Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment [1 ed.] 0323988172, 9780323988179

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MOTOR SYSTEM DISORDERS, PART II: SPINAL CORD, NEURODEGENERATIVE, AND CEREBRAL DISORDERS AND TREATMENT

HANDBOOK OF CLINICAL NEUROLOGY Series Editors

MICHAEL J. AMINOFF, FRANÇOIS BOLLER, AND DICK F. SWAAB VOLUME 196

MOTOR SYSTEM DISORDERS, PART II: SPINAL CORD, NEURODEGENERATIVE, AND CEREBRAL DISORDERS AND TREATMENT Series Editors

MICHAEL J. AMINOFF, FRANÇOIS BOLLER, AND DICK F. SWAAB

Volume Editor

DAVID S. YOUNGER VOLUME 196 3rd Series

ELSEVIER Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2023 Elsevier B.V. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-323-98817-9 For information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

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79, The human hypothalamus: Basic and clinical aspects, Part I, D.F. Swaab, ed. ISBN 9780444513571 80, The human hypothalamus: Basic and clinical aspects, Part II, D.F. Swaab, ed. ISBN 9780444514905 81, Pain, F. Cervero and T.S. Jensen, eds. ISBN 9780444519016 82, Motor neurone disorders and related diseases, A.A. Eisen and P.J. Shaw, eds. ISBN 9780444518941 83, Parkinson’s disease and related disorders, Part I, W.C. Koller and E. Melamed, eds. ISBN 9780444519009 84, Parkinson’s disease and related disorders, Part II, W.C. Koller and E. Melamed, eds. ISBN 9780444528933 85, HIV/AIDS and the nervous system, P. Portegies and J. Berger, eds. ISBN 9780444520104 86, Myopathies, F.L. Mastaglia and D. Hilton Jones, eds. ISBN 9780444518996 87, Malformations of the nervous system, H.B. Sarnat and P. Curatolo, eds. ISBN 9780444518965 88, Neuropsychology and behavioural neurology, G. Goldenberg and B.C. Miller, eds. ISBN 9780444518972 89, Dementias, C. Duyckaerts and I. Litvan, eds. ISBN 9780444518989 90, Disorders of consciousness, G.B. Young and E.F.M. Wijdicks, eds. ISBN 9780444518958 91, Neuromuscular junction disorders, A.G. Engel, ed. ISBN 9780444520081 92, Stroke – Part I: Basic and epidemiological aspects, M. Fisher, ed. ISBN 9780444520036 93, Stroke – Part II: Clinical manifestations and pathogenesis, M. Fisher, ed. ISBN 9780444520043 94, Stroke – Part III: Investigations and management, M. Fisher, ed. ISBN 9780444520050 95, History of neurology, S. Finger, F. Boller and K.L. Tyler, eds. ISBN 9780444520081 96, Bacterial infections of the central nervous system, K.L. Roos and A.R. Tunkel, eds. ISBN 9780444520159 97, Headache, G. Nappi and M.A. Moskowitz, eds. ISBN 9780444521392 98, Sleep disorders Part I, P. Montagna and S. Chokroverty, eds. ISBN 9780444520067 99, Sleep disorders Part II, P. Montagna and S. Chokroverty, eds. ISBN 9780444520074 100, Hyperkinetic movement disorders, W.J. Weiner and E. Tolosa, eds. ISBN 9780444520142 101, Muscular dystrophies, A. Amato and R.C. Griggs, eds. ISBN 9780080450315 102, Neuro-ophthalmology, C. Kennard and R.J. Leigh, eds. ISBN 9780444529039 103, Ataxic disorders, S.H. Subramony and A. Durr, eds. ISBN 9780444518927 104, Neuro-oncology Part I, W. Grisold and R. Sofietti, eds. ISBN 9780444521385 105, Neuro-oncology Part II, W. Grisold and R. Sofietti, eds. ISBN 9780444535023 106, Neurobiology of psychiatric disorders, T. Schlaepfer and C.B. Nemeroff, eds. ISBN 9780444520029 107, Epilepsy Part I, H. Stefan and W.H. Theodore, eds. ISBN 9780444528988 108, Epilepsy Part II, H. Stefan and W.H. Theodore, eds. ISBN 9780444528995 109, Spinal cord injury, J. Verhaagen and J.W. McDonald III, eds. ISBN 9780444521378 110, Neurological rehabilitation, M. Barnes and D.C. Good, eds. ISBN 9780444529015 111, Pediatric neurology Part I, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444528919 112, Pediatric neurology Part II, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444529107 113, Pediatric neurology Part III, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444595652 114, Neuroparasitology and tropical neurology, H.H. Garcia, H.B. Tanowitz and O.H. Del Brutto, eds. ISBN 9780444534903 115, Peripheral nerve disorders, G. Said and C. Krarup, eds. ISBN 9780444529022 116, Brain stimulation, A.M. Lozano and M. Hallett, eds. ISBN 9780444534972 117, Autonomic nervous system, R.M. Buijs and D.F. Swaab, eds. ISBN 9780444534910 118, Ethical and legal issues in neurology, J.L. Bernat and H.R. Beresford, eds. ISBN 9780444535016 119, Neurologic aspects of systemic disease Part I, J. Biller and J.M. Ferro, eds. ISBN 9780702040863 120, Neurologic aspects of systemic disease Part II, J. Biller and J.M. Ferro, eds. ISBN 9780702040870 121, Neurologic aspects of systemic disease Part III, J. Biller and J.M. Ferro, eds. ISBN 9780702040887 122, Multiple sclerosis and related disorders, D.S. Goodin, ed. ISBN 9780444520012 123, Neurovirology, A.C. Tselis and J. Booss, eds. ISBN 9780444534880 124, Clinical neuroendocrinology, E. Fliers, M. Korbonits and J.A. Romijn, eds. ISBN 9780444596024 125, Alcohol and the nervous system, E.V. Sullivan and A. Pfefferbaum, eds. ISBN 9780444626196 126, Diabetes and the nervous system, D.W. Zochodne and R.A. Malik, eds. ISBN 9780444534804 127, Traumatic brain injury Part I, J.H. Grafman and A.M. Salazar, eds. ISBN 9780444528926 128, Traumatic brain injury Part II, J.H. Grafman and A.M. Salazar, eds. ISBN 9780444635211

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AVAILABLE TITLES (Continued)

Vol. 129, The human auditory system: Fundamental organization and clinical disorders, G.G. Celesia and G. Hickok, eds. ISBN 9780444626301 Vol. 130, Neurology of sexual and bladder disorders, D.B. Vodušek and F. Boller, eds. ISBN 9780444632470 Vol. 131, Occupational neurology, M. Lotti and M.L. Bleecker, eds. ISBN 9780444626271 Vol. 132, Neurocutaneous syndromes, M.P. Islam and E.S. Roach, eds. ISBN 9780444627025 Vol. 133, Autoimmune neurology, S.J. Pittock and A. Vincent, eds. ISBN 9780444634320 Vol. 134, Gliomas, M.S. Berger and M. Weller, eds. ISBN 9780128029978 Vol. 135, Neuroimaging Part I, J.C. Masdeu and R.G. González, eds. ISBN 9780444534859 Vol. 136, Neuroimaging Part II, J.C. Masdeu and R.G. González, eds. ISBN 9780444534866 Vol. 137, Neuro-otology, J.M. Furman and T. Lempert, eds. ISBN 9780444634375 Vol. 138, Neuroepidemiology, C. Rosano, M.A. Ikram and M. Ganguli, eds. ISBN 9780128029732 Vol. 139, Functional neurologic disorders, M. Hallett, J. Stone and A. Carson, eds. ISBN 9780128017722 Vol. 140, Critical care neurology Part I, E.F.M. Wijdicks and A.H. Kramer, eds. ISBN 9780444636003 Vol. 141, Critical care neurology Part II, E.F.M. Wijdicks and A.H. Kramer, eds. ISBN 9780444635990 Vol. 142, Wilson disease, A. Członkowska and M.L. Schilsky, eds. ISBN 9780444636003 Vol. 143, Arteriovenous and cavernous malformations, R.F. Spetzler, K. Moon and R.O. Almefty, eds. ISBN 9780444636409 Vol. 144, Huntington disease, A.S. Feigin and K.E. Anderson, eds. ISBN 9780128018934 Vol. 145, Neuropathology, G.G. Kovacs and I. Alafuzoff, eds. ISBN 9780128023952 Vol. 146, Cerebrospinal fluid in neurologic disorders, F. Deisenhammer, C.E. Teunissen and H. Tumani, eds. ISBN 9780128042793 Vol. 147, Neurogenetics Part I, D.H. Geschwind, H.L. Paulson and C. Klein, eds. ISBN 9780444632333 Vol. 148, Neurogenetics Part II, D.H. Geschwind, H.L. Paulson and C. Klein, eds. ISBN 9780444640765 Vol. 149, Metastatic diseases of the nervous system, D. Schiff and M.J. van den Bent, eds. ISBN 9780128111611 Vol. 150, Brain banking in neurologic and psychiatric diseases, I. Huitinga and M.J. Webster, eds. ISBN 9780444636393 Vol. 151, The parietal lobe, G. Vallar and H.B. Coslett, eds. ISBN 9780444636225 Vol. 152, The neurology of HIV infection, B.J. Brew, ed. ISBN 9780444638496 Vol. 153, Human prion diseases, M. Pocchiari and J.C. Manson, eds. ISBN 9780444639455 Vol. 154, The cerebellum: From embryology to diagnostic investigations, M. Manto and T.A.G.M. Huisman, eds. ISBN 9780444639561 Vol. 155, The cerebellum: Disorders and treatment, M. Manto and T.A.G.M. Huisman, eds. ISBN 9780444641892 Vol. 156, Thermoregulation: From basic neuroscience to clinical neurology Part I, A.A. Romanovsky, ed. ISBN 9780444639127 Vol. 157, Thermoregulation: From basic neuroscience to clinical neurology Part II, A.A. Romanovsky, ed. ISBN 9780444640741 Vol. 158, Sports neurology, B. Hainline and R.A. Stern, eds. ISBN 9780444639547 Vol. 159, Balance, gait, and falls, B.L. Day and S.R. Lord, eds. ISBN 9780444639165 Vol. 160, Clinical neurophysiology: Basis and technical aspects, K.H. Levin and P. Chauvel, eds. ISBN 9780444640321 Vol. 161, Clinical neurophysiology: Diseases and disorders, K.H. Levin and P. Chauvel, eds. ISBN 9780444641427 Vol. 162, Neonatal neurology, L.S. De Vries and H.C. Glass, eds. ISBN 9780444640291 Vol. 163, The frontal lobes, M. D’Esposito and J.H. Grafman, eds. ISBN 9780128042816 Vol. 164, Smell and taste, Richard L. Doty, ed. ISBN 9780444638557 Vol. 165, Psychopharmacology of neurologic disease, V.I. Reus and D. Lindqvist, eds. ISBN 9780444640123 Vol. 166, Cingulate cortex, B.A. Vogt, ed. ISBN 9780444641960 Vol. 167, Geriatric neurology, S.T. DeKosky and S. Asthana, eds. ISBN 9780128047668 Vol. 168, Brain-computer interfaces, N.F. Ramsey and J. del R. Millán, eds. ISBN 9780444639349 Vol. 169, Meningiomas, Part I, M.W. McDermott, ed. ISBN 9780128042809 Vol. 170, Meningiomas, Part II, M.W. McDermott, ed. ISBN 9780128221983 Vol. 171, Neurology and pregnancy: Pathophysiology and patient care, E.A.P. Steegers, M.J. Cipolla and E.C. Miller, eds. ISBN 9780444642394 Vol. 172, Neurology and pregnancy: Neuro-obstetric disorders, E.A.P. Steegers, M.J. Cipolla and E.C. Miller, eds. ISBN 9780444642400 Vol. 173, Neurocognitive development: Normative development, A. Gallagher, C. Bulteau, D. Cohen and J.L. Michaud, eds. ISBN 9780444641502 Vol. 174, Neurocognitive development: Disorders and disabilities, A. Gallagher, C. Bulteau, D. Cohen and J.L. Michaud, eds. ISBN 9780444641489 Vol. 175, Sex differences in neurology and psychiatry, R. Lanzenberger, G.S. Kranz, and I. Savic, eds. ISBN 9780444641236 Vol. 176, Interventional neuroradiology, S.W. Hetts and D.L. Cooke, eds. ISBN 9780444640345 Vol. 177, Heart and neurologic disease, J. Biller, ed. ISBN 9780128198148 Vol. 178, Neurology of vision and visual disorders, J.J.S. Barton and A. Leff, eds. ISBN 9780128213773 Vol. 179, The human hypothalamus: Anterior region, D.F. Swaab, F. Kreier, P.J. Lucassen, A. Salehi and R.M. Buijs, eds. ISBN 9780128199756

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Vol. 180, The human hypothalamus: Middle and posterior region, D.F. Swaab, F. Kreier, P.J. Lucassen, A. Salehi and R.M. Buijs, eds. ISBN 9780128201077 Vol. 181, The human hypothalamus: Neuroendocrine disorders, D.F. Swaab, R.M. Buijs, P.J. Lucassen, A. Salehi and F. Kreier, eds. ISBN 9780128206836 Vol. 182, The human hypothalamus: Neuropsychiatric disorders, D.F. Swaab, R.M. Buijs, F. Kreier, P.J. Lucassen, and A. Salehi, eds. ISBN 9780128199732 Vol. 183, Disorders of emotion in neurologic disease, K.M. Heilman and S.E. Nadeau, eds. ISBN 9780128222904 Vol. 184, Neuroplasticity: From bench to bedside, A. Quartarone, M.F. Ghilardi, and F. Boller, eds. ISBN 9780128194102 Vol. 185, Aphasia, A.E. Hillis and J. Fridriksson, eds. ISBN 9780128233849 Vol. 186, Intraoperative neuromonitoring, M.R. Nuwer and D.B. MacDonald, eds. ISBN 9780128198261 Vol. 187, The temporal lobe, G. Miceli, P. Bartolomeo, and V. Navarro, eds. ISBN 9780128234938 Vol. 188, Respiratory neurobiology: Physiology and clinical disorders, Part I, R. Chen and P.G. Guyenet, eds. ISBN 9780323915342 Vol. 189, Respiratory neurobiology: Physiology and clinical disorders, Part II, R. Chen and P.G. Guyenet, eds. ISBN 9780323915328 Vol. 190, Neuropalliative care: Part I, J.M. Miyasaki and B.M. Kluger, eds. ISBN 9780323850292 Vol. 191, Neuropalliative care: Part II, J.M. Miyasaki and B.M. Kluger, eds. ISBN 9780128245354 Vol. 192, Precision medicine in neurodegenerative disorders: Part I, A.J. Espay, ed. ISBN 9780323855389 Vol. 193, Precision medicine in neurodegenerative disorders: Part II, A.J. Espay, ed. ISBN 9780323855556 Vol. 194, Mitochondrial diseases, R. Horvath, M. Hirano, and P.F. Chinnery, eds. ISBN 9780128217511 Vol. 195, Motor system disorders, Part I: Normal physiology and function and neuromuscular disorders, D.S. Younger, ed. ISBN 9780323988186 All volumes in the 3rd Series of the Handbook of Clinical Neurology are published electronically, on Science Direct: http://www.sciencedirect.com/science/handbooks/00729752.

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Foreword

It is a pleasure to introduce Volumes 195 and 196 of the Handbook of Clinical Neurology, devoted to the motor system. In Volume 195, there are sections on normal physiology and function, diagnostic approaches, and neuromuscular disorders occurring in patients of all ages. In Volume 196, the focus is on spinal cord disorders, progressive neurodegenerative diseases, nonprogressive cortical and subcortical disorders, and therapeutics. A detailed summary about the content of these various sections is provided in the Preface. It must be made clear, however, that these volumes cover more than is generally subsumed by the designation “motor system,” as they provide an account of virtually any disorder with motor manifestations through the perspective of many different subspecialties, thereby providing a truly comprehensive account of the subject matter. The editor, David S. Younger, is an Affiliated Professor of Neuroscience at the City University of New York School of Medicine and Attending Physician at White Plains Hospital, New York. He is a neuromuscular specialist, teacher, and clinical neurophysiologist who has authored studies on many different aspects of neurologic function. More than 20 years ago, he edited a book that provided a detailed and practical account of motor disorders, and he has continued to maintain an encyclopedic knowledge of these disorders ever since. We were therefore delighted when he accepted our invitation to edit a volume in the Handbook of Clinical Neurology series to provide a comprehensive account of these disorders and how they have been impacted by advances in the neurosciences. As he proceeded, however, it became apparent that two volumes would be required to cover the subject adequately, providing clinicians with an up-to-date summary of the investigation, diagnosis, management, and treatment of various motor disorders, and neuroscientists with an account of the many different approaches to determine their fundamental bases through the perspective of molecular biology, immunology, neurophysiology, imaging, and pharmacology. To do so, he has attracted an outstanding group of authors—many of whom are internationally recognized experts in the field—to contribute to these volumes, ensuring a consistently high standard throughout them. Moreover, as the sole volume editor, he has edited the chapters so that there is a pleasing uniformity of style and they fit together seamlessly. As series editors, we reviewed all the chapters and made suggestions for improvement, but it was clear that the volume editor and chapter authors had produced scholarly and comprehensive accounts of different aspects of the topic. We thank Dr. Younger and all the contributors for their work. It is our hope that the volumes will have wide appeal to clinicians and scientists alike. As always, it is a pleasure to thank Elsevier, our publisher, and in particular Nikki Levy and Kristi Anderson in San Diego, and Punithavathy Govindaradjane at Elsevier Global Book Production in Chennai, for their assistance in the development and production of the Handbook of Clinical Neurology. Michael J. Aminoff Franc¸ois Boller Dick F. Swaab

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Preface

A striking aspect of the history of motor disorders has been the persistence of generations of neuroscientists and neurologists in searching for a more cohesive understanding of the motor system in health and disease. Remarkable progress has been achieved over the past 30 years in the classification, diagnosis, etiopathogenesis, and treatment of many peripheral and central nervous system motor disorders since the publication of the last handbook volume on this subject (Volume 59, edited by JMB V De Jong, published in 1991). These advances have occurred along the diverse lines of electrophysiology, immunology, molecular genetics, and ultrastructural analysis, as well as through technical advances in translational methods applicable to neurologic therapeutics, neurosurgery, and rehabilitative care. Such advances have, in turn, fostered more effective and innovative treatments confirmed to be efficacious in randomized clinical trials, showing improved outcomes and enhanced independence. My goal in developing the present work was to produce two classic volumes with unsurpassed depth and breadth along a list of interrelated topics on the motor system and its disorders. The first volume (Volume 195 of the Handbook) is divided into three sections. Section 1 covers normal physiology and function encompassing basic concepts of skeletal muscle function, upper and lower motor neuron control, the vestibular and autonomic nervous system and autonomic failure, and immunology and Coronavirus-2 illness. Section 2 overviews the topic of clinical and laboratory diagnosis, beginning with genetics, electrodiagnosis, neuromuscular pathology, autonomic physiology, imaging, sleep disorders, and the path to evidence-based therapy for neuromuscular diseases. Section 3 delves into the neuromuscular disorders, covering classic topics such as infant hypotonia, inflammatory myopathy, childhood muscular dystrophy, distal and congenital myopathies, channelopathies, mitochondrial encephalomyopathies, autoimmune and hereditary polyneuropathies, neuromuscular junction disorders, and adult and childhood vasculitis. The second volume (Volume 196) is divided into four sections. Section 1 covers spinal cord diseases, spinal muscular atrophy, hereditary spastic paraplegias and primary lateral sclerosis, transverse myelitis, and motor aspects of multiple sclerosis. Section 2 addresses progressive neurodegenerative diseases involving the cerebellum, extrapyramidal system, tauopathies, paraneoplastic disorders, motor neuron disease, and Alzheimer disease. Section 3 addresses nonprogressive cortical and subcortical disorders exemplified by motor seizure disorders, stroke, brainstem nuclei and cortical motor control disturbances, antineuronal antibodies, autoimmune encephalopathy, tremor, dystonia, frontal and parietal lobe syndromes, and bowel, bladder, and sexual disorders. Section 4 concludes with a comprehensive list of topics addressing neurologic therapeutics that includes the treatment of spasticity, use of botulinum toxin, enzyme replacement therapy, growth factors, applied strategies of neuroplasticity, tau-based immunotherapies, and novel uses of brain–computer interfaces. The invited authors, all experts in their fields, have been drawn from all parts of the United States and abroad, covering a multitude of traditions and heritages in neurology. As the sole editor of these two volumes, I was overjoyed at the prospect of instilling my own voice to assure consistency of style and readability. I appreciate the extreme tolerance of each of the contributors in allowing me to edit their work no matter how much it appeared to be at the point of finality so that there would be cohesiveness and consistency beyond just the apparent flow of titles. I thank the series editors for their tolerance and for their style setting and content-oriented benchmarks that made my job easier. I have been privileged to have been trained with, mentored by, or closely associated with many preeminent clinicians beginning at Columbia University’s Neurological Institute with Lewis P (“Bud”) Rowland, a former editor of the journal Neurology, whose unselfish guidance to become the best clinical investigator and author fostered the careers of many of my contemporaries, some of whom have contributed chapters to these two volumes. Most of all, I am continuously instructed and humbled by my patients, whose never-ending battles with debilitating illness are always fought with dignity.

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PREFACE

I am pleased to dedicate these two volumes to the spouses, children, and significant others of all of the contributors, and to my own family, who patiently sat by and were often displaced while the process of writing and editing took place. David S. Younger

Contributors

F. Agosta San Raffaele Scientific Institute, Division of Neuroscience, InsPE; Vita-Salute San Raffaele University, Milan, Italy

R. Erro Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, Neuroscience Section, University of Salerno, Baronissi, Salerno, Italy

K.P. Bhatia Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom

J.K. Fink Department of Neurology, University of Michigan, Ann Arbor, MI, United States

R.H. Brown Jr. Department of Neurology, UMass Chan Medical School, Donna M. and Robert J. Manning Chair in Neurosciences and Director in Neurotherapeutics, Worcester, MA, United States N. Bukhari-Parlakturk Department of Neurology, Movement Disorders Division, Duke University (NBP), Durham, NC, United States N. Cashman Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada L.G. Cohen Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States

I. Franco Yale School of Medicine, Yale-New Haven Children's Bladder and Continence Program, Yale New Haven Children's Hospital, New Haven, CT, United States S.J. Frucht Department of Neurology, NYU Grossman School of Medicine (SJF), New York, NY, United States C. Gaig Neurology Service, Hospital Clínic of Barcelona, Barcelona, Spain A. Ghirelli San Raffaele Scientific Institute, Division of Neuroscience, InsPE; Vita-Salute San Raffaele University, Milan, Italy E.A. Grasso Department of Neurosciences, Imaging and Clinical Sciences, Institute of Advanced Biomedical Technologies (ITAB), University G. d’Annunzio of Chieti-Pescara, Chieti, Italy

A. Daniele Department of Neuroscience, Catholic University of Sacred Heart; Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy

F. Graus Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

G. Devi Department of Neurology and Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, Hempstead, NY, United States

A. Hartmann Department of Neurology; National Reference Center for Tourette Disorder, Piti
e-Salp^etrière Hospital, Paris, France

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CONTRIBUTORS

B. Jabbari Department of Neurology, Yale University School of Medicine, New Haven, CT, United States L. Jarrett Department of Neurology, Royal Devon and Exeter Hospital, Exeter, United Kingdom B.P. Johnson Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States G. Lamotte Department of Neurology, University of Utah, Salt Lake City, UT, United States E.D. Louis Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States M. Lozupone Department of Translational Biomedicine and Neuroscience (DiBrain), University of Bari Aldo Moro, Bari, Italy F. Magrinelli Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom M. Manto Unit
e des Ataxies C
er
ebelleuses, Service de Neurologie, CHU-Charleroi, Charleroi; Service des Neurosciences, Universit
e de Mons, Mons, Belgium J. Marsden School of Health Professions, Faculty of Health, University of Plymouth, Plymouth, United Kingdom D. Martino Department of Clinical Neurosciences, Cumming School of Medicine; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada G. Martino San Raffaele Scientific Institute, Division of Neuroscience, InsPE; Vita-Salute San Raffaele University, Milan, Italy S. Marzoughi Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada

A.V. Masurkar Department of Neurology; Division of Cognitive Neurology, Center for Cognitive Neurology, NYU School of Medicine, New York, NY, United States J.R. Mendell Department of Neurology and Pediatrics, Center for Gene Therapy, Abigail Wexner Research Institute, The Ohio State University, Nationwide Children's Hospital, Columbus, OH, United States H. Mitoma Department of Medical Education, Tokyo Medical University, Tokyo, Japan L. Muzio San Raffaele Scientific Institute, Division of Neuroscience, InsPE, Milan, Italy C. Nilles Department of Clinical Neurosciences, Psychiatry, Pediatrics and Community Health Sciences, University of Calgary, Calgary, AB, Canada; Department of Neurology, Piti
e-Salp^etrière Hospital, Paris, France D.R. Nordli Department of Pediatrics and the Comprehensive Epilepsy Center, The University of Chicago, Chicago, IL, United States F. Panza Unit of Research Methodology and Data Sciences for Population Health, National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, Bari, Italy G.M. Pastores Department of Medicine (Clinical Genetics), National Center for Inherited Metabolic Disorders, Mater Misericordiae University Hospital; Department of Medicine (Genetics), University College of Dublin School of Medicine, Dublin, Ireland G. Pfeffer Department of Neurosciences, Division of Neurology, University of Calgary, Calgary, AB, Canada V. Pozzilli Department of Neurosciences, Imaging and Clinical Sciences, Institute of Advanced Biomedical Technologies (ITAB), University G. d’Annunzio of Chieti-Pescara, Chieti, Italy

CONTRIBUTORS T. Pringsheim Department of Clinical Neurosciences, Psychiatry, Pediatrics and Community Health Sciences; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada G.C. Román Department of Neurology, Methodist Neurological Institute, Weill Cornell Medical College, Houston Methodist Hospital, Houston, TX, United States E. Roze Department of Neurology, Piti
e-Salp^etrière Hospital, Paris, France; Faculty of Medicine of Sorbonne University, Institut du Cerveau et de la Moelle
epinière, Paris, France D. Safarpour Department of Neurology, Oregon Health & Science University, Portland, OR, United States W. Singer Department of Neurology, Mayo Clinic, Rochester, MN, United States

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A.E. Thompson Department of Neurology, Flinders Medical Centre, Adelaide, South Australia P.D. Thompson University of Adelaide, Adelaide, South Australia V. Tomassini Department of Neurosciences, Imaging and Clinical Sciences, Institute of Advanced Biomedical Technologies (ITAB), University G. d’Annunzio of Chieti-Pescara, Chieti, Italy T. Wisniewski Departments of Neurology, of Pathology and of Psychiatry; Division of Cognitive Neurology, Center for Cognitive Neurology, NYU School of Medicine, New York, NY, United States S. Wu Department of Neurology and the Comprehensive Epilepsy Center, The University of Chicago, Chicago, IL, United States

V. Solfrizzi “Cesare Frugoni” Internal and Geriatric Medicine and Memory Unit, University of Bari “Aldo Moro”, Bari, Italy

D.S. Younger Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York; and Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States

V. Stevenson Department of Therapies and Rehabilitation, National Hospital for Neurology and Neurosurgery UCLH, London, United Kingdom

D.W. Zochodne Division of Neurology, Department of Medicine and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada

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Contents Foreword ix Preface xi Contributors xiii SECTION 1

Spinal cord diseases

1. Spinal cord motor disorders D.S. Younger (New York City, United States)

3

2. Childhood spinal muscular atrophy D.S. Younger and J.R. Mendell (New York City and Columbus, United States)

43

3. The hereditary spastic paraplegias J.K. Fink (Ann Arbor, United States)

59

4. Primary lateral sclerosis S. Marzoughi, G. Pfeffer, and N. Cashman (Vancouver and Calgary, Canada)

89

5. Transverse myelitis in children and adults E.A. Grasso, V. Pozzilli, and V. Tomassini (Chieti, Italy)

101

6. Multiple sclerosis: Motor dysfunction D.S. Younger (New York City, United States)

119

7. Tropical spastic paraparesis G.C. Román (Houston, United States)

149

SECTION 2

Progressive neurodegenerative diseases

8. Cerebellum: From the identification of the cerebellar motor syndrome to the internal models M. Manto and H. Mitoma (Charleroi and Mons, Belgium and Tokyo, Japan)

159

9. Synucleinopathies G. Lamotte and W. Singer (Salt Lake City and Rochester, United States)

175

10. Amyotrophic lateral sclerosis D.S. Younger and R.H. Brown Jr. (New York City and Worcester, United States)

203

11. Paraneoplastic motor disorders D.S. Younger (New York City, United States)

231

12. The tauopathies G. Devi (Hempstead, United States)

251

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CONTENTS

13. Gait dysfunction in Alzheimer disease T. Wisniewski and A.V. Masurkar (New York, United States) SECTION 3

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Non-progressive cortical and subcortical disorders

14. Motor symptoms in nonparaneoplastic CNS disorders associated with neural antibodies C. Gaig and F. Graus (Barcelona, Spain)

277

15. Motor seizure semiology S. Wu and D.R. Nordli (Chicago, United States)

295

16. Motor sequela of adult and pediatric stroke: Imminent losses and ultimate gains D.S. Younger (New York City, United States)

305

17. Paroxysmal movement disorders: Paroxysmal dyskinesia and episodic ataxia R. Erro, F. Magrinelli, and K.P. Bhatia (Salerno, Italy and London, United Kingdom)

347

18. Pediatric neuropsychiatric disorders with motor and nonmotor phenomena D.S. Younger (New York City, United States)

367

19. Essential tremor E.D. Louis (Dallas, United States)

389

20. Anatomy, physiology, and evaluation: Bowel, bladder, and sexual disorders I. Franco (New Haven, United States)

403

21. Isolated and combined dystonias: Update N. Bukhari-Parlakturk and S.J. Frucht (Durham and New York, United States)

425

22. Frontal lobe motor syndromes A.E. Thompson and P.D. Thompson (Adelaide, South Australia)

443

23. Tourette syndrome and other tic disorders of childhood C. Nilles, A. Hartmann, E. Roze, D. Martino, and T. Pringsheim (Calgary, Canada and Paris, France)

457

24. Mild traumatic brain injury and sports-related concussion D.S. Younger (New York City, United States)

475

SECTION 4

Therapeutics

25. Treatment of spasticity J. Marsden, V. Stevenson, and L. Jarrett (Plymouth, London, and Exeter, United Kingdom)

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26. Novel therapeutic approaches for motor neuron disease L. Muzio, A. Ghirelli, F. Agosta, and G. Martino (Milan, Italy)

523

27. Botulinum toxin for motor disorders D. Safarpour and B. Jabbari (Portland and New Haven, United States)

539

28. Lysosomal storage disorders: Clinical and therapeutic aspects G.M. Pastores (Dublin, Ireland)

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CONTENTS

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29. Growth factors and molecular-driven plasticity in neurological systems D.W. Zochodne (Edmonton, Canada)

569

30. Applied strategies of neuroplasticity B.P. Johnson and L.G. Cohen (Bethesda, United States)

599

31. Passive tau-based immunotherapy for tauopathies F. Panza, V. Solfrizzi, A. Daniele, and M. Lozupone (Bari and Rome, Italy)

611

Index

621

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Section 1 Spinal cord diseases

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00007-7 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 1

Spinal cord motor disorders DAVID S. YOUNGER1,2* 1

Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States

2

Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States

Abstract Spinal cord diseases are frequently devastating due to the precipitous and often permanently debilitating nature of the deficits. Spastic or flaccid paraparesis accompanied by dermatomal and myotomal signatures complementary to the incurred deficits facilitates localization of the insult within the cord. However, laboratory studies often employing disease-specific serology, neuroradiology, neurophysiology, and cerebrospinal fluid analysis aid in the etiologic diagnosis. While many spinal cord diseases are reversible and treatable, especially when recognized early, more than ever, neuroscientists are being called to investigate endogenous mechanisms of neural plasticity. This chapter is a review of the embryology, neuroanatomy, clinical localization, evaluation, and management of adult and childhood spinal cord motor disorders.

INTRODUCTION Embryology The developmental anatomy of the primitive human spinal cord and its vascular elements have been recognized since the early 20th century (Evans, 1912). The section below is an introduction to the embryology of the spinal cord and vascular system.

SPINAL CORD The spinal cord develops from the wall of the neural tube composed of a single layer of columnar ectodermal cells that divide rapidly from the central canal along three layers from internal to external including ependymal, mantle, and marginal. The ependymal layer is converted into the ependyma that lines the central canal with processes that pass outward to the periphery. The mantle portion develops into the future gray columns with

differentiation from interconnected spongioblasts into syncytia of neuroglial cells. Germinal cells develop into neuroblasts and nerve cells defined by their shape and location in the gray substance. The marginal layer, devoid of nuclei, forms the supporting substance of white matter tracts. The sulcus limitans which extends from the lateral wall of the neural tube to the midbrain delimits the dorsal and ventral lamina with afferent fibers that synapse on cells derived from the former, and efferent connections arising from cells of the latter. In its final postnatal form, the vertical organization of the spinal cord shows superimposed segments, each relating to a specific peripheral myotome and dermatome through the attachment of paired spinal nerves that become oriented progressively more obliquely and downward from their initial adjacent position in embryogenesis as a consequence of the relative inequality in growth rates of the spinal cord and the vertebral column. Two enlargements, one cervical and the other lumbar, correspond to the nerves that innervate the arms and legs.

*Correspondence to: David S. Younger, MD, DrPH, MPH, MS, 333 East 34th Street, Suite 1J, New York, NY 10016, United States. Tel: +1-212-213-3778, Fax: +1-212-213-3779, E-mail: [email protected]

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VASCULAR SYSTEM Primitive paired aortic dorsal branches form capillary loops delineating future intersegmental arteries (ISAs) that are drained by intersegmental veins. Anterior and posterior radicular arteries that derive from ISAs participate in the formation of a plexus on the ventral and dorsal surfaces of the cord along with the emergence of bilateral longitudinal channels continuous with cranial longitudinal neural arteries that will become the future anterior (ASA) and posterior spinal arteries (PSA). The primitive configuration of the ISAwith its medial (spinal) contribution, and dorsal (muscular) and lateral (intercostal, subcostal, or lumbar) secondary branches representative of the basic anatomy of the adult thoracolumbar ISA are secondarily modified at cervical and sacral levels with the formation of vertebral and sacral arteries, notable for anastomoses linking the first six cervical ISAs to form the V2 segment of the extracranial vertebral artery. While the spinal branch of a given ISA follows a posteromedial course accompanying the nerve root to enter the neural foramen, a radicular branch passes across the dura to supply the spinal cord either as a radiculomedullary artery (RMA) connected to a longitudinal ASA or PSA, or as a radiculopial vessel. Only a few of the future RMAs remain in the adult, notably in cervical and lumbosacral enlargements, to meet their higher metabolic demands. The thoracolumbar spinal cord relies on a dominant lower thoracic or lumbar anterior RMA, the artery of Adamkiewicz, that originates between T8 and L3, most often from the left T9 ISA (Rodriguez-Baeza et al., 1991), and a smaller upper thoracic branch, the artery of von Haller that predominantly originates from the left T5 ISA (Gailloud, 2013). The vasocorona arterial network established around the spinal cord comprising longitudinal anastomotic chains of anterior RMAs from each ISA, supplying the spinal gray and white matter that form ASAs, spans from the level of the medulla from the junction of small vertebrospinal trunks provided by each vertebral artery, uninterrupted to its termination along the filum terminale. Near the tip of the conus medullaris, the ASA gives off two small arcuate branches that course laterally and posteriorly to reach the dorsal surface of the cord and anastomose with the caudal end of the posterior spinal chains to constitute the periconal anastomotic circle. There are three potential watershed zones in the spinal cord with clinical significance. The first is due to the usual direction of flow in the periconal anastomotic circle that is craniocaudal in the distal ASA and caudocranial in the distal PSAs, creating a watershed territory in the dorsal lumbosacral region. As sulcal arteries reach the depth of the anterior-median fissure, they divide into sulcocommissural branches which typically have a unilateral distribution with alternating left and right branches. This

interface of central (or centrifugal) sulcal arteries that enter the anterior-median fissure produces a second potential watershed, while perforating branches of the PSAs and vasocorona provide the peripheral (or centripetal) cord supply zone. The pronounced elongation of thoracic segments in development in conjunction with a reduced number of radicular contributions, their smaller diameter, and increased distance between sulcal arteries together, contribute to a third watershed zone in the thoracic cord (Gregg and Gailloud, 2021), although that issue is unsettled.

NEUROANATOMY The section below reviews the anatomy of the bony spine that contains the spinal cord and its vascular elements.

Bony spine The spinal cord rests in a flexible column termed as the bony spine, formed by 33 vertebrae including 7 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 4 coccygeal; however the number may be increased or decreased in the lower spine, and those found in the sacral and coccygeal areas are united as the sacrum and coccyx. Each vertebra contains an anterior solid body and a posterior arch, the latter formed by 2 pedicles and 2 lamina supporting 7 processes including 4 articular, 2 transverse, and 1 spinous process surrounding the vertebral foramen. The vertebrae are stacked for the support of the cranial and trunk, comprising a vertical spinal canal for passage of the spinal cord and thecal sac. The bodies articulate one to the other via articular processes and intervertebral ligaments. Cervical vertebrae are generally smaller, denser, and readily distinguished by foramina in the transverse process for vertebral arteries with pedicles directed outward and backward, and spinous processes short and bifid, and its lamina enclosing a triangular spinal canal that confers the heightened risk for cord compression. Thoracic vertebrae have facets and half-facets that articulate with the ribs, and backward and inferiorly projected pedicles and lamina that overlap delineating a more circular spinal canal. Lumbar vertebrae are the largest segments of the movable vertebral column, distinguished by the absence of foramina in the transverse processes, with facets on the side of the body and broader pedicles and lamina that delimit a copious canal. The sacrum articulates with the last lumbar vertebra above, the coccyx below, and the hip bones of either side. The spine presents several curves; a convex cervical curve spans the axis of the odontoid process to the middle of the second thoracic vertebra. The thoracic curvature is concave forward from the second to the middle of the 12th thoracic vertebra. The lumbar curve spans from

SPINAL CORD MOTOR DISORDERS the twelfth thoracic to the sacral vertebral angle, with an anterior convexity that is much more pronounced for the third to fifth lumbar vertebra than the upper two. Intervertebral fibrocartilaginous discs interposed between adjacent vertebral bodies constitute about one-fourth of the length of the vertebral column. Lamina of fibrous tissue and fibrocartilage forming the annulus fibrosis surrounds the highly elastic nucleus pulposus that functions as a shock absorber, which under pressure becomes flatter and broader, pushing the most resistant fibrous lamina in all directions.

Spinal cord Viewed in the horizontal plane in cross section, two fissures, one anterior and another posterior, divide the spinal cord into two symmetrical parts joined in the middle by anterior and posterior white matter commissures, delineating the position of future spinal tract and cell groups. The internal structure of the spinal cord reveals symmetrical anterior, lateral, and posterior columns of gray substance, the quantity of which varies on the transverse section with the spinal level, namely small in the thoracic level and increased in the cervical and lumbar enlargements, joined in the middle around the central canal. The anterior columns contain somatic motor neurons separated from the cord surface by bundles of intramedullary nerve root fibers yet to emerge. The lateral gray column, identified mainly in the upper cervical, thoracic, and mid sacral levels, corresponds to preganglionic cells of the autonomic nervous system. The posterior column corresponds to the central processes of corresponding dorsal roots separated from the cord surface by a thin layer of white matter termed the tract of Lissauer. Incoming fibers of the posterior column give rise to long fibers that divide in a T-shaped fashion with some remaining in a single segment, others ascending or descending to adjoining segments, or traversing longer distances before synapsing at a distance. Longitudinal fiber tracts of the spinal cord group into three bundles or fasciculi including the anterior, lateral, and posterior best appreciated in Weigert myelin-stained preparations after lesion of the cell body of origin. Three fiber tracts of importance to motor function in the anterior fasciculus include the direct and indirect vestibulospinal fasciculi that derive from ipsilateral vestibular nuclei that descend to spinal levels for the modification of equilibratory and antigravity reflexes, and the medial longitudinal fasciculus that interconnects the cervical cord, vestibular complex, and oculomotor nuclei for visual fixation. Four descending fiber tracts located in the lateral fasciculus with additional motor importance include the lateral corticospinal, rubrospinal, reticulospinal, and olivospinal tracts.

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Vasculature The adult arterial supply of the spinal cord is thus provided by the spinal branches of the cervical, thoracic, and lumbar ISAs that coalesce into an anterior and posterior arterial system (de Girolami and Bale, 2017) (Fig. 1.1). The anterior arterial system is comprised of the ASA, a single vessel formed by the convergence of branches from the vertebral arteries at the level of the cervicomedullary junction. The vessel runs down the ventral surface of the spinal cord and supplies the anterior two-thirds of the cord, including the corticospinal and spinothalamic tracts. As the ASA descends, it received vascular supply from RMAs arising from the vertebral, ascending cervical, intercostal, and lumbar arteries. These vessels enter the dura at the root sleeve and supply the dura and nerve root at each segmental level (Fig. 1.2). Additionally, some of the radicular arteries give off medullary branches that contribute to the anterior or posterolateral spinal arteries. The largest medullary branch, the artery of Adamkiewicz, supplies the majority of the thoracic cord and conus medullaris. A second

Fig. 1.1. The arterial blood supply of the spinal cord. Reproduced from de Girolami U, Bale TA (2017). Spinal cord. Handb Clin Neurol 145: 405–425 with permission of the publisher.

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Fig. 1.2. Segmental arterial supply of the spinal cord. Schematic transverse section of the spinal cord depicting segmental arterial supply (left) and distribution of major neuronal groups (right). Reproduced from de Girolami U, Bale TA (2017). Spinal cord. Handb Clin Neurol 145: 405–425 with permission from the publisher.

prominent radicular feeder, the artery of the cervical enlargement, arises from the C5 or C6 level. The mid thoracic region has a tenuous vascular supply secondary to poor collaterals, resulting in a watershed zone that is more susceptible to vascular insults than the rest of the spinal cord. The posterior arterial supply is comprised of paired vessels running along the dorsolateral surface of the spinal cord that perfuses the posterior columns and small portions of the lateral columns. The PSAs arise from the vertebral arteries and receive vascular supply from radiculomedullary branches of the vertebral, intercostal, and lumbar arteries. The posterior anastomosis is more abundant than the anterior one, but less prominent and more variable. The dorsal arteries are much smaller than the anterior arteries and are more difficult to visualize angiographically. The anterior and posterior systems collateralize though the circumferential arteries of the spinal cord and through the cruciate anastomosis at the conus medullaris. The venous system of the spinal cord is less complex than the arterial system and tends to be more diffuse over the dorsal aspect of the cord. The surface veins converge laterally to form medullary veins that subsequently exit the spinal canal at each root sleeve level.

SPINAL MOTOR CONTROL Voluntary motor control is a product of complex interactions between topographically and functionally diverse brain structures and pathways, including the motor and sensory cortex, basal ganglia, thalamus, cerebellum,

brainstem, and spinal cord. Coordinated movement is achieved through the integration and modulation of cortical signals by these interconnected structures that are transmitted to the thousands of motor neurons and interneurons at the corresponding level of the spinal cord. The motor neuron and the muscle fibers that it innervates constitute the motor unit, which is the final common pathway and the smallest functional unit of the motor system. The motor unit and all its associated muscle fibers, tendon, bones, and joints work together to produce movement or isometric force.

Supraspinal connections Each corticospinal tract (CST) originates from upper motor neurons (UMNs) in the primary motor cortex of Brodmann’s area 4, the premotor cortex in Brodmann’s area 6, and the parietal cortex in somatosensory areas 3, 1, and 2, at a ratio of 3:3:4, respectively (Martin, 2022) (Fig. 1.3). These glutaminergic fibers travel through the posterior internal capsule into the brainstem, forming the pyramids. They adopt a somatotopic arrangement in the spinal cord with ventromedial subdivisions projecting onto spinal motor neurons and interneurons to innervate axial and proximal muscles; dorsolateral subdivisions project onto the dorsolateral motor neuron and interneuron pools that innervate limb muscles. The CST fibers originating from the primary somatosensory parietal cortex project primarily onto the dorsal horn of the spinal cord. Corticobulbar fibers originating in a

SPINAL CORD MOTOR DISORDERS

Fig. 1.3. Normal organization of the motor systems. (A) The corticospinal motor system is comprised of the direct spinal pathway, the corticospinal tract, and the indirect spinal pathways, the corticoreticulospinal and corticorubrospinal tracts. All descending pathways synapse on spinal interneurons. Synapses on motoneurons tend to be more system-specific. (B) Spinal interneurons and motoneurons receive input from descending motor pathways (left) and from afferent fibers (right); shown are the projections from the large diameter 1a fibers. The monosynaptic 1a motoneuronal connection is shown, as are converging inputs from the corticospinal tract onto spinal neurons. Reproduced from Martin JH (2022). Neuroplasticity of spinal cord injury and repair. Handb Clin Neurol 184: 317–330, with permission of the publisher.

similarly somatotopic pattern project to nuclei of the brainstem, dorsal columns, and pons, some of which then project to the cerebellum and others that continue to the spinal cord ending upon lower motor neurons (LMNs) in the anterior horns of cervical and lumbar cord enlargements to innervate muscles of the arms and legs. The basal ganglia, which comprise groups of subcortical nuclei in the telencephalon with functionally segregated circuits, receive input from different areas of the cortex organized into different functional loops.

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The caudate nuclei and putamen function together to form the striatum and serve as the primary input nuclei to the basal ganglia, which receive glutaminergic excitatory input from primarily cortical and some thalamic regions, as well as neuromodulatory dopaminergic input from the substantia nigra pars compacta and the ventral tegmental area. The major output nuclei of the basal ganglia are the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata, which ultimately project back to the cortex largely through projections to the ventrolateral (VL) and ventroanterior (VA) nuclei of the thalamus. In addition to these established basal ganglia nuclei, other structures such as the pedunculopontine nucleus (PPN), lateral habenula, and zona incerta (ZI) may be investigated as potential contributors to motor control processing in the basal ganglia. The cerebellum, which plays an important role in the regulation and real-time adjustment of movement and the coordination of motor control and sensory information, receives cortical input via pontine nuclei and afferent somatic sensory information from the dorsal spinocerebellar and cuneocerebellar tracts. Feedback from spinal motor pathways travel directly to the cerebellum in the ventral and rostral spinocerebellar tracts, and indirectly through projections from the inferior olivary nucleus and reticular formation. These pathways convey information about ongoing movements and are processed in local synaptic relays that eventuate on cerebellar Purkinje cells, which project to the deep cerebellar nuclei and the vestibular nuclei. The output of the deep cerebellar nuclei is transmitted through the superior cerebellar peduncle to the VL thalamus and the red nucleus, and represents motor control information that has been scaled, focused, refined, and/or corrected, in order to optimize motor control. In addition to its involvement in skeletal and eye muscle movement, the cerebellum also plays a role in balance, sensory perception, cognition, and affective functions; moreover, connections between the cerebellum and the basal ganglia are more direct than previously thought. Descending ventromedial and dorsolateral pathways from the brainstem are the most primitive phylogenic motor pathways and critical to motor control. The ventromedial pathway includes the reticulospinal tract originating from the reticular formation in the medulla and pons, the lateral and medial vestibulospinal tracts originating from the lateral and medial vestibular nuclei, and the tectospinal tract originating from the tectum and superior colliculi. The fibers of these pathways project bilaterally and widely over disparate segments of the spinal cord and synapse on motor neurons and interneurons, including long propriospinal neurons that control the proximal and axial muscles. These tracts mediate gross postural adjustments, particularly the reticulospinal tract, and head control and eye movement

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coordination mostly by the tectospinal tract. The reticulospinal pathways have been shown to be important in the generation of the startle response to sudden and intense acoustic stimuli. The ventromedial pathways receive multiple inputs from the interstitial nucleus of Cajal, the serotonergic raphe, and the noradrenergic locus coeruleus nuclei. Dorsolateral pathways include the rubrospinal and rubrobulbar fibers. The former originates from the magnocellular red nucleus and projects onto the dorsolateral motor neurons and interneurons of a small number of spinal segments. These neurons innervate the muscle of the limbs in parallel to the dorsolateral division of the CST. Similarly, the rubrobulbar fibers project to the facial nuclei, the sensory trigeminal nuclei, and the cuneate and gracile dorsal column nuclei. The spinal cord has interconnected segmental circuits consisting of motor and sensory neurons and hundreds of thousands of interneurons at each level, all of which work together to mediate movement, sensation, and virtually all reflexes below the neck. Injections of spinal cord axons with anatomic tracers show that corticospinal neurons and spinal motor neurons have a connection pattern that is somatotopically both convergent and divergent; specifically, a corticospinal neuron synapses on several motor neurons and an individual motor neuron receives projections from several corticospinal neurons. This arrangement ensures synchrony and balance between neighboring motor neurons that innervate muscle fibers of functionally related muscles.

Posture and gait integration The upright posture and stance involve maintaining the body center of mass (COM) vertically aligned over the feet which serve as the base of support (BOS). The vertical line passing through the COM, known as the line of gravity, is approximately 3–8 cm anterior to the ankles. The movement that occurs as this line fluctuates during real-time corrections and adjustments to muscle activity and position is called postural sway. Maintenance of postural control requires continuous CNS processing, based on feedback provided by the special senses mainly visual and vestibular, as well as information from muscles, joints, and cutaneous receptors. It can be separated into static postural control, in which COM can be variable, but the BOS and supporting surface are fixed, and dynamic postural control, which begins when the BOS begins to vary as well, such as during the initiation of walking. Gait is achieved through a repeating series of rhythmic leg and hip flexion and extension movements with concomitant hip and trunk stabilization in the supporting leg. This is achieved though the crucial integration of sensory and motor feedback information, allowing the

maintenance balance and proper posture in an environment that can be constantly changing. The step cycle in locomotion is divided into the swing phase, when the foot is swinging forward as in stepping, and the support or stance phase, when the foot is planted with the leg moving backward. The rhythmic alternation between flexion and extension that occurs during walking is mediated by neural networks in the spinal cord, termed Central Pattern Generators (CPGs), that receive sensory information from the limbs and project to the higher central nervous system (CNS) structures. These spinal CPGs are responsible for the elementary locomotion that occurs in felines with spinal cord transections. The primary sensory and motor cortices, supplementary motor area, frontal and parahippocampal cortex, basal ganglia, and the cerebellum are all active during human locomotion, and impact localized in specific locomotor regions of the pontomedullary reticular formation, mesencephalon, subthalamic nucleus, cerebellum, and the PPN. Signals underlying fine control of locomotion are transmitted from higher brain structures through the corticospinal and rubrospinal pathways, while vestibulospinal, propriospinal, and reticulospinal pathways transmit information relating to initiation of gait and continued maintenance of postural control. Normal ambulation first requires the ability to choose the most appropriate route and navigate obstacles in real time and the capacity to judge the risk of falling in different situations, and secondarily, the facility to execute appropriate responses to these decisions, while integrating and multitasking concurrent physical and situational demands. Gait abnormalities are vastly more complicated than direct deficits in static postural control and recovery from perturbation or the initiation and maintenance of locomotion. Gait disorders can be classified by level of dysfunction within the nervous system as low, middle, and high, or by the specific clinical syndromes that characterize them. A spastic limb produces circumduction and scissoring typical of a spastic or hemiparetic gait, while cerebellar involvement results in the wide-based ataxic staggering gait. Advances in computer processing, technology, and newer acquisition techniques that allow detailed quantitative and objective assessment of gait can be combined for more comprehensive analysis. For example, walkways with embedded, pressure-sensitive sensors allow measurement of step rate, length, and width, as well as the percentage time spent in the various phases of phases of gait and the stride speed in cm/s. A passive multicamera system can be used in conjunction with infrared lights and reflective markers to capture kinematic data of walking in three dimensions. As technological advances continue, objective quantitative gait analysis will likely become more readily available and commonly used in clinical settings.

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SPINAL CORD LESIONS The pathologic anatomy of the spinal cord began to be defined in the latter part of the 19th century and during a brief period, specific spinal cord illnesses were separated from the atrophic paralyses first by Duchenne (1867) and later by Charcot (1877). Classic teaching (Guttmann, 1969) suggests that the clinical symptomatology and signs of spinal cord lesions relate to several characteristics of the offending lesion. (1) The proximate etiologic basis for the insult or lesion, since knowing that will define the natural history and mechanism of the disease injury from among possible vascular, infectious, hematologic, autoinflammatory, and neurogenetic causes. (2) The duration and tempo of the lesion since progressive lesions will show increasing damage over time compared with static processes. (3) The extent of the lesion in the transverse plane associated with complete transverse damage and irrevocable deficits compared to incomplete injury with the possibility of partial recovery. (4) The segmental level of the damage, because the higher the lesion and the greater number of segments involved, the greater the loss of motor, sensory, and autonomic functions at and below the level of the lesion. For example, acute traumatic disruption of the spinal cord irreversibly injures nerve cells, axon, synaptic connections with a clinical pattern of complete or incomplete disturbances of motor function with paralysis below the level of the lesion that is first flaccid, and changes in character in due course to become spastic due to the increase in muscle tone and pathologically increased reflexes along a predictable pattern of spinal shock. The topographic distribution of lesions and the vulnerability of certain regions to disease are related to many factors: the extended length and small diameter of the spinal cord, the external position of white matter and central position of gray matter, the clustering of neurons in nuclear aggregates, the tight encirclement by pia arachnoid, the proximity of the spina cord to the bony spine and the vascular supply, and the extensive exposure of spinal roots, especially lumbosacral ones, to cerebrospinal fluid (CSF) (Brodal, 1969; Bican et al., 2013). The various diseases that affect the gray matter nuclei and the white matter tracts of the spinal cord, whether vascular, neoplastic, traumatic, metabolic, or inflammatory, differ in their mode of onset, clinical course, potential reversibility and response to therapy, and ultimate prognosis. In general, destructive lesions are irreversible because clinically significant regeneration does not occur in the adult. However, over time, the resolution of reactive damage around destructive lesions may occur and allow for considerable reversal of clinical deficits. Seen under the microscope, there are a finite number

Fig. 1.4. (A, B) Wallerian degeneration. There is a degeneration of ascending tracts (posterior columns) above the level of the lesion (top) and descending tracts (lateral and anterior corticospinal tracts) below the level of the lesion (bottom).

of reactions captured by staining procedures on spinal cord tissue. The reaction of Wallerian degeneration is central to all forms of disease processes associated with transection of the cord (Fig. 1.4A and B) whereupon descending supraspinal pathways will degenerate in all spinal segments below the level of the lesion particularly evident in the lateral CST in the posterior part of the lateral funiculi and the anterior CST in the medial parts of the anterior funiculi. Further, ascending tracts from segmental neurons lying below the level of the lesion will degenerate above the lesion, as is evident in the posterior columns (fasciculus gracilis and cuneatus) and in the ventral and dorsal spinocerebellar tracts. Ascending degeneration of spinothalamic tracts may be poorly demarcated, although scattered macrophages and swollen axons may occur; and in time, as astrocytes proliferate in the damaged regions, their glial fibrils become oriented in the longitudinal plane of the tract leading to isomorphic gliosis. The symptoms and signs of transverse spinal syndromes at different levels are easily recognized by pattern of loss of motor, sensory, and autonomic or sudomotor deficits, especially in severe cases, in relation to the segmental innervation of the spinal cord, guided by

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standard myotomal and dermatomal maps. By comparison, insidious spinal cord compression by tumor, cervical spondylosis, or other lesions unassociated with vascular compromise may be amenable to surgery with the expectation of at least partial functional recovery. Clues to an underlying neurogenetic etiology of a spinal cord disease may be suggested by the precipitous onset in early to late childhood with precipitous deficits, or in later decades with insidious progression, in either case after initial normal or near normal growth and development.

Spinal cord syndromes in the transverse plane Acute spinal cord ischemic syndromes (ASCISs) associated with vascular ischemia or infarction, albeit an uncommon cause of acute myelopathy (Nedeltchev et al., 2004), provide an instructive framework to the approach of spinal cord syndromes reflecting the distribution of tissue damage in the longitudinal and transverse planes. Ischemia and infarction of the spinal cord develops acutely in most cases, typically over minutes to hours, depending on the rate of occlusion, accompanying reflex factors, and activation of compensatory mechanisms. Individual variability of spinal vascular anatomy may preclude precise prediction of the location of the vascular insult based on symptoms alone. However, clinical signs will determine a proposed location of infarctions in relation to the transverse and longitudinal segments of the involved spinal cord. The spinal blood supply is likely to be interrupted or impaired at an extramedullary site, and as ischemia often develops in distal areas of the occluded artery territory, the lesion source may in fact be a distance from the location of the ischemic tissue insult. Multiple or single deficits of transient limb paresis may appear days to weeks before ischemic infarction leading to variants of quadri-, para-, hemi-, and monoparesis accompanied by sensory loss and autonomic disturbances. Such an intermittent limb weakness may result from transient spinal ischemia that is rapidly compensated by collateral flow. Back pain often precedes or accompanies the onset of acute spinal ischemia but ceases after weakness or anesthesia appears. Four incomplete spinal cord syndromes are associated with infarction in the territory of the ASA (ventral, anterior horn, centromedullary, and Brown-S
equard); and a dorsal syndrome is associated with a PSA territory lesion. Complete spinal cord transection results after ischemic infarction in both ASA and PSA territories and in cases when the anterior RMA participates in the formation of the anterior and posterior longitudinal arterial tracts.

ANTERIOR SPINAL CORD Lesions in the territory of the ASA, its RMA branches (including Adamkiewicz), as well as the intercostals, lumbar, sacral arteries, and aortic branches thereof (Baba et al., 1993; Yadav et al., 2018), lead to ischemic infarction of the anterior two-thirds of the spinal cord with prominent clinical motor involvement. Affected cases develop acute flaccid paralysis of all limbs or the legs depending on the longitudinal segments involved, with loss of pain and temperature sensation and bladder control due to interruption of the corticospinal, spinothalamic, and sympathetic pathways, with preserved light touch and discriminative sensation due to the intact dorsal column tracts. The initial flaccidity and loss of tendon reflexes associated with spinal shock is gradually replaced by spasticity in all muscles below the level of the lesion, with brisk tendon reflexes and Babinski signs. Ischemic necrosis of the ventral horn of anterior horn cells (AHCs) leads to residual flaccid paralysis due to denervation of segmental muscles at the level of the occlusion which then atrophy.

ANTERIOR HORN A selective lesion of motor neurons in the anterior horn syndrome is explained by higher sensitivity of the gray matter to ischemia as compared with white matter. The anterior horn syndrome is caused by occlusion of the anterior median spinal artery itself and its intramedullary branches (Skinhoj, 1954; Garcin, 1964). The clinical picture of acute flaccid paralysis of legs without sensory loss with a stroke-like onset and frequent association with alterations in systemic blood circulation, and absence of infectious signs differentiates it clinically from poliomyelitis.

CENTROMEDULLARY Infarctions developing in the central zone surrounding the central channel occur in the course of cervical spine injury, syphilitic arteritis, aortic graft insertion or thrombosis, vertebral dissection, and consequent compression and occlusions of segmental and RMAs. Such cases present with flaccid paralysis in trunk and limb muscles, gait disturbance, patchy weakness of homolateral and contralateral limbs, and segmental dissociated loss of pain and temperature sensations. The central cord syndrome is the most common incomplete spinal cord syndrome with the first account (Schneider et al., 1954) of disproportionately more motor impairment in the arms than the legs that continues to be the core element of the syndrome (Pouw et al., 2010).

SPINAL CORD MOTOR DISORDERS Brown-S
equard The syndrome of hemisection of the cord that was described in detail by Brown-S
equard more than a century ago (Brown-S
equard, 1855) is a rare occurrence in its classical form. More commonly, traumatic, ischemic, or hemorrhagic insults may not only damage one half of the cord, but somewhat encroach upon the other half, thus producing bilateral symptoms. The typical hemisection of the cord, when it occurs, is characterized by ipsilateral supranuclear motor paralysis below the level of the lesion due to interruption of the CST leading to hyperreflexia and pathological UMN signs (Hoffman, Babinski, etc.) once the initial spinal shock has subsided. There can be some motor paralysis of the peripheral type due to destruction of AHCs of the segment at the level of the lesion. This is particularly conspicuous in the hemisection of the cervical cord. In addition, there is vasomotor paralysis, hypo- or anhidrosis and loss of posterior column sensibility on the ipsilateral side. There may also be some cutaneous hyperpathia, spontaneous pain and itching ipsilaterally that is especially distressing for patients. On the contralateral side, pain and temperature sensitivity is lost. The upper level of this sensory loss is likely to be a few segments below the level of the lesion, as fibers entering the spinothalamic tract do not cross the cord for a few segments. On the other hand, the fibers entering the cord just below the lesion are caught before they cross the midline and thus cause a small zone of analgesia and thermoanesthesia just below the lesion on the ipsilateral side. This syndrome occurs with a variety of insults, especially vascular, when sulcal and sulcal–commissural arteries from one side of the transverse section of the spinal cord occlude as well as the anterior median spinal artery and its sources. The unilateral character of the spinal cord blood supply explains the possibility of developing the Brown-S
equard syndrome under conditions of spinal blood supply impairment. The syndrome can develop at the level of the cervical segments, where areas of duplication of the anterior median spinal artery are more frequently seen (Baumgartner and Waespe, 1992), and in the thoracic region, but not typically in the lower lumbar and sacral areas. Readers interested in the namesake’s life and legacy will find more information in the historical review by Aminoff (2017).

POSTERIOR SPINAL ARTERY SYNDROME Infarcts in the territory of the PSA present with variable loss of vibratory sensation and proprioception due to damage of the posterior column, suspended global anesthesia, segmental tendon areflexia, and paresis below the level at which the posterior portion of the lateral column

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containing the crossed CST is affected. The more extensive lesions involve the posterior portion of the lateral column, the posterior column, and the posterior gray horns, either bilaterally or unilaterally, while anastomoses of the pial network are so extensive that any one or even several of the ramifications can be occluded without the production of a clinical deficit. Such infarcts predominate at thoracolumbar, thoracic, and cervical levels (Garcin, 1964; Kaneki et al., 1994), averaging two spinal cord segments (range 1–6 segments). Proximate etiologies include syphilitic arteritis, cholesterol emboli from atheromatous aortic plaques, intrathecal injections, vertebral artery dissection, plasmacytoma, and unrecognized entities (Schott et al., 1959).

TRANSVERSE COMPLETE SPINAL CORD SYNDROME Ischemic necrosis of the whole transverse section of the spinal cord develops under conditions of simultaneous interruption of blood supply in the anterior median and PSA territories. Ischemia reaches the maximal extent and occupies the transverse section of the spinal cord at the level where the radicular–medullary artery enters it. Above and below this level, a compensatory blood supply develops, and necrosis appears to be more restricted, occupying predominantly the central areas of the gray matter. The clinical picture of the complete spinal cord transection syndrome is represented by quadri- or lower paraplegia, anesthesia of all sensation modalities below the lesion, disturbances of pelvic sphincters, and development of autonomic and trophic disturbances.

Spinal cord syndromes in the longitudinal axis The clinical variation in ASCIS in the longitudinal axis is governed by the pattern of anterior RMAs that enter the thoracic cord. The most common is when all segments below T2 are supplied by a single artery of Adamkiewicz.

ISCHEMIA OF THE CERVICAL REGION Infarction in the ASA territory at the level of the superior cervical segments can be maximally manifested by spastic quadriparesis, anesthesia of pain and temperature sensations below the lesion, and loss of sphincter control, with intact vibratory sensation and proprioception. Partial ischemia of the cervical enlargement due to transient or persistent ischemia may develop due to insufficiency of the blood supply to a large RMA branch of the deep cervical artery that approaches the cord together with one of the roots from C5 to C8 and, less frequently, a branch of the vertebral artery. This can be

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seen in cases of protrusion of a nucleus pulposus at the cervical level, fracture with dislocation, and flexionand-extension injuries of the cervical spine producing whiplash injury. The frequent vascular reserve of the cervical enlargement is provided by branches of the vertebral arteries and adjacent RMA such that only local restricted infarction such as the anterior horn or centromedullary zones develops. An exception is acute brachial diplegia with normal findings of the legs in the “man-in-the barrel” syndrome that is generally a consequence of bilateral supratentorial brain lesions of the prerolandic cortical and subcortical area but may also follow unilateral vertebral artery dissection (Berg et al., 1998).

ISCHEMIA OF THE THORACIC REGION Ischemia of the superior thoracic segments occurs in the watershed boundary zone between the superior and inferior spinal arterial regions leading to paraparesis, anesthesia of all sensation modalities, which in many instances is due to compression of the artery of Adamkiewicz that enters the spinal cord on the left side from T5 to L5, supplying the thoracic cord and the whole lumbosacral region (Corbin, 1961) and is susceptible to compression by protrusion of a nucleus pulposus or tumor, or atherosclerotic occlusion from the aorta to its proximal origin. In patients with a magistral type of spinal vascularization, the insufficiency of blood flow through the artery of Adamkiewicz leads to spinal cord ischemia in the T4 to the T6 segments to the conus which cannot be compensated for by the collateral flow, and that causes development of expanded infarction of the whole inferior half of the spinal cord. When an additional inferior RMA accompanies the lumbar or sacral roots in cases of plurisegmental type of blood supply, the zone of spinal cord ischemia is far more restricted within the longitudinal axis due to collateral flow. Rare cases can be associated with the Brown-S
equard syndrome (Mansour et al., 1987).

ISCHEMIA OF THE LUMBAR REGION Infarctions of the lumbosacral region are generally characterized by flaccid paresis or paraplegia with reduction of knee and Achilles reflexes, segmental anesthesia, and anesthesia below the level of T12–L1, with pelvic sphincter impairment, and trophic skin disturbances and pressure sores of the sacrum, buttocks, and heels.

progression, and comparing them to the aforementioned patterns of spinal cord topography, the clinician should be able to formulate a categorical diagnosis and localize the disease process to the spinal cord. A detailed neurological motor examination includes assessment of cranial motor function in ocular motility, facial and neck muscle strength and lingual function in speech, as well as individual limb muscle, and graded on a scale of 0–5 according to criteria of the Medical Research Council or revisions thereof (Medical Research Council, 1943; Vanhoutte et al., 2012). The patient should be observed erect with eyes open and closed to differentiate balance deficits due to cerebellar and sensory loss; and gait assessed walking tandem, on toes, and on heels. Hopping tests strength and coordination; however, the latter should be affirmed by rapid successive movements and finger-to-nose pointing. Tendon reflexes are best tested in the seated position with the hands folded in the lap and the legs dangling. Knee jerks are considered absent only after reinforcement, and similarly ankle reflexes in the kneeling position. Clues to the cause of spinal cord related motor dysfunction may be obtained in a pedigree that includes the name, sex, age, and specific symptoms and physical characteristics of similarly affected members. The pedigree usually indicates the pattern of inheritance in an affected cohort, but may not be informative if the patient is an index case or when failure of expressivity of the gene defects leads to a phenotypically normal heterozygote. Single-gene inheritance includes autosomal dominant (AD), autosomal recessive (AR), X-linked (XL) dominant, and mitochondrial DNA maternal inheritance patterns.

LABORATORY EVALUATION Although the diagnosis of a spinal cord disease is guided first and foremost by the clinical presentation and neurological localization, examination by magnetic resonance imaging (MRI) and other so-called “paraclinical” tests (Gelfand, 2014) are often helpful in establishing the diagnosis and prognosis in individual patients, included among them, neurophysiological examination by recording evoked somatosensory (SSEPs) and motor evoked potentials (MEPs), respectively, by mixed peripheral nerve and transcranial magnetic stimulation (TMS) of the primary motor cortex (M1), and analysis of CSF.

HISTORY AND PHYSICAL EXAMINATION

Noninvasive spinal cord imaging

The history and neurological examination and genetic pedigree are important first steps in the approach to a spinal cord motor disorder. In eliciting the neurological symptoms and signs, along with their temporal

Localization of a spinal lesion to the intramedullary, intradural extramedullary, or extradural compartment employing spinal cord neuroimaging is the first step in establishment of a differential diagnosis of a spinal cord

SPINAL CORD MOTOR DISORDERS motor disorder. MRI is preferred over other imaging modalities, surpassing plain spine radiographs, computed tomography (CT) alone or combined with myelography that often fail to demonstrate spinal cord or spinal canal lesions until gross expansion of them occur. It produces superior contrast resolution that facilitates characterization of spinal canal contents including spinal cord parenchyma, CSF, epidural fat that surrounds the thecal sac, vertebral venous structures, bone, and ligaments. A routine MRI examination of the spinal cord commences with unenhanced sagittal and axial T1-weighted spin-echo sequences utilizing short repetition time (TR), short echo time (TE), and T2-weighted spin-echo sequences with long TR, and long TE. Sagittal short T1 inversion recovery sequence is useful in detecting subtle intramedullary lesions, while gadoliniumenhanced sagittal and axial T1-weighted images should be performed for suspected tumors to better characterize them and delineate their extent.

Neurophysiology SOMATOSENSORY EVOKED POTENTIALS Neurophysiological testing of the spinal cord in clinical practice has been synonymous with SSEPs that are time-locked responses evoked by electrical stimulation of sensory or mixed peripheral nerves and recorded along large myelinated fiber somatosensory (dorsal columnmedial lemniscal) pathways (Muzyka and Estephan, 2019). Stimulation of mixed rather than purely sensory nerves has recording advantages, by incorporating contribution from muscle afferents to produce recordings of higher amplitude and shorter latency. Near-field potentials at the generator sites of lumbar and cervical enlargements are followed by far-field, short-latency responses, named for the negative (N) or positive (P) polarity deflection and latency (ms) corresponding to the sequential activation of sensory relay stations in the dorsal column-medial lemniscal pathway, ultimately synapsing in the contralateral somatosensory cortex following median (P13/N13 and N20) or tibial (N22 and P37) mixed nerve stimulation. While abnormal SEPs can be a nonspecific clue to the presence of myelopathy, with sensitivities that vary between 24% and 74% in the arm and 43%–100% in the leg, its greater utility is in MS to substantiate lesions with dissemination in space (DIS), especially clinically silent ones, with an equal yield (of 51%) to visual evoked responses, exceeding that of brainstem evoked responses (of 38%) (Purves et al., 1981). Multimodal evaluation using a combination of the three increased its yield in the setting of clinically definite MS (Aminoff, 1988).

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Transcranial magnetic stimulation TMS has recently been investigated as a neurophysiologic tool for safely and noninvasively studying excitability of the corticospinal system in humans by eliciting MEPs evoked by a single TMS pulse delivered over the M1 hotspot for the specific target muscles. According to Faraday’s law, TMS produces a rapid change in the induced magnetic field that in turn elicits intracranial eddy currents, which activate the layer 5 neurons of the pyramidal tract directly as well as indirectly through depolarization of horizontal axons in superficial layers 2 and 3 projecting to the corticospinal neuron (Di Lazzaro et al., 2018). Stimulation of the motor cortex with TMS can be used to calculate a central motor conduction time (CMCT) reflecting the time taken for neural impulses to reach bulbar or spinal motor neurons (MNs) (Udupa and Chen, 2013). As the latency of the muscle response to cortical stimulation represents the sum of central and peripheral conduction times, CMCT is calculated by subtracting the peripheral conduction time (PMCT) from the MEP latency elicited by motor cortical TMS. However, as a reflection of the sum of time required to excite motor cortical neurons, and conduction along corticospinal and corticobulbar tracts, as well as excitation of the cranial nerve nucleus or spinal cord MN, measuring CMCT using TMS incurs MEPs that are smaller and more variable due to phase cancellation and desynchronization, repetitive discharges, and variability in the number of spinal MN recruited. These variables can be reduced by a triple stimulation technique (TST) (Lefaucheur, 2019). In this method, three stimuli are given to various parts of the motor system. The first stimulus is to the motor cortex by TMS, the second to a nerve distally (closer to the target muscle), and the third stimulus to the nerve proximally. The collisions of the evoked action potentials depend on the excitability of spinal MN. The only action potentials to descend on the axons are those that were excited initially by TMS; and in contrast to the original desynchronized action potentials evoked by TMS, the action potentials are now synchronized because they are elicited by a single proximal nerve stimulus. Compared with CMCT, the advantages of TST are that it can measure the degree of corticospinal conduction and is about three times more sensitive in detecting conduction defects. The disadvantages of TST are that it is more difficult to perform, may be uncomfortable for subjects, and cannot be used for all muscles. Whether obtained by the calculated method or via TST, CMCT will have a low overall specificity for diagnosis but when used in conjunction with clinical measures, other electrophysiological measures, and neuroimaging, it can be a useful prognostic tool in various disorders that have in common slowing of conduction

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through rapidly conducting corticospinal fibers (Segura et al., 1992) including MS, ALS, stroke, and compressive myelopathy, and diverse neurodegenerative disorders such as ALS, multiple system atrophy, and progressive supranuclear palsy A further application of TMS has been to investigate M1 plasticity that commonly refers to postintervention changes in MEP amplitudes outlasting brain stimulation by seconds (short-term plasticity) or minutes (long-term plasticity) (Huang et al., 2017). Such activity-dependent phenomena, which consisted of the measurement of the long-lasting increase or decrease in the excitatory postsynaptic potentials following high-frequency stimulation of presynaptic terminals in brain slices (Larson and Lynch, 1989), termed long-term potentiation (LTP) or long-term depression (LTP), reflect postsynaptic calcium (Ca2+) influx, activation of the N-methyl-D-aspartaterelated transmission and changes in gamma-aminobutyric acid interneuronal activity. There are potentially farreaching implications in exploratory techniques of TMS for synaptic plasticity, since the amount of M1 LTP/LTD-like plasticity induced by noninvasive brain stimulation not only reflects intrinsic state-dependent changes in M1 but also depends on ongoing functional connectivity between M1 and other brain regions (Suppa et al., 2022).

Cerebrospinal fluid analysis CSF is both easily accessible and the most proximate to the pathological alterations of spinal cord diseases; consequently, the analysis of CSF provides an important window into the differential diagnosis, pathology, and prognosis of the affected patient (Giovannoni, 2014). Derived predominantly from the choroid plexus and interstitial fluid of the brain, spinal cord, meninges, and blood vessels that traverse the subarachnoid space, CSF admixes fluids to a final volume of 125–150 mL, which turns over about four times a day. The qualitative and quantitative contents of CSF constituents, especially total protein content, are influenced by the integrity of the blood–CSF barrier that filtrates serum constituents and the outflow foramen of the fourth ventricle, rendering lumbar CSF a potentially less accurate inflammatory index of pathology along the surface of the cerebral hemispheres, brainstem, and cranial nerves. One particular exception to this is the measurement of CSF oligoclonal bands (OCBs) secreted by activated B-cells and plasma cells, frequently used in supporting the diagnosis of MS. Since the discovery of CSF oligoclonal immunoglobulins in 1960 (Lowenthal et al., 1960), it has become an important factor in the diagnosis of presumptive MS, especially in clinically isolated (CIS) and primary progressive (PPMS) cases (Swanton et al., 2007;

Polman et al., 2011). According to the 2017 revisions of the McDonald criteria (Thompson et al., 2018), the demonstration of CSF-specific OCBs may be considered a substitute for, but not a demonstration of, dissemination in time (DIT), in presumptive cases of MS, with a single documented clinical attack and objective clinical evidence of 2 lesions. Immunoelectrophoresis (IEF) of paired serum and CSF on agarose gel, followed by immunoblotting, is the gold standard for the detection of oligoclonal Ig bands (Freedman et al., 2005). Although the eliciting antigens to the CSF oligoclonal response in MS is unknown, it is nonetheless one of the most useful paraclinical markers, and such an unvarying feature of the disease, that its absence in subjects who meet contemporary criteria may actually have a different disease. In that regard, an oligoclonal response to another antigen or sets or antigens may rarely occur (in 1 g/L that may instead occur in occasional cases of spinal block associated with acute transverse myelitis and cord swelling; and other cases with a leukocyte count in excess of 5 cells/mm3 and certainly >50 cells/mm3 that should raise doubts about the diagnosis of MS. The effect of treatment on the persistence of B-cells and CSF-specific OCB is in keeping with its usefulness as a biological marker of MS rather than an index of disease activity, in light of its persistence despite successful treatment of diverse presentations of MS with disease modifying therapies including rituximab in PPMS (Monson et al., 2005), natalizumab (Stuve et al., 2005), and fingolimod (Kowarik et al., 2011) in RRMS.

Vascular imaging Appropriate diagnosis and treatment of myelopathy are dependent on an adequate imaging evaluation in all new onset cases and in others where the progression is unexplained.

SPINAL CORD MOTOR DISORDERS

CONVENTIONAL MRI Conventional MRI has poor sensitivity and specificity for the diagnosis of most spinal vascular malformations (SVMs). This applies to the evaluation of myelopathies secondary to congenital high-flow SVMs in children and young adults associated with vascular disturbance related to steal phenomena; and acquired low-flow SVMs in older men with progressive myelopathy due to spinal venous hypertension (SVH) where focal cord damage is less common and the absence of abnormal cord signals in symptomatic cases is exceptional. Flow voids on T2-weighted images strongly support the diagnosis of a SVM, but their absence cannot be used to rule out a fistula. Flow voids are subtle or absent in the majority of cases, but may be topographically mismatched with perimedullary venous enhancement. Central cord edema in axial T2-weighted images with concomitant arterial ischemia is suggested by “snakeeye” or “butterfly” patterns in SVMs; likewise, the hemorrhagic transformation of central areas of hypointensity surrounded by edema in the late stages of evolution on axial T2-weighted images in the Foix–Alajouanine syndrome associated with spinal epidural arteriovenous fistula (SEAVF) all point to a less favorable outcome. A majority of low-flow SVMs remain undiagnosed because of the exaggerated confidence placed on the absence of flow voids to rule out vascular anomalies (El Mekabaty et al., 2017).

ADVANCED MRI TECHNIQUES Advanced MRI sequences employing contrast-enhanced magnetic resonance angiography (CE-MRA) or gradientecho MRI sequences with 3D constructive interference in steady state (CISS) efficiently detect SVMs and SDAVFs in >80% of cases (Lindenholz et al., 2014; Unsrisong et al., 2016). However, as flow voids were a selection criterion for further imaging with CE-MRA, its yield for the detection of low-flow SVMs without flow voids or as a screening tool for myelopathies is not known; nor is its ability to correctly and reliably identify the site of the arteriovenous shunt. While CE-MRA is a useful adjunct tool planning angiographic exploration or surgical treatment of suspected low-flow lesions, overreliance on it may lead to missed diagnoses (Sharma and Westesson, 2008). CE-MRA reliably detects or excludes various types of SVMs and localizes the predominant arterial feeder of most spinal AV shunts. Although classification of the subtypes of spinal AV malformations remains difficult, it does visualize and localize the level of the anterior RMA (Adamkiewicz artery); and albeit of inferior quality, it can focus subsequent digital subtraction angiography (DSA) (Nijenhuis et al., 2006;

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Mull et al., 2007). However, overreliance on noninvasive imaging data to plan the angiographic exploration or surgical treatment of suspected low-flow lesions may lead to missed diagnoses and devastating surgical outcomes (Sharma and Westesson, 2008). Combined low-dose, time-resolved (TR), and 3D single-phase high-resolution (hr) CE-MRA based on a sagittal 3D gradient-echo sequence that can be performed with a small dose of contrast media may give better temporal and spatial resolution for spinal vascular disease (Shin et al., 2019). 3-Tesla (3T) 3D CISS sequences have additive value for conventional MRI and complimentary information for CE-MRA in providing higher spatial resolution of contiguous thin-slice sections to detect the detailed structure and extent of abnormal vessels within the CSF (Uetani et al., 2018). There is a limited role for CT, especially CTA, in the routine investigation of myelopathy and SVMs due to its poor longitudinal coverage and prohibitive radiation exposure. Neither CE-CT nor CT-myelography is the first-choice imaging technique for the diagnosis of myelopathy and SVM, even though they can exceed the sensitivity of conventional MRI and should be considered when MRI is contraindicated.

DIGITAL SUBTRACTION ANGIOGRAPHY Spinal digital subtraction angiography (SpDSA) is the gold standard imaging modality for the evaluation of the spinal vasculature, especially since endovascular techniques have become a valid minimally invasive option either complementary to or as an alternative to open surgery. An adequate angiography technique reduces the contrast load, the radiation exposure, and the risk of vascular or cerebrospinal complications. Catheterization methods are influenced by the type of catheter selected and by locoregional anatomical factors (e.g., aortic atheroma, scoliosis). A 5-Fr Cobra 2 catheter is used for the aortic component of the angiogram. Catheterizing ISAs in a caudocranial sequence, one side at a time, takes advantage of the longitudinal alignment of the intersegmental ostia. There are available low-dose, pulsed fluoroscopy, and variable and high-frame rate protocols to adjust contrast and radiation exposures. 3D-SpDSA, similar to standard cranial studies, is useful for high-flow lesions. Flat-panel catheter angiotomography with simultaneous imaging of arteries and veins, unaltered by respiratory or intestinal motion, is used for spinal venous system lesions and anomalies without arteriovenous shunts, especially low-flow lesions that may be undetectable or missed on a standard angiograph. Low-flow PmAVFs, like SDAVFs and low-flow SEAVFs and related SVMs, all acquired anomalies predominantly affecting older men and presenting with

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progressive myelopathy secondary to SVH (Aminoff et al., 1974) and concomitant venous drainage impairment (Logue, 1979) due to an age-related reduction in the number of functional RMVs, causally related to venous thrombosis (Gailloud, 2014) and low-output arterialization of the perimedullary veins (Merland, 1980), resulting in a flow-induced venopathy. Hemorrhagic complications while extremely uncommon (Rosenblum et al., 1987; Murphy et al., 2020) with the exception of hemorrhagic transformation of venous infarcts associated with late stage SVH in the Foix– Alajouanine syndrome (Foix, 1926). The abnormal connection of low-flow PmAVF between a spinal artery and a spinal vein, whether deep in the anterior-median fissure or along the filum-terminate, makes affected patients ideal candidates for combined invasive imaging endovascular imaging and treatment to half the progression of deficits, and potentially render clinical improvement so noted in a majority of cases, as assessed by the modified Aminoff–Logue scale for myelopathy, and the modified Rankin scale for general quality of life (QoL) in a majority of cases (Andres et al., 2008), even those with profound disability (Aghakhani et al., 2008).

TUMORS Spinal cord neoplasms account for 4%–10% of CNS tumors (Van Goethem et al., 2004; Zorlu et al., 2005) as well as 20% of adult tumors and 35% of pediatric tumors (Constantini et al., 1996). While the majority of spinal cord neoplasms are low-grade lesions that enhance with contrast placing MRI on the forefront of the initial diagnosis, the treatment and prognosis have evolved with the insights of molecular diagnosis. Surgery continues to be a mainstay in the first-line management gliomas both in improved approaches to resection and to safely obtain formalin-fixed tumor tissue for mutation-specific immunohistochemistry and genetic sequencing.

Advances in tumor classification In 2021, the World Health Organization (WHO) responded to recommendations of the 2019 Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW). Louis et al. (2020) issued the fifth edition of the classification of CNS tumors (WHO CNS5) (WHO Classification of Tumours Editorial Board, 2021) updating the 2007 WHO Histological Classification (Louis et al., 2007) and WHO CNS4, and introducing widely used biological markers in the molecular diagnosis and classification of common CNS tumors. WHO CNS5 has moved tumor grading to within tumor types more similar to non-CNS organs. In prior WHO classifications, similarly graded

tumors in different categories such as astrocytomas and meningioma were expected to have similar idealized clinical–biological behaviors. But they were only roughly similar as, for example, the course of an anaplastic astrocytoma that may be quite different from an anaplastic (malignant) melanoma. While all WHO grade I tumors may be considered curable if they can be surgically removed, at the other end of the spectrum, WHO grade IV tumors were considered highly malignant, leading to death in a relatively short period of time in the absence of effective therapy. The tissue and molecular diagnosis and tumor grade are combined according to the WHO CNS5 into a layered report structure. Spinal tumors are classified as primary when they arise from the spinal cord, spinal nerve root, and dura, in contrast to metastatic spinal tumors that derive from systemic cancers spreading to the cord or osseous spine. They are further subdivided according to their location as intramedullary, intradural extramedullary, or extradural. In individuals 20 years of age, meningeal tumors are the most common primary spinal cord tumors (36.7%), followed by nerve sheath tumors (24.3%) and ependymal tumors (19.8%) (Ostrom et al., 2016). In children and adolescents (infants to 19 years of age), ependymomas are the most common tumors (22%) of the spinal cord, spinal meninges, and cauda equina and are followed by astrocytomas (19.8%) and other neuroepithelial tumors (16.3%) (Ostrom et al., 2016). Metastatic tumors constitute the most common type of spinal tumors, and the spine is the most common site of bone metastasis (Ostrom et al., 2016). Spinal metastases are typically extradural in location, although intramedullary metastases may also rarely be seen. Lung, breast, prostate, thyroid, and renal cell cancers constitute the majority of the spinal metastatic tumors (Ratliff and Cooper, 2004; Ostrom et al., 2016). Spinal tumors that arise from bone, such as osteoid osteoma, plasmacytoma, chondrosarcoma, and chordoma and extradural in location, are all relatively uncommon (Ciftdemir et al., 2016). Three principles should be applied to the MRI evaluation of intramedullary spinal lesions including the presence of expansion, enhancement, and concomitant cystic changes. The absence of expansion suggests a nonneoplastic process (Takemoto et al., 1988), while enhancement of a lesion, especially in two orthogonal planes after the intravenous administration of gadolinium contrast, is an important determinant of intramedullary spinal neoplasms and essential in the planning of surgery. The absence of both spinal cord expansion and contrast enhancement does not exclude an intramedullary neoplasm. Both tumoral and nontumoral cysts are associated with intramedullary spinal tumors, although nontumoral cysts are typically located at the rostral or caudal pole of the solid tumor. Such cysts,

SPINAL CORD MOTOR DISORDERS which generally represent reactive dilatation of the central canal or hydromyelia, do not enhance with contrast, while tumoral cysts, which may be part of the tumor, will demonstrate peripheral contrast enhancement.

Gliomas Among all age groups taken together, gliomas comprised of ependymomas and astrocytomas are probably the most common intramedullary primary spinal cord tumor, followed by hemangioblastomas, gangliogliomas, germinomas, and primary CNS lymphomas (Tobin et al., 2015).

ASTROCYTOMAS Classically, up to a third of these tumors present in the spinal cord, and while second in prevalence after ependymomas in adults, spinal astrocytomas are the most common pediatric intramedullary tumors. Unlike those of the brain, spinal cord astrocytomas are usually low grade. Although low-grade astrocytomas may lack objective signs of neurologic dysfunction resulting in delayed detection, patients with high-grade lesions often present with rapidly progressive symptoms of shorter duration (Epstein et al., 1992). Spinal cord astrocytomas typically produce local or radicular pain, paresthesia, and dysesthesia (Houten and Cooper, 2000). Midline back pain is the most common initial symptom; however, leg

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weakness and sensory changes usually bring the patient to diagnostic evaluation. Autonomic involvement leading to bowel and bladder incontinence are late symptoms, and the presence of a Brown-S
equard syndrome characterized by vibration sensory loss and weakness of one leg, and loss of pain sensation in the other unequivocally suggests the presence of an intramedullary lesion, with the rate of progression correlating with the tumor grade. Pain, motor regression, gait abnormalities, torticollis, and progressive kyphoscoliosis prompted radiological investigation in one-third or more of patients under age 3 years, while prominent limb weakness which nearly always accompanies later stage cord lesions is accompanied by gait disturbances, spasticity, bowel and bladder incontinence (Constantini et al., 1996). Hydrocephalus, which indicates widespread leptomeningeal spread of the tumor, is more common in high-grade spinal astrocytomas than low-grade tumors (Cohen et al., 1989), as well as 60% of preoperative intramedullary glioblastoma multiforme (GBM) (Bell et al., 1988) in which there can be leptomeningeal spread. Neuroimaging reveals poorly defined margins in most tumors, with iso- to hypointense signals relative to the spinal cord on T1-weighted images, and hyperintense signal intensities on T2-weighted images (Fig. 1.5A–C), often in association with fusiform spinal cord expansion. Contrast enhancement of the tumor may be faint or

Fig. 1.5. (A–C) Astrocytoma. Sagittal T2-, and T1-weighted pre-, and postcontrast MRI demonstrates an infiltrate mass within the spinal cord with poorly defined margins. The mass is hyperintense to the spinal cord signal on T2-weighted images and isointense on T1-weighted images with cord expansion and abnormal enhancement following administration of intravenous contrast.

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prominent, and located in a central, peripheral, or diffuse distribution; however, nonenhancing spinal cord PA can also occur. The T1 and T2 signal intensity will vary depending on the presence of secondary calcification and alterations in the structural complexity of cystic portions of the tumor, the latter of which occurs in 25%–38% of lesions; however, hemorrhage, necrosis, and hypervascularity are uncommon features. The length of spinal cord involvement is usually up to seven vertebral segments, and since astrocytomas arise from cord parenchyma and not from the central canal, they are located eccentrically within the posterior columns in more than one half of patients; holocord astrocytomas by comparison involve the entire cord. Three molecular tumor markers, including O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, codeletion of 1p and 19q, and isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) mutations, transformed the classification, diagnosis, and prognosis of astrocytomas, oligodendrogliomas, and glioblastomas leading to advances in management. As early as 2005, investigators (Hegi et al., 2005) studied the epigenetic silencing of the MGMT DNA repair gene by promoter methylation that compromised DNA repair yet conferred improved outcome in patients with GBM and an overall better prognosis to temozolamide, whereas those without a methylated MGMT promoter did not have such benefit. In 2009, investigators (Yan et al., 2009) determined the sequence of the IDH1 and IDH2 genes in CNS tumors noting mutations in amino acid 132 in >70% of WHO grade II and II astrocytomas and oligodendrogliomas, and in glioblastoma that developed from lower-grade lesions. Patients with such tumors had a more favorable outcome than those with wild-type IDH genes. Recognizing that it had previously been impossible to distinguish a secondary glioblastoma, defined as a tumor that was previously diagnosed as a lower-grade glioma, this new subgroup could be based on the recognition that IDH1 mutations might occur after formation of a low-grade glioma and drive the progression of the tumor to a higher grade. Moreover, several genes, including tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), cyclin-dependent kinase inhibitor 2a (CDKN2A), and epidermal growth factor receptor (EGFR), were altered in gliomas, and these tended to occur in a defined order during the progression to a high-grade tumor. The TP53 mutation appeared to be a relatively early event during the development of an astrocytoma, whereas the loss or mutation of PTEN and amplification of EGFR were characteristic of higher-grade tumors. Four years later, in 2013, subjects with anaplastic oligodendrogliomas chemosensitive to procarbazine, lomustine, and vincristine (PCV) were

found to survive considerably longer with 1p/19q codeletions than those without codeleted tumors, with or without radiation therapy (RT), revealing a survival twice that of RT alone (Cairncross et al., 2013). By 2016, the WHO Classification of Tumors of the Central Nervous System (WHO CNS4) (Louis et al., 2007) integrated molecular criteria in their classification of gliomas; followed by the WHO CNS5 that recognized all IDH-mutant diffuse astrocytic tumors as a single type (astrocytoma, IDHmutant), and graded them as CNS WHO grade II, III, or IV. However, the latter is no longer entirely histological since the presence of CDKN2A/B homozygous deletion results in a CNS WHO grade of IV, even in the absence of microvascular proliferation or necrosis. Adult glioblastoma, IDH-wild type is diagnosed in the setting of an IDH-wild-type diffuse and astrocytic glioma if there is microvascular proliferation, necrosis, telomerase reverse transcriptase (TERT) promoter mutation, EGFR gene amplification or +7/ 10 chromosome copy number changes.

EPENDYMOMAS Ependymomas originate from radial glial stem cells (Taylor et al., 2005), not from the ependymal lining of the ventricular system of the CNS as had long been believed. These tumors were previously classified into grade I (myxopapillary ependymoma, subependymoma), grade II (ependymoma), and grade III (anaplastic ependymomas) (Louis et al., 2007) based on histopathologic similarity and the level of differentiation; however, these categories did not consistently correlate with the biological behavior of the tumors. In 2015, Pajtler et al. (2015) profiled a cohort of 500 ependymal tumors across age groups using DNA methylation that outperformed the WHO classification with regard to prognosis in identifying nine molecular subgroups, three each in the spinal cord, posterior fossa, and supratentorial CNS anatomic compartments, that were genetically, epigenetically, transcriptionally, demographically, and clinically distinct. Patients with intraspinal ependymomas often present with mild symptoms without focal deficits leading to a delay and neuroimaging and detection; subarachnoid hemorrhage is infrequently encountered. Two-thirds of patients complain of neck or back pain, and roughly one half have a sensory deficit and motor weakness, with bowel or bladder dysfunction in about 15% of cases (Epstein et al., 1993). The predominance of sensory symptoms so noted in 85% of patients (Epstein et al., 1993) is likely related to the central location of most tumors, although dominant motor symptoms are associated with very large tumors. There may be a long

SPINAL CORD MOTOR DISORDERS antecedent history of dysesthesia or frank pain related to the central location in the cord, which expands symmetrically and circumferentially, and interrupts ascending and crossing spinothalamic fibers. Depending on the tumor site, arms or hands are involved in cervical tumors, the chest wall in high thoracic lesions, and the legs in low thoracic tumors. With cervical and cervicothoracic tumors, the motor dysfunction so noted in more than half of the patients takes the form of a spastic paraparesis with limb weakness in 58%, hyperreflexia in 69%, bowel and bladder dysfunction, particularly in those presenting with tumors arising above T11 than those below (Hanbali et al., 2002), often associated with thinning of the surrounding spinal cord. Plain radiographic studies of patients with spinal ependymomas may show scoliosis, spinal canal widening, and scalloping of the vertebral bodies (Ferrante et al., 1992). However, MRI typically reveals isoor hypointense signals relative to the spinal cord on T1-weighted sequences, with signal hyperintensity on T1-weighted images suggesting underlying hemorrhage; and T2-weighted images demonstrating heterogeneous signal intensity. Intravenous administration of gadolinium typically shows well-defined margins and some degree of enhancement (Kahan et al., 1996). A cap sign so noted in 20%–33% of tumors, presents as a rim of signal hypointensity on T2-weighted images due to hemosiderin deposition at the poles of the tumor (Fig. 1.6A–C). Hemorrhage is common in ependymomas and other vascular tumors such as paragangliomas and hemangioblastomas (Fine et al., 1995). Patients with solitary intramedullary lesions should undergo contrast-enhanced MRI of both the spine and brain because of infrequent intracranial seeding.

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Molecular profiling has provided valuable risk stratification to histopathological grading in anaplastic ependymoma characterized classically by increased cellularity, mitotic activity, microvascular proliferation, and pseudopalisading necrosis (Pajtler et al., 2015) revealing yes1-associated transcriptional regulator (YAP1) and RELA protooncogene, NFKB subunit (RELA) type 1 and 2 fusions in supratentorial and posterior fossa tumors, and in neurofibromatosis type 2 (NF2) expression in spinal anaplastic tumors. Both posterior fossa anaplastic and supratentorial RELA-fusion molecular subgroups showed a dismal outcome, with 10-year overall survival rates of 50% and progression-free survival rates of 20%, most of whom were pediatric, while all other subgroups had a much better outcome, with 5-year overall survival rates around 100% and 10-year overall survival rates ranging of 88%–100%. It is well known that patients with spinal cord ependymal tumors are usually cured by complete neurosurgical resection alone, with gross total resection reportedly achieved in up to 82% of patients, and subtotal resection achieved in 18% of patients, the latter of whom are treated with adjuvant radiation therapy (Kucia et al., 2011). Nevertheless, subtotal resection with or without radiation therapy, recurrences, and a large tumor mass have a more unfavorable outcome.

Meningiomas Meningiomas constitute 25% of primary spinal tumors, and about 8%–12% of all meningiomas are located in the spinal column (Westwick et al., 2015). Within the spine, the most common location is thoracic, followed by cervical and, least frequently, lumbosacral

Fig. 1.6. (A–C) Ependymoma. Sagittal T2-, and T1-weighted pre-, and postcontrast MRI demonstrates a well-defined mass with a fluid level expanding the spinal cord. The rim of signal hypointensity noted on all sequences is due to hemosiderin deposition at the poles of the tumor, a classic finding for ependymoma.

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(Sandalcioglu et al., 2008). These tumors that arise from meningeal arachnoid cells are firm and encapsulated and attach to the subdural surface, where they are often dumbbell-shaped with intradural and extradural extensions in the spinal region leaving pathognomonic tails on contrast neuroimaging (Sotoudeh and Yazdi, 2010). Focal pain is the most common presenting symptom which may precede segmental sensory or motor deficits. Symptoms may manifest for up to 3 years before a formal diagnosis is made. With nearly 85% of spinal cord meningiomas both intradural and extramedullary, and the thoracic region the most commonly involved area, there can be insidious signs of spinal cord compression leading to asymmetric progressive paralysis and sensory disturbances. Tumor grading according to the 2007 WHO histological classification (Louis et al., 2007), and WHO CNS4 (Louis et al., 2007) based on increasing severity (enumerated grades I–III: grade I referred to typical benign lesions, while grade II corresponded to atypical meningioma when there are increased mitoses and any of the three features of sheeting architecture, hypercellularity, macronuclei or small cell formation; or parenchymal invasion; and grade III corresponded to anaplastic meningioma with excessive mitotic activity, focal or diffuse loss of light microscopic meningothelial differentiation resulting in a similarity to a sarcoma, carcinoma, or melanoma). WHO CNS5 (WHO Classification of Tumours Editorial Board, 2021) instead considers meningioma as a single type with a broad morphological spectrum in 15 subtypes, and recognizes several molecular biomarkers associated with classification and grading including: SMARCE1 (clear cell subtype), BAP1 (rhabdoid and papillary subtypes), and KLF4/TRAF7 (secretory subtype) mutations, TERT promoter mutation at codon 61 and/or homozygous deletion of CDKN2A/B (CNS WHO grade III), H3K27me3 loss of nuclear expression 63 (potentially worse prognosis), and methylome profiling (prognostic subtyping). As in prior classifications, chordoid and clear cell meningiomas are noted to have a higher likelihood of recurrence than the average CNS WHO grade I meningioma and have hence been assigned to CNS WHO grade II. Historically, rhabdoid and papillary morphology qualified for CNS WHO grade III irrespective of any other indications for malignancy. While papillary and rhabdoid features are often seen in combination with other aggressive features, more recent studies suggest that the grading of these tumors should not be on the basis of a rhabdoid cytology or papillary architecture alone (Vaubel et al., 2016). The criteria defining atypical or anaplastic (grade II and III) meningioma are applied regardless of the underlying subtype. Spinal meningiomas are isointense or hypointense on T1-weighted images and hypointense or slightly

hyperintense on T2-weighted images. They demonstrate heterogeneous enhancement with gadolinium. MR spectroscopy displays increased intratumoral alanine and pyruvate (Demir et al., 2006; Sibtain et al., 2007), allowing for the differentiation of meningeal from nonmeningeal tumors. Perfusion-weighted MRI detects hypervascularized tumor foci and areas of hypovascularized necrosis. Preoperative PET imaging can be used to examine differences in the tumor-to-gray matter ratio in benign and atypical-malignant lesions, WHO grade, and brain parenchymal invasion (Lee et al., 2009; Weber et al., 2010). Total surgical resection is obtained in 82% of patients who underwent dorsal microneurosurgery between 1995 and 2009 at a single institution (Postalci et al., 2011), 78% of whom presented with back pain followed by leg weakness and sensory loss; the recurrences so noted in 17% were ascribed to tumor regrowth in those who were incompletely resected due to a predominantly ventral location.

Metastases A retrospective autopsy study of 627 patients with systemic cancer (Costigan and Winkelman, 1985) disclosed 153 patients with metastasis to the CNS and 13 patients with intramedullary spinal cord metastasis. Thus, the frequency of ISM was 8.5% of cases of metastasis to the CNS and 2.1% of all cases of cancer. Bronchogenic carcinoma accounted for 11 cases, and breast carcinoma and melanoma for the other 2. A primary source is unknown in 5% of cases (Takemoto et al., 1988). There were two distinct patterns of spinal cord involvement, indicating the spread of tumor to the cord by two different routes. In 9 out of the 13 patients reported by Costigan and Winkelman (1985), a metastasis was found deep within the spinal cord, unassociated with leptomeningeal carcinomatosis; this most likely resulted from the hematogenous spread of tumor from a pulmonary source; the arterial supply and Batson venous plexus are postulated spreading routes (Richard, 1972). In the other 4 cases, there was focal or multifocal direct extension of leptomeningeal metastatic tumor across the pia into the parenchyma of the cord. Only 4 of the 13 patients had a clinical myelopathy, which was the presenting feature of an occult lung cancer. Motor weakness is the most common symptom, followed by paresthesia, local or radicular pain, and sphincter disturbance. The Brown-S
equard syndrome is seen in one-fifth of patients with a site of hemicord interruption due to cervical (41%–42%) or thoracic cord (26%–34%) metastases (Kalayci et al., 2004; Sung et al., 2013). The metastatic tumor is usually well circumscribed on MRI without an associated intralesional cystic component typically present in spinal cord gliomas.

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Fig. 1.7. (A–C) Spinal cord metastases. Sagittal T2- and T1-weighted pre-, and postcontrast MRI demonstrates a well-defined mass which is isointense to the spinal cord signal on T2-, and T1-weighted images with abnormal enhancement following the administration of intravenous contrast. Extensive edema is present throughout the visualized portion of the spinal cord.

On T2-weighted MRI, a high-intensity signal is usually seen, suggesting marked perilesional edema disproportionate to the underlying solitary tumor that extends over several vertebral segments. On postcontrast T1-weighted images, the typical appearance is that of a ring-enhancing lesion, suggesting central necrosis and rapid tumor growth. Metastases demonstrate hypointense signal changes on T1-weighted images, and hyperintense signal changes on T2-weighted images with postcontrast enhancement (Fig. 1.7A–C). However, these MRI findings are not specific for metastases and can be seen in hemangioblastomas, MS, transverse myelitis, acute disseminated encephalomyelitis, sarcoidosis, and transverse myelitis. Although RT with corticosteroids is effective palliative therapy, when a spinal cord metastasis is the outcome of rapidly progressing systemic malignancy, the underlying cancer dictates the overall poor prognosis and short life expectancy (Wu, 2010). There are isolated reports of the successful removal of intramedullary spinal cord metastases employing microsurgical resection (Findlay et al., 1987; Iplikcioglu et al., 2010).

Lymphoma Primary intramedullary spinal lymphoma is exceedingly rare (Flanagan et al., 2011). In a series of 14 histologically studied cases, most had initial presumptive diagnoses of CNS demyelinating disease and definitive diagnosis of lymphoma was delayed a median of 8 months (range 1–22 months). Nine patients (64%) had back pain prior to

diagnosis that was the presenting symptom in 29%. Six patients (43%) had clinical evidence of LMN involvement (areflexia or flaccid paralysis) compared to 3 who presented with UMN and tandem brain involvement (confirmed by MRI head) at the time of diagnosis including encephalopathy (in 2 patients) and facial numbness and diplopia (in 1). The CSF findings of markedly elevated protein (usually greater than 100 mg/dL), lack of OCBs, and elevated white cell count (median 92/mL) distinguished lymphoma from typical MS; however, these findings can also be seen in neuromyelitis optica (NMO). CSF hypoglycorrhachia, when present, also differentiates lymphoma from MS and NMO but can rarely be also seen in infectious etiologies. CNS lymphoma was pathologically confirmed by brain biopsy (in 6 patients), spinal cord biopsy (in 4), CSF cytology (in 3), or autopsy (in 1). The findings of MRI in spinal lymphoma include isointense signal changes relative to spinal cord signal on T1-weighted images, and hyperintense signal changes on T2-weighted images, with enhancement intensely after contrast administration that may be focal, multicentric, irregular, or homogenous (Fig. 1.8A–C). In the series of Flanagan et al. (2011), gadolinium-enhancement of at least 1 lesion was present in all 14 patients (100%) and the lesions persistently enhanced in 7 patients (median enhancement duration 3 months; range 2–15). Involvement of the cauda equina or conus medullaris each in 1 patient, or both (in 5), was noted on MRI, in addition to spinal cord expansile lesions in 8 cases. The combination of expansile cord lesions associated with edema and

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Fig. 1.8. (A–C) Lymphoma. Sagittal T2- and T1-weighted pre-, and postcontrast MRI demonstrates edema within the spinal cord from C1 to C4. Abnormal enhancement following the administration of intravenous contrast is noted within the spinal cord.

abnormal enhancement (Fig. 1.15A–C) as well as leptomeningeal involvement are all abnormalities in neurosarcoid (Saleh et al., 2006). Spinal cord PET carried out in 2 cases demonstrated hypermetabolism corresponding to MRI lesions. Brain MRI gadoliniumenhancing lesions consistent with lymphoma were seen in 9 (64%) cases, of which 7 (50%) had multiple brain lesions. High-dose methotrexate chemotherapy alone or in combination with radiotherapy substantially prolongs survival beyond 30 months (Abrey et al., 2000); however, corticosteroids may have a short time benefit (Herrlinger et al., 1996), suggesting the importance of early diagnosis and initiation of treatment. Most patients with intramedullary spinal cord lymphoma have recurrences, and up to one half are wheelchair dependent before a year, with a 2-year survival of 36% (Flanagan et al., 2011).

CNS DEMYELINATING DISEASES Prototypical CNS demyelinating diseases are characterized pathologically by plaques of inflammation, demyelination, and gliosis. The signs and symptoms depend on the location of the lesions within the brain and spinal cord. Motor dysfunction, which includes spasticity, weakness, tremor, ataxia, and visuomotor deficits, is the most common disabling aspect but not necessarily the earliest presenting features with spinal cord involvement. Up to 95% of cases of multiple sclerosis, the most common CNS autoimmune demyelinating disease, follow a relapsing–remitting pattern (RRMS), with one half of cases converting to a secondary progressive form

(SPMS) over time, while the remaining 5% follow a more aggressive, primary progressive form (PPMS) contributed by relentless spinal involvement. The clinical presentation of MS varies with the segment and extent of spinal cord involvement in the transverse and longitudinal planes. Motor symptoms and signs are the most salient features in those with spinal cord involvement alone or in association with lesions of the brain, manifesting hyperreflexia, clonus and Babinski signs, long tract sensory signs, cerebellar disturbances, bladder, bowel and sexual dysfunction. Spinal lesions occur most often in the cervical cord but are also common in the thoracic cord and conus regions. Exclusive spinal cord involvement occurs in 2%–10% of patients. There are two MS variants that occur in both children and adults, identified by pathogenic IgG serum autoantibodies, optic neuritis, brain, brainstem, and extensive spinal cord lesions that are predominantly central and extend longitudinally to three or more vertebral segments. The first targets the aquaporin-4 (AQP4) water channel (Zekeridou and Lennon, 2015), aquaporin-4 or NMO antibody that is abundant in loosely apposed astrocytic foot processes of subpial and subependymal zones with fenestrated capillaries that facilitate IgG access to the CNS. This immune astrocytopathy, associated with anti-AQP4 antibodies, constitutes the NMO-spectrum disorders (NMOSDs) (Tackley et al., 2014). The second variant is associated with an autoantibody targeting myelin oligodendrocyte glycoprotein (MOG) located on the outermost lamellae of CNS myelin sheaths (Hemmer et al., 2002), likewise designating MOG-IgG-antibody disease (MOGAD) (Hacohen et al., 2015) with a different expected clinical outcome.

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Multiple sclerosis Early criteria for the diagnosis of MS emphasized the total number of brain lesions (Fazekas et al., 1988), with later appraisals emphasizing the sort of lesion and where they were found (Barkhof et al., 1997). Of 4 possible MRI parameters, gadolinium-enhancement, infratentorial, juxtacortical, and periventricular lesions that were investigated to build a regression model with a diagnostic accuracy of 80% for developing MS (Barkhof et al., 1997), abnormal gadolinium-enhancement and juxtacortical lesions emerged with predictive value, with the former associated with lesions in the phase of inflammation and active axonal demyelination, most evident on FLAIR sequences. Lesions undetected on conventional axial T2-weighted sequences were more readily visualized on 1-mm sagittal sections using 3D fast FLAIR sequences. Initial guidelines that defined the certainty of MS for the purposes of epidemiologic studies and clinical trials (Poser et al., 1983) were superseded by the McDonald criteria of the International Panel on Diagnosis of MS (McDonald et al., 2001; Polman et al., 2005) emphasizing that while the diagnosis could be made on clinical grounds alone, MRI of the CNS could support, supplement, or even replace some clinical criteria, resulting in earlier detection of MS with a high degree of specificity and sensitivity, especially in clinically isolated syndromes (CISs) (Dalton et al., 2002), in the early conversion to clinically definite MS (CHAMPS Study Group, 2002), and in predicting response to immunotherapy including interferon b-1a (Barkhof et al., 2003), and in documenting the first demyelinating episode (Tintore et al., 2003). Revisions to the McDonald criteria (Polman et al., 2011) incorporated criteria for demonstration of DIS (Swanton et al., 2006, 2007) and DIT (Montalban et al., 2010). Recognizing the special diagnostic needs of PPMS, revisions to the McDonald criteria (Polman et al., 2005) maintained two of three MRI or CSF findings for PPMS, replacing previous brain imaging criteria for DIS (Swanton et al., 2007). The final criteria for PPMS were 1 year of retrospective or prospective disease progression, plus two of the following three criteria: 1 or more T2 lesions in at least one area characteristics for MS (periventricular, juxtacortical, or infratentorial), 2 or more T2 lesions in the cord, or positive CSF (isoelectric focusing evidence of OCBs and/or elevated IgG index). Gadolinium-enhancement of lesions was not required. In 2018, the International Panel on Diagnosis of Multiple Sclerosis issued revisions to the 2010 McDonald criteria (Thompson et al., 2018) that apply primarily to patients experiencing a typical CIS, defining what is needed to fulfill CNS DIT and DIS, and stressing the need for no better explanation for the presentation:

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adding CSF OCBs as a substitute for DIT, and symptomatic and asymptomatic MRI lesions in the determination of DIS and DIT, with cortical lesions being equivalent to juxtacortical lesions. Thus, the early diagnosis of MS can be ascertained with a single attack and clinical evidence of two or more lesions meeting DIT criteria by manifesting CSF OCBs; and in others by a single attack and clinical evidence of one CNS lesion that concomitantly meets DIS and DIT, respectively, with an additional attack and CSF OCBs, or one or more typical T2 lesions in two or more areas of the CNS (periventricular, cortical, juxtacortical, infracortical, or spinal cord) and the simultaneous presence of enhancing and nonenhancing or a new T2 or enhancing MRI lesion compared to baseline. Affected patients with 1 year of retrospective or prospective steady disease progression may meet DIS with one or more typical T2 brain lesions or two or more T2 spinal cord lesions, and CSF OCBs. Careful differential diagnosis is still essential in patients with atypical clinical manifestations to avoid misdiagnoses.

NMO-spectrum disorders NMOSD in children and adults (Rubiera et al., 2006) presents with recurrent attacks of ON and longitudinally extensive transverse myelitis (TM) that is distinct from MS. MRI is the first-line test in aiding the diagnosis of NMOSD. Optic nerve, spinal cord, and brain lesions are often distinctive. Imaging of the optic nerve distinguishes NMOSD from MS (Tackley et al., 2014). Optic nerve MRI abnormalities in NMOSD are commonly extensive with more posterior involvement and enhancement of the chiasm, and spinal cord lesions are predominantly central and extend longitudinally for several vertebral segments. Lesions may be spotty with central necrosis and cavitation. In a study of 137 cases reported by Jarius et al. (2012), the initial spinal cord MRI had at least one cord lesion extending over 3 or more vertebral segments in 127 cases (92.7%), with a median extension of 6 segments with a trend longer lesions in APQP4-IgG seropositive cases. Lesions often occupy more than half of the spinal cord in cross section (Nakamura et al., 2008) and may have a patchy or continuous in-distribution appearance with diffuse swelling in cervical, thoracic, or both locations (Asgari et al., 2013). However, commonly long, 17% of seropositive patients presented with short TM lesions (Flanagan et al., 2015). Brain MRI lesions were detected in 60% of NMOSD cases and were often nonspecific at first relapse, and increased with disease progression (Pittock et al., 2006). Early, accurate diagnosis of patients with NMOSD permits treatment with appropriate acute and long-term immunosuppressive agents that are critical to mitigate the risk of disability associated with this disease. Therapeutic options of NMOSD have been shaped by randomized clinical trials

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(RCTs) of monoclonal antibodies (Pittock et al., 2019; Yamamura et al., 2019). Unanswered questions remain, including the cause of AQP4-IgG-negative disease, how astrocyte-mediated damage leads to demyelination, the role of T-cells, why peripheral AQP4-expressing organs are undamaged, and how circulating AQP4-IgG enters NMO lesions.

MOG-antibody disease Patients with MOGAD have attacks of optic neuritis, myelitis, brain or brainstem inflammation, or combinations thereof (Wynford-Thomas et al., 2019). Seropositivity for MOG-IgG1 confirms the diagnosis with a compatible clinical and radiologic phenotype according to recent international recommendations (Jarius et al., 2018). Although no age group is exempt, the median age of onset is in the fourth decade of life, with ON and TM being frequent presenting phenotypes. Typical symptoms include limb weakness, sensory deficits including neuropathic pain, and sphincter and erectile dysfunction. The disease course can be monophasic or

relapsing with subsequent relapses most commonly involving the optic nerve. MRI characteristics help differentiate MOGAD from other neuroinflammatory disorders, including MS and NMOSD, revealing inflammatory swelling of the anterior and retrobulbar aspects of the optic nerve, rarely the chiasm; and short myelitis with lesions spanning fewer than three vertebral segments in a third of cases (Ciron et al., 2020); sphincter involvement is more prevalent in MOGAD patients, especially those with longitudinally extensive TM. Cerebrospinal fluid OCBs are uncommon. RCTs are limited in MOGAD; however, there is a role for high-dose corticosteroids and plasma exchange in the treatment of acute attacks, as well as oral immunosuppressants, and other immunotherapies that target various B cellrelated proteins (Graf et al., 2021a, 2021b). Residual motor disability culminates in flaccid paraplegia in the majority of cases, with TM at onset being the most significant predictor of long-term outcome. The MRI appearances of a new attack of MS in the spinal cord (Fig. 1.9A–E) and TM (Fig. 1.10A–E) are shown for comparison.

Fig. 1.9. (A–E) Multiple sclerosis. Sagittal T2- and T1-weighted pre-, and postcontrast axial T2-, and T1-weighted postcontrast MRI demonstrates edema within the spinal cord with focal abnormal enhancement after the administration of intravenous contrast at C6. Axial imaging depicts the abnormal enhancement as less than two-thirds of the cross-sectional area of the spinal cord, a classic finding for multiple sclerosis.

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Fig. 1.10. (A–E) Transverse myelitis. Sagittal T2-, and T1-weighted pre-, and postcontrast axial T2- and T1-weighted postcontrast MRI demonstrates an abnormal area of signal hyperintensity throughout the cervical spinal cord on T2-weighted images with abnormal enhancement following the administration of intravenous contrast. Axial imaging depicts the abnormal enhancement as more than two-thirds of the cross-sectional area of the spinal cord, a classic finding for transverse myelitis.

STROKE Spinal cord infarction Spinal cord infarction (SCI) is relatively rare, accounting for approximately 1% of strokes. The spinal cord is supplied by a single ASA, two PSAs, and the artery of Adamkiewicz, a branch of a lower left intercostal artery arising from the aorta. SCI results from any etiology that interrupts blood flow to the spinal cord, including aortic aneurysm rupture or repair, aortic dissection, spinal artery embolism, atherosclerotic disease, surgical cross-clamping, vasculitis, coagulopathy, hypotension, and venous congestion. ASA occlusion may result in an anterior spinal cord syndrome manifesting paralysis, pain, and loss of temperature sensation, whereas

occlusion of PSA occlusion leads to the posterior column syndrome of impaired sensation of touch, position, and vibration. The clinical history is important in distinguishing SCI from similar appearing entities, as for example the suddenness of the neurological deficit in SCI. Common locations for infarct are the thoracic and thoracolumbar cord, due to tenuous watershed blood supply. Neuroradiological evaluation employing MRI demonstrates abnormal hyperintense signal intensity on T2-weighted images within the central gray matter or the entire cross-sectional area of the spinal cord (Fig. 1.11A and B). The spinal cord may be of normal caliber or mildly expanded. Susceptibility artifacts from a heterogeneous magnetic environment limit the use of diffusion-weighted imaging (DWI) for detection

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Fig. 1.11. (A, B) Infarction. Sagittal T2- and axial T1-weighted MRI demonstrates an abnormal area of signal hyperintensity within the conus due to infarction and edema involving the gray matter.

and early diagnosis of cord infarction. Acute SCI can be distinguished from neoplastic processes by enhancement after contrast injection in the latter; and demyelinating lesions which typically involve the dorsolateral regions of the cord and occupy less than one half of the crosssectional spinal cord area.

VASCULAR MALFORMATIONS Vascular malformations of the CNS are characterized by direct shunting of the arterial vasculature into the venous system without interposed capillaries. Refinements in the classification system, based on improvements in the understanding of the feeding and draining patterns of this heterogeneous group of malformations, have led to improved classifications schemes (Prestigiacomo et al., 2003; Si-jia et al., 2009; Lv et al., 2012), while treatment strategies have led to improved outcome and diminished morbidity and mortality in affected children and adults (Zuccaro et al., 2010). Arteriovenous fistula Arteriovenous fistulas consist of single or multiple arterial feeding vessels that lead to a common fistula site and draining vein. They are categorized into extradural and intradural fistula, the latter further subdivided into dorsal and ventral types. Extradural fistulas demonstrate a direct connection between an extradural artery and vein resulting in engorgement of the epidural venous system (Arnaud et al., 1994; Graziani et al., 1994). The enlarged epidural veins can cause compression on the underlying spinal cord resulting in a progressive myelopathy. High flow fistulas can shunt blood flow away from the spinal cord, resulting in a steal phenomenon with elevation of venous pressure resulting in venous hypertension.

The vast majority of the lesions can be treated by closed endovascular techniques and do not require an open operation. Dorsal and ventral intradural spinal AVF are located in the subarachnoid space. Dorsal AVF are fed by one or more vascularized pedicles in the dural root sleeve. Such lesions are often referred to as dural fistulas, suggesting that the fistula is within the dura. Blood flow through these lesions is directed into the higher resistance coronal venous plexus rather than the lower resistance epidural or dural venous system, suggesting that the fistula exists in the subdural rather than dural space (Spetzler et al., 2002). Ventral AVF are much less common than dorsal lesions and are located centrally within the subarachnoid space, usually along the ventral surface of the spinal cord. They originate directly from the ASA and have a direct connection to the venous network. Smaller ventral lesions have a relatively slow flow rate and moderate venous engorgement. Larger ventral shunts have progressively higher flow rates and can develop extremely large, tortuous veins. Spinal AVF rarely present with a hemorrhage; instead, the clinical manifestations are secondary to venous hypertension. Affected patients usually present in later life with progressive myelopathy; however, some patients note exacerbation of symptoms with increased physical activity likely due to transient elevation of their venous hypertension. The majority of such lesions occur in the thoracic region leading to predominant leg manifestations. Ventral fistulas can become quite large and associated with markedly distended veins. Symptoms attributable to progressive vascular steal and spinal cord compression become more pronounced in these larger lesions. Sagittal T2-weighted MRI may disclose serpiginous flow voids of the dorsal subarachnoid

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Fig. 1.12. (A–B) Intradural dorsal spinal AVF. Sagittal T2-weighted MRI on the left shows serpiginous flow voids in the dorsal subarachnoid space (arrow). T2-weighted image on the right shows abnormal signal intensities at the level of the conus (arrow). The patient presented with a progressive myelopathy that improved after surgical ligation of the fistula.

space and abnormal signal intensities in cases of progressive myelopathy (Fig. 1.12A and B). Treatment employing simple obliteration of the fistula is advocated over extensive stripping of the lesions. The surgical management of dorsal AVF is generally safer and more efficacious than embolization, whereas ventral AVF that are often more difficult to reach surgically and intimately associated with the ASA require closure of the fistulous connection between the ASA and the dilated draining veins for definitive management. This process can be accomplished by preoperative embolization rendering them easier to resect surgically. Embolization may not be possible for smaller ventral lesions making surgical management the only reasonable option. Friable giant ventral fistulas, with the high risk of associated rupture and vascular injury from surgical manipulation, are best treated with endovascular techniques. Arteriovenous malformations Arteriovenous malformations appear grossly as a tangle of vessels, often with a fairly well-circumscribed center or nidus, and arterialized veins. In contrast to AVFs, single or multiple dilated arterioles in the AVM connect directly to a vein without a nidus. Extradural–intradural spinal AVMs are large, complex malformations with multiple arterial feeders originating from multiple vertebral levels that respect no tissue boundaries and have extensive intramedullary, extramedullary, and extraspinal involvement. The occurrence of these lesions is fortunately rare. The presence of multiple large-caliber

arterial feeders with tortuous engorged veins renders them susceptible to extensive blood loss, with an overall poor prognosis due to the elevated risk of neurological morbidity and mortality. Treatment is generally comprised of a multiple staged endovascular embolization followed by surgical resection of the residual components. Intramedullary AVMs are supplied by multiple arteries arising from both the anterior and PSAs, and drained by the coronal venous plexuses, which are often enlarged and tortuous. Spinal cord AVMs have no sex predilection and are commonly diagnosed in childhood and early adulthood (Panciani et al., 2010). The absence of a capillary bed allows arterial pressures to be transmitted directly to the venous system, resulting in elevated venous pressures and venous engorgement. Venous hypertension reduces perfusion to the spinal cord resulting in progressive ischemia of the cord. The distended vessels can become quite large, causing progressive deficits from mass effect on the underlying parenchyma resulting in myelopathy due to cord compression. Hemorrhage into spinal cord parenchymal typically results in sudden and severe neurological deficits, while bleeding into the subarachnoid space leads to localized back pain, headaches, and diffuse meningeal signs. Like cerebral AVM, spinal intramedullary AVM also have a true parenchymal nidus (Fig. 1.13). These lesions can be supplied by multiple branches of the anterior and PSAs, and subsequently drain into the coronal venous plexus, often with associated aneurysms. Surgical resection of spinal intramedullary AVM can be challenging

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Fig. 1.13. Spinal intramedullary AVM. Lateral vertebral angiogram on the left side and anteroposterior view on the right side show the diffuse vascular malformation lesion at the cervicomedullary junction.

because the lesions can be incorporated within the spinal cord often sharing arterial blood supply. Preoperative embolization is employed to reduce flow through the malformation, significantly improving the ease of surgical resection. Neuroradiological evaluation of spinal cord AVM employing MRI reveals conglomerates of dilated vessels, devoid of signal due to flow best demonstrated on T2-weighted sequences, whereas heterogeneous signal changes due to blood products are noted on T1-weighted images; contrast enhancement is variable. Serpiginous structures along the surface of the cord representing tortuous feeding arteries and distended draining veins may be appreciated. Cavernous malformations Spinal cord cavernous malformations or cavernomas are well-circumscribed lesions that consist of irregular thick and thin-walled sinusoidal vascular channels without intervening neural parenchyma, large feeding arteries, or large drainage veins. They can present with an acute deterioration from a large hemorrhage, but more commonly with insidious chronic or progressive deterioration from recurrent small hemorrhages, neither of which result in a catastrophic event. However, relapsing symptoms may coalesce, leading to the erroneous diagnosis of multiple sclerosis. These angiographically occult lesions are diagnosed with hrMRI appearing as a central area of heterogeneous signal intensity of various age thrombi, surrounded by a thin rim of hemosiderin staining best seen on T2-weighted or gradient-echo

Fig. 1.14. Cavernous spinal malformation. Sagittal T2weighted MRI shows an abnormal central heterogeneous signal intensity surrounded by a dark rim of hemosiderin.

images (Fig. 1.14). The hemorrhage risk of intracranial cavernomas has been estimated at 0.6% per year (Kondziolka et al., 1995), such that there is little urgency and perhaps no need for treatment of asymptomatic lesions. Surgical resection is instead reserved for wellcircumscribed symptomatic lesions amenable to a complete resection (McCormick et al., 1988). Larger lesions that rise to the pial surface surrounded by a gliotic margin are easier to resect, whereas smaller, ventrally located lesions are associated with higher surgical risks (Liang et al., 2011), whereas symptomatic lesions with a very benign course can be observed without surgery (Kharkar et al., 2007).

MOTOR NEURON DISEASE The challenge and controversies in accurately classifying and diagnosing living cases of motor neuron diseases (MNDs) begin with correctly identifying clinical and pathological UMN and LMN signs, the combination of which characterizes classical amyotrophic lateral sclerosis (ALS), and differentiates it from isolated LMN signs indicative of SMA and PMA and isolated UMN signs indicative of primary lateral sclerosis (PLS).

Spinal muscular atrophy Spinal muscular atrophy (SMA) designates rare autosomal recessive inherited MNDs of infancy and childhood. SMA is categorized into four types: type I is the most

SPINAL CORD MOTOR DISORDERS severe and primarily affects newborns, types II and III are intermediate forms, and type IV is the mildest form with adult onset. Children with the SMN1 mutation who survive infancy have primarily proximal weakness and lose milestones in walking as one of the first clues to diagnosis. However, infants with SMA type I have hypotonia, poor head control, and intercostal muscle weakness with respiratory compromise. Tongue fasciculation is a typical feature. Type II patients also have marked proximal-extremity weakness with hypotonia and areflexia, and they are prone to scoliosis and joint contractures, although cognition remains normal. Type III patients have proximal weakness in the legs more than the arms. They eventually become wheelchair-bound, but they generally do not develop scoliosis or respiratory failure. Occasional patients present at birth with arthrogryposis due to decreased fetal movement, sometimes referred to as type 0, or with milder manifestations and onset in adulthood (type IV). The laboratory evaluation of SMA has evolved with discovery of the underlying genetic defect. The diagnosis in a suspected patient can be ascertained by DNA analysis for the causative mutation or deletion at the 5q13.2 chromosome locus of the survival motor neuron genes SMN1 and SMN2, with SMN1 the primary disease-causing gene. Infants with deletions or truncation of exons 7 and 8 of SMN1 require no further workup. Although most patients have deletions in SMN, rare patients with duplication or heterozygous point mutations have been described. If gene sequencing is normal, a more traditional approach is warranted that includes measurement of serum CK, which is usually normal in types I and II, and elevated in type III; NCS and needle electromyography (EMG) reveal the anticipated features of MND. The electrodiagnostic evaluation of SMA can be challenging because of small-sized limbs in children leading to relatively short distances between stimulus and recording electrodes, and profound muscle wasting that alters the reliability of motor NCS, which in SMA should remain normal (Iijima et al., 1991). Needle EMG shows evidence of acute denervation including fibrillation potentials and reinnervation in the form of large polyphasic motor unit potentials (MUPs) with reduced recruitment. In infants, EMG may be normal or suggest a primary myopathic process because of small amplitude, short duration, and polyphasic MUPs. Motor unit number estimation (MUNE), a methodology that assesses the number of motor neurons innervating a muscle group with utility in MND, notably ALS (Bromberg, 1993) and SMA due to homozygous deletion in SMN1, including asymptomatic patients age 16 days to 45 years (Bromberg and Swoboda, 2002), shows a fall in MUNE values to low levels early in the progression of weakness,

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with test–retest reliability that shows consistent values making it a desirable methodology for following disease progression. Skeletal muscle biopsy is warranted when mutation analysis is uninformative. Skeletal muscle biopsy in affected patients shows large group atrophy of large type 1 myofibers and clumps of type 1 hypertrophic fibers that stain with ATPase with angulated fibers that increase with age from mid-childhood due to reinnervation. The most important neuropathological changes in SMA are degeneration of spinal cord AHCs which correlates with the course of neurogenic muscular atrophy. This is seen as a prominent loss of spinal AHC while the remaining ones may be in various stages of degeneration. In the earliest stage, the nucleus moves from its central position and Nissl bodies take on a crumbled appearance with expansion of the cytoplasm (chromatolysis). Eventually, the cytoplasm shrinks in size and disappears leaving behind light spaces. Small glial cells gather around the shrunken neurons until they completely disappear (neuronophagia). Such images of cellular degeneration are generally observed when axons have been severed, suggesting degenerative changes are acute. The disease is caused by mutation or deletion in the SMN1 gene within a region of chromosome 5q that has a high degree of genomic instability. Humans possess a near duplication of SMN1, SMN2, which consistently differs from SMN1 by a single nucleotide. This translationally silent, single-nucleotide change in exon 7 disrupts an exonic splice enhancer, leading to exclusion of exon 7 in 90% of transcripts from SMN2 (Cartegni and Krainer, 2002). The resulting protein from this transcript missing exon 7, SMND7, is unstable and has reduced functionality. Complete absence of SMN protein is lethal in patients and in multiple model systems (Burghes and Beattie, 2009). All SMA patients lack a functional copy of SMN1, but retain a variable number of copies of SMN2. In patients, higher copy numbers of SMN2 correlate inversely with disease severity (Lefebvre et al., 1997), as a small percentage of SMN2 transcripts are full-length and encode functional SMN protein. In unaffected individuals, the SMN2 copy number varies between zero and three copies. Severe type I patients may have one or two SMN2 copies, and mild type II or III patients typically have three or more copies of SMN2 (Prior et al., 2004). Individuals with four or five copies of the SMN2 gene may be clinically normal despite complete loss of SMN1. The encoded SMN gene protein plays a critical role in spliceosome assembly and other cellular functions including messenger ribonucleic acid (mRNA) transport. Successful therapy targets the increase in SMN levels through the development and delivery of small molecules, oligonucleotides, and gene replacement therapies.

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The identification and extensive characterization of the elements governing SMN2 exon 7 splicing and inclusion has led to the successful development of antisense oligonucleotides that increase SMN exon 7 inclusion (Lorson et al., 1999) with practical application to patients approved by the US Food and Drug Administration (nusinersen) for intrathecal delivery based on randomized-controlled trials (RCTs) under the ENDEAR (ClinicalTrials.gov number, NCT02193074) (Finkel et al., 2017), CHERISH (ClinicalTrials.gov number, NCT02292537) (Mercuri et al., 2018), and NUTURE (ClinicalTrials.gov number, NCT02386553) (De Vivo et al., 2019) Study Groups. The identification of self-complementary adenoassociated virus serotypes that cross the blood–brain barrier and target cells in the CNS was critical to the development of gene replacement therapies for SMA; subsequent studies demonstrated the efficacy of intravenous, systemic, and intramuscular administration with AAV9-mediated delivery of SMN (Duque et al., 2009). This in turn led to RCTs with onasemnogene abeparvovec-xioi or onasemnogene delivering a single intravenous dose injection carrying SMN complementary DNA encoding the missing SMN protein in the Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1 (ClinicalTrials.gov Identifier: NCT02122952) (Mendell et al., 2017) and the Gene Replacement Therapy Clinical Trial for Participants with Spinal Muscular Atrophy Type 1 (STR1VE) (ClinicalTrials.gov number NCT03306277) (Day et al., 2021) for symptomatic SMA1, and a presymptomatic trial for patients with multiple copies of SMN2 in SPRINT (ClinicalTrials.gov number NCT03505099). This was followed by RCTs of the orally administered, centrally and peripherally distributed small molecule risdiplam to modulate SMN2 pre-mRNA splicing toward the production of full-length SMN2 mRNA to increase SMN protein levels in the FIREFISH Working Group (Baranello et al., 2021; Darras et al., 2021).

Progressive muscular atrophy While SMA is a hereditary disease of childhood, PMA is a disease of adult onset and is almost always sporadic. Important controversies focus on the very concept of the conditions. In theory, PMA is a disease of the LMNs as diagnosed clinically and proven at postmortem examination (den Berg-Vos et al., 2003). In this regard, the disease would differ from ALS in which both UMNs and LMNs are involved clinically and at autopsy, and also from PLS, in which only UMN abnormalities are evident. It is estimated that PMA accounts for about 5% of all cases of adult-onset MNDs. The requirements for the diagnosis of PMA have been difficult to meet for

several reasons (Rowland et al., 2001). The most important uncertainty arises from the evolution of symptoms and signs. Sometimes within months after symptom onset, the clinical evidence of LMN disease is complicated by the later appearance of UMN signs. Furthermore, in life, what may seem to be PMA introduces a differential diagnosis with other hereditary and sporadic disorders (Rowland, 2010). Among cases of purely or predominantly LMN disease, clinical manifestations include some with SOD1 mutations which may be overwhelmingly associated with syndromes that compromise clinical signs of both UMN and LMN disease (meeting formal criteria for the diagnosis of ALS) but are nevertheless sometimes seen with the clinical picture of PMA (Cudkowicz et al., 1998; Restagno et al., 2008; Suzuki et al., 2008). Historically, Lawyer and Netsky (1953) described a PMA patient with a 6-year course of progressive paraplegia and only clinical and postmortem LMN signs, excluding another with a 35-year course of arm diplegia who developed a Babinski sign and pathologically evident CST demyelination. Brownell et al. (1970) described 2 PMA patients who presented with slow progression of clinical LMN signs lasting 4 and 10 years, respectively, with widespread LMN changes and no detectable loss of giant pyramidal cells or evidence of CST degeneration. Leung et al. (1999) described 2 PMA patients (2.6%) among 76 autopsies with the clinical or pathologic diagnosis of ALS or MND who demonstrated LMN pathology alone; however, there was no mention of the precentral gyrus. Ince et al. (2003) described the course of 81 patients for whom case notes, immunocytochemistry, and CD68 immunoreactivity in spinal and brainstem tissue were available at postmortem examination, enabling them to reassign 6 of 12 PMA cases to sporadic or familial ALS or SMA. Kim et al. (2009) compared the survival of patients with PMA (91 patients) or ALS (871 patients) using pure LMN clinical findings and El Escorial criteria for ALS (Brooks, 1994), noting no significant difference in median survival time among PMA patients who did (41 months) or did not (36 months) develop UMN signs. More recently, Younger and Qian (2015) described a patient with pathologically proven PMA in whom their patient, a 41-year-old man, developed bilateral leg and right upper arm weakness without a family history of MND but with suggestive features of an inflammatory autoimmune disorder of postinfectious tick-borne disease-related illness. Neurological examination demonstrated flail right leg function, near-flail function in the left leg, and weakness against gravity in the upper arms and hands, with widespread fasciculation and intact sensation. Tendon reflexes were absent. Nerve conduction studies of the legs and right arm were normal except

SPINAL CORD MOTOR DISORDERS for marginal slowing of right tibial motor nerve conduction velocity and mildly reduced right fibular and median compound muscle action potential amplitudes. Electromyography showed 3+ active spontaneous activity in muscles of 3 limbs. CSF was normal. Sural nerve biopsy showed perivascular epineurial inflammation. Soleus and vastus lateralis muscles showed severe neurogenic changes. Bulbar and respiratory symptoms later supervened, and he expired in April 2014. The general autopsy was unrevealing. Specifically, there was no evidence for an underlying systemic or inflammatory autoimmune process. Neuropathological examination (Fig. 1.15A–H) showed severe bilateral AHC loss and gliosis, most notable in the lumbar cord, where there was severe loss of anterior nerve root fibers, and normal posterior roots. Sections of the motor cortex including Betz cells were normal. There was no evidence of CST

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degeneration based on axonal loss, abnormal myelin staining, or excessive CD68 macrophage immunoreactivity; and no pathognomonic neuronal ubiquitinated inclusions, Bunina bodies, tauopathy, or TAR deoxyribonucleic acid-binding protein 43 kDa skein-like inclusions suggestive of ALS. However, new problems have arisen in the differentiation of neuronopathies, diseases that affect the cell body of a motor neuron (rather than the axon). Aside from the overlap with ALS, there is potential overlap with motor neuropathies such as neuronal Charcot–Marie–Tooth disorders in which the legs may be affected more than the hands, the striking appearance of distal muscle wasting, and characteristically normal NCS. Thus, are motor neuropathies to be classified with PMA or with peripheral nerve disorders? There are inherited or familial forms linked to specific mutations, yet many are sporadic

Fig. 1.15. Progressive muscular atrophy. (A) Paraffin sections of the sural nerve show mild perivascular epineurial chronic inflammation. Semithin sections (not shown) demonstrate minimal focal axonal loss (hematoxylin and eosin stain, 100). (B) Cryosections of the vastus lateralis muscle reveal significant myofiber atrophy forming large and small groups. Several remaining myofibers are hypertrophic (hematoxylin and eosin stain; original magnification, 200). (C) Low power view of the lumbar cord shows reduced neuronal density in the anterior horn (hematoxylin and eosin stain; original magnification, 2.5). (D, E) Higher magnification shows reactive astrocytes in the background. Yellow arrows point to a surviving AHC neuron (hematoxylin and eosin stain [D] and glial fibrillary acidic protein stain [E]; original magnifications, 20). (F–H) Sections of the precentral gyrus show well-preserved cytoarchitecture, laminar and columnar arrangements, without loss of neurons or gliosis. Large pyramidal cells, including Betz cells in the deep cortical layers, are intact and contain Nissl substance and lipofuscin (hematoxylin and eosin stain [F–H]; original magnifications, 10 [F], 20 [G], and 40 [H]).

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or uncertain in causation. As research accelerates in this area, combined with the more we learn about PMA, the closer we will get to the cause and treatment of the more lethal and more prevalent forms of MND.

Primary lateral sclerosis Adults with slowly progressive noninherited gait disorders may show no abnormalities on examination other than signs implicating the CSTs. That is the syndrome of PLS, a clinical diagnosis that has been avoided because it is a diagnosis of exclusion, proven only at autopsy. Brain and spinal cord neuroimaging excludes other disorders that can cause the syndrome with an accuracy of about 95% including bilateral strokes, compressive lesions at the foramen magnum or cervical spinal cord, multiple sclerosis, ALS, Chiari malformation, syringomyelia, biochemical abnormality, and persistent infection with human immunodeficiency virus type 1 or human T-lymphotropic virus type I. Since Younger et al. (1988) studied 3 autopsy-proved cases of PLS as well as 6 living patients in whom PLS was diagnosed clinically after comprehensive evaluations that excluded the alternative diagnoses more than 3 decades ago, consensus criteria (Turner et al., 2020) have been proposed resting on similar clinical and laboratory measures mainly to exclude LMN disease and forme-fruste cases of ALS. However, validating isolated UMN dysfunction is potentially more challenging and has therefore become the subject of a flourishing industry of electrodiagnosis employing a variety of testing modalities: beta-band EMG (Fisher et al., 2012), neurophysiology employing magnetoencephalography (Proudfoot et al., 2018); brain MRI employing diffusion tensor imaging (Ciccarelli et al., 2009), quantitative susceptibility mapping of iron deposition in the motor cortex (Schweitzer et al., 2015); PET imaging (Pringle et al., 1992), TMS for central conduction along CSTs and cortical excitability (Kuipers-Upmeijer et al., 2001; Geevasinga et al., 2015); and CSF biomarkers including phosphorylated neurofilaments (NFs) (Steinacker et al., 2016) and chitinase protein levels (Thompson et al., 2019). However, the profusion of these different methods as a proxy for PLS suggests that none are yet sufficiently sensitive, specific, or validated in determining an index case.

Poliomyelitis In the first half of the 20th century, epidemics of poliomyelitis (polio) ravaged the world. In the epidemic of 1952, over 20,000 Americans developed paralytic polio. With the introduction of the Salk inactivated polio vaccine in 1954 and the Sabin oral polio vaccine (OPV) in 1961, the number of paralytic cases decreased to a handful per year. Polio essentially vanished and no

longer was on the consciousness of Americans. However, in the late 1970s, survivors of paralytic polio began to notice new health problems that included fatigue, pain, and new weakness though not considered real by the medical establishment. The term “postpolio syndrome” (PPS) was later coined to emphasize the new health problems. Polio and PPS have been recently reviewed (Lo and Robinson, 2018; Menant and Gandevia, 2018). Poliovirus infections are divided into minor and major forms. The minor form occurs 1–3 days before the onset of paralysis along with gastrointestinal complaints of nausea and vomiting, abdominal cramps and pain, and diarrhea and systemic manifestations of sore throat, fever, malaise, and headache. The major spinal cord illness includes aseptic meningitis or nonparalytic polio, recognized by stiff neck, back pain, photophobia, and headache. Polioencephalitis generally precedes paralysis and rarely occurs alone. It manifests as tremulousness, obtundation, agitation, and autonomic dysfunction with labile hypertension, hypotension, tachycardia, arrhythmias, and excessive sweating. UMN signs of spasticity, hyperreflexia and Babinski signs are usually lost as paralytic disease ensues. Paralytic poliomyelitis follows the minor illness immediately or more often within 3–4 days wherein paralysis results from selective vulnerability of AHC similar to wild-type mice inoculated with human poliovirus (Ford et al., 2002). Serologic testing and polymerase chain reaction DNA amplification is needed to confirm the responsible virus in tissue specimens from the oropharynx, serum, stool, and especially CSF where an increased CSF/serum antibody ratio exceeding 1:150, with increased titers of IgM specific antibody supports the diagnosis of CNS poliovirus infection. A fourfold or greater rise in the serum poliovirus antibody titer between acute and convalescent specimens is considered diagnostic of infection; however, it is important to obtain the acute phase specimen as early as possible in the course of the illness, and the convalescent phase sample at 2 and preferably 4 weeks after the former to detect the diagnostic fourfold rise. CSF examination shows findings similar to those of other CNS viral infections (Jubelt and Lipton, 1989). Axial and sagittal T2-weighted MRI of the spinal cord shows a T2 hyperintense signal involving the AHC regions that localize acute inflammation and sclerosis (Choudhary et al., 2010). There is no effective therapy to avert paralysis; however, affected patients should be hospitalized to assure stability of cardiovascular, respiratory, and autonomic nervous system functions, food, and nutritional status. Appropriate positioning and placement of splints prevent muscle contracture, while footboards avert foot drop, and turning which prevents decubiti ulcer. Physical therapy commencing with passive movement followed

SPINAL CORD MOTOR DISORDERS by active physical therapy with nonfatiguing musclestrengthening exercises and hydrotherapy are necessary. Braces and other orthotics facilitate ambulation after paralysis peaks and strength begins to return, while orthopedic consultation for arthrodesis, tendon transference, and leg-shortening procedures are generally deferred for up to 2 years after when maximum recovery occurs. Concentric needle EMG of patients with prior polio show chronic denervation and reinnervation with increased amplitude of voluntary MUPs and neurogenic patterns of reduced recruitment in previously involved as well as uninvolved muscles. New weakness due to PPS is generally associated with active and chronic denervation; however, nerve conduction studies are typically normal. Single fiber EMG of newly symptomatic muscle shows increased fiber density and neuromuscular transmission defects of increased jitter and blocking, the latter varying with the number of years since acute poliomyelitis. Macro-EMG shows large reinnervated motor units that develop by collateral sprouting and decrease over time from recovery of acute polio most likely due to loss of terminal sprouts due to less efficient reinnervation. MUNE is abnormal in patients with a history of prior polio and in those with PPS, with no clear distinction between the patient’s groups with respect to either the number of motor units measured or the rate of decline of motor units. The biopsy findings of patients with old poliomyelitis reveal evidence of chronic denervation and reinnervation indicated by fiber type grouping, and active denervation evidenced by small angulated fibers, often in association with neural-cell adhesion molecules on the surface of muscle fibers. The large group atrophy so noted in MND is a much less common finding in PPS. The likeliest mechanism for the development of PPS is the loss of AHC and motor units with normal aging that does not become prominent until after the age of 60 years. More important than chronologic age in PPS, is failure of compensation of progressive motor neuron loss by reinnervation and collateral sprouting with progressively larger motor unit territories, especially in patients with longer intervals of recovery from prior polio. The CSF of persons with PPS display a disease-specific and highly predictive differential expression of five distinct proteins: gelsolin, hemopexin, peptidylglycine alphaamidating monooxygenase, glutathione synthetase, and kallikrein 6, respectively, in comparison with the control groups (Gonzalez et al., 2009). Intravenous immune globulin has effects on relevant quality of life (QoL) variables and inflammatory cytokines up to 1 year in patients with PPS (Gonzalez et al., 2012). The OPV contains live-attenuated polioviruses that induce immunity by causing low virulence infections in vaccine recipients and their close contacts. While

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widespread immunization with OPV has reduced the annual global burden of paralytic poliomyelitis by a factor of 10,000 or more and has driven wild poliovirus to the brink of eradication, there are still rare instances of vaccine recipient paralysis that may continue to generate polio outbreak (Famulare et al., 2018).

SPINAL CORD INJURY Intramedullary insults The sudden loss of motor function following spinal cord injury (SCI) with its life-altering effects, is the driving force to understand the mechanisms of spinal cord motor system plasticity with the hope of devising novel repair strategies. The common neuropathologic appearance of traumatic SCI that damages the descending motor pathway connections is a central lesion at the injury site (Brown and Kakulas, 2012) contributed by hemorrhage and ischemia. The injury site forms a cavity that displaces axons, neurons, and glia, as it expands it entrails further axotomy and demyelination with neural tissue loss and conduction block that worsens motor disability. The damage to supporting glia and interneurons eliminates the various anatomic routes by which descending motor control signals can reach motoneurons. These descending motor pathways include the direct CST that projects from the primary motor cortex as well as several premotor areas, and indirect cortical projections from the red nucleus and pontomedullary reticular formation brainstem relay nuclei via the corticoreticulospinal and corticorubrospinal tracts. The direct CST has a predominantly contralateral projection, especially to the limb segments, but there is also a smaller ipsilateral projection which in humans projects to cervical spinal segments. The indirect corticoreticulospinal tract and the reticulospinal tracts both have a strongly bilateral organization. Their differential descending axon locations in a cross section of the spinal cord, whether contralateral or ipsilateral or both, enable their supraspinal signals to be rerouted along spared pathways after SCI. The descending supraspinal motor pathways synapse on motor neurons and interneurons (Ueno et al., 2018; Yoshida and Isa, 2018). Loss of the CST after SCI leads to activity-dependent degeneration of type 2 cholinergic muscarinic receptor interneurons providing monosynaptic excitation to motor neurons. These are the source of large cholinergic C-boutons and cluster near the central canal. Direct current neuromodulation prevents their degeneration after experimental lesioning. The synaptic competition between deficient CST connections to LMNs and the increased activity of sprouting proprioceptive muscle afferent fibers, particularly IA,

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substantially contributes to weakness, increased muscle tone, and hyperreflexia.

Muscle and motor neuron excitability At the level of the muscle, the increased tone initially results from the combination of denervation supersensitivity, or the increase in the sensitivity of postsynaptic structures to the transmitter that has been withdrawn. This occurs as AChR are redistributed from its confined location at the neuromuscular junction to cover the entire myofibers (Guth et al., 1980) as a consequence of the synthesis of extrajunctional AChR at remote sites along the muscle. The increase in the synthesis of AChR by myofibers is associated with increased expression of receptor mRNA (Merlie et al., 1984). Following SCI, aberrant sprouting of 1A fibers contacts excitatory interneurons and motor neurons that affect segmental excitability (Tan et al., 2012). Two other mechanisms alter intrinsic motor neuron excitability. There is altered constitutive activity due to persistent inward currents in HT2c receptors (Murray et al., 2010). There is also downregulation of the potassium-chloride cotransporter (KCC2) (Boulenguez et al., 2010) that normally establishes a chloride ion gradient across a neuron’s membrane necessary for postsynaptic inhibition.

Short- and long-term potentiation and depression Both short- and long-term potentiation and depression involve changes in the amount of neurotransmitter released by incoming impulses that generate an AP (Katz and Miledi, 1968). They are generally restricted to synapses activated during a conditional stimulus. However, STP/STD, unlike LTP/LTD, is not expected to impact long-lasting forms of synaptic plasticity in SCI that alters the sensitivity of the postsynaptic membrane. Though less intensively studied in recent years, short-term plasticity is also found in the spinal cord (Eccles and Krnjevic, 1959) where it probably forms the first stage, like a booster, of longer-lasting synaptic plasticity important in recovery from SCI. The CST circuit undergoes plasticity in the spinal cord. Tetanic stimulation of the motor cortex evokes LTP (Iriki et al., 1990) and upregulates multiple intracellular signaling pathways, including the mTOR and Jak/Stat pathways; and when these signaling pathways are active for several days, there is an increase in both CST axon length and synapse number (Zareen et al., 2018). Electrical stimulation activating proprioceptive muscle afferents leads to a substantial increase in their intraspinal terminations.

Implications for neural plasticity Phasic electrical stimulation of spinal motor circuits has been used to promote walking in individuals with SCI (Harkema et al., 2011). It is thought to activate large diameter afferent fibers that in turn activate CPGs for hind limb joints (Edgerton et al., 2004; Gerasimenko et al., 2008). Much clinical experience has been gained by the use of this stimulation approach. After suitable training and body support, subjects are capable of stepping on a treadmill. However, for most subjects, as a recent report indicated, their locomotor capacity ceases when the stimulator is turned off (Rejc et al., 2017). In an important series of recent studies, several subjects with motor incomplete injuries who have experienced extensive training (in excess of 80 sessions) were able to walk overground with an assistive device after the stimulator was turned off (Angeli et al., 2018). The working model for epidural spinal stimulation efficacy is that the largely denervated motor circuits require an external source (i.e., the stimulation) to raise their level of excitability above the threshold for function. Epidural repetitive stimulation has been shown to be remarkably effective in promoting the functions of not only CPG circuits, but also posture as well as bladder and bowel functions. Repetitive spinal stimulation also can be implemented using surface electrodes (Ievins and Moritz, 2017; Inanici et al., 2018).

COLLATERAL SPROUTING After an SCI, descending control signals are minimized or largely eliminated, depending on the extent of the lesion, leaving afferent signaling as the major extrinsic drive to spinal circuits. Thus, much of the intrinsic circuitry of the spinal cord shifts to more sensory feedback than feed-forward motor control from supraspinal levels. This is accompanied by sprouting of proprioceptive muscle IA afferents throughout the spinal gray matter on the denervated side (Tan et al., 2012), especially in the ventral horn, directly on the cell bodies of motoneurons in a time course of sprouting that correlates with the development of hyperreflexia and increased muscle tone. The lack of regeneration in mature axons contrasts with their capacity to sprout. There are two classes of sprouting (Tuszynski and Steward, 2012). First, branches from intact axons that sprout into denervated areas of the spinal cord, both ipsilateral to the spared axons and across the midline through lamina X and the anterior spinal commissure. The second is sprouting from the undamaged part of the axotomized fiber located proximally to the cut, which may find their way to the level of the lesion or even farther caudally. However, these sprouting axons are not likely to recapitulate the extent and pattern of their original set of connections. Sprouting of spared

SPINAL CORD MOTOR DISORDERS axons, as opposed to true axon regeneration, poses several advantages as targets for therapy to promote structural plasticity. First, the axons are at and beyond the injury site, so there is no need to cross an injury barrier. Whereas injury-dependent sprouting is well documented to occur in a variety of animal injury models, the amount of sprouting is modest and, for more severe injuries that produce paralysis, does not lead to passage of lost control signals caudally to the lesion. Second, axons in the injured nervous system respond to electrical stimulation to enhance sprouting and the formation of functional synaptic contacts (Zareen et al., 2017).

REGENERATION If all axons in a functionally defined pathway are severed, collateral sprouting is not likely to be effective in restoring that function. The majority of studies conducted on regeneration in the mammalian spinal cord have generally employed partial surgical lesions in order to sever specific descending tracts such as the CST. The resulting anatomical data attributed to regeneration in such instances have generally resulted from other forms of spinal cord plasticity, such as axon sprouting and dendritic remodeling or even experimental error. Encouraging the growth of supraspinal axons requires two major strategies: first, to overcome the highly inhibitory environment of the injured spinal cord, and second, to facilitate neuron-intrinsic mechanisms of axon growth. Several inhibitory molecules are associated with CNS glial cells, including myelin-associated inhibitors, all of which bind to the same Nogo receptor, myelinassociated glycoprotein, and MOG; and the axon guidance molecules semaphorins, ephrins, and repulsive guidance molecule (Hata et al., 2006). Those associated with glial scar formation after SCI, such as chondroitin sulfate proteoglycans (Galtrey et al., 2007), bind to specific receptors that stimulate the Rho/Rho kinase (ROCK) intracellular signaling pathway (Mueller et al., 2005). As these inhibitory molecules converge on intracellular signaling pathways, it remains important to determine what component of the pathway can be targeted effectively to maximize regenerative benefit and minimize adverse side effects. The facilitation of neuron-intrinsic mechanisms of axon growth has also been pursued by targeting factors shown to mediate neurotrophic and axon-extending effects principally via the cyclic AMP (cAMP)–protein kinase A second messenger signaling pathway (Carballosa-Gonzalez et al., 2014; Batty et al., 2017). Thus far, the removal of inhibitory cues alone and cAMP manipulation have yielded limited results. Another theoretical approach to promote proliferation after SCI targets the rapamycin (mTOR) pathway. Developmentally, this pathway is downregulated and correlated

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with loss of regenerative ability of CST axons. Manipulating the negative regulator of the mTOR pathway in knockout experimental mice with a PTEN deletion enhanced the regenerative ability of adult corticospinal neurons (Liu et al., 2010); however, this approach is also unlikely to be used therapeutically in human SCI because of the risk of tumor formation. Combining cell- and tissue-based therapies has been envisioned to replace lost cells and tissues with transplanted cells and deliver trophic factors or other molecular agents which are both neuroprotective and promote regeneration (Goldman and Windrem, 2006; Pearse and Bunge, 2006). In the process, a microenvironment can be created to allow for sprouting, regeneration, and the formation of local connections between injured and viable areas. Early studies employing embryonic stem cell-derived motoneurons (Harper et al., 2004) and neurosphere-derived neural stem cells (Ikegami et al., 2005) transplanted into the injured spinal cord to integrate and form connections with the host tissue yielded anatomical and functional results that were better than the individual therapies alone. Pluripotent stem cells do not differentiate into neurons when transplanted into the spinal cord, even though the same cells can become neurons when transplanted into some areas of the brain (Shihabuddin et al., 2000). Therefore, investigators have used predifferentiated embryonic stem cells recognizing the trade-off between the degree of predifferentiation and neuronal survival. Nonetheless, when administered in combination with regenerative promoters, transplanted cells have shown outgrowth of processes and, when tested, functional recovery. Treatment with db-cAMP or an Rho inhibitor caused transplanted stem cell-derived motor neurons to send axons into white matter and db-cAMP encouraged axons to project out the ventral roots (Harper et al., 2004).

FUTURE RESEARCH In a top-down and bottom-up approach to SCI plasticity, Martin (2022) has focused on the two principal targets for adaptive forms of plasticity to restore function after SCI, the motor cortex and the spinal cord. First, in a modified protocol, TMS stimulation via iTBS is used to produce motor cortex LTP (Wu et al., 2018) and MEP facilitation that substantially outlasts the stimulation period (Song et al., 2016) as well as LTP at the CST-spinal interneuron synapse (Amer et al., 2021). Second, cathodal tsDCS is used to augment spinal neural activity. In the absence of dual stimulation, the spared CST axons make only a small number of spinal connections with reduced axon length: spared descending CST axon number relationship. After stimulation, however, that slope increases, and while the number of spare descending CST axons does not change, there is a larger gray matter axon length

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for each spared descending axon. Combined motor cortex and spinal cord stimulation resulted in significant improvement in skilled locomotor function and forepaw use after a C4 contusion injury (Zareen et al., 2017) that was replicated by an independent group (Yang et al., 2019). Dual motor cortex-spinal stimulation combined with rehabilitation produced a 51% improvement relative to peak impairment before rehabilitation; and reduced the density of proprioceptive afferents caudal to the lesion compared with rehabilitation alone, likely reflecting the competitive interaction between CST and spinal cord afferents (Jiang et al., 2016). Future research will be focusing on applying activity-based plasticity principles and interventions to those with chronic injury in whom the opportunity for early intervention has passed.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00030-2 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 2

Childhood spinal muscular atrophy DAVID S. YOUNGER1,2⁎ AND JERRY R. MENDELL3 1

Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States

2

Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States

3

Department of Neurology and Pediatrics, Center for Gene Therapy, Abigail Wexner Research Institute, The Ohio State University, Nationwide Children’s Hospital, Columbus, OH, United States

Abstract Spinal muscular atrophy (SMA) is caused by biallelic mutations in the SMN1 (survival motor neuron 1) gene on chromosome 5q13.2, which leads to a progressive degeneration of alpha motor neurons in the spinal cord and in motor nerve nuclei in the caudal brainstem. It is characterized by progressive proximally accentuated muscle weakness with loss of already acquired motor skills, areflexia and, depending on the phenotype, varying degrees of weakness of the respiratory and bulbar muscles. Over the past decade, disease-modifying therapies have become available based on splicing modulation of the SMN2 with SMN1 gene replacement, which if initiated significantly modifies the natural course of the disease. Newborn screening for SMA has been implemented in an increasing number of centers; however, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage.

HISTORY In 1891, Guido Werdnig (Groger, 1990), a retired battalion physician working at the Institute of Anatomy and Physiology of the Central Nervous System at the University of Vienna, gave a lecture titled, “On a case of muscular dystrophy with positive spinal cord findings.” One year later, Hoffmann employed the term spinale muskelatrophie (Hoffmann, 1892) first referencing spinal muscular atrophy (SMA). Their combined observations characterized the clinical and pathologic aspects of infantile SMA that included onset in siblings with normal parents in the first year of life of progressively lethal hypotonia, weakness, and hand tremor culminating in early childhood.

CLASSIFICATION The slowly progressive forms of SMA noted by Werdnig and Hoffmann were incorporated into the classification of Byers and Banker (1961), and the observations of

⁎

Dubowitz (1964) that correlated age at onset and disease severity with prognosis. International collaborations beginning in 1991 (Munsat and Davies, 1992; Dubowitz, 1995; Zerres and Davies, 1999) prompted adoption of currently employed nomenclature based on agent at onset, with type I before age 6 months, type 2 with onset between 6 and 18 months, and type 3 after 18 months. The three types were further differentiated by the highest achieved motor milestone and mortality. An adult-onset form (Pearn et al., 1978), later termed SMA type 4, described patients older than 18 years who were still walking in adulthood without respiratory involvement. Patients with SMA type 1 almost never sit after being placed without support, and with onset before 3 months of age, had a mortality rate of 90%, whereas those with onset after age 3 months could survive to adulthood, albeit with severe motor handicap; type 3 patients ambulated independently for part of their life with normal life expectancy.

Correspondence to: David S. Younger, MD, DrPH, MPH, MS, 333 East 34th Street, Suite 1J, New York, NY 10016, United States. Tel: +1-212-213-3778, Fax: +1-212-213-3779, E-mail: [email protected]

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EPIDEMIOLOGY

SMA type 2

The SMA types are rare inherited disorders with an estimated incidence of 10 per 100,000 live births and a carrier frequency of 1 in 50 in the United States and Germany (Thieme et al., 1993; Mailman et al., 2002). It is the most common fatal neuromuscular disease of infancy and the third most common neuromuscular diagnosis seen in children’s clinics of less than 18 years of age. SMA type I has the highest incidence followed respectively by types 2 and 3. Considering the relative mortality rate of SMA type 1, it is not surprising that the highest prevalence is for types 2 and 3.

Juvenile, intermediate, and chronic SMA are all synonyms for SMA type 2. Affected patients usually achieve normal milestones up to 6–8 months of age in spite of relative hypotonicity. The legs are weaker than the arms resulting in paraparesis, and there may be a clubfoot deformity affecting gait. The DTRs are preserved in stronger muscles. Minipolymyoclonus is often combined with fasciculation of intrinsic hand muscles. Infants with SMA type 2 are able to sit without support when placed in a position during all or some of their life but are rarely able to stand; nevertheless, it is customary to classify a child who walks at any time as type 3. The age for sitting or standing is nearly always delayed. Many children survive to the third and fourth decade. One contributing factor between survivors and nonsurvivors is maintaining adequate pulmonary function. SMA type 2 is caused by homozygous or compound heterozygous mutation in the SMN1 gene on chromosome 5q13, which in most cases have three copies of SMN2.

CLASSIFICATION SMA type 1 Infantile onset SMA and Werdnig-Hoffmann disease are synonyms for SMA type 1, the most severe form of the autosomal recessive disease beginning at birth or afterward in the first few months, resulting in death from respiratory failure before age 2. Physical examination in the characteristic frog-leg position reveals a relative absence of spontaneous movements except for the hands and feet that show a fine tremor termed polyminimyoclonus. Affected infants have severe weakness and profound hypotonia with striking discrepancy in the level of social interaction and a paucity of motor skills. Tongue fasciculation is superimposed upon lingual wasting and scalloping at its borders. The combination of pectus excavatum combined with bell-shaped deformity of the lower rib cage, with weakened intercostal muscles and diaphragmatic breathing, lead to inefficient respiration; however, rare individuals develop frank diaphragm paralysis. Deep tendon reflexes (DTRs) are absent with intact sphincter tone and intact sensation. SMA type 1 infants tire quickly during feeding and, if breast-fed, may begin to lose weight before it is evident that they are not taking in appropriate calories. Malnutrition and respiratory insufficiency exacerbate fatigue and cause susceptibility to aspiration. Any minor upper respiratory infection may quickly become a life-threatening crisis. The commonest cause of death is respiratory failure often preceded by several months of subtle changes due to complications associated with weakness. Neuropathological studies show evidence of neuronal loss in the ventral horn of the spinal cord, with degenerative features: chromatolysis, neuronophagia, and gliosis (Fig. 2.1A–E) (Osawa, 1991). SMA type 1 is caused by mutation or deletion in the telomeric copy of the SMN1 gene on chromosome 5q13. Two copies of SMN2 are typical for SMN type 1.

SMA type 3 Wohlfart-Kugelberg-Welander and mild SMA are synonyms for SMA type 3, which typically presents in late childhood or adolescence with proximal neurogenic muscular atrophy that may be confused with limb girdle muscular dystrophy (LGMD). The serum creatine kinase (CK) level is typically elevated. Patients with SMA type 3 usually achieve independent ambulation and remain ambulatory during part or all of their lives with a typical waddling gait, lumbar lordosis, genu recurvatum, and protuberant abdomen or stick man appearance. Although not always elicited, DTRs are almost never hyperactive. Six of 8 children described by Byers and Banker (1961) stood without assistance from 1 to 2 years of age, whereas only 2 ever walked without assistance. The prognosis for continued independent ambulation is correlated with age at onset. Children showing onset of weakness before age 2 were unlikely to continue ambulating after age 15 years. Onset after 2 years predicted ambulation into the fifth decade. SMA type 3 is caused by homozygous or compound heterozygous mutation in the SMN1 gene on chromosome 5q13. Patients with SMA type 3 generally have three or four copies of SMN2.

SMA type 4 Onset of SMA type 4 is not strictly defined and may overlap with type 3. Type 4 is an adult-onset condition. The clinical phenotype is mild. All motor milestones are achieved and ambulation is usually maintained throughout

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Fig. 2.1. (A–E) Neuropathology of SMA 1. The most important change seen in SMA 1 is degeneration and prominent loss of anterior horn cells, which correlates with the course of neurogenic muscular atrophy. Various stages of degeneration and chromatolysis (A, B, D) can be seen in the remaining neurons with a move of the nucleus from its central position, along with Nissl bodies that take on a crumbled appearance as the cytoplasm expands. Eventually, no Nissl bodies remain and the cytoplasm shrinks and disappears. Small glial cells gather around the shrunken neurons until they have completely disappeared (E) leaving behind empty cell beds in the anterior horn (C) (A, D, E: Hematoxylin and eosin,
20; B: Nissl,
40; C: Bielschowsky,
17). Reproduced from Osawa M (1991). Werdnig-Hoffmann disease and variants. Disease of the motor system, handbook of clinical neurology vol. 15: 51–80 with permission.

life. SMA type 4 is caused by mutation or deletion in the SMN1 gene on chromosome 5q13 and usually has four to eight copies of SMN2. Wirth et al. (2006) analyzed SMN2 copy number in 115 patients with SMA type 3 or SMA type 4 who had confirmed homozygous absence of SMN1 and found that 62% of SMA type 3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA type 3 patients with age of onset greater than 3 years had 4–5 SMN2 copies. Of the 4 adult-onset (SMA type 4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. The authors (Wirth et al., 2006) concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis. SMA type 4 is caused by mutation or deletion in the SMN1 gene on chromosome 5q13.

LABORATORY EVALUATION The laboratory evaluation of SMA has evolved with discovery of the underlying genetic defect. The diagnosis in a suspected patient can be ascertained by DNA analysis for the causative mutation or deletion at the 5q13.2 chromosome locus of the survival motor neuron genes SMN1 and SMN2, with SMN1 the primary disease-causing gene. Infants with homozygous deletions or truncation of exons 7 and 8 of SMN1 require no further workup. Although most patients have deletions in SMN, rare patients with duplication or heterozygous point mutations have been identified. If gene sequencing is normal, a more traditional approach is warranted that includes measurement of serum CK, which is usually normal in types 1 and 2 and elevated in type 3; nerve conduction studies (NCS) and needle electromyography (EMG)

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reveal the anticipated features of motor neuron disease (MND). The electrodiagnostic evaluation of SMA can be challenging because of small-sized limbs in children leading to relatively short distances between stimulus and recording electrodes, and profound muscle wasting that alters the reliability of motor NCS, which in SMA should remain normal (Iijima et al., 1991). Needle EMG shows evidence of acute denervation including fibrillation potentials and reinnervation in the form of large polyphasic motor unit potentials (MUPs) with reduced recruitment. In infants, EMG may be normal or suggest a primary myopathic process because of small amplitude, short duration, and polyphasic MUPs. Motor unit number estimation (MUNE), a methodology that assesses the number of motor neurons innervating a muscle group with utility in amyotrophic lateral sclerosis (ALS) (Bromberg, 1993), was applied to the ulnar nerve-hypothenar muscle group in 14 patients with SMA due to homozygous deletion in SMN1, including asymptomatic patients age 16 days to 45 years (Bromberg and Swoboda, 2002). The results included a fall in MUNE values to low levels early in the progression of weakness. Test–retest reliability showed consistent values making it a desirable methodology for following disease progression. The finding of progressive selective degeneration of motor neurons in SMA was similar to experimental mutant mice harboring a deletion at exon 7 in SMN1 (Ferri et al., 2004). Skeletal muscle biopsy is warranted when mutation analysis is uninformative. Skeletal muscle biopsy in affected patients shows large group atrophy of large type 1 myofibers and clumps of type 1 hypertrophic fibers that stain with ATPase with angulated fibers that increase with age from mid-childhood due to reinnervation.

GENETICS In 1990, Gilliam et al. (1990) linked SMA to chromosome 5q11.2-q13.3. By 1994, Melki et al. (1990, 1994) had assigned SMAI to 5q12-q13.3 and analyzed allele segregation at the closest genetic loci in more than 200 SMA families. The severe form of SMAwas statistically associated with deletion events. A year later, Thompson et al. (1995) identified several coding sequences unique to the SMA region. Lefebvre et al. (1995) identified the SMN gene within the SMA candidate region on chromosome 5q13 and demonstrated deletion or disruption of the gene in nearly all SMA patients so studied. That same year, Roy et al. (1995) identified a different gene at 5q13.1 encoding the neuronal apoptosis inhibitory protein (NAIP) at the first 2 coding exons of the gene. The latter was deleted in two-thirds of SMA I patients so studied compared to 2% of normal controls. This suggested that mutations in the latter locus resulted in failure of a normally occurring

inhibition of motor neuron apoptosis and contributed to the SMA phenotype. One year later, Matthijs et al. (1996) identified homozygous deletion of exon 7 of the SMN1 gene in 34 of 38 SMA patients so studied, as well as homozygous deletion of exon 8 in 31 patients. Other patients were reported with homozygous deletion of exon 7 but not exon 8 (Hahnen et al., 1996). A similar experience of homozygous absence of exons 7 and 8 of SMN1 was found in 90% of Spanish SMA kindreds (Alías et al., 2009). Jedrzejowska et al. (2008) later reported asymptomatic carriers of biallelic deletion of SMN1, all having 4 copies of the SMN2 gene, confirming that an increased number of SMN2 copies in healthy carriers of biallelic SMN1 deletion were an important phenotype modifier. The most valuable mouse model for SMA is referred to as the Delta 7 mouse, widely used for screening therapies. The genotype is Smn/;SMN2;SMND7. It simulates the clinical disease with a life span of 17 days with a median survival of 12 days. Experimental mutant NSECre+, SMnF7/F7 mice carrying an experimental deletion of the SMN exon 7 generated by crossing smnF7/F7 mice homozygous for the loxP-flanked SMN exon 7 with smnF7/+NSE-cre+ in the Cre recombinase specifying neuron specific enolase (NSE) underwent selective degeneration of motor neurons (Ferri et al., 2004). Other experimental animal models, including the wobbler mouse model of ALS (Kaupmann et al., 1992) and autosomal dominant (AD) canine SMA (Blazej et al., 1998), were phenotypically similar but molecularly distinct from human SMA. The SMN1 gene encodes the full-length 294 amino acid protein molecules necessary for lower motor neuron (LMN) function (Lefebvre et al., 1995), whereas the SMN2 gene encodes an SMN protein that lacks exon 7, thereby producing a less stable protein. When full-length SMN (fl-SMN) protein levels approach 23% of normal, LMN function is normal, whereas SMA is associated with lower SMN protein levels rather than its complete absence. Thus, individuals with SMA 1 have as little as 9% fl-SMN; SMA 2, 14%, SMA 3, 18%; and carriers 45%–55% of the normal fl-SMN protein. The presence of 3 or more copies of SMN2 leads to small amounts of fl-SMN transcripts that compensate for the lack of SMN1 expression, and to the less severe SMA 2 and SMA 3 phenotypes (Mailman et al., 2002).

OTHER FORMS OF SPINAL MUSCULAR ATROPHY Very severe SMA Very severe SMA phenotypes have been described in association with SMN1 at the 5q13 locus associated with reduced fetal movements in utero and severe weakness at birth (Macleod et al., 1999), fetal hypokinesia and asphyxia

CHILDHOOD SPINAL MUSCULAR ATROPHY and severe contractures (Devriendt et al., 1996), neurogenic arthrogryposis (B€ urglen et al., 1995; Bingham et al., 1997), and multiple contractures and bone fractures (García-Cabezas et al., 2004) at birth, suggesting a relation to SMA. Commenting on the 5 patients described by Macleod et al. (1999), Dubowitz (1999) considered the severe cases of SMA an expanding clinical phenotypic spectrum of prenatal onset and intrauterine death, with severe asphyxia at birth or early neonatal death that fit into the category of very severe SMA (type 0) and an extension of the previous severe SMA type 1. He suggested the decimal designation of 0.1–0.9 depending on whether there was early intrauterine death or viability at birth (Dubowitz, 1999). The presence of multiple joint contractures has been an exclusionary research criterion for SMA (Munsat and Davies, 1992).

SMA-plus types Even prior to SMN1 gene analysis, three categories of SMA-plus syndromes were excluded by the International SMA consortium in 1992 because of atypical features or additional organ involvement (Munsat and Davies, 1992), and subsequently none had informative SMN1 gene findings. Mellins et al. (1974), Bertini et al. (1989) described diaphragmatic SMA as a type 1 variant. In a series of more than 200 patients with early-onset SMA, RudnikSch€ oneborn et al. (1996) found that 1% presented with diaphragmatic SMA but did not have a deletion of the SMN gene at chromosome 5q. Affected infants presented with a weak cry, inspiratory stridor, and life-threatening respiratory distress due to diaphragmatic paralysis, followed later by distal weakness and wasting. The now known entity of SMA with respiratory distress type 1 (SMARD1) was further characterized by Grohmann et al. (1999, 2003) demonstrates autosomal recessive (AR) inheritance associated with mutation at the 11q13.3 locus of the IGHMBP2 gene encoding immunoglobulin m-binding protein 2. A second category of SMA-plus syndromes is X-linked SMA (SMAX) or Kennedy disease (SMAX1) of X-linked (XL) spinal and bulbar muscular atrophy. Kennedy et al. (1968) described nonlethal, slowly progressive bulbar and limb weakness, wasting, and fasciculation in men of average age 40 years with gynecomastia, dysphagia, and absent corticospinal, sensory, and cerebellar long tract signs. La Spada et al. (1991) identified an expanded CAG repeat in the first exon of the androgen receptor (AR) gene at the Xp12 locus. The AR CAG is normally polymorphic with an average of 22 repeats; however, patients with SMAX1 have 40–52 CAG repeats. Further investigation (La Spada et al., 1992) established the relation between disease severity and CAG repeat length.

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X-linked arthrogryposis (SMAX2) was the second XL SMA disorder described by Greenberg et al. (1988) manifesting X-linked hypotonia, areflexia, chest deformity, facial dysmorphic features, and congenital joint contractures with a disease course similar to SMA type 1. Later linkage and marker studies (Baumbach et al., 1994) of SMAX2 revealed causative deletion, missense, and C-to-T substitution mutation at the Xp11.23 locus of the UBE1 gene encoding ubiquitin-activating enzyme-1. Distal SMA (SMAX3) was the third X-linked disorder described by Takata et al. (2004) in a Brazilian family that manifested initial pes cavus and varus foot deformity followed by slowly progressive distal leg weakness and wasting, and later involvement of the hands; however, gait was maintained into late life without cognitive, corticospinal tract or sensory signs. A three-generation family of SMAX3 manifesting XL distal motor neuropathy was described by Kennerson et al. (2009) allelic to that reported by Takata et al. (2004), and mapped to the juvenile distal spinal muscular atrophy (DSMAX) gene at the Xq13.1-q21 chromosome locus. Kennerson et al. (2009) later identified disease-causing mutations at the Xq21.1 locus of the ATPase, Cu(2+)-transporting, alpha polypeptide (ATP7A) gene among affected members of the two families reported by Takata et al. (2004) and Kennerson et al. (2009). A third SMA-plus category is pontocerebellar hypoplasia (PCH) with infantile SMA. Pontocerebellar hypoplasia refers to abnormal growth and function of the brainstem and cerebellum resulting in little or no development. The combination of AR PCH and infantile SMA (PCH1) was first described by Norman (1961), and later by Chou et al. (1990), Barth (1993), Rudnik-Sch€oneborn et al. (2003), and Renbaum et al. (2009), and still later by Najmabadi et al. (2011). Early features include microcephaly, poor suck, lingual fasciculation, swallowing difficulty, and hypotonia, followed by limb ataxia, weakness, hyperreflexia, developmental delay, and mental retardation in surviving children. Neuroimaging disclosed cerebellar hypoplasia associated with cisterna magna and midline cerebellar atrophy. The disorder is due to homozygous missense mutations at the 14q32.2 chromosome locus of the vaccinia-related kinase 1(VRK1) gene. There are five different types (PCH2 to 6) based on the clinical and pathological changes. Type 1 has central and peripheral motor dysfunction associated with infantile SMA. Other types manifest microcephaly with extrapyramidal dyskinesia (PCH2); hyporeflexia, hyperreflexia, microcephaly, optic atrophy, and seizures (PCH3); hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death (PCH4); second trimester cerebellar and seizures (PCH5); and mitochondrial respiratory chain defects (PCH6) (Graham Jr. et al., 2010).

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ETIOPATHOGENESIS The exact function of the SMN protein is not well understood (Sumner, 2007). Reduced amounts of functional SMN protein are found in all cell types of patients with SMA, and messenger ribonucleic acid (mRNA) splicing is probably dependent on the abundance of SMN protein (Jablonka et al., 2000). Knockdown of the SMN protein in zebrafish causes defects in motor axonal outgrowth and pathfinding (Mcwhorter et al., 2003), and the SMN protein has an experimentally protective role for motor neurons against mutant superoxide dismutase 1 (SOD1) by increasing chaperone activity (Zou et al., 2007). Substantial progress has been made in understanding the molecular genetic aspects of SMA. This has been prompted by recognition that the disease phenotype is proportional to the amount of full-length SMN. In monumental terms, rarely encountered in a rare lethal disease, clinical investigation has envisioned several paths to improve outcome in SMA to increase expression of SMN protein levels and improve the life span of affected children including: enhancing transcriptional activity of SMN2 to increase full-length SMN RNA, translational activation and stabilization of full-length SMN protein, and the administration of neuroprotective or neurotrophic agents (Hirtz et al., 2005). Progress has also been made in identifying candidate genetic, epigenetic, proteomic, electrophysiological, and neuroimaging disease biomarkers to guide management (Kariyawasam et al., 2019).

SMN protein Circulatory biomarkers have garnered significant attention to date as tools for biomarker-guided therapy in SMA. Their role spans a spectrum from prognostication, to prediction of treatment response, to monitoring therapeutic effects. SMA is caused by insufficient levels of the SMN protein due to biallelic SMN1 deletion or mutation. The severity of SMA varies across a spectrum and is modified by the number of copies of the paralogous SMN2 gene in humans with the major difference conferred by a C to T nucleotide change in exon 7. This nucleotide change, though translationally silent, results in predominant skipping of exon 7 during SMN2 pre-mRNA splicing, giving rise to a truncated transcript and protein. Alternative splicing enables 10% of SMN2 transcripts to include exon 7 and produce a small amount of functional SMN. SMN RNA and protein are ubiquitously expressed and have multiple roles in normal biological processes. These include cell-specific roles in ribonucleoprotein assembly, RNA metabolism, macromolecular trafficking, actin dynamics, and signal transduction. Alterations at any

level of transcription, translation, or splicing can lead to dysregulation of pathways involved in SMN protein production and potentially modified disease phenotypes. Posttranslational modification of SMN highlights phosphorylation in the regulation of multiple functions and processes, including activity, cellular trafficking, and stability (Detering et al., 2022). SMN protein levels are also dependent on degradation pathways. As such, the pathogenesis of SMA has been linked to mutations in the ubiquitin-activating enzyme (UBA1) gene encoding UBA1. It plays a crucial role in the ubiquitin proteasome system (UPS). UPS makes it a potential therapeutic target for SMA to regulate SMN protein levels. Previous studies showed that pharmacological inhibition of the proteasome and UPS downstream targets led to phenotypic improvements in SMA mice and identified an important role of SMN in the maintenance of ubiquitin homeostasis with decreased levels of UPS as a driving factor in SMA pathogenesis (Matthijs et al., 1996). There is a need for future studies to evaluate if different aspects of the UPS that are perturbed in SMA could act as potential drug targets independently or in combination with other SMN-dependent strategies. With this clarification, ubiquitin pathways may in the future be proposed as putative mechanistic biomarkers of pharmacodynamic response to SMNenhancing therapies. The SMN protein is an obvious pharmacodynamic biomarker that can be measured from biological samples. This is aligned with therapeutic approaches designed to increase SMN levels. For example, preliminary data from clinical trials evaluating risdiplam, a small molecule that modifies SMN2 premessenger RNA (pre-mRNA) splicing, showed a two- to threefold increase in SMN protein in SMA type 1 infants (Poirier et al., 2018; Baranello et al., 2021). Validation of the importance of SMN levels was the observation in this same patient population that 1- to 7-month-old patients achieved milestones not previously seen. At 12 months of risdiplam treatments, 12 infants (29%) were able to sit without support for at least 5 s and CHOP-INTEND scores reached 40 or higher in 90% of participants as compared to 17% of historical controls (Darras et al., 2021). These studies support potential methods of tracking functional outcomes in molecular therapy of SMA. Similar results have been seen with salbutamol, a compound that increases SMN2 full-length transcript and SMN protein (Angelozzi et al., 2008). In this study, a subjective improvement of motor function was noted in all patients with a statistically significant improvement in validated functional scores in a proportion of patients. This suggests target engagement and a potential method of tracking treatment response. Future studies are needed

CHILDHOOD SPINAL MUSCULAR ATROPHY to determine the utility of SMN protein levels as a biomarker to guide dose optimization or frequency of the therapeutic regime.

Neurofilaments

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not always possible to predict phenotype by SMN2 copy number (Calucho et al., 2018). Despite its potential limitations as a biomarker of disease onset and prognosis, SMN2 copy number acts in a dose-dependent manner to ameliorate the SMA phenotype. In observational studies, those with higher copy numbers do not always have a mild disease phenotype (Darras and De Vivo, 2018). Considerable overlap in copy number exists among phenotypic subgroups of patients with SMA (Calucho et al., 2018). Furthermore, discordance in phenotype and response to therapy is noted in siblings with the same copy number, showing that there are other modifiers of disease at work in these individuals. For example, sequence variations within the SMN2 gene may positively modify phenotype, particularly the c.859G > C variant, which increases inclusion of exon 7 and the amount of the full-length SMN transcript (Bernal et al., 2010). The latter is being used to stratify data analysis in current clinical trials (NCT03505099). Additional variants in SMN2 introns 6 and 7 have been shown to alter the incorporation of exon 7 (Wu et al., 2017). Intron 6 variants (A-44G, A-549G, and C-1897T) have also been associated with milder SMA phenotypes in further studies (Ruhno et al., 2019).

Neurofilaments (NF) are cytoplasmic proteins abundantly expressed in axons that are promising diagnostic, prognostic, and monitoring biomarkers in a range of neurological disorders associated with axon loss. Initial studies focused on modulation of SMN2 encoded transcripts in children with SMA identifying NFs as potential biomarkers of disease activity and therapeutic response (Darras et al., 2019). Across large nusinersen clinical trials with SMA types 1, 2, and presymptomatic infants (2 or 3 SMN2 copies), plasma phosphorylated neurofilament heavy chain (pNF-H) differentiated SMA individuals from healthy controls. However, a small number of healthy pediatric age-matched controls limited conclusions. Treatment initiation with nusinersen was associated with rapid decline followed by stabilization of pNF-H at levels close to those of healthy controls. PNF-H declined with advancing age in untreated patients, possibly due to reductions in the motor neuron pool or disease activity. This raises uncertainty about its ability to demarcate whether the decline is due to physiological aging or a surrogate marker for treatment response. Serum neurofilament light chain (NfL) levels have also been evaluated in clinical trials investigating the safety and efficacy of branaplam, a small-molecule RNA splicing modulator. Preliminary results identified an inverse correlation between pretreatment NfL levels and motor function scores in participants with SMA type I (Jullien De Pommerol et al., 2018). It is not yet clear which proteins released from motor neurons (NfL, Nf-H, or others) will be more sensitive in detecting the earliest stages of degeneration. These may have utility in the “presymptomatic” patient, helping guide decisions regarding when to start treatment. In addition, these may serve as pharmacodynamic markers, to verify suppression of continuing degeneration. Further evaluation of NFs across SMA populations and evaluation of potential correlations with efficacy outcomes is required.

Aberrant splicing plays a significant role in SMA pathogenesis. Consequently, the development of biomarkers that accurately capture splicing events would greatly advance understanding of the control of SMN gene expression. Splicing regulators such as microRNA (miRNA), epigenetic modifications, and long noncoding RNA (lncRNA) have emerged as putative biomarkers. MicroRNA regulates gene expression. Studies show their potential as noninvasive biomarkers in SMA (Catapano et al., 2016). Differential expression of miRNAs (miR-9, miR-206, and miR-132) in spinal cord, skeletal muscle, and serum from SMA and control mice is related to differing clinical severity (severe SMA-mild SMA 3 and 1) and disease stages (presymptomatic, midsymptomatic, and late stage).

SMN2 copy number

Epigenetic modifications: Methylation

The SMN2 copy number is the most important modifier of the clinical course in SMA, correlating inversely with age of symptom onset and severity, albeit with limitations in precision. Epidemiological studies demonstrate that more than 95% of individuals with 2 copies of SMN2 have SMA type 1 with symptom onset in the first 6 months of life. Furthermore, 2 copies of SMN2) (Kolb et al., 2017). In comparison to clinical measures of strength, fatigue, and contractures, MUNE assesses the number of axons and the capacity for reinnervation as represented by the size of the average single MUP (SMUP) and the related electrophysiology (Gawel et al., 2015). MUNE values appear to be highly dependent on, yet inversely related to, disease duration in untreated SMA patients;

however, stability in the chronic phase may be apparent for many individuals. While SMA is considered a primary neurogenic process, it is increasingly recognized that it is associated with concomitant dysfunction at the level of the neuromuscular junction (NMJ) secondary to lack of the SMN protein required for normal NMJ development and maturation. Abnormalities in NMJ impulse transmission may be responsible for significant degrees of fatigability commonly reported by affected individuals (Pera et al., 2017), and clinically observed when using validated measures of endurance such as the 6-min walk test (Montes et al., 2010). Therefore, an electrophysiological biomarker such as repetitive nerve stimulation (RNS) to determine the presence and extent of NMJ dysfunction facilitates a different modality of looking at pathophysiology and response to novel therapies. In a recent study of SMA cohorts, a pathological decrement on lowfrequency RNS was noted in 49% of patients with SMA but not in healthy controls or patients with other motor neuron diseases (Wadman et al., 2012). This decrement was independent of SMA subgroup, clinical score, and disease duration.

Neuroimaging Magnetic resonance imaging (MRI) of skeletal muscle has been used in small numbers of preclinical and clinical studies to provide alternative markers of disease. Muscle composition changes with disease duration in SMA (Durmus et al., 2017). Changes in parameters such as muscle fat fraction correlate well with validated functional motor scores in non-SMA motor neuropathies and are highly sensitive to disease progression. Ultrasound (US) offers a different modality for assessment of muscle composition in patients with motor neuropathies. Muscle thickness and echo intensity have been reviewed to a limited extent in ALS, where one study showed use in prognosticating survival (Arts et al., 2011). Longitudinal studies note a reduction in the hand muscle cross-sectional area in ALS disease cohorts (Schreiber et al., 2016), but these changes correlate poorly with functional abilities and may therefore not be a sensitive representative of disease progress. Significant work needs to be done before MRI or US can be purported as a suitable method for producing viable biomarkers in SMA.

MANAGEMENT SMA directly causes muscle weakness, leading to numerous downstream complications, many of which are amenable to supportive care that has been outlined in standard-of-care consortia (Wang et al., 2007) and consensus reports of SMA Care experts (Finkel et al.,

CHILDHOOD SPINAL MUSCULAR ATROPHY 2018; Mercuri et al., 2018b). Respiratory treatment with bilevel positive airway pressure (BiPAP) support when appropriate, orthopedic deformities, and nutritional support make a meaningful difference in clinical outcome (Swoboda et al., 2005; Oskoui et al., 2007), notwithstanding addressing the prevention and treatment of the expected complications (Eng et al., 1984) of restrictive lung disease, poor nutrition, osteopenia, orthopedic deformities, immobility, and psychosocial problems. Restrictive lung disease results from weakness of intercostal muscles and diaphragm, causing hypoventilation and weak cough. Aggressive prophylaxis against pneumonia and atelectasis may include assisted cough, chest percussion therapy, and intermittent positive pressure breathing can be used together to provide adequate airway clearance. Mechanical in-exsufflation is a safe, well-tolerated, and effective modality for those with impaired cough (Miske et al., 2004) and in others to maintain adequate pulmonary toilet to prevent progressive atelectasis (Bach, 1994). With aggressive ventilator support, the life expectancy and quality of life of children with neuromuscular disease has improved remarkably in the last 2 decades (Wallgren-Pettersson et al., 2004). Noninvasive ventilation is successful in children with sleep hypoventilation and hypercapnia (Manzur et al., 2003). The risk of pneumonia increases as forced vital capacity (FVC) decreases without a significant change in limb or trunk strength. Influenza and pneumococcal vaccination should be offered to all patients. COVID19 vaccination is now offered for ages 6 months and older as advised by the primary care physician. Poor nutrition with failure to thrive occurs because of a weak suck, unprotected airway, and easy fatigability. A team of occupational therapists should do a feeding evaluation and speech therapists and dieticians should adjust the feeding schedule, and reposition during feedings, and adjust food textures to maximize caloric intake. If necessary, the child should be examined during a modified barium swallow using several food textures, including liquid, semiliquid, soft, and solid food. If aspiration occurs, a gastrostomy may be necessary for supplemental gastrostomy feedings. Constipation is common, noted because of immobility, but responds to increasing fluid and fiber intake. Scoliosis is a serious orthopedic problem in patients with SMA (Shapiro and Specht, 1993), and nonambulatory children tend to develop spinal deformities earlier than those who are still ambulatory. The goal of spinal surgery is to maximize growth before surgery. Clubfoot deformity may be a presenting feature of infantile SMA. Walking can be facilitated by lightweight orthoses for the legs, although it will likely be a temporary device (Russman et al., 1996). Power chairs prescribed before the second birthday can provide independent mobility

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at an appropriate developmental age (Siegel and Silverman, 1984), and the high cognitive function of most patients allows them to maneuver a joystick (Whelan, 1987). School-aged children generally benefit from a full-time aid to assist in toileting, feeding, and maintenance of physical, occupational, and respiratory therapy regimens during the school day. Psychometric evaluation can be performed starting at an early age, even by age 4.

NATURAL HISTORY AND PROGNOSIS Until recently, the prognosis for the individual form and type of SMA appeared to be set in stone. An observational study of SMA type 1 (Finkel et al., 2014) provided a look into the natural history and examined methodologic parameters for clinical trial design. Altogether, 50% of 34 enrolled subjects completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 h/day of ventilation support was 13.5 months (interquartile range 8.1–22.0 months). The requirement for nutritional support preceded that for ventilation support. The distribution of age reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before and after 3 months of age. Two 2 copies of SMN2 were associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures of CMAP and MUNE indicated substantial motor neuron loss. By comparison, subjects with SMA type II who lost sitting ability had higher motor function, MUNE and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. Motor status, as measured by a 64-point scale shown to be reliable and sensitive to change over time for SMA type 1 (Glanzman et al., 2010), showed a steady decline in all subjects. The investigators found that SMN2 copy number was associated with severity of disease and with the time to reach the combined endpoint. There were a series of recommendations, such as limiting a clinical trial to subjects with a copy number of 2 would yield a higher number of participants reaching the combined endpoint. It would therefore seem useful to stratify by SMN2 copy. Prior to approval for newborn screening, now available in 48 states, enrollment at early stages of disease, when treatment is potentially more beneficial, was challenging. SMA subjects tolerate extensive testing with appropriate rest periods. For natural history studies, repeat testing can be variable for the subjects with SMA type 1 who miss many study visits because of illness. To maximize retention, study visits could be minimized with the use of remote assessments. Multiple pulmonary-related adverse events and minor laboratory abnormalities should be anticipated in an

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intervention study. SMN2 copy number serves as a predictive biomarker potentially useful for stratification.

DISEASE-MODIFYING MOLECULAR THERAPY The outcome of SMA has mainly been affected by a robust drug development pipeline involving several different therapeutic strategies evolving over the last decade resulting in effective disease-modifying therapy (DMT).

Nusinersen, antisense oligonucleotide treatment to promote full-length SMN protein The first such drug to receive FDA licensing approval (Biogen December, 2016) was the intrathecally injectable drug nusinersen that modified splicing of premessenger RNA producing full-length SMN protein. Three clinical trials supported efficacy using this approach including The ENDEAR (ClinicalTrials.gov number, NCT02193074) (Finkel et al., 2017), CHERISH (ClinicalTrials.gov number, NCT02292537) (Mercuri et al., 2018a), and NUTURE (ClinicalTrials.gov number, NCT02386553) (De Vivo et al., 2019) Study Groups. Treatment with nusinersen in the phase 3 efficacy and safety sham-controlled ENDEAR study of infants age 6 months or younger with 2 copies of the SMN2 (Finkel et al., 2017) demonstrated that a higher percentage in the nusinersen group than in the control group had a motor-milestone response [37 of 73 infants (51%) vs 0 of 37 (0%), P < 0.001] on the Hammersmith Infant Neurological Examination (HINE), Section 2 (HINE-2). This testing included eight items: voluntary grasp, ability to kick, head control, rolling, sitting, crawling, standing, and walking. Based on this outcome, nusinersen predicted a higher overall survival and prompted early termination of the trial. In a later onset SMA group [>6 months of age (Mercuri et al., 2018a)], a double-blind, shamcontrolled, phase 3 trial (CHERISH) of 126 SMA children, nusinersen treatment demonstrated improvement in motor function compared to controls. The primary endpoint for this study was the least-square mean change from baseline in an expanded Hammersmith Functional Motor Scale-Expanded (HFMSE) scale. At 15 months posttreatment, there was a least-square mean increase in the nusinersen group by 4.0 points compared to a decrease in the control group of 1.9 points (least-squares mean difference of 5.9 points; 95% confidence interval, 3.7–8.1; P < 0.001). This result again prompted early termination of the study. Subsequently, nusinersen showed further benefit in a phase 2, open-label, single-arm, multicenter, doseescalation study. When first presented, the study was ongoing. The NUTURE trial (De Vivo et al., 2019)

included 25 children prior to onset of symptoms of SMA. Interim results as reported favored efficacy and safety. At the completion of the trial, the final results at 36.2 months (Finkel et al., 2021) provided a comprehensive detailed analysis of the longitudinal clinical benefit of nusinersen. The end-of-study efficacy and safety findings were consistent with the interim results (De Vivo et al., 2019). Steady improvements and attainment of developmental motor milestones and motor function continued through the final study visit and beyond 2 years of age. Nusinersen is commercially available for SMA treatment. The drug is well tolerated. There is also evidence that adults with SMA type 3 can benefit. In a clinical trial, motor function in ambulatory and nonambulatory adults with SMA showed 2-point improvement in both the HFMSE and Revised Upper Limb Measure (RULM) after 12 months of treatment (Yeo et al., 2020). This is particularly relevant since nusinersen might be preferred in older patients compared to gene therapy. The older SMA patients may be more likely to have preexisting AAV antibodies that would preclude gene delivery. Nusinersen has a relatively low side effect profile. The most common adverse events include pyrexia, headache, and vomiting as part of a postlumbar puncture syndrome. This is a minimal deterrent to its clinical use.

Onasemnogene Gene therapy for SMA designed to deliver and replace the mutant SMN gene was based on two key preclinical observations: the SMND7 mouse model that simulated the clinical phenotype of type 1 SMA patients (Angelozzi et al., 2008) and AAV9 was shown to target neonatal neurons following intravascular delivery (Foust et al., 2009). Self-complementary (sc)AAV9 infused on day 1 rescued the SMND7 mice from early death and defined the dose for the clinical trial. The first clinical trial (START) initially enrolled SMA type 1 subjects with 2 copies of SMN in 2014 (Mendell et al., 2017). This was a doseescalation trial with the primary outcome safety and the secondary outcome time to death or need for permanent ventilatory assistance (reported for >90% SMA at 20 months) (Finkel et al., 2014). CHOP-INTEND scores enabled assessment of motor function during the trial. In all, 15 patients were enrolled in this single, one-time, intravenous dosing of scAAV9.CB.SMN (AVXS-101). Cohort 1 included three SMA type 1 infants (mean age 6.3 months). A serious adverse event was encountered in patient 1 of the trial. An elevation of aspartate aminotransferase (AST) reaching 14 X ULN had a profound effect on this trial. Prednisolone was used to suppress the liver toxicity and the protocol was amended so that all subsequent patients enrolled were treated with oral

CHILDHOOD SPINAL MUSCULAR ATROPHY prednisolone, 1 mg/kg/day, starting 24h before gene delivery and continued for 30 days. A second cohort was introduced (n ¼ 12) and received a higher dose of vector. The mean age of SMA participants was also younger (mean age 3.4 months). By August 2017, patients in both cohorts reached age 20 months without need for permanent mechanical ventilation, a significant milestone compared to historical controls (Finkel et al., 2014). Other notable improvements included 11 of 12 patients in cohort 2 able to speak, able to sit independently, and all increased their baseline CHOP-INTEND scores. There was an obvious age-related efficacy most dramatically illustrated as the oldest patient in the trial showed virtually no clinical benefit while the youngest participants achieved the highest CHOP-INTEND scores (C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor. J Med Genet 47: 640–642. Bertini E, Gadisseux JL, Palmieri G et al. (1989). Distal infantile spinal muscular atrophy associated with paralysis of the diaphragm: a variant of infantile spinal muscular atrophy. Am J Med Genet 33: 328–335.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00022-3 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 3

The hereditary spastic paraplegias JOHN K. FINK* Department of Neurology, University of Michigan, Ann Arbor, MI, United States

Abstract The hereditary spastic paraplegias (HSPs) are a group of more than 90 genetic disorders in which lower extremity spasticity and weakness are either the primary neurologic impairments (“uncomplicated HSP”) or when accompanied by other neurologic deficits (“complicated HSP”), important features of the clinical syndrome. Various genetic types of HSP are inherited such as autosomal dominant, autosomal recessive, X-linked, and maternal (mitochondrial) traits. Symptoms that begin in early childhood may be nonprogressive and resemble spastic diplegic cerebral palsy. Symptoms that begin later, typically progress insidiously over a number of years. Genetic testing is able to confirm the diagnosis for many subjects. Insights from gene discovery indicate that abnormalities in diverse molecular processes underlie various forms of HSP, including disturbance in axon transport, endoplasmic reticulum morphogenesis, vesicle transport, lipid metabolism, and mitochondrial function. Pathologic studies in “uncomplicated” HSP have shown axon degeneration particularly involving the distal ends of corticospinal tracts and dorsal column fibers. Treatment is limited to symptom reduction including amelioration of spasticity, reducing urinary urgency, proactive physical therapy including strengthening, stretching, balance, and agility exercise.

INTRODUCTION1 The hereditary spastic paraplegias (HSPs) are a large group of genetic disorders, many of which have markedly different clinical presentations that share the common feature of lower extremity spasticity and weakness, each of variable magnitude and proportion. Spastic paraparesis (typically accompanied by urinary urgency) may exist alone (“uncomplicated HSP”); may predominate the clinical presentation yet be accompanied by other neurologic impairments (“complicated HSP”); or may be an element of a more complex neurodegenerative or neurodevelopmental disorder. More than 90 types of HSP have been described, each due to mutations in a different gene. Our understanding of the HSPs is advancing rapidly. We are learning, for example, that a number of genetic types of HSP (e.g., SPG7 HSP due to mutations in the paraplegin gene; see Table 3.1) may be transmitted as

either autosomal dominant (AD) or autosomal recessive (AR) traits. Increasingly, we are learning that other neurologic syndromes (particularly those manifesting as spinocerebellar ataxia) may be due to mutations in genes identified as causing HSP. The reader is referred to the Online Mendelian Disorders in Man (OMIM) (www. omim.org) for updates. Clinical information for patients and their families is available at the National Organization of Rare Disorders (www.nord.org) and the Spastic Paraplegia Foundation (www.sp-foundation.org). This review focuses on aspects of HSP that are important for the practicing neurologist, describing clinical features, diagnostic evaluation, genetic types, treatment approach, and the pathologic basis. See Refs. (Engelen et al., 2012; Fink, 2013; Elsayed et al., 2021; Martinuzzi et al., 2021) for a discussion of diverse molecular mechanisms underlying the HSPs and for additional reviews.

1

Abbreviations used in the chapter are listed at the end of the chapter before References section.

*Correspondence to: Dr. John K. Fink, MD, NCAC, Neurology, 2901 Hubbard Dr. Suite 2723, Ann Arbor, MI 48109-2435, United States. Tel: +1-734-9369010, Fax: +1-734-6154991, E-mail: [email protected]

Table 3.1 Genetic types of HSP, their encoded proteins, and clinical syndromes (updated from Refs. Fink, 2019; Elsayed et al., 2021) Inherited as either autosomal dominant (heterozygous mutation) or autosomal recessive (homozygous or compound heterozygous mutation) disorder Spastic gait (SPG) locus and OMIM numbera SPG7 607259 SPG9A 601162

SPG9B (AR) 616586

SPG18 611225

Protein Paraplegin

Clinical syndrome

Uncomplicated or complicated: variably associated with mitochondrial abnormalities on skeletal muscle biopsy and dysarthria, dysphagia, optic disc pallor, axonal neuropathy, and evidence of “vascular lesions,” cerebellar atrophy, or cerebral atrophy on cranial MRI ALDH18A1 Adolescent- to adult-onset spastic paraplegia with various additional features including, ocular abnormalities (for example, cataracts or chorioretinal dystrophy), motor neuropathy, ataxia, spastic dysarthria, cognitive impairment, short stature, developmental delay, and skeletal abnormalities (including dysplastic skull base, delayed bone age, shallow acetabulum, and small carpal bones) ALDH18A1 Childhood-onset marked spastic paraplegia, variably involving upper extremities; associated with marked intellectual disability, microcephaly, variable facial dysmorphism; neuroimaging imaging (one patient) showed atrophy of the corpus callosum, periventricular white matter abnormalities, and mild cortical atrophy ERLIN2 Spastic paraplegia complicated by mental retardation and thin corpus callosum. Endoplasmic reticulum, lipid raft associated protein 2 (ERLIN2) mutations also identified in subjects with juvenile primary lateral sclerosis

SPG30 610357

KIF1A

SPG58 611302

KIF1C

SPG72 615625

REEP2

References DeMichele et al. (1998); Garner et al. (1990) Seri et al. (1999); Meijer et al. (2004); Panza et al. (2016); Coutelier et al. (2015); Slavotinek et al. (1996) Horibata et al. (2018)

Al-Yahyaee et al. (2006); Alazami et al. (2011); Al-Saif et al. (2012); Yildirim et al. (2011); Rydning et al. (2018) Complicated: spastic paraplegia, distal wasting, saccadic ocular pursuit, peripheral neuropathy, mild Klebe et al. (2006); Esteves et al. cerebellar signs (2014); Erlich et al. (2011) Spastic-Ataxia. Subjects described from four, unrelated consanguineous kindreds: following normal Dor et al. (2014); Novarino et al. development, progressive ataxia began between ages 1 and 17 years and was associated with (2014); Caballero et al. (2014) lower extremity spasticity which was nonprogressive. MRI in one subject showed some evidence of demyelination of posterior limb of internal capsule and occipital cortex; and cerebellar and cortical atrophy in another, unrelated subject. Subjects in one family had short stature and microcephaly. Subjects in another family had chorea, developmental delay, and cognitive impairment Note: subjects who have heterozygous, pathogenic KIF1C mutations may have mild symptoms (consistent with autosomal dominant inheritance Uncomplicated spastic paraplegia manifesting as childhood onset (infancy to age 8 years) of toe Esteves et al. (2014) walking or progressive spastic gait. Two of ten subjects had upper extremity spasticity. Cognition, speech, and vision were normal. REEP2 mutations may cause both autosomal dominant HSP (due to heterozygous mutation); or autosomal recessive HSP due to compound heterozygote mutations

Autosomal dominant HSP Spastic gait (SPG) locus Protein and OMIM numbera SPG3A 182600

SPG4 182601

SPG6 600363

SPG8 603563

SPG10 604187 SPG12 604805 SPG13 605280

SPG17 270685 SPG19 607152 SPG29 609727 SPG31 610250

Clinical syndrome

References

Atlastin (ATL1)

Uncomplicated HSP: symptoms usually begin in childhood (and may be nonprogressive); Khan et al. (2014); Zhao et al. symptoms may also begin in adolescence or adulthood and worsen insidiously. Rarely (2001); Hazan et al. (1993); presents in infancy with generalized hypotonia, feeding difficulty, growth failure, and Paternotte et al. (1998); upper extremity involvement. Genetic nonpenetrance reported. De novo mutation Haberlová et al. (2008); reported presenting as spastic diplegic cerebral palsy Yonekawa et al. (2014) One family reported with autosomal recessive inheritance (Khan et al., 2014) Spastin Uncomplicated HSP, symptom onset in infancy through senescence, single most common Hazan et al. (1994); Roll-Mecak and cause of autosomal dominant HSP (
40%); some subjects have late-onset cognitive Vale (2005); Charvin et al. (2003); impairment Evans et al. (2005); Hentati et al. (1994) Rare subjects have infantile onset generalized hypotonia followed by quadriparesis Not imprinted in Prader Uncomplicated HSP: prototypical late-adolescent, early-adult onset, slowly progressive Rainier et al. (2003); Fink et al. Willi/Angelman 1 uncomplicated HSP (1995,b); Chen et al. (2005); (NIPA1) Rarely complicated by epilepsy or variable peripheral neuropathy. One subject with Martinez-Lage et al. (2012); uncomplicated HSP later died from amyotrophic lateral sclerosis Svenstrup et al. (2013); Du et al. (2011) KIAA0196 Uncomplicated HSP, prototypical adult-onset slowly progressive uncomplicated HSP Hedera et al. (1999,b); Reid et al. (Strumpellin) (2000); Valdmanis et al. (2007); Bian et al. (2011) Kinesin heavy chain Uncomplicated HSP or complicated by distal muscle atrophy. Reid et al. (1999); Fichera et al. (KIF5A) (2004) Reticulon 2 (RTN2) Uncomplicated HSP Reid et al. (2000); Montenegro et al. (2012) Uncomplicated HSP: adolescent and adult onset Chaperonin 60 (heat Fontaine et al. (2000); Hansen et al. shock protein 60, (2002); Bross et al. (2008) HSP60) BSCL2/seipin Complicated: spastic paraplegia associated with amyotrophy of hand muscles (Silver Patel et al. (2001); Auer-Grumbach syndrome) et al. (2005); Windpassinger et al. (2004) Unknown Uncomplicated HSP Valente et al. (2002) Unknown Complicated: spastic paraplegia associated with hearing impairment; persistent vomiting Ashley-Koch et al. (2005) due to hiatal hernia inherited Uncomplicated HSP or occasionally associated with peripheral neuropathy Receptor expression Zuchner et al. (2006,b); Beetz et al. enhancing protein 1 (2008) (REEP1) Continued

Table 3.1 Continued Autosomal dominant HSP Spastic gait (SPG) locus and OMIM numbera Protein SPG33 610244 SPG36 613096 SPG37 611945 SPG38 612335 SPG40 SPG41 613364 SPG42 612539 SPG73 616282 615290

Clinical syndrome

References

ZFYVE27/protrudin}

Uncomplicated HSP

Mannan et al. (2006)

Unknown Unknown Unknown

Onset age 14–28 years, associated with motor sensory neuropathy Uncomplicated HSP One family, 5 affected subjects, onset age 16–21 years. Subjects had atrophy of intrinsic hand muscles (severe in one subject at age 58) Uncomplicated spastic paraplegia, onset after age 35, known autosomal dominant HSP loci excluded Single Chinese family with adolescent onset, spastic paraplegia associated with mild weakness of intrinsic hand muscles Uncomplicated spastic paraplegia reported in single kindred, onset age 4–40 years, possibly one instance of incomplete penetrance Single, 3-generation family reported in which 5 affected subjects had autosomal dominant uncomplicated spastic paraplegia beginning in adulthood (age range: 19–48) Two mutation-associated phenotypes have been reported: autosomal dominant, congenital spinal muscular atrophy; and autosomal dominant adult onset, progressive spastic paraplegia Single, 3-generation family reported in which 5 affected subjects had autosomal dominant uncomplicated spastic paraplegia beginning in adulthood (age range: 19–48) Childhood- through adulthood-onset progressive spastic gait associated with upper extremity involvement (one patient), variable cerebellar involvement (two families). Reported in 14 ethnically diverse kindreds TUBB4A mutation has presented as childhood-onset, slowly progressive spastic paraparesis associated with mild cognitive impairment and mild hypomyelinating leukodystrophy. Mutations in TUBA4 are also associated with autosomal dominant, hypomyelinating leukodystrophy type 6 (MIM: 612438) and autosomal dominant torsion dystonia (DYT4, MIM: 128101) Childhood-onset intellectual impairment and progressive spastic paraparesis and ataxia. KCNA2 mutations also cause episodic ataxia type 1 (EA1, 160120) and early infantile epileptic encephalopathy (MIM: 616366)

Schule et al. (2009) Hanein et al. (2007) Orlacchio et al. (2008)

Unknown Unknown Acetyl CoA transporter (SLC33A1) CPT1C BICD2

SPG73 616282 SPG80 618418

CPT1C

612438a 128101a

TUBB4A

160120a 616366a

KCNA2

UBAP1

Subramony et al. (2009) Zhao et al. (2008) Lin et al. (2008, 2010); Schlipf et al. (2010) Rinaldi et al. (2015) Oates et al. (2013)

Rinaldi et al. (2015) Farazi Fard et al. (2019); Lin et al. (2019) Pizzino et al. (2014); Hersheson et al. (2013); Sagnelli et al. (2016)

Manole et al. (2017); Bayrakli et al. (2015)

601042a 606777a 612126a

SLC2A1

606482a 160150a 615368a

DNM2

Unknown

Two unrelated subjects with childhood onset initially progressive spastic gait (subsequently Bawazir et al. (2012); Nicita et al. non-progressive) were discovered to have heterozygous potentially pathogenic de novo (2019); Verrotti et al. (2019); SLC2A1 mutations. Seizures occurred in one subject Weber et al. (2011); Wang et al. (2005) SLC2A1 mutations cause autosomal dominant paroxysmal choreoathetosis associated with spastic paraplegia (dystonia type 9, MIM: 601042) and autosomal dominant and autosomal recessive GLUT1 deficiency syndromes (MIM: 606777. 612126) and Stomatin-deficient cryohydrocytosis with neurologic defects, a complex autosomal dominant neurologic disorder delayed psychomotor development, seizures, cataracts, hemolytic anemia, and pseudohyperkalemia (reviewed in Ref. Bawazir et al., 2012) Nine subjects in a four-generation Siberian kindred exhibited young-adult onset progressive Sambuughin et al. (2015) spastic paraplegia associated with mild motor-sensory axonal neuropathy Note that dynamin mutations are also associated with Charcot-Marie-Tooth neuropathy (MIM: 606482) and centronuclear myopathy (MIM: 160150), and lethal congenital contracture syndrome (MIM: 615368) Five individuals in a 3-generation family are described with distal arthrogryposis (affecting Hedera et al. (2018) hands and feet) and childhood-onset toe-walking, followed by adult-onset, progressive spastic gait and episodic rhabdomyolysis

Autosomal recessive HSP Spastic gait (SPG) locus Protein and OMIM numbera SPG5 270800

CYP7B1

SPG11 604360

Spastacin (KIAA1840)

SPG14 605229

Unknown

SPG15 270700

Spastizin/ZFYVE26

Clinical syndrome

References

Uncomplicated or complicated by axonal neuropathy, distal or generalized muscle atrophy, Hentati et al. (1994); Muglia et al. and white matter abnormalities on MRI (2004); Tang et al. (2004); Wilkinson et al. (2003); Tsaousidou et al. (2008); Criscuolo et al. (2009); Biancheri et al. (2009) Uncomplicated or complicated: spastic paraplegia variably associated with a thin corpus Martinez-Murillo et al. (1999); callosum, mental retardation, upper extremity weakness, dysarthria, and nystagmus; may Winner et al. (2004) have “Kjellin syndrome”: childhood-onset, progressive spastic paraplegia accompanied by pigmentary retinopathy, mental retardation, dysarthria, dementia, and distal muscle atrophy; juvenile, slowly progressive ALS reported in subjects with SPG11 HSP; 50% of autosomal recessive HSP is considered to be SPG11 Single consanguineous Italian family, three affected subjects, onset age
30 years; Vazza et al. (2000) complicated spastic paraplegia with mental retardation and distal motor neuropathy (sural nerve biopsy was normal) Complicated: spastic paraplegia variably associated with pigmented maculopathy, distal Hughes et al. (2001); Hanein et al. amyotrophy, dysarthria, mental retardation, and further intellectual deterioration (Kjellin (2008) syndrome) Continued

Table 3.1 Continued Autosomal recessive HSP Spastic gait (SPG) locus and OMIM numbera Protein SPG20 607211

SPG21 248900 SPG23 270750

SPG24 607584 SPG25 608220

SPG26 609195

SPG27 609041

SPG28 609340

SPG32 611252 SPG35 612319

SPG39 612020

Spartin

Clinical syndrome

References

Complicated: spastic paraplegia associated with distal muscle wasting (Troyer syndrome) Crosby et al. (2002); Cross & McKusick (1967); Patel et al. (2002); Proukakis et al. (2004); Lu et al. (2006) Maspardin Complicated: spastic paraplegia associated with dementia, cerebellar and extrapyramidal Simpson et al. (2003) signs, thin corpus callosum, and white matter abnormalities (Mast syndrome) DSTYK Complicated: childhood onset HSP associated with skin pigment abnormality (vitiligo), Blumen et al. (2003); Lee et al. premature graying, characteristic facies. and variable neuropathy (Lison syndrome). (2017); Sanna-Cherchi et al. Mutations in this gene also cause congenital kidney and urinary tract anomalies (OMIM (2013) 610805) Unknown Complicated: childhood onset HSP variably complicated by spastic 25 generalize and Hodgkinson et al. (2002) pseudobulbar signs Unknown Consanguineous Italