palmitoyltransferase II deficiency, 855–856 Carotid revascularization carotid endarterectomy, 396 carotid stenting, 396 intracranial stenting, 396 vertebral artery stenting, 396–397 Carotid stenting, 396 Carpal tunnel syndrome, 804–805 Cataplexy, 892–893 Catatonia, 201 Catechol-O-methyltransferase (COMT), 570, 571 Catheter contrast angiography, 374, 374–375 Cauda equina, 21, 27 Cavernous malformations, 349–350 Cavernous sinus syndrome definition, 489 diagnosis, 490 differential diagnosis, 490 etiology, 489–490 investigations, 490 pathophysiology, 489 prognosis, 490 treatment, 490 CBD, see Corticobasal disease Celiac disease, 777 Central apneas, 884 Central cord syndrome, 720 Central core disease, 858 Central or transtentorial herniation, 96 Central sleep apnea, 902 Centronuclear myopathy, 841, 858 Cerebellar ataxia, 594; see also Ataxia clinical features, 595 diagnosis, 597

Index

918 differential diagnosis, 595–596, 595–597 investigations, 597 prognosis, 597 treatment, 597 Cerebellar tremor, 190 Cerebellar vermis hypoplasia, 219–220 clinical features, 220 etiology and pathogenesis, 219 investigations, 220 Cerebellar vermis, midline lesions, 24 Cerebral amyloid angiopathy (CAA), 335 Cerebral arteriovenous malformations, 346–349, 347–349 Cerebral cavernous malformations, 389 Cerebral circulation, imaging, 59–60 CT angiography, 59, 59–60, 60 Doppler ultrasound, 59, 59 Cerebral edema, 391, 391–392, 392 Cerebral infarction (ischemic stroke), 95, 322, 322–323 Cerebral microbleeds, 351 Cerebral venous thrombosis (CVT), 96, 350 Cerebrospinal fluid (CSF), 373, 536–537 analysis AIDP, 779 antigen testing, 28 minimum volumes, 27 parameters tested, 28–29 peripheral neuropathies, 769 components, 652 production, 652, 653 shunt and drain infections clinical features, 419–420 definition, 418 diagnosis, 420 differential diagnosis, 420 epidemiology, 418 etiology and pathophysiology, 418–419 investigations, 420 pathology, 418 treatment, 420–421, 421 Cerebrovascular syncope, 108 Cestodes echinococcosis, 454 neurocysticercosis, 452–454 Charcot–Marie–Tooth (CMT) disease, 75, 790–794 Chemotherapy agent, 512 alkylating agents, 505 brain metastases, 523 causing neuropathy, 771–772 cytotoxic, 444 gliomas, 506 intrathecal, 523 platin-based, 518 platinum agents, 772 toxicity, 525 vestibular tumors, 236 Chest X-ray, 368–369, 369, 824 Cheyne–Stokes respiration, 901 Chiari’s malformations, 659, 659–660, 660 Chloroquine/hydroxychloroquine, 773 Cholesterol emboli, 15 Cholinergic toxidrome, 645, 645–646 Cholinesterase inhibitors (CIs), 820 Chorea benign hereditary chorea, 189

chorea-acanthocytosis, 189 C9ORF72 mutations, 189 definition, 186 etiology acquired, 187 differential diagnosis, 188 history, 187 inherited, 186–187 investigations, 188 physical examination, 187–188 prognosis, 188 treatment, 188 Huntington’s disease, 188 pathophysiology, 186 Sydenham’s (rheumatic) chorea, 189 Choroid plexus tumors, 504 Chromosome anomalies, 68–69, 69, 69 Chronic acquired demyelinating polyneuropathy, 780–784 Chronic autonomic neuropathy, 751–752 Chronic idiopathic sensory neuropathy, 752 Chronic inflammatory demyelinating polyneuropathy (CIDP), 770, 780, 780–784, 781, 789 Churg–Strauss syndrome, 784 CIDP, see Chronic inflammatory demyelinating polyneuropathy Cingulate herniation, 96 Circadian mechanism, 880 Circadian rhythm sleep–wake disorders (CRSWDs) advanced sleep–wake phase disorder, 904 delayed sleep–wake phase disorder, 903–904 irregular sleep–wake rhythm disorder, 904–905 jet lag disorder (JLD), 907 non–24-hour sleep–wake rhythm disorder, 905–907 shift work disorder (SWD), 907–908 treatment, 903 Circadian system synchronizing agents, 881 Cisplatin, 772 CJD, see Creutzfeldt–Jakob disease Clinical classification, 317, 319–322 Clinical signs, interpretation, 24–25 Clonus, 21 Clozapine, 575 Cluster headache; see also Headache chronic, 157 clinical features, 156 definition and epidemiology, 156 diagnosis chronic, 157 episodic, 156 differential diagnosis, 156 etiology and pathophysiology, 156 primary short-lasting headache, 157–158 prognosis, 157 secondary headaches, 158 treatment acute attack, 157 preventive, 157 Cobalamin C deficiency and other combined disorders, 276 Cocaine eye drops, 754 Coccidioidomycosis, 448–450 clinical features, 449

definition, 448 diagnosis, 449 differential diagnosis, 449 epidemiology, 448 etiology and pathophysiology, 448 investigations, 449 pathology, 448 treatment, 449–450 Cognitive behavioral therapy for insomnia (CBT-I), 890 Cognitive function, evaluation, 8 Colchicine, 773 Collier’s sign, 18 Colloid cysts, 653–655, 654 Color vision (CV), 12–13 Combined anterior horn cell and corticospinal tract syndrome, 721 Common comorbid disorder with OSA, 900–902 Commonly performed sleep tests maintenance of wakefulness test (MWT), 889 multiple sleep latency test (MSLT), 888 polysomnography, 882–885 portable polysomnography, 885–888 Common peroneal nerve, 812–814 Communicating hydrocephalus, 657–658 Communication, 4–5, 100 Comorbid disorders, common cognitive comorbidities, 123–124 psychiatric comorbidities, 122–123 Complement-mediated lysis of muscle, 820 Complex multifactorial trait inheritance, 78–79 Compound muscle action potential (CMAP), 40–41 Comprehension, testing, 11 Computed tomography or MRI brain scan, 146, 147, 147 COMT, see Catechol-O-methyltransferase Concussion definition and etiology, 292 evaluation, 292 Confrontation testing, 13 Confusional arousals, 908 Congenital disorders, muscular dystrophy, 858–859 Congenital fiber type disproportion, 858 Congenital myasthenic syndrome (CMS), 828, 828–829 Congestive heart failure, 901 Conjunctival telangiectases, 609 Consciousness, disorders of brain death, 99–100 hypoxic–ischemic encephalopathy, 108–111 impaired consciousness, 91–99 locked-in syndrome, 102–103 minimally conscious state, 102 osmotic demyelination syndrome, 111–113 persistent/permanent vegetative state, 101–102 syncope, 103–108 Constipation, 576 Consultation, 4–5

Index Continuous positive airway pressure (CPAP), 886 Continuous vertigo (s-AVS), 165–166 Conus medullaris syndrome, 21 Convergence testing, 17 Coordination, testing, 21–22 Copper deficiency, 776 Copy-number variants (CNVs), 68 C9ORF72 mutations, 189 Cori–Forbes disease, 855 Corneal reflex, 18 Coronary artery disease, 901 Corpus callosotomy, 136 Cortical-based discriminative sensation, 24 Cortical organization disorders clinical features, 227 definition, 226 epidemiology, 226–227 etiology and pathophysiology, 227 investigations and diagnosis, 227 prognosis, 227 treatment, 227 Corticobasal disease (CBD), 541 clinical features, 586, 586 definition, 586 diagnosis, 587 differential diagnosis, 586, 587 epidemiology, 586 etiology, 586 investigations, 587 pathology, 587 pathophysiology, 586 prognosis, 588 treatment, 587–588 Corticobasal syndrome (CBS), 541 Corticosteroid treatment, side effects, 825 Corynebacterium diphtheriae, 789 Cover tests, 16 Cover–uncover test, 16 COVID-19 acute host immune responses, 468 acute neurologic complications, 468–469 ageusia and anosmia, 469 encephalopathy, 468–469 meningoencephalitis, 469 parainfectious complications, 469 postinfectious complications, 469 stroke, 469 chronic neurologic complications, 469 cognitive function, 469 demyelinating disease, 469 current antiviral and anticytokine treatment, 469–470 development of host immunity, 468 diagnostic testing for SARS-CoV-2, 467–468 SARS coronaviruses, 467, 468 Cowden’s syndrome clinical features, 245 definition and epidemiology, 245 diagnosis, 245 etiology and pathogenesis, 245 investigations, 245 prognosis, 246 treatment, 246 CPAP, see Continuous positive airway pressure (CPAP) Cranial encephalocele, 215

919 Cranial nerves assessment, 12–20 III (oculomotor nerve), 706, 707–710, 708 III/IV/VI, 703, 705–707 IV (trochlear nerve), 710–711, 710–711 VI (abducens nerve), 711, 711–713, 712 Craniopharyngioma clinical features, 512 definition and epidemiology, 512 diagnosis, 513 differential diagnosis, 512–513 investigations, 512, 513 pathology, 513 prognosis, 513 treatment, 513 Creatine kinase (CK), 841, 842 Creutzfeldt–Jakob disease (CJD), 29, 455–458, 890 clinical features, 457 definition, 455 diagnosis, 457, 457–458, 458 differential diagnosis, 457 epidemiology, 455–456 etiology and pathophysiology, 456–457 investigations, 457 pathology, 456, 456 treatment, 458 Critical illness myopathy, 849–850 Critical pressure, 900 CRSWDs, see Circadian rhythm sleep–wake disorders Cryoglobulinemia, 785 Cryptococcosis, 446–448 clinical features, 446 definition, 446 diagnosis, 447 differential diagnosis, 446–447 epidemiology, 446 etiology and pathophysiology, 446 investigations, 447 pathology, 446 prognosis, 448 treatment, 447–448 Cryptogenic (of unknown cause) ischemic strokes, 341 CSF analysis, 99 CT angiography, 59, 59–60, 60, 360, 360–361, 361 CT cisternography, 64, 65 CT imaging of brain, 53–55 CT myelography, 67, 67 CT perfusion, 63, 63–64, 364–365, 366, 367, 367 CT venography (CTV) CT cisternography, 64, 65 CT perfusion, 63, 63–64 digital subtraction cerebral angiography, 62–63, 63 magnetic resonance angiography, 60, 61 magnetic resonance venography (MRV), 60, 61–62 Cushing’s syndrome, 842, 851 Cyclophosphamide, 783, 786, 847 Cyclosporine, 826, 843, 847 Cystathionine β-synthase deficiency (CBS), 274 Cytomegalovirus (CMV), 681 Cytosine arabinoside, 771 Cytotoxic edema, 379

D Dandy–Walker malformation clinical features, 220 etiology and pathogenesis, 218–219, 219 investigations, 220 prognosis, 221 treatment, 221 Dapsone, 773 DBS, see Deep brain stimulation Deafness–dystonia–optic neuronopathy syndrome (Mohr–Tranebjaerg), 184 Debranching enzyme deficiency, 855 Deep brain stimulation (DBS), 576–577 Deep breathing, 753 Deep perforating vasculopathy, 345, 346 Deep tendon reflexes, 22 Deflazocort, 861 Delayed sleep–wake phase disorder (DSWPD), 902–904 Dementia assessment, 8 with Lewy bodies clinical features, 545 definition, 545 epidemiology, 545 etiology, 545 pathophysiology, 545 Demyelinating disease, 469 Demyelinating polyneuropathy, 780–781 Demyelination chronic acquired poly neuropathies, 780–784 segmental, 765 Depression, pseudo-dementia, 8 Dermatomyositis, 841, 844 , 846 Developmental diseases of nervous system clinical features, 215–217 anterior closure defects, 215 diagnosis, 216 investigations, 216 prevention, 216 prognosis, 217 spinal dysraphisms, 215–216 treatment, 216–217 embryonic development, 209–211 forebrain defects and cerebral development, 221 hereditary hemorrhagic telangiectasia, 241–248 hindbrain development, defects in, 217–221 malformations, 211–212 neuronal proliferation, disorders of, 223–241 prosencephalic development, disorders of, 221–223 spinal dysraphisms, 212–215 Diabetes mellitus, 755 Diabetic neuropathy, 769–770, 769–771 Diagnosis communication, 4–5 hypothesis, 6–7 questions, 4 Diagnostic process, neurology active listening, 5 body systems review, 6 communication, 4–5 diagnostic questions, 4

Index

920 elements, consultation process, 4 facilitating, 5 family history, 6 hypothetico-deductive system, 4 medications, 6 neurologic history structure functional neurologic disorders, 5–6 problem/complaint, 5 past medical history, 6 pattern recognition, 4 questioning, 5 relevance, 5 smoking and alcohol intake, 6 social history, 6 summarizing, 5 Diarrhetic shellfish poisoning (DSP), 649 Diffuse astrocytic tumors, 503–504 Diffusion-weighted (DWI), 552 Digital subtraction cerebral angiography, 62–63, 63 Diphtheria, 789 Diplopia, 16–17, 821 Disorders of arousals confusional arousals, 908 sleep terrors, 908 sleepwalking (somnambulism), 908 treatment, 909 Disorders of cobalamin (vitamin B12) metabolism, 275, 275–276 Distal acquired demyelinating symmetric neuropathy (DADS), 782–783 Disturbed nocturnal sleep, 893 Disulfiram, 773 Dominant optic atrophy, 704 Donepezil, 539 Dopamine receptors ergot-derived dopamine agonists, 572 nonergot dopamine agonists, 572–573 Dopaminergic drugs, 570 Dopaminergic transplantation strategies, 577 Doppler ultrasound, 59, 59 Dorsal scapular nerve, 796–797 Down’s syndrome, 534 Doxepin, 892 Dropped head syndrome, 822 Drug-induced dyskinesias, 198–199 Drug-induced movement disorders catatonia, 201 clinical features, 201 diagnosis, 201 investigations, 201 neuroleptic malignant syndrome, 199–200 parkinsonism–hyperpyrexia disorder, 201 serotonin syndrome, 200–201 treatment, 200–201 Drusen, 15 Duchenne’s/Becker’s dystrophy, 75 Duchenne’s muscular dystrophy, 857, 860 Duloxetine, 771 Duplex ultrasound, 362–363 Dural arteriovenous fistulae, 389 Dysarthria, 822 Dysautonomia, 575–576 Dyskinesias, 574–575 definition, 198 drug-induced, 198–199

drug-induced movement disorders, 199–201 unusual focal dyskinesias, 198 Dysphagia, 10–11, 822 Dyspraxia, 11–12 Dystonia approach to patient, 179 childhood-onset, 180 classification, 178 clinical features, 180–181 combined, 180 definition, 177 epidemiology, 178 etiologic considerations, 178–179 etiology, 178 examination, 179 history, 179 idiopathic focal isolated dystonia syndromes, 180–181 investigations, 180 pathophysiology, 178 selected combined genetic dystonia syndromes, 181–182 ADCY5-related dystonia, 182 ATP1A3-related dystonia (DYT12), 182 GCH1-associated dystonia (doparesponsive dystonia, Segawa’s disease) (DYT5), 182 HPCA-related dystonia, 182 KMT2B-related dystonia (DYT28), 181 PRKRA-related dystonia (DYT16), 182 SGCE-related dystonia (DYT11), 182 TAF1-related dystonia (DYT3), 182 selected isolated genetic dystonia syndromes, 181 Dystonia–deafness syndrome, 184 Dystonic tremor, 191 Dystrophic neurites, 538 Dystrophin–glycoprotein complex (DGC), 839, 857, 859, 864, 867 Dystrophinopathies, 857, 859–862

E Ear, anatomy of, 682 Eculizumab, 825 Edinger–Westphal nucleus, 751 Edrophonium chloride (Tensilon) test, 822 Efferent fibers, 751 Ehlers–Danlos syndrome type IV, 327 Electrocardiography, 368, 368 Electroencephalography (EEG), 30–39, 99, 126, 126–128, 127 abnormal, 32–38 absent brain waves, 34, 36 artifact, 37 epilepsy/seizures, 37 interpretation, 39–40 normal, 32–34 PLEDs, 38 role, 38–39 sleep, 34 slow waves (delta/theta), 36 technique, 30–32 Electromyography (EMG), 44–48, 767–768 abnormal, 45–46 interpretation, 48 normal, 44–45

radial nerve, 802 role, 47 voluntary muscle activation, 46–47 Embolic stroke of undetermined source, 341–342 Embryonic development of nervous system, 210, 210–211, 211 Emery–Dreifuss muscular dystrophy, 863–864 EMG, see Electromyography Encephalopathic crises, 264 Encephalopathy, hepatic, 39 Endocrine and metabolic myopathies, 850–857 Endocrine disorders, 776, 850–857 Endovascular mechanical thrombectomy efficacy, 385–386 safety, 386 uncertainties, 386 Endovascular therapy, acute ischemic stroke, 401–402 Enhanced physiological tremor, 190–191 Environmental modifier mechanism, 77 Environmental toxins, 563 Eosinophilic meningitis, 454–455 clinical features, 455 definition, 454 diagnosis, 455 differential diagnosis, 455 epidemiology, 454 etiology and pathophysiology, 454–455 investigations, 455 pathology, 454 treatment, 455 Ependymal tumors, 504 Ependymomas, 234, 235 clinical features, 508 definition and epidemiology, 508 diagnosis, 509 differential diagnosis, 508 investigations, 508–509 pathology, 509 treatment, 509 Epilepsy, 263, 263–264 antiepileptic drugs (AEDs), 121, 121–122 classification of seizures, 116, 117–118 common comorbid disorders cognitive comorbidities, 123–124 psychiatric comorbidities, 122–123 diagnosis, 37, 119, 119–120 electroencephalography (EEG), 126, 126–128, 127 neuroimaging studies, 128 neuropsychiatric evaluation, 128 neuropsychological evaluation, 128 new-onset seizures/epilepsy, evaluation of, 125 other diagnostic studies, 128–129 differential diagnosis, 121, 121–122 epidemiology, 116 gender-related variables gender and sexual comorbidities, 124 menstrual disturbances, 124 generalized, 38 neurologic comorbidities dementia, 124 migraines, 124 stroke, 124 palliative surgeries corpus callosotomy, 136

Index neuromodulation therapies, 136–137, 137 pathophysiology, 124–125 patient treatment with newly diagnosed epilepsy choice of ASD, 129, 130, 131, 131, 132 pharmacologic treatment, 129 therapy with intravenous loading, 131–132 premature mortality, 125 status epilepticus (SE), 137–138 evaluation and management of, 137–138 treatment of, 138 treatment-resistant epilepsy definition of, 132–133 patients evaluation, 133–134, 134–135 surgical treatment of, 135, 135–136 Epileptic seizures, 392 Epinephrine, 754 Episodic memory function, 9 Episodic triggered vertigo (t-EVS), 165–166 Episodic vertigo (s-EVS), 165 Epstein–Barr virus (EBV), 681 Essential palatal tremor (myoclonus), 191 Essential tremor, 190 Ethylene oxide, 774 Etiologic classification of ischemic stroke, 342, 342–343 Etoposide, 772 Eulenburg’s disease, 869–870 Evoked potentials, 48–51 BAEPs, 49 bereitschaftspotential, 51 MEPs, 50–51 role, 51 SSEPs, 49–50 VEPs, 48 Excessive daytime sleepiness (EDS), 892 Exophthalmic ophthalmoplegia, 850 Extracranial to intracranial bypass surgery, 397 Extramedullary spinal cord lesions, 721–724, 723–724 Extrinsic myelopathy, see Extramedullary spinal cord lesions Eye cataracts and, 236 examination, 12–18 eyelids, 18 movements, 16–18 seizures, 235 sensory complaints, 235 skin, 235

F Fabry’s disease (FD), 328, 328, 794–795 definition and etiology, 279 diagnosis and investigations, 279 symptoms, 279 treatment, 280 Face–Arm–Speech Test (FAST), 309, 309 Facial muscles, 821, 821 Facial nerve (CN VII) dysfunction, 19 testing, 19 Facial neuropathy (cranial Nerve VII)

921 anatomy, 677, 678 brainstem nuclei, 677 causes, 680 definition, 677 epidemiology, 677 facial canal lesions, 679 motor branches, 678 nuclear and fascicular lesions, 679 nuclear and infranuclear control, 677–678 physical examination, 679 sensory component, 678–679 supranuclear control, 677 supranuclear lesions, 679 Facial recognition, 11 Facial sensation, 18 Facial weakness, 235 Facioscapulohumeral muscular dystrophy (FSHD), 21, 862,863 Familial AD, 534–535 Familial amyloid polyneuropathies, 792 Familial dysautonomia, 752 Familial fatal insomnia (FFI), 552 Family history, 6 Fasciculations, 44–46, 768 Fatal insomnia, 552 Fatty acid hydroxylase-associated neurodegeneration, 185 Femoral nerve, 810 Femoral neuropathy, 809–810 Fibrillation potentials, 44–46 Fibromuscular dysplasia, 327, 328 Finger-nose test, 21–22 Finger-rolling tests, 20 Finger tapping, rapid, 20 Flexor carpi ulnaris, 806–807 Fludrocortisone, 755 Flurazepam, 892 Focal neurologic symptoms, 304–305, 305, 319 Folate, 775 Food-borne botulism, 831 Foot tapping, rapid, 20 Forearm rolling test, 20 FOUR (Full Outline of UnResponsiveness) score, 91 Fourth ventricular obstruction, 656–657, 657 Fragile X-associated tremor/ataxia syndrome, 191 clinical features, 268 definition and etiology, 268 diagnosis, 268–269 Fragile X-associated tremor ataxia syndrome (FXTAS), 611–613 Friedreich’s ataxia; see also Ataxia cerebellar cortex, 608 clinical features, 605 definition, 605 diagnosis, 608 differential diagnosis, 606 epidemiology, 605 gene expression, 605 gene mutation, 605 hexosaminidase A deficiency, 606 history, 605 investigations, 607–608 leukodystrophies, 606 multiple sclerosis, 606

pathology, 608 physical examination, 605–606 prognosis, 609 Refsum’s disease, 606 spinal cord lesion, 607 subacute combined degeneration, 607 syphilitic pachymeningitis, 607 tendon reflexes, 606 treatment, 608 T1W midline sagittal, 607 vitamin E deficiency, 606 Frontal assessment battery (FAB), 10 Frontal lobe function, assessment, 10 Frontal release signs, 10 Frontotemporal dementia (FTD), 588 behavioral variant, 541 brain imaging, 542 clinical features, 541 corticobasal degeneration, 542 definition, 540–541 diagnosis, 543 differential diagnosis, 542 epidemiology, 540–541 etiology, 541 FTD-MND/FTD-ALS, 542 gross brain atrophy, 543 histopathologies, 544 investigations, 542–543 logopenic variant PPA, 541 nonfluent variant PPA, 541 pathology, 543–544 pathophysiology, 541 prognosis, 545 progressive supranuclear palsy, 542 semantic variant PPA, 541 subtypes, 541 treatment, 544–545 Frontotemporal lobar degeneration (FTLD), 543 Functional hyperkinetic movement disorders approach to psychogenic movement disorders, 202 definition, 201 epidemiology, 201 examination, 202 history, 201 Functional MRI, 57 Functional neurologic disorders, 5–6 Fundoscopy, 14 F-wave, 42–43 FXTAS, see Fragile X-associated tremor ataxia syndrome

G Gabapentin, 899 Gadolinium contrast, 316 Gait assessment, 24 Galantamine, 540 Gamma aminobutyric acid (GABA), 539 Gastroparesis, 756 Gaze, six cardinal positions, 16 GCH1-associated dystonia (dopa-responsive dystonia, Segawa’s disease) (DYT5), 182 GCI, see Glial cytoplasmic inclusions Gene conversion, 76, 76–77 Gene therapies, muscular dystrophy, 862

Index

922 Genetic and metabolic neurological diseases, 268 Genome-wide association study (GWAS), 78 Germ cell tumors of CNS clinical features, 517 definition and epidemiology, 517 diagnosis, 517–518 investigations, 517, 517 prognosis, 518 treatment, 518 Germline mosaicism, 75 Gerstmann’s syndrome, 12 Giant cell arteritis, 331, 331–332 Glasgow Coma Scale, 91 Glial cytoplasmic inclusions (GCI), 580 Glioblastoma multiforme and anaplastic astrocytoma, 505–506 clinical features, 505 diagnosis, 505 investigations, 505 pathology, 505, 505 treatment, 505–506 Gliomas classification by cell of origin, 503–504 choroid plexus tumors, 504 diffuse astrocytic tumors, 503–504 ependymal tumors, 504 oligodendroglial tumors, 504 definition, 503 epidemiology, 504, 504 pathogenesis, 504–505 Globus pallidus (GPi), 564 Globus pallidus externus (GPe), 564 Glossopharyngeal nerve (CN IX), 19 Glossopharyngeal neuralgia, 687 Glossopharyngeal neuropathy (cranial nerve IX), 685, 685–687, 686 Glucose blood levels, 770 CSF, 28 Gluteal neuropathy, 811 Gluten-sensitive enteropathy, 777 Glycogen metabolism disorders, 852–855 Gottron’s papules, 844–845 GPe, see Globus pallidus externus GPi, see Globus pallidus Granulomatosis, Wegener’s, 784 Grasp reflex, 10 Graves’ eye disease, 703 Guillain–Barré syndrome, 771, 778–780, 789, 795

H Hallucinations, 893 Hamartomas, 234, 235 Hammer, 22 Hand mononeuropathies, 802–808 movements, alternating, 10 Hashimoto’s encephalopathy (HsE), 637–638 Headache cluster headache, 156–158 definition and etiology clinical classification and prevalence of, 144, 144–145 definition and etiology, 144 etiology of, 145

physical examination, 145, 145 diagnosis and investigations, 147, 148 computed tomography or MRI brain scan, 146, 147, 147 differential diagnosis primary headache disorders, 146, 146 secondary headaches, 146, 146 lumbar puncture patients, 27–28 migraine, 148–155 tension-type headache, 155–156 treatment, 147 Head impulse test, 18 Head injury definition and etiology, 286 diagnosis and investigations, 289–290 etiology and clinical features, 286, 286–289, 287–288 management, 290–292 emergency department, 290 intensive care unit, 290–291 prehospital management, 290 surgical decompression, 291 Health care access and quality (HAQ) index, 81 Health care transformation evidence-based medicine and clinical guidelines, 84 in high-income countries, 84, 84–85 leadership, 83 medical waste, 83–84 payment models, 84, 84 strategic development, 83 team or interdisciplinary care, 83 triple aim, 83 Hearing assessment, 19 loss and vestibular complaints, 235 Heart diseases, 336–337 atrial fibrillation, 336–337, 337 infective endocarditis, 338, 338 intracardiac tumors, 339 left ventricular mural thrombus, 339, 339 nonbacterial thrombotic (marantic) endocarditis, 339 paradoxical embolism, 339 patent foramen ovale, 339, 340 sinoatrial disease (sick sinus syndrome), 339 valvular heart disease, 337–338 Heart rate (HR), 753 Heart rhythm, 376 Heavy metals, 774–775 Heel-knee-shin test, 22 “Heel-to-toe” walking, 24 Hemispatial neglect, 11 Hemorrhage, lumbar puncture, 26, 28 Hemorrhagic stroke intracerebral hemorrhage, 310, 310 patients, preventing stroke in, 400 subarachnoid hemorrhage, 310, 310 Hemorrhagic transformation, acute brain infarction, 350 Hepatic encephalopathy (HE), 39 blood ammonia levels, 633 cerebrospinal fluid, 631–632 clinical features, 631 definition, 630 diagnosis, 632

EEG, 631 epidemiology, 630 etiology, 630 imaging, 631 neurotoxins, 630–631 pathology, 632–633 pathophysiology, 630 possible mechanisms, 630 precipitating factors, 630 prognosis, 633 signs of comorbidities, 631 treatment, 633 triphasic morphology, 632 T1W axial, 632 West Haven classification, 631 Hereditary and metabolic diseases, CNS in adults acute intermittent porphyria, 272–273 adult neuronal ceroid lipofuscinoses, 277 chronic presentations epilepsy, 263, 263–264 neurodegeneration, 259, 261–262 diagnostic approach, 254–267 acute encephalopathy, 254, 254–256, 256–257 psychiatric symptoms, 257, 259, 260–261 stroke, 257, 258–259 Fabry’s disease, 279–280 Fragile X-associated tremor/ataxia syndrome, 268–269 genetic and metabolic neurological diseases, 268 homocystinurias and disorders of cobalamin metabolism, 273–276 Lafora’s body disease, 276–277 late-onset GM2 gangliosidosis, 277–278 late-onset Krabbe’s disease, 278–279 late-onset metachromatic leukodystrophy, 278 mitochondrial disorders, 280–281 mitochondrial DNA, diseases of, 281–282 movement disorders, 264, 264–265, 266, 267 neurodiagnostic evaluation, 253–254 Niemann–Pick type C, 280 pantothenate kinase–associated neurodegeneration, 270–271 Wilson’s disease, 271–272 X-linked adrenoleukodystrophy, 269 Hereditary ataxias, see Cerebellar ataxia Hereditary hemorrhagic telangiectasia Cowden’s syndrome, 245–246 hypomelanosis of ITO, 247–248 incontinentia pigmenti, 246–247 Lhermitte–Duclos disease, 245–246 linear nevus sebaceous syndrome, 244 Osler–Rendu–Weber syndrome, 241–244 PTEN hamartoma tumor syndrome, 245–246 Von Hippel–Lindau disease, 246 Hereditary motor sensory neuropathy (HSMN1), 75 Hereditary neuropathies, 793–794 Hereditary neuropathy with tendency to pressure palsies (HNPP), 75 Hereditary spastic paraplegia, 733, 733–735, 735

Index Heredity/genetic susceptibility, 563 Heredodegenerative parkinsonism clinical features, 588 definition, 588 differential diagnosis, 588, 588–589 epidemiology, 588 etiology, 588 pathophysiology, 588 Herpes simplex virus (HSV), 681 Herpesviruses, 436–437, 437–438 Herpes zoster oticus, 681–682 Hexacarbons, 774 Highly active antiretroviral therapy (HAART), 790 Hindbrain developmental defects Arnold–Chiari malformations, 218–221 cerebellar vermis hypoplasia, 219–220 Dandy–Walker malformation, 218–221 definition, 217 epidemiology, 217 etiology and pathogenesis, 217–218 Joubert’s syndrome, 219–221 History, 6–7 HIV/AIDS, 434, 789–790 neuropathy, 789–790 HMG-CoA reductase inhibitors (statins), 773 Holmes’ tremor (midbrain or rubral tremor), 190 Holoprosencephaly, 221 alobar, 221, 221, 222, 222 lobar, 221–222 semilobar, 221–222, 222 Home sleep apnea test (HSAT), 888 Homocystinurias and disorders of cobalamin metabolism, 273 cobalamin C deficiency and other combined disorders, 276 cystathionine β-synthase deficiency (CBS), 274 disorders of cobalamin (vitamin B12) metabolism, 275, 275–276 isolated methionine synthase dysfunction, 276 methylenetetrahydrofolate reductase deficiency, 274–275 treatment, 274 Horner’s syndrome, 751–752 HPCA-related dystonia, 182 H-reflex, 43 Human immunodeficiency virus (HIV)associated neuropathy, 752 Huntington’s disease, 188 Hyperhydrosis, 576 Hyperkalemic periodic paralysis, 868, 870 Hyperkinetic movement disorders chorea, 186–189 drug-induced movement disorders, 199–201 dyskinesias, 198–199 dystonia, 177–182 EMG testing, 47 etiologic classification and differential diagnosis, 177 acquired, 177 inherited, 177 functional hyperkinetic movement disorders, 201–202 myoclonus, 192–196

923 neurodegeneration with brain iron accumulation syndromes, 184–186 paroxysmal dyskinesia syndromes, 183–184 tics, 196 Tourette’s syndrome, 196–198 tremor, 189–192 Hyperparathyroidism, 851–852 Hypersomnias, 895 cataplexy, 892–893 idiopathic hypersomnia, 894–895 insufficient sleep syndrome, 895–896 Kleine–Levin syndrome, 895 narcolepsy type 1, 892 narcolepsy type 2, 893–894 sleep paralysis, 893 Hypertensive encephalopathy, 636–637 Hyperthermia, malignant, 858, 860, 871–872 Hypnic headache, 157–158 Hypnic (physiologic) myoclonus, 899 Hypoadrenalism, 851 Hypoglossal nerve (CN XII), 20 Hypoglossal neuropathy (cranial nerve XII), 690, 690–691 Hypokalemic periodic paralysis, 850, 870–871 Hypomelanosis of ITO clinical features, 248 definition and epidemiology, 247–248 diagnosis, 248 etiology and pathogenesis, 248 investigations, 248 prognosis, 248 treatment, 248 Hypomyelination with basal ganglia and cerebellar atrophy (H-ABC) syndrome, 184 Hypopneas, 884 Hypothyroidism, 776, 841–842, 851 Hypotropia, 16 Hypoxic–ischemic encephalopathy, 93, 108–111 clinical features delayed postanoxic encephalopathy, 110 mild hypoxia, 109 moderate hypoxia, 109 severe and sustained hypoxia, 109 severe but not sustained hypoxia, 109 definition and epidemiology, 108 diagnosis carbon monoxide poisoning, 109, 110 hypoxic encephalopathy, 110 differential diagnosis, 110 etiology, 109 imaging, 110 investigations, 110 pathophysiology, 108 acute, global brain hypoxia and/or hypoperfusion, 108, 108 delayed postanoxic encephalopathy, 108 prognosis biochemical markers, 111 clinical factors, 111 neuroimaging, 111, 111 neurophysiologic tests, 111 treatment carbon monoxide poisoning, 111 postcardiac arrest, 110–111

I Ibuprofen, 755 Ice pack test, 822 Idiopathic focal isolated dystonia syndromes, 180–181 Idiopathic hypersomnia, 894–895 Idiopathic inflammatory myopathy, 842–849 Idiopathic intracranial hypertension (IIH), 662–664, 664 Idiopathic PD, 567–568 Idiopathic RBD (iRBD), 911 Ifosfamide, 772 Immune-mediated brachial plexus neuropathy, 786–787 Immune-mediated necrotizing myopathy (IMNM), 845–846 Immunoglobulin G4 autoantibodies, 783–784 Immunoglobulin G (IgG) autoantibodies, 820 Immunosuppressive therapy, 782, 783, 844, 845 Impaired consciousness, 91–99 classification, 91 clinical assessment, 97 general appearance, 98 neurologic function, 98–99 physical examination, 97 respiratory, 98 vital signs, 98 definition, 91 etiologic classification, 93 autoimmune encephalitis (AE), 94–95, 95 hypoxic–ischemic encephalopathy, 93 meningoencephalitis, 94, 94 nonvascular causes, 96 Prion diseases (transmissible spongiform encephalopathies), 95, 95 psychogenic causes, 96 seizures and status epilepticus, 95 toxic metabolic encephalopathy, 93–94 vascular causes, 95 hypoxic–ischemic encephalopathy, 93 investigations, 99 CSF analysis, 99 EEG, 99 laboratory assessment, 99 pathophysiology, 91–93, 92–93 prognosis, 99 structural lesions, 96 supratentorial brain shift, patterns of, 96–97 toxic metabolic encephalopathy, 93–94 Impotence, 576 Imprinting, neurogenetics, 72–74 Impulse control disorders, 575 IMS, see Intermediate syndrome Inadvertent botulism, 831–832 Inclusion body disorders, 841, 847–849 Incomplete penetrance, 77 Incontinentia pigmenti clinical features, 246–247 definition and epidemiology, 246 diagnosis, 247 etiology and pathogenesis, 246, 246 investigations, 247 prognosis, 247 treatment, 247

Index

924 Industrial agents, 774 Infantile botulism, 831 Infectious myelopathy, 725–728, 726, 727 Infectious neuropathy diphtheria, 789 HIV, 789–790 leprosy, 787–788 Lyme disease, 788–789 Infective endocarditis, 350 Inflammatory bowel disease, 777 Inflammatory disorders of nervous system acute disseminated encephalomyelitis, 475–477 acute hemorrhagic leukoencephalitis, 477 acute necrotizing encephalopathy/ acute hemorrhagic necrotizing encephalopathy, 477 cavernous sinus syndrome and orbital inflammatory disease, 489–490 multiple sclerosis, 477–486 neuromyelitis optica spectrum disorder (Devic’s disease), 486 neurosarcoidosis, 486–489 Inflammatory myelopathy, 724, 724–725, 725 Infratentorial ICH, 389 Inherited metabolic disorder, 257 Insertion/deletion from unequal crossover, 75–76 Insomnia disorder clinical features, 890 definition, 889 diagnosis, 890 epidemiology, 889 etiology and pathophysiology, 889 FDA-approved medications for, 891 pathology, 890 treatment, 890–892 Insufficient sleep syndrome, 895–896 Intermediate syndrome (IMS), 646 Internet resources, 3 Intoxication-type metabolic disorder, 257, 259 Intracavernous schwannoma of V1, 674 Intracerebral hemorrhage, 343, 343–345, 345 Intracranial aneurysms, 402, 403–404 Intracranial hemorrhage, 95, 96 Intracranial neoplasm, 97 Intracranial pressure (ICP), elevation (hypertension), 7 Intracranial stenting, 396 Intramedullary spinal cord lesions, 724–728 Intraneuronal pathology, 569 Intravenous immunoglobulin (IVIG), 770, 779–780, 782, 846 Intraventricular ICH, 389 Intrinsic airway obstruction, 900 Intrinsic myelopathy, see Intramedullary spinal cord lesions Ionic edema, 379 Irregular sleep–wake rhythm disorder (ISWRD), 902, 904–905 Isolated arteritis/vasculitis, 332 Isolated focal tremor, 191 Isolated methionine synthase dysfunction, 276 Isolated position-specific or task-specific tremors, 191 Isometric contraction, 754 Isoniazid, 773

J Jaw jerk, 19 Jet lag disorder (JLD), 902, 907 JLD, see Jet lag disorder Joubert’s syndrome, 594, 594, 594–597 clinical features, 220 etiology and pathogenesis, 219, 219 investigations, 220 prognosis, 221 treatment, 220 Juvenile dystonic lipidosis, 606

K Kayser–Fleischer ring, 16, 180, 183, 271, 271, 631 Kearns–Sayre syndrome (KSS), 282, 857 Kennedy’s syndrome, 745–746, 746 Kernig’s sign, 414 Kernohan’s notch, 92 Kleine–Levin syndrome, 895 KMT2B-related dystonia (DYT28), 181 Korsakoff syndrome, 535, 628 Kuru plaques, 557

L Lafora’s body disease clinical features, 276 definition and etiology, 276 diagnosis and investigations, 276–277 treatment, 277 Lambert–Eaton myasthenic syndrome (LEMS), 44, 526, 751, 829–831 clinical features, 830 definition, 829 differential diagnosis, 830–831 epidemiology, 829 investigations and diagnosis, 830 pathophysiology, 829–830 treatment, 831 Lamotrigine, 771 Lance–Adams syndrome, 195 Language assessment, 11 Large artery diseases, 323, 323 Late-onset AD, see Sporadic AD Late-onset GM2 gangliosidosis definition and etiology, 277, 277–278 Sandhoff’s disease, 278 Tay–Sachs disease, 278 Late-onset Krabbe’s disease, 278–279 Late-onset metachromatic leukodystrophy, 278 Lateral femoral cutaneous neuropathy, 808–809 Lead toxicity, 647, 774–775 Leber’s hereditary optic neuropathy (LHON), 281, 704 Left atrial appendage closure, 399–400 Left hemisphere function, 11–12 Lemborexant, 892 Leprosy, 787–788 Leukodystrophies, 606 Levator palpebrae superioris dehiscence, 18 Levodopa, 570–572 formulations, 571 metabolism, 570–571, 571 symptoms, 571–572

Lewy body dementia (LBD) AD relationship, 547 cognitive decline, 545–546 definition, 581 delusions and hallucinations, 546 diagnosis, 546 differential diagnosis, 545–546 epidemiology, 581 FDG-PET, 546 investigations, 546 multiple, 547 pathology, 547–548 prognosis, 548 transient loss, 546 treatment, 548 Lhermitte–Duclos disease clinical features, 245 definition and epidemiology, 245 diagnosis, 245 etiology and pathogenesis, 245 investigations, 245 prognosis, 246 treatment, 246 LHON, see Leber’s hereditary optic neuropathy Lid lag, 18 Lidocaine topical, 771 Lid retraction, 18 Light reflex, 751–752 Limb fatigue, 822 Limb-girdle dystrophies, 864–867 Linear nevus sebaceous syndrome, 244 Lipid metabolism disorders, 855–856 Lissencephaly 1 clinical features, 225 definition, 223–224 epidemiology, 224 etiology and pathophysiology, 225 Liver disease, neuropathy, 776 LMN, see Lower motor neuron Local sweating, 754 Locked-in syndrome, 102–103 definition, 102 etiology and pathophysiology clinical features, 103 diagnosis, 103 investigations, 103 polyneuropathy, 102–103 prognosis, 103 treatment, 103 ventral brainstem (bilateral midbrain or upper pontine) lesion, 102, 102 Long loop reflex, 43 Long thoracic nerve dysfunction, 797–798 Louis–Bar syndrome, 609–611 Low-density-lipoprotein (LDL), 534 Lower extremity neuropathy, 808–816 Lower motor neuron (LMN), 720 Low-grade glioma: astrocytoma, oligoastrocytoma, and oligodendroglioma clinical features, 507 definition and epidemiology, 507 diagnosis, 507 investigations, 507, 507 pathology, 507–508, 508 prognosis, 508 treatment, 508

Index Lumbar puncture (LP), 25–29 complications, 28 contraindications, 26 headache patient, 27–28 indications, 26 problems, 27 technique, 26 Lumbosacral plexus, 770, 808 Lumbosacral radiculoplexus neuropathy, 770 Luria three-step test, 10 Lyme disease, 424–426, 788–789 clinical features, 425, 426 definition, 424 diagnosis, 425 differential diagnosis, 425 epidemiology, 424 etiology and pathophysiology, 424–425 investigations, 425 pathology, 424 treatment, 425–426

M Macroglossia, 900 Macula, examination, 15 Magnetic resonance angiography, 60, 61, 361, 361–362, 362 Magnetic resonance imaging (MRI), 4, 28, 49–51, 56–58, 65, 66, 536 advantages, 56, 56 brain scan, 359–360 contraindications, 56 functional, 57 spectroscopy, 58, 58 spinal, 781 spine imaging, 65 tissues, appearances of, 56, 56–57, 57 Magnetic resonance venography (MRV), 60, 61–62 Main immunogenic region (MIR), 820 Maintenance of wakefulness test (MWT), 889 Malignant hyperthermia, 858, 871–872 Mammalian master clock, 880–881 Manganese transporter deficiency syndrome, 184 MAO-B, see Monoamine oxidase type B Marchiafava–Bignami disease, 627–628 Marfan’s syndrome, 327–328 Martin–Gruber anastomosis, 803, 804 Masticatory muscles, 18 McArdle’s disease, 853–854 Mechanical heart valves, 399 Median nerve, 41–42, 50, 802–805 Median neuropathy, 805 Medical history, 6, 8 Melatonin, 881, 892 Memantine, 540, 575 Memory, assessment, 9 Mendelian inheritance, 69–71, 70 Ménière’s syndrome, 168 Meningioma clinical features, 510 definition and epidemiology, 509 diagnosis, 511 differential diagnosis, 510 etiology, 509 investigations, 510–511

925 cerebral angiography, 511, 511 CT brain, 510, 510 MRI brain, 510–511, 511 pathology, 511, 511–512 prognosis, 512 treatment, 512 Meningoencephalitis, 94, 94, 469 Mental arithmetic, 754 Mental state, assessment, 8–10 Mercury toxicity, 775 Mestinon, 755 Metabolic and toxic myelopathies, 728–729 Metabolic disorders, 104, 180, 198, 254, 257, 596, 752 Metacholine, 754 Metals heavy, 774–775 poisoning arsenic, 648 lead, 647 mercury, 647–648 Metastases to CNS clinical features, 521 definition and epidemiology, 520–521 diagnosis, 522 differential diagnosis, 521 etiology and pathophysiology, 521 investigations, 521, 521–522 pathology, 522 prognosis, 523 treatment, 522–523 Methotrexate, 782, 783 Methylenetetrahydrofolate reductase deficiency, 274–275 Metoclopramide, 755 Metronidazole, 773 Mexiletine, 771 Microaneurysms, 15 Micrognathia, 900 Microscopic polyangiitis, 784 Migraine, 169–170; see also Headache abrupt onset of headache primary, 151 secondary, 151 unilateral headache, 151 aura and headache, 150 and brain, 149, 149 brainstem aura, 151 in childhood, 151 clinical features, 150 continuous or daily headache primary, 151 secondary, 151 definition, epidemiology, and etiology, 148 with aura, 149 chronic, 149 familial hemiplegic migraine (FHM), 149 ophthalmoplegic migraine, 150–151 diagnosis, 152 hemiplegic migraine, 151 investigations, 152 menstrual migraine, 151, 154 migraine aura without headache, 151 migrainous infarction, 151 pathophysiology, 149 pattern attack features, 150

phase one: premonitory, 150 phase two: aura, 150 phase three: headache, 150 phase four: postdrome, 150 quality, 150 site, 150 prevention nonpharmacologic, 153 pharmacologic, 153–154, 154 prognosis, 154–155 putative triggers, 149 treatment of acute migraine attack, 152 ditans, 153 gepants, 153 neuromodulation approaches, 153 second-generation triptans, 153 sumatriptan – the first triptan, 152–153 triptans, 152 without aura, 148–149 Miller Fisher syndrome (MFS), 778 Minimally conscious state, 102 Mini-Mental State Examination (MMSE), 8 Misonidazole, 772 Mitochondrial deletion syndromes, 282 Mitochondrial disorders, 280–281, 856–857 Mitochondrial DNA diseases definition and etiology, 281 Kearns–Sayre syndrome, 282 Leber’s hereditary optic neuropathy, 281 mitochondrial deletion syndromes, 282 mitochondrial encephalomyopathy, 281 mitochondrial encephalopathy, 281 neurogenic weakness with ataxia and retinitis pigmentosa, 281 Pearson’s syndrome, 282 progressive external ophthalmoplegia, 282 subacute necrotizing encephalomyelopathy, 282 Mitochondrial inheritance, 74–75, 75 Mitochondrial protein–associated neurodegeneration, 185 Mixed apneas, 884, 885 Mixed dementia, 548 Mmarcus gunn pupil, 696 Mobile phone, 3, 13 MoCA, see Montreal Cognitive Assessment Modified Rankin Scale Score, 317, 317 MOG-ON, see Myelin oligodendrocyte glycoprotein optic neuritis Monitoring of heart rate and rhythm, 368 Monoamine oxidase type B (MAO-B), 573 Monoclonal antibodies, 783 Mononeuropathies, 765, 796 diabetic, 770 lower extremity, 808–816 upper extremity, 796–808 Montreal Cognitive Assessment (MoCA), 8, 9, 536 Mood disorders, 575 Mosaicism, 75 Motor evoked potentials (MEPs), 50–51 Motor impairment, 235 Motor neuron disorders, 824 Motor system, assessment, 20–25 Motor unit, 768

Index

926 Motor unit action potential (MUP), 44–45, 768–769 Movement disorders, 264, 264–265, 266, 267 Moyamoya disease and syndrome, 328, 328–329, 329–330, 350, 402 MRI, 56–58, 65, 66; see also Magnetic resonance imaging advantages, 56, 56 brain scan, 359–360 contraindications, 56 functional, 57 spectroscopy, 58, 58 spine imaging, 65 tissues, appearances of, 56, 56–57, 57 MRI spectroscopy (MRS), 58, 58 MR perfusion, 367 MSLT, see Multiple sleep latency test Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), 783 Multifocal motor neuropathy (MMN), 782, 783 Multiminicore disease, 858 Multiple additive genes for same disease, 77–78 Multiple intracerebral hemorrhages, 350, 350 Multiple sclerosis (MS), 48–49, 751 altered sensation of face, trunk, or limbs, 479 clinical features, 478 definition, 477 differential diagnosis acute noncompressive spinal cord syndrome, 480 chronic noncompressive spinal cord syndrome, 480–482 multifocal neurologic syndrome, 480 optic neuropathy, 480 double vision, 479 epidemiology, 477–478 epileptic seizures, 479 etiology, 478 fatigue, 479 mental changes, 479 pain, 479 pathology, 478 pathophysiology, 478 reduced visual acuity, 478 sphincter and sexual disturbances, 479 treatment primary or secondary progressive MS, 484 relapsing–remitting MS, 482–484 symptomatic relief, 484 unsteady gait, 479 vertigo, 479 weakness in one or more limbs or face, 478 Multiple sleep latency test (MSLT), 888, 888 Multiple system atrophy (MSA), 751 alpha-synuclein, 580 autonomic failure, 579 cerebellar ataxia, 579 clinical features, 578 diagnosis, 578, 580 differential diagnosis, 578–579 dystonic symptoms, 578 etiology, 578 investigations Axial T2-weighted image, 579

cardiovascular autonomic function tests, 580 CT brain scan, 579 gastrointestinal testing, 580 MRI brain, 579 PET, 580 respiratory testing, 580 thermoregulatory testing, 580 transcranial ultrasonography, 580 urologic testing, 580 pathology, 580–581 pathophysiology, 578 prognosis, 581 pyramidal signs, 579 treatment, 581 Multisystem degenerations (parkinsonism plus/atypical parkinsonism), see Multiple system atrophy Muscle biopsy, 769 carnitine deficiency, 855 channelopathies, 869–872 myopathic changes, 842 power, 19–20 structure, 839–840 tone, 20 Muscle fiber action potential (MFAP), 820 Muscle-specific receptor tyrosine kinase (MuSK), 820 Muscular dystrophy, 21, 45, 46, 857–872 congenital, 858–859 dystrophinopathies, 857, 859–862 Emery–Dreifuss, 863–864 fascioscapulohumeral, 862–863 limb-girdle, 864–867 Musculocutaneous nerve, 787 Musculocutaneous neuropathy, 799–800 M-wave, 42, 43 MWT, see Maintenance of wakefulness test Myasthenia gravis (MG), 820–828 clinical features, 18, 821–822 definition, 820 differential diagnosis, 824 epidemiology, 820 immunotherapy in, 826 investigations and diagnosis, 822–824 pathophysiology, 820–821 in pregnancy, 827 short-term immunotherapy, 827 transient neonatal, 827 treatment, 828 cholinesterase inhibitors – pyridostigmine, 824–825 chronic immunotherapy, 825 corticosteroids, 825 cyclosporine, 826 eculizumab, 825–826 rituximab, 827 tacrolimus, 826 thymectomy, 825 Myasthenic crisis, 822 Myasthenic snarl, 821 Mycophenolate mofetil (MMF), 782, 783, 825 Myelin, 765 Myelin oligodendrocyte glycoprotein optic neuritis (MOG-ON), 699 Myelopathy

clinical myelopathy syndromes, 720–721 etiology, 719, 719–720, 720 spinal cord lesions, 720 Myeloradiculopathy syndrome, 720 Myoclonus classification, 192 definition, 192 etiology, 193–194 epileptic myoclonus, 193 focal cerebral injury, 193–194 generalized multifocal myoclonus with encephalopathy, 193 Myoclonus–dystonia, 193 paraneoplastic and autoimmune encephalopathies, 194 physiological myoclonus, 193 progressive myoclonic ataxia, 193 progressive myoclonic epilepsy, 193 symptomatic myoclonus, 193 familial cortical tremor and epilepsy, 195 hereditary hyperekplexia, 195 neurodegenerations, 194–195 approach to the patient with myoclonus, 194 basic tests, 194 dementia with myoclonus, 194 electrophysiological tests, 194–195 examination, 194 history, 194 investigations, 194 leukodystrophies, 194 motor syndromes, 194 startle syndromes, 194 opsoclonus–myoclonus syndrome, 195 orthostatic myoclonus, 195 physiological classification based on anatomical site of origin, 192–193 posthypoxic myoclonus, 195 special syndromes, 195 startle syndromes, 195 treatment, 195–196 Myofibers myopathic changes, 842 structure, 839–840 Myokymia, 46 Myopathy, 841–842 congenital, 858–859 critical illness, 849–850 endocrine, 850–857 inflammatory, 841, 842–849 metabolic, 850–857 mitochondrial, 856–857 patterns of weakness, 841 Myositis, 846 Myotonia congenita, 868, 869 Myotonias, 18, 21, 46, 869–870 Myotonic dystrophy, 841, 867–869

N Narcolepsy associated conditions, 893 diagnosis, 893–894 medications, 894 type 1, 892 type 2, 893–894 National Institutes of Health Stroke Scale (NIHSS), 316, 316

Index National Poison Data System (NPDS), 641 Nausea, 575 Neck muscle power, 21 and oropharyngeal muscle weakness, 822 Necrotizing muscle disease, 45 Nemaline myopathies, 858 Neoplasia clinical features, 498 definition and epidemiology, 496 differential diagnosis for nervous system neoplasms, 498 incidence, 496 investigations, 498–499 biopsy/resection and surgical interventions, 499–500 computed tomography, 498–499 lumbar puncture, 499 MRI of the brain/spine, 499 positron emission tomography (PET) imaging, 499 pathology, 496, 496–498, 497 risk factors for developing nervous system tumors, 496 treatment, 499–503, 501 adverse effects, 502–503 medical therapy, 500–501 radiation therapy, 501–502 Nerve biopsy, 769 chronic inflammatory demyelinating polyneuropathy, 770, 780–782 hereditary neuropathies, 794 vasculitic neuropathy, 785–786 Nerve conduction studies (NCS), 40–44, 766–767, 767 axillary nerve, 799 axonal degeneration, 42 brachial plexopathy, 787 chronic inflammatory demyelinating polyneuropathy, 780–781 demyelinating polyneuropathy, 780–781 femoral nerve, 810 F-wave, 42–43 GBS, 778 hereditary neuropathies, 793–794 H-reflex, 43 long loop reflex, 43 median neuropathy, 805 motor, 40–41 multifocal motor neuropathy, 782 musculocutaneous nerve, 787 neuronopathy or primary nerve cell degeneration, 42 peroneal nerve, 813 radial neuropathy, 802 repetitive stimulation, motor nerves, 43–44 segmental demyelination, 42 sensory, 41–42 technique, 40 tibial nerve, 815 ulnar neuropathy, 807 vasculitic neuropathy, 785 Wallerian degeneration, 42 Nerve fibers, myelination, 765 Nerve growth factor (NGF), 538 Nervous system diseases, tools for diagnosis and management of brain imaging scan, 55–56

927 cerebral circulation, imaging, 59–60 CT imaging of brain, 53–55 CT venography (CTV), 60–65 imaging spine, 65–67 MRI, 56–58 positron emission tomography (PET), 58 precautions, 55 single photon emission tomography (SPECT), 58 technique, 54, 54–55, 55 Nervus intermedius, 679 Neurally mediated reflex syncope, 107 Neurapraxia, 765 Neuritic plaque, 538 Neurocognitive dysfunction, 901 Neurocutaneous disorders, mTOR pathway activation, 227, 228 Neurocysticercosis clinical features, 453 definition, 452 diagnosis, 453 differential diagnosis, 453 echinococcosis, 454 epidemiology, 452 etiology and pathophysiology, 452–453 investigations, 453 pathology, 452 treatment, 453–454 Neurodegeneration, 259, 261–262 with brain iron accumulation syndromes aceruloplasminemia, 185 beta-propeller protein-associated, 185 fatty acid hydroxylase-associated, 185 mitochondrial protein-associated, 185 neuroferritinopathy, 185 pantothenate kinase–associated, 184–185 PLA2G6-associated, 185 treatment, 185–186 Woodhouse–Sakati syndrome, 185 Neurodegenerative Parkinsonian disorders, 562 Neurodegenerative toxicities carbon monoxide, 645 nitrous oxide, 644–645 peripheral neuropathies, 645 toxic leukoencephalopathy, 645 Neurodiagnostic evaluation, 253–254 Neurofascin-155 (NF155), 783–784 Neuroferritinopathy, 185 Neurofibrillary tangles (NFTs), 535, 539 Neurofibromatosis type 1, 329 clinical features, 228–229 brain, 229–230 cardiovascular, 230 eye, 230 skeletal/orthopedic, 230–231 skin, 229 definition and epidemiology, 228 endocrine/growth, 231 etiology and pathogenesis, 228 investigations, 232 brain, 232 cardiovascular, 232 eye, 232 skeletal/orthopedic, 232

malignancies, 231–232 prognosis, 233 treatment, 233 Neurofibromatosis type 2 clinical features, 234–235 facial weakness, 235 hearing loss and vestibular complaints, 235 motor impairment, 235 definition and epidemiology, 234 diagnosis, 235–236 ependymomas and hamartomas, 234, 235 etiology and pathogenesis, 234 eye, 235 seizures, 235 sensory complaints, 235 skin, 235 investigations, 235 meningiomas, 234, 234 prognosis, 236 schwannoma, 234, 234 treatment cataracts and eyes, 236 ependymomas, 236 genetic counseling, 236 hearing loss, 236 meningiomas, 236 vestibular tumors, 236 Neurogenetics chromosome anomalies, 68–69 complex multifactorial trait inheritance, 78–79 environmental modifier mechanism, 77 gene conversion, 76–77 imprinting, 72–74 incomplete penetrance, 77 insertion/deletion from unequal crossover, 75–76 Mendelian inheritance, 69–71 mitochondrial inheritance, 74–75 mosaicism, 75 multiple additive genes for same disease, 77–78 non-Mendelian patterns of inheritance, 71–72 Neuroinfectious diseases acute bacterial meningitis, 412–416 aseptic meningitis, 432–435 botulism, 428–430 brain abscess, 416–418 cerebrospinal fluid shunt and drain infections, 418–421 cestodes: neurocysticercosis and echinococcosis, 452–454 coccidioidomycosis, 448–450 Creutzfeldt–Jakob disease (CJD), 455–458 cryptococcosis, 446–448 eosinophilic meningitis, 454–455 Lyme disease, 424–426 neurosyphilis, 421–424 poliomyelitis, 441–443 progressive multifocal leukoencephalopathy, 443–446 rabies, 439–441 tetanus, 430–432 Toxoplasma gondii, 450–452 tuberculosis, 426–428 viral encephalitis, 435–439

Index

928 Neuroleptic malignant syndrome, 199–200 Neurological systems of care South Korea, 85–86 stroke systems of care, 85 United States, 85 Neurologic comorbidities dementia, 124 migraines, 124 stroke, 124 Neurologic examination, 7–25 Neuromodulation therapies, 136–137, 137 Neuromuscular junction (NMJ) disorders, 47, 820 botulism, 831–832 congenital myasthenic syndrome (CMS), 828, 828–829 Lambert–Eaton myasthenic syndrome, 829–831 myasthenia gravis, 820–828 Neuromyelitis optica spectrum disorder (Devic’s disease), 486, 698 clinical features, 486 definition, 486 diagnosis, 486 Neuromyotonia, 46 Neuronal migration disorders clinical features, 225 definition, 223–224 epidemiology, 224–225 etiology and pathophysiology, 225 investigations and diagnosis, 225 prognosis, 225–226 treatment, 225 Neuronal proliferation disorders cortical organization, disorders of, 226–227 neurocutaneous disorders, 227 neurofibromatosis type 1, 228–233 neurofibromatosis type 2, 234–236 neuronal migration, disorders of, 223–226 primary microcephaly, 223 Sturge–Weber syndrome, 240–241 tuberous sclerosis, 236–240 Neuronopathy or primary nerve cell degeneration, 42 Neuropathic pain, treatment, 771 Neuropathic tremor, 191 Neuropathy in systemic disease, 776–778 Neuropsychiatric symptoms, 128, 575 Neuropsychological evaluation, 128 Neurosarcoidosis clinical features, 487–488 definition, 486 diagnosis, 489 differential diagnosis, 488 epidemiology, 486 etiology and pathogenesis, 487 investigations, 487–488 pathology, 486–487 prognosis, 489 treatment, 489 Neurosyphilis, 421–424 clinical features, 422, 423 definition, 421 diagnosis, 423–424 differential diagnosis, 423 epidemiology, 421 etiology and pathophysiology, 421–422

investigations, 423 pathology, 421, 422 treatment, 424 Neurotmesis, 766 Neurotoxic shellfish poisoning (NSP), 649 Neurotoxins, bacterial botulism, 648 tetanus, 648 New-onset seizures/epilepsy, evaluation of, 125 NGF, see Nerve growth factor Niemann–Pick disease, 606 Niemann–Pick type C (NPC), 280 Nightmares, 910 Nimodipine after aneurysmal subarachnoid hemorrhage, 401 Nitrofurantoin, 773 Nitrous oxide, 644–645, 774–775 Nizatidine, 755 N-methyl-daspartate (NMDA), 540 NMOSD, see Neuromyelitis optica spectrum disorder Nodes of Ranvier, 764, 765 Nonarteritic anterior ischemic optic neuropathy (NAION), 700–701 Noncommunicable diseases (NCDs), 81 Nonfocal neurologic symptoms, 305, 305 Non–24-hour sleep–wake rhythm disorder (N24SWD), 902, 905–907 Non-Mendelian patterns of inheritance, 71–72, 72, 73–74 Nonstroke pathologies, 311 contrast-enhanced CT scan of the head, 311, 312, 313, 313 CT perfusion of brain, 313 diffusion-weighted imaging, 313–315, 314–315 gradient echo T2-weighted susceptibility images, 315, 315 magnetic resonance imaging of the head, 313 Nonvascular causes, 96 Normal pressure hydrocephalus (NPH), 658–659, 659 clinical features, 558 definition, 557–558 differential diagnosis, 558 epidemiology, 557–558 etiology, 558 investigations, 558 pathophysiology, 558 prognosis, 559 treatment, 558 Normal sleep definition, 877 N1 (formerly S1 or Stage 1), 878 N2 (formerly S2 or Stage 2), 878, 878 N3 (replaced S3 and S4), 878, 879 R (REM sleep), 878–879, 879 sleep–wake cycles, 879–880 sleep–wake regulation, 880–882 staging, 877 NREM parasomnias, 908 Numb chin syndrome, 676–677 Nutrition-related neuropathy, 775–776 Nystagmus, 18 Nytrigeminal nerve (CN V), 18–19

O Obesity hypoventilation syndrome, 901 Obstructive apneas, 884, 885 Obstructive hydrocephalus, 653 Obstructive hypoventilation, 901 Obstructive sleep apnea (OSA), 576, 886, 899–900 Obturator neuropathy, 810–811 Ocular MG, treatment, 824, 827; see also Myasthenia gravis Ocular muscles, 821, 821 Ocular oscillations, 18 Oculocephalic maneuver, 18 Oculomotor nerve (CN III), assessment, 16–17 Olfactory dysfunction, 669–670 Olfactory nerve (CN I), 12 Olfactory neuropathy (cranial nerve I) anatomy, 668–669 central neural impairment, 670 clinical features, 670–671 conductive impairment, 670 definition, 668 diagnosis, 671 epithelium/bulb/tract, 669 etiology, 669 idiopathic, 670 investigations, 671 pathophysiology, 669 pathway, 669 physiology, 668–669 prognosis, 671 psychiatric, 670 sensorineural impairment, 670 treatment, 671 Oligodendroglial tumors, 504 Olivopontocerebellar atrophy (OPCA), 578 Ophthalmoplegia exophthalmic, 850 internuclear (INO), 17 migraine, 150–151 Ophthalmoscope, 14–16 OPIDP, see Organophosphate-induced delayed polyneuropathy Opsoclonus–myoclonus syndrome, 195, 526 Optical coherence tomography (OCT), 697 Optic nerve CN II, assessment, 12–16 gliomas, 703–704 head drusen, 15 examination, 15, 696 Optic neuritis, 14 Optic neuropathies (cranial nerve II) AION, 699 anatomy, 694–695 clinical assessment examination, 695 history, 695 clinical features, 698 colobomas, 704 color perception, 696 compressive, 702–703 congenital, 703 definition, 694 diagnosis, 698 dominant optic atrophy, 704 etiology, 698

Index hereditary, 704 hypoplasia, 703 investigations, 698 ischemic, 699 layers of the retina, 694 malnutrition, 705 methanol toxicity, 705 mitochondrial diseases, 698 MOG-ON, 699 monocular vision loss, 696–697 morning glory discs, 703 multiple sclerosis, 698 neuromyelitis optica, 698–699 optic disc drusen, 702, 702 optic nerve gliomas, 703–704 optic nerve head examination, 696 papilledema, 701, 701–702 prognosis, 698 pseudopapilledema, 702 pupillary light reflex, 697 RAPD, 696 recessive optic atrophy, 704 retinotopic organization, 695 sarcoidosis, 699 sheath meningiomas, 703, 703 Susac’s syndrome, 697–698 swinging flashlight test, 697 TAO, 703 TON, 705 toxic, 704 treatment, 698 visual acuity, 695 visual field defects, 695 visual field testing, 696 vitamin B12, 705 Oral anticoagulation acute ischemic stroke, 399 anticoagulant-associated hemorrhage, 399 atrial fibrillation, 399 direct (non-VKA) antiplatelet medications, 388 recombinant factor VIIa, 389 tranexamic acid, 389 mechanical heart valves, 399 patent foramen ovale, 399 Orbicularis oculi, 18–19 Orbital inflammatory disease definition, 489 diagnosis, 490 differential diagnosis, 490 etiology, 489 investigations, 490 pathophysiology, 489 prognosis, 490 treatment, 490 Organophosphate (OP), 645–646 Organophosphate-induced delayed polyneuropathy (OPIDP), 646 Organophosphates, 774 Orientation, 9 Orthostatic hypotension, 576 Orthostatic myoclonus, 195 Oscillopsia, 18 Osler–Rendu–Weber syndrome, 241–244 clinical features, 242–243 definition and epidemiology, 241–242 diagnosis, 243

929 etiology and pathophysiology, 242, 242–243 investigations, 243 prognosis, 244 treatment, 243–244 AVMs, 244 liver, 244 pregnancy, 244 telangiectases, 243 Osmotic demyelination syndrome, 111–113 clinical features, 112 predisposing illness, 112 variable clinical illness, 112 definition and epidemiology, 111 diagnosis, 112 differential diagnosis, 112 etiology and pathophysiology, 111–112 investigations, 112 macroscopic, 112–113 microscopic, 113 pathology, 112, 113 prevention, 113 prognosis, 113 risk factors, 112 treatment, 113 Oxaliplatin, 772

P PAF, see Pure autonomic failure Painful sensation, 751 Pain management, 770 Palliative surgeries corpus callosotomy, 136 neuromodulation therapies, 136–137, 137 Pallidotomy, 577 Pancreatic encephalopathy (PE), 638 Pandysautonomia, 751 PanOptic ophthalmoscope (Welch Allyn), 15, 15–16 Pantothenate kinase–associated neurodegeneration, 184–185, 270–271 clinical features, 270 definition and etiology, 270 diagnosis, 270–271 treatment, 271 Papilledema, 7, 14–15 Para-airway adipose tissue, 900 Paralytic shellfish poisoning (PSP), 649 Paramyotonia congenita, 869–870 Paraneoplastic cerebellar degeneration, 524, 525 Paraneoplastic disorders, neuropathy, 777 Paraneoplastic encephalomyelitis, 525 Paraneoplastic neurologic disease clinical features/diagnostic therapy, 524–526 definition and epidemiology, 523–524 etiology, 524, 524 prognosis, 527 treatment, 527 Paraneoplastic sensory neuronopathy, 525 Paraproteinemia, 777 Parasomnias nightmares, 910 NREM parasomnias, 908 REM parasomnia, 910

REM sleep behavior disorder, 910–911 sleep-related eating disorder, 909 Parasympathetic afferent fibers, 751 Parasympathetic efferent impulses, 751 Parasympathetic failure, 752 Parasympathetic nervous system, 750 Paratonia (gegenhalten), 10 Parieto-occipital cortex, 751 Parkinsonian tremor, 190 Parkinsonism cassification, 562 causes, 561 Parkinsonism–hyperpyrexia disorder, 201 Parkinson’s disease, 78 axial section, 568 basal ganglia, 563–564, 564 clinical features facial features, 564 motor features, 564–565 nonmotor features, 565, 565–566 COMT inhibition, 573 DBS, 576–577 definition, 562–563 diagnosis, 567 differential diagnosis DaTSCAN, 567, 567 neuropsychiatric features, 566 parkinsonism, 566 tremor, 566 dopamine receptors ergot-derived dopamine agonists, 572 nonergot dopamine agonists, 572–573 dopaminergic drugs, 570 dopaminergic transplantation strategies, 577 dysautonomia, 575–576 dyskinesias, 574–575 environmental toxins, 563 epidemiology, 562–563 etiology, 563 heredity/genetic susceptibility, 563 idiopathic PD, 567–568 intraneuronal pathology, 569 investigations, 566–567 investigations and diagnosis, 20 lesional surgery, 577 MAO-B, 573 medical therapies amantadine, 572 anticholinergics, 572 levodopa, 570–572 motor fluctuations, 573–574, 574 nonmotor symptoms impotence, 576 impulse control disorders, 575 mood disorders, 575 neuropsychiatric symptoms, 575 sleep disorders, 576 pathology, 568–570 pathophysiology, 563 posture, 565 prognosis, 577 risk and protective factors, 563 substantia nigra, 568, 570 subtypes, 566 surgical therapies, 576 therapeutic window, 574 treatment, 570

Index

930 Paroxysmal dyskinesia syndromes, 183 deafness–dystonia–optic neuronopathy syndrome (Mohr–Tranebjaerg), 184 differential diagnosis of, 183 dystonia–deafness syndrome, 184 hypomyelination with basal ganglia and cerebellar atrophy (H-ABC) syndrome, 184 manganese transporter deficiency syndrome, 184 other genetic disorders that can cause paroxysmal dyskinesias, 183 paroxysmal exercise-induced dystonia, 183 paroxysmal kinesigenic dystonia, 183 paroxysmal nonkinesogenic dyskinesia, 183 thiamine responsive basal ganglia disease, 184 Wilson’s disease, 183 Paroxysmal exercise-induced dystonia, 183 Paroxysmal hemicrania, 157 Paroxysmal kinesigenic dystonia, 183 Paroxysmal nonkinesogenic dyskinesia, 183 Parsonage–Turner syndrome, 786 Patent foramen ovale, 399, 400 Pathophysiology, 91–93, 92–93 PD, see Parkinson’s disease Peak nasal pressure transducer airflow, 884 Pearson’s syndrome, 282 Penumbral imaging, 363 Periodic lateralized epileptiform discharges (PLEDs), 38 Periodic leg movement (PLM), 885, 886 Periodic limb movement disorder (PLMD), 897 Periodic limb movements in sleep (PLMS), 897–898 Peripheral nerves, anatomy, 764–765 Peripheral neuropathies, 645, 764–769; see also Mononeuropathies brachial plexus, 786–787 chronic demyelinating disorders, 780–784 classification, 765 disorders associated with, 751–752 etiology and pathophysiology, 765–766 hereditary, 790–794 infectious, 787–790 lower extremity, 808–816 nutritional, 775–776 paraneoplastic, 777 in systemic disease, 776–778 toxic, 771–775 upper extremity, 796–808 vasculitic, 784–786 Periventricular nodular heterotopia clinical features, 225 definition, 223 epidemiology, 223 etiology and pathophysiology, 225 Peroneal nerve, 812–814, 813 conduction studies, 41 dysfunction, 812–814 Persistent/permanent vegetative state, 101–102 definition and clinical features, 101 diagnostic criteria, 101 differential diagnosis, 101, 101–102 etiology and pathophysiology, 101 prognosis, 102 PET, see Positron emission tomographic

Pharyngeal dilator muscle activity, 900 Phenytoin, 773 Phoria, 16 Phosphofructokinase (PFK) deficiency, 854–855 Photic stimulation, 31 Pimavanserin, 575 Piriformis syndrome, 811 Pituitary tumors clinical features, 513–514 definition and epidemiology, 513 diagnosis, 514 differential diagnosis, 514 investigations, 514, 514 pathology, 514 prognosis, 514 treatment, 514 PLA2G6-associated neurodegeneration, 185 Plantar response, 23 Plasma exchange (PE), 779, 782 Platinum agents, 772 Platysma, 19 PLM, see Periodic leg movement PLMD, see Periodic limb movement disorder Pneumonia, 391 POEMS syndrome, 777 Poisoned patient activated charcoal (AC), 642 care, 641–642 decontamination, 642 physical examination, 642 toxicologic history, 642 Poliomyelitis, 441–443 clinical features, 442, 442 definition, 441 diagnosis, 443 differential diagnosis, 442 epidemiology, 441 etiology and pathophysiology, 441–442 investigations, 442–443 pathology, 441 post-polio syndrome, 443 prevention, 443 treatment, 443 Polyarteritis nodosa, 784, 786 Polyglucosan body disease, 855 Polymerase chain reaction (PCR) testing, 28 Polymicrogyria bilateral frontal polymicrogyria, 226 bilateral perisylvian polymicrogyria, 226 clinical features, 227 definition, 226 epidemiology, 226 etiology and pathophysiology, 227 Polymyositis, 526, 841–842, 843, 844 Polyneuropathy chronic acquired demyelinating, 780–784 defined, 765 Polysomnography, 882–885, 887 Pompe disease, 852–853 Population-attributable risk, 355, 355–356 Population health complementary approaches to chronic disease prevention, 82, 82 definition of, 82 health care spending in United States, 84–85

health care transformation, 83–84 interventions, 82 risk, approaches to reduce, 82 social determinants of health, 82, 83 Porphyria, 795–796 Portable polysomnography, 885–888 Positive airway pressure, 901 Positron emission tomographic (PET), 58, 536, 566 Posterior closure defects, 217 Posterior column syndrome, 720 Posterior femoral cutaneous neuropathy, 809 Posterior inferior cerebellar artery (PICA), 656 Posterior interosseous nerve, 800–802 Posterior reversible encephalopathy syndrome (PRES), 634–636 Posterolateral column degeneration, 720 Postganglionic fibers, 750 Postural hypotension, 755 Postural (righting) reflexes, 24 Potassium-related myotonias, 869–870 Praxis, 11–12 Prednisone, 783, 786–787 Pregabalin, 771 Preganglionic parasympathetic fibers, 750 Presenting complaint, 8, 19 Primary central nervous system lymphoma clinical features, 516 definition and epidemiology, 516 diagnosis, 516 etiology and pathophysiology, 516 investigations, 516, 516 pathology, 517 prognosis, 517 treatment, 517 Primary intraventricular hemorrhage, 351 Primary microcephaly, 223 Primary orthostatic tremor, 191 Primary (idiopathic) parkinsonism, see Parkinson’s disease Primary progressive aphasia (PPA), 541 Primary short-lasting headache associated with sexual activity, 158 headache associated with sexual activity, 158 hypnic headache, 157–158 paroxysmal hemicrania, 157 primary cough headache, 158 primary exertional headache, 158 primary stabbing headache, 157 SUNCT/SUNA syndrome, 157 Prion diseases acquired, 551 brain biopsy, 556 brain CT/MRI, 553 clinical features, 552 clinical variants CJD, 552 CSF, 554 definition, 551 diagnosis familial CJD, 556 iatrogenic CJD, 556 sporadic CJD, 556 vCJD, 556 differential diagnosis, 553 diffusion-weighted MRIs, 553 EEG, 554 electroencephalograph, 554

Index epidemiology, 551 etiology, 551 fatal insomnia, 552 genetic susceptibility, 552 glial cells, 557 GSS, 552–553 hypothesis, 551–552 investigations, 553 molecular genetic analysis, 554, 556 pathology, 556–557 pathophysiology, 551 prognosis, 557 proton-weighted imaging, 553 risk factors, 552 serial electroencephalographs, 555 spongiform degeneration, 557, 557 tonsil biopsy, 556 transmissible spongiform encephalopathies, 95, 95 treatment, 557 variably protease-sensitive prionopathy, 553 variant CJD, 552 Western blots, 557 Prion protein gene (PRNP), 554 PRKRA-related dystonia (DYT16), 182 Progressive external ophthalmoplegia, 282 Progressive multifocal leukoencephalopathy, 443–446 clinical features, 444–445 definition, 443 diagnosis, 445, 445–446 differential diagnosis, 445 epidemiology, 444 etiology and pathophysiology, 444 investigations, 445 pathology, 444, 444 treatment, 446 Progressive or static encephalopathy, 193 Progressive supranuclear palsy (PSP) atypical presentations, 582 clinical features, 581–582 definition, 581 diagnosis, 582–584, 584 differential diagnosis, 582–583 etiology, 581 investigations, 583 mandatory exclusion criteria, 584 mandatory inclusion criteria, 584 pathological nosological syndromes, 582 pathology, 584, 584–585, 585 pathophysiology, 581 prognosis, 585 treatment, 585 Proprioception, assessment, 23 Propriospinal myoclonus, 899 Prosencephalic development disorders clinical features, 222–223 diagnosis, 223 epidemiology, 221 etiology and pathophysiology, 221–222 investigations, 223 prognosis, 223 treatment, 223 Prosopagnosia, 11 Protein aggregate myopathies, 858–859 CSF, 28

931 Protomutations, 71 Pseudodementia, 8, 535–536 Pseudopapilledema, 702 Pseudotumor cerebri, see Idiopathic intracranial hypertension Pseudoxanthoma elasticum (PXE), 328 Psychogenic disorders, 50–51 PTEN hamartoma tumor syndrome clinical features, 245 definition and epidemiology, 245 diagnosis, 245 etiology and pathogenesis, 245 investigations, 245 prognosis, 246 treatment, 246 Pterygoid power, 18 Ptosis, 14, 16–18 Pudendal neuropathy, 815–816 Pull test, 24 Pupillary defects, afferent, 13 Pupillary pathways and common disorders, 712, 713–715, 714 Pupillary reflexes, 751 Pupillary responses, 13–14 Pupilloconstrictor fibers, 751 Pure autonomic failure (PAF), 579

Q Quantitative Myasthenia Gravis (QMG) Score, 827 Quazepam, 892 Quetiapine, 575

R Rabies, 439–441 clinical features, 440 definition, 439 diagnosis, 440 differential diagnosis, 440 epidemiology, 439 etiology and pathophysiology, 439–440 investigations, 440 prevention, 440–441 treatment, 440 Radial nerve dysfunction, 800, 801, 802 Radial neuropathy, 802 Radiation, adverse effects, 787 Ramelteon, 891 Ramsay Hunt syndrome, 681–682 RAPD, see Relative afferent pupillary defect Rapid alternating movements, 22 Rapid Arterial Occlusion Evaluation (RACE) Scale, 309, 309 Rapid eye movement (REM), 545 Rapid plasma reagin (RPR), 536 Rebound phenomenon, 22 Recessive optic atrophy, 704 Red reflex, 14 Reflex testing, 22 Refsum’s disease, 606, 794–795 Relative afferent pupillary defect (RAPD), 696 REM parasomnia, 910 REM sleep behavior disorder, 910–911 Renal failure, 39, 776

Repetitive nerve stimulation (RNS), 43–44, 822–823 Repetitive stimulation, motor nerves, 43–44 Respiratory crisis treatment, 827 Respiratory effort-related arousal (RERA), 884–885, 886 Respiratory failure, 779 Response inhibition, 10 Response to emotional and other stimuli, 754 Restless leg syndrome diagnosis, 896 differential diagnosis, 896 epidemiology, 896 pathophysiology, 896 treatment, 897 Retina; see also Eye; Kayser–Fleischer ring diseases, 697 examination, 15 Reversible cerebral vasoconstriction syndrome (RCVS), 96, 332–333 Rheumatoid vasculitis, 785 Riche–Cannieu anastomosis, 803 Right hemisphere function, 10–11 Rinne test, 19 Rituximab, 783, 827, 847 Rivastigmine, 539–540 RNS, see Repetitive nerve stimulation Romberg’s test, 24 RPR, see Rapid plasma reagin

S Saccades, 18 Saccular aneurysms, 350 Salicylates, 644 Sandhoff’s disease, 278 Sarcomere, 839, 840, 850 SARS coronaviruses, 467, 468 SARS-CoV-2, diagnostic testing for, 467–468 Scapular winging, 797–798 Schizencephaly clinical features, 227 definition, 226 epidemiology, 227 etiology and pathophysiology, 227 Schwann cells, 765, 778, 787, 789 Sciatic nerve disorders, 811–812 Sciatic neuropathy, 811–812 Secondary headaches acute sinusitis (frontal, ethmoidal, and maxillary), 158 giant cell (cranial) arteritis, 158 glaucoma, 158 investigations, 158 other conditions, 158 Secondary parkinsonism, 589–591 clinical features, 590 drugs, 589 toxic exposures, 589 Segmental demyelination, 42 Seizures accompanied by myoclonus, 193 neurofibromatosis type 2, 235 and status epilepticus, 95 Selective serotonin reuptake inhibitors (SSRI), 540 Semantic variant (svPPA), 541 Senile plaques, 538

Index

932 Sensation, assessment, 23–24 Sensory nerve action potential (SNAP), 41–42, 805, 808 Septo-optic dysplasia clinical features, 222–223 etiology and pathophysiology, 222 Serotonin syndrome (SS), 200–201, 646, 646–647, 647 Sex chromosome aneuploidy (SCA), 68 SGCE-related dystonia (DYT11), 182 Shift work disorder (SWD), 902, 907–908 Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT/SUNA) syndrome, 157 Short-term immunotherapy, myasthenia gravis (MG) IV immunoglobulin (IVIG), 827 plasma exchange (PE), 827 Shy–Drager syndrome (SDS), 578 Sialorrhea, 576 Sicca symptoms, 785 Sickle cell disease, 329, 331 Single-fiber electromyography (SFEMG) needle electrodes, 823, 823 Single-nucleotide polymorphisms (SNPs), 78 Single photon emission tomography (SPECT), 58, 536 Sinus arrhythmia, 753 Sjögren’s syndrome, 752, 784–785, 790 Skew deviation, 17 Skin disease cryoglobulinemia, 785 dermatomyositis, 841, 844–846, 846 Skin vasomotor reflexes, 754 Sleep disorders, 576 log, 890 normal, 34, 36 paralysis, 893 terrors, 908 Sleep-promoting inhibitory system, 882 Sleep-related breathing disorders central sleep apnea, 902 common comorbid disorder with OSA, 900–902 obstructive sleep apnea, 899–900 Sleep-related bruxism, 898, 899 Sleep-related cramps, 899 Sleep-related eating disorder, 909 Sleep-related hypoventilation, 901 Sleep-related movement disorders, 899 hypnic (physiologic) myoclonus, 899 periodic limb movements in sleep (PLMS), 897–898 restless leg syndrome, 896–897 sleep-related bruxism, 898 sleep-related cramps, 899 Sleep–wake cycles, 879–880 Sleep–wake regulation circadian mechanism, 880–881, 881 homeostatic mechanism, 880, 880 neural networks, 881–882, 882 wake-promoting system, 882 Sleepwalking (somnambulism), 908 Slow-wave sleep, 880 Small-vessel disease arteriolosclerosis, 335, 335

cerebral amyloid angiopathy (CAA), 335 inflammatory and immunologically mediated small-vessel diseases, 336 inherited and genetic small-vessel diseases, 335–336 intracranial small-vessel disease, 333, 334 venous collagenosis, 336 SNc, see Substantia nigra pars compacta Social history, 6 Sodium channel-blocking antiepileptic drug, 899 Somatic fibers, 751 Somatosensory evoked potentials (SSEPs), 49–50 SPECT, see Single photon emission tomography Speech disorders, 11 Spinal accessory nerve (CN XI), 796 Spinal accessory neuropathy, 689, 689–690, 796 Spinal cord lesions, 751 tumors, 737–739, 737–739 Spinal cord injury (SCI) clinical features, 294 clinical patterns, 293 complete, 293 complications of cardiovascular, 295 genitourinary and gastrointestinal, 295 neuropathic arthropathy, 295 neuropathic pain, 295 spasticity, 295 syringomyelia, 295 decompression and stabilization, 294 definition and etiology, 292 diagnosis and investigations, 294–295 high-dose methylprednisolone, 295 incomplete, 293–294 neurogenic shock, 293 pathophysiology, 292 prognosis, 296 spinal shock, 293 surgical treatment, 295 treatment, 295 Spinal dysraphisms clinical/radiologic classification of, 212 cranial defects, 212 anencephaly, 212 cranial meningocele, 213 encephalocele, 212–213 diastematomyelia/split spinal cord malformation, 214, 215 embryologic classification of, 212 epidemiology, 212 etiology and pathophysiology, 212 isolated vertebral defect/spina bifida occulta, 215, 216 meningocele, 213, 215 meningomyelocele, 213, 215 occult spinal dysraphism, 214–215 spina bifida occulta or isolated vertebral defect, 213–214 split spinal cord malformation/ diastematomyelia, 216 tethered cord syndrome (TCS), 216 Spinal muscular atrophy (SMA), 76, 76, 744–745, 745

Spine imaging, 65–67, 66 CT myelography, 67, 67 MRI, 65, 66 Spongiform degeneration, 557, 557 Spontaneous intracranial hypotension, see Idiopathic intracranial hypertension Sporadic AD, 534, 537 differential diagnosis, 535 positive family history, 537 Sporadic fatal insomnia, 890 Sporadic inclusion body myositis, 847–849 Stance, assessment, 24 Startle syndromes, 194–195 Statins, 773 Status epilepticus (SE), 137–138 evaluation and management of, 137–138 treatment of, 138 Stereotypies definition, 197 differential diagnosis, 198 epidemiology, 197 etiology—classification, 197–198 pathophysiology, 198 treatment, 198 Sternocleidomastoid muscle, 19–20 Steroid myopathy, 842, 851 Stiff-person syndrome (SPS), 526 St. Louis’ encephalitis, 438–439 STN, see Subthalamic nucleus Striatonigral degeneration (SND), 578 Stroke, 257, 258–259, 300–301, 751, 901 advanced investigation, 371–373 anatomical localization, 317, 318 arteritis, 331–332, 333 artery diseases, 323 blood coagulation disorders, 340–351 blood tests, 316 arterial hypercoagulable state, 376 venous hypercoagulable state, 376 brain imaging features, 309 cerebrospinal fluid (CSF), 373 chest X-ray, 368–369, 369 clinical classification, 317, 319–322 clinical evalution, 304 clinical severity of stroke, 316–317 definition of, 300 diagnosis of, 304–316 differential diagnosis, 307, 307–308 epidemiology cost, 304 global disability-adjusted life years, 303 incidence in communities, 302, 302 lifetime risk of stroke, 302 mortality, 303 prevalence, 303 focal neurologic symptoms, 304–305, 305, 319 gadolinium contrast, 316 heart diseases, 336–337 heart rate and rhythm, monitoring of, 376, 368 investigation blood tests, 367–368 CT angiography, 360, 360–361, 361 CT perfusion, 364–365, 366, 367, 367 duplex ultrasound, 362–363

Index magnetic resonance angiography, 361, 361–362, 362 MRI brain scan, 359–360 MR perfusion, 367 penumbral imaging, 363 standard investigation, 357, 357–358 12-lead electrocardiography, 368, 368 nonfocal neurologic symptoms, 304, 305 nonstroke pathologies, 311, 311–315 pathology and etiology, 317–357, 319 population-attributable risk, 355, 355–356 prognosis functional outcome, 377–378 hemorrhagic stroke, 378 recurrent stroke, 378, 378 survival, 377–378 reversible cerebral vasoconstriction syndrome (RCVS), 332–333 risk factors, 354–355 small-vessel disease, 333–336 specialized investigations blood, 377 brain biopsy, 377 genetic testing, 376 heart rhythm and structure, 376 occult malignancy screening, 377, 377 vasculitis, 376 standard diagnostic tests, 357 subarachnoid hemorrhage perimesencephalic hemorrhage, 353 saccular aneurysms, 351–353 symptoms, 305 systems of care, 386–387 and TIA, 301–302 transesophageal echocardiography (TEE), 370–371, 371 transthoracic echocardiography (TTE), 369, 369–370, 370 treatment, 378–405 acute ischemic stroke, 379–405 triggers, 357 unit, 390, 390 vascular imaging catheter contrast angiography, 374, 374–375 transcranial Doppler ultrasonography, 373–374 vasculitis testing, 374, 375, 376 Strychnine, 644 Sturge–Weber syndrome clinical features, 241 definition and epidemiology, 240 diagnosis, 241 etiology and pathogenesis, 240–241 investigations, 241 prognosis, 241 treatment, 241 Subacute necrotizing encephalomyelopathy, 282 Subacute sclerosing panencephalitis (SSPE), 28 Subarachnoid hemorrhage (SAH) anatomical localization, 317 clinical diagnosis of, 308 differential diagnosis of, 308, 309 features of, 308 headache, 308 lumbar puncture and cerebrospinal fluid examination, 316

933 perimesencephalic hemorrhage, 353 saccular aneurysms, 351–353 Subcortical band heterotopia clinical features, 225 definition, 224 epidemiology, 225 etiology and pathophysiology, 225 Substantia nigra pars compacta (SNc), 564 Subthalamic nucleus (STN), 564 Subthalamotomy, 577 Superficial abdominal reflexes, 22 Superior or anterior canal dehiscence syndrome (Minor’s syndrome), 170 Supine hypertension, 755 Suprascapular neuropathy, 798–799 Supratentorial brain shift, patterns of central or transtentorial herniation, 93, 96, 97 cingulate herniation, 96 infections, 97, 97 intracranial neoplasm, 97 traumatic brain injury, 97 uncal herniation, 92, 96 Supratentorial ICH, 389 Sural neuropathy, 815 Suramin, 772 Survival motor neuron gene (SMN), 76, 76–77 Susac’s syndrome, 697–698 Suspected paraneoplastic syndrome, 526 Suvorexant, 892 Swallowing and feeding, 390 SWD, see Shift work disorder Sweating, 751, 754 Swinging flashlight test, 13–14, 697 Sydenham’s (rheumatic) chorea, 189 Sympathetic adrenergic failure, 752 Sympathetic afferent fibers, 751 Sympathetic cholinergic failure, 752 Sympathetic efferents, 751 Sympathetic nervous system, 749–750 Symptomatic palatal tremor (myoclonus), 191 Symptomatic treatment, 540 Syncope, 103–108 cardiac arrhythmias, 107 cardiologic diagnosis, 107 invasive, 107 noninvasive, 105–106, 106 treatment, 107 cerebrovascular syncope, 108 clinical assessment duration, 104 features during attack, 104 history, 104 precipitating/contributory factors, 104 presyncopal symptoms, 104 sequelae, 104 systemic enquiry, 104 definition and epidemiology, 103 etiology, 103 neurally mediated reflex syncope, 107 orthostatic hypotension, 107 pathophysiology basic neurophysiology, 103 basic vascular physiology, 103 physical examination cardiovascular, 104 differential diagnosis, 104–105, 105

investigations, 105 neurologic, 104 prognosis, 108 structural cardiopulmonary disease, 107 Syndromic hereditary peripheral neuropathies, 794–796 Syringomyelia (syringohydromyelia), 660–662, 661–662, 732–733 Systolic blood pressure, 753–754

T Tacrolimus, 773–774, 826, 846 TAF1-related dystonia (DYT3), 182 Takayasu’s arteritis, 331 TAO, see Thyroid-associated ophthalmopathy Tarsal tunnel syndrome, 813–815 Tarui’s disease, 854–855 Taste, assessment, 19 Taxanes, 772 Tay–Sachs disease, 278 Telangiectases, 243, 609, 609–611, 610 Tele-neurology, 3 Temporoparietal stroke, 11 Tenecteplase, 381–383 Tension-type headache; see also Headache clinical features, 155 definition and epidemiology, 155 differential diagnosis, 155 etiology and pathophysiology, 155 predisposing factors, 155 genetic factors, 155 investigations and diagnosis, 155 physical abnormalities, 155 psychologic factors, 155 treatment nonpharmacologic, 155–156 pharmacologic, 156 Tetanus, 430–432, 648 clinical features, 430–431, 431 definition, 430 diagnosis, 431 differential diagnosis, 431 epidemiology, 430 etiology and pathophysiology, 430 investigations, 431 pathology, 430 prophylaxis, 432 treatment, 431–432 Thalamic neuronal loss in fatal insomnia, 891 Thalamotomy, 577 Thalidomide, 772 Thallium, 775 Thiamine, 776; see also Wernicke–Korsakoff syndrome disease, 616–619, 617–619 responsive basal ganglia disease, 184 Thunderclap headache, 151 Thymoma, MG associated, 822 Thymus gland, 821 Thyroid-associated ophthalmopathy (TAO), 703 Thyroid disease, 776, 850 Tibial nerve, 41, 43, 50, 814–815 Tic douloureux, 675–676 Tics, 196 Tongue, 19

Index

934 Tonsil biopsy, 556 Topiramate, 771 Tourette’s syndrome clinical features, 197 diagnosis, 197 epidemiology, 197 investigations, 197 pathophysiology, 197 Toxic leukoencephalopathy, 645 Toxic metabolic encephalopathy acute thiamine depletion (Wernicke’s encephalopathy), 94 antibiotics, 93–94 electrolyte disturbances, 93 endocrine dysfunction, 93 hepatic failure, 93 intoxication and pharmacologic causes, 94 renal failure, 93 sepsis, 93 Toxic neuropathies, 752 Toxin-induced seizures AED, 643, 643 barbiturates, 643 empiric treatment, 642–643, 643 isoniazid and hydrazines, 643–644 local anesthetics, 644 salicylates, 644 strychnine, 644 Toxins causing neuropathies, 771–775 Toxoplasma gondii clinical features, 450–451 definition, 450 diagnosis, 451 differential diagnosis, 451 epidemiology, 450 etiology and pathophysiology, 450 investigations, 451 pathology, 450 prevention, 452 treatment, 451–452 Tramadol, 771 Transcranial Doppler ultrasonography, 373–374 Transesophageal echocardiography (TEE), 370–371, 371 Transient ischemic attack (TIA); see also Stroke anatomical localization, 317 clinical evalution, 304 definition of, 300–302 diagnosis of, 304–316, 305 differential diagnosis, 306, 306 standard diagnostic tests, 357 vertigo: central versus peripheral, 306–307 Transient neonatal myasthenia gravis (MG), 827 Transmissible spongiform encephalopathies (TSE), 551 Transthoracic echocardiography (TTE), 369, 369–370, 370 Traumatic brain injury (TBI), 97 concussion, 292 head injury, 286–292 spinal cord injury, 292–296 Traumatic optic neuropathy (TON), 705 Treatment-resistant epilepsy definition of, 132–133 evaluation of patients, 133–134, 134–135

surgical treatment of, 135, 135–136 Tremor cerebellar tremor, 190 definition, 189 dystonic tremor, 191 enhanced physiological tremor, 190–191 essential palatal tremor (myoclonus), 191 essential tremor, 190 fragile X tremor ataxia syndrome, 191 Holmes’ tremor (midbrain or rubral tremor), 190 isolated focal tremor, 191 isolated position-specific or task-specific tremors, 191 neuropathic tremor, 191 parkinsonian tremor, 190 pathophysiology, 189–190 primary orthostatic tremor, 191 prognosis, 192 symptomatic palatal tremor (myoclonus), 191 treatment, 191–192 Tricyclic antidepressants, 771 Trigeminal nerve (CN V), 18–19 Trigeminal neuralgia (TN), 675–676 Trigeminal neuropathy (cranial nerve V), 671, 671–675, 672, 673, 673–674 Trigeminal reflexes, 672, 673 Trigeminothalamic pathways, 673 Trochlear nerve (CN IV), 16–17 TSE, see Transmissible spongiform encephalopathies Tuberculosis clinical features, 426–427 definition, 426 diagnosis, 427 differential diagnosis, 427 epidemiology, 426 etiology and pathophysiology, 426 investigations, 427 pathology, 426, 426 treatment, 427–428 Tuberous sclerosis (TSC), 8 clinical features, 238–239 brain, 238 eye, 239 heart, 239 kidney, 238–239 lungs, 239 skin, 238, 239 definition and epidemiology, 236 diagnosis, 239 etiology and pathogenesis, 236–238 brain, 237, 237–238 heart, 238 kidney, 237–238, 238 lungs, 238 investigations, 239 prognosis, 240 treatment, 239–240 Tumors of nervous system anaplastic oligodendroglioma and oligoastrocytoma, 506–507 craniopharyngioma, 512–513 ependymomas, 508–509 germ cell tumors of CNS, 517–518 glioblastoma multiforme and anaplastic astrocytoma, 505–506

gliomas, 503–505 low-grade glioma: astrocytoma, oligoastrocytoma, and oligodendroglioma, 507–508 meningioma, 509–512 metastases to CNS, 520–523 neoplasia, 496–503 paraneoplastic neurologic disease, 523–527 pituitary tumors, 513–514 primary central nervous system lymphoma, 516–517 vestibular schwannoma (acoustic neuroma), 514–515 Von Hippel–Lindau disease, 518–520

U Ulnar nerve, 40, 41, 43, 49, 806–808 Ulnar neuropathy, 807 UMN, see Upper motor neuron Uncal herniation, 96 Unusual focal dyskinesias, 198 Upper extremity neuropathy, 796–808 Upper motor neuron (UMN), 720 Uremic encephalopathy, 633–634 Urinary dysfunction, 576 Utilization behavior, 10 Utrophin, 862

V Vagus nerve (CN X), 19 Vagus neuropathy (cranial nerve X), 687, 687–688 Varicella-zoster V1, 674 Varicella-zoster virus (VZV), 681 Vascular causes, 95 Vascular dementia (VaD), 550 blood tests, 550 clinical assessment neurologic examination, 549 neuropsychologic examination, 549 definition, 548 diagnosis, 550–551 differential diagnosis, see Alzheimer’s disease diffuse white matter infarction, 549 epidemiology, 548 etiology, 548 investigations, 550 multiple infarcts/hemorrhages, 549 other tests, 550 pathophysiology, 548–549 prognosis, 551 risk factors, 549 single infarct/hemorrhage, 548 treatment, 551 T2-weighted MRI, 550 Vascular myelopathies, 729–732, 729–732 Vascular parkinsonism, 590 Vasculitis, 376 peripheral neuropathy, 784–786 testing, 374, 375, 376 Vasogenic edema, 380 Venlafaxine, 771 Venous collagenosis, 336 Venous hypercoagulable state, 376

Index Venous thromboembolism, 390–391 Ventrolateral preoptic (VLPO) nucleus, 881 Verbal fluency, 10 Vertebral artery stenting, 396–397 Vertebrobasilar migraine, 774–775 Vertigo benign paroxysmal positional vertigo (BPPV), 169 bilateral simultaneous vestibular loss, 170 classification based on timing and triggers acute syndromes, 165 chronic syndromes, 165 clinical features and diagnosis, 165 classification on basis of timing/duration, 164 continuous vertigo (s-AVS), 165–166 definitions, 164 epidemiology, 164 episodic triggered vertigo (t-EVS), 165–166 episodic vertigo (s-EVS), 165 etiology and pathophysiology, 164 localization, 166, 167 Ménière’s syndrome, 168 migraine, 169–170 superior or anterior canal dehiscence syndrome (Minor’s syndrome), 170 symptoms, 163 treatment, 166–168 vascular disorders of inner ear, 169 vestibular neuritis/labyrinthitis, 169 vestibular paroxysmia, 170 Vestibular nerve (CN VIII), 19 Vestibular neuritis/labyrinthitis, 169 Vestibular paroxysmia, 170 Vestibular schwannoma (acoustic neuroma) clinical features, 515 definition and epidemiology, 514–515 differential diagnosis, 515 etiology, 515 investigations and diagnosis, 515, 515 prognosis, 515 treatment, 515

935 Vestibular tumors, 236 Vestibulocochlear neuropathy (cranial nerve VIII), 682–685, 684 Vestibulo-ocular reflex (VOR), 17–18 Vibration sense, 23–24 Vinca alkaloids, 772 Viral encephalitis California encephalitis viruses, 439 clinical features, 435, 435–436 definition, 435 differential diagnosis, 436 etiology and pathophysiology, 435 herpesviruses, 436–437, 437–438 investigations, 436 St. Louis’ encephalitis, 438–439 West Nile virus, 437–438 Visual evoked potentials (VEPs), 48 Visual fields testing, 13 Vitamins B3 (niacin or nicotinic acid) deficiency, 626–627 B6 (pyridoxine) deficiency, 625–626 B9 (folic acid or folate) deficiency, 623–624 B12 (cobalamin) deficiency, 619–623, 620, 622 D deficiency, 628 E deficiency, 624, 624–625 vitamin B1 (thiamine), 776 vitamin B6 (pyridoxine), 775–776 vitamin B12 (cobalamin), 775 Voltage-gated calcium channel (VGCC) antibodies, 824 Von Hippel–Lindau disease, 246 additional lesions, 520 clinical features, 518–519 definition and epidemiology, 518 differential diagnosis, 519 etiology and pathophysiology, 518 investigations, 519, 519–520 pathology, 520 prognosis, 520 treatment, 520

W Wake, 877 Wakefulness, 881 Wallerian degeneration, 42, 766, 785 Weber test, 19 Wegener’s granulomatosis, 784 Wernicke–Korsakoff syndrome, 616–619, 617–619 Wernicke’s encephalopathy, 94, 751 West Nile virus, 437–438 Whole-exome sequencing (WES), 71 Wilson’s disease, 183, 271, 271–272, 272, 589 clinical features, 271 CNS findings, 271 diagnosis and investigations, 271–272 liver disease, 271 treatment, 272 Woodhouse–Sakati syndrome, 185 Wound botulism, 831 Wrist, mononeuropathies, 801–807

X X-linked adrenoleukodystrophy, 269, 270 clinical features, 269 definition and etiology, 269 diagnosis and investigations, 269 treatment, 269 X-linked bulbospinal muscular atrophy, 745–746

Y Young-onset familial AD, 537

Z Zaleplon, 892 Zonisamide, 121, 123–124, 132 Zoonotic toxins ciguatera, 648–649 shellfish poisoning, 649, 649 tetrodotoxin (TTX), 648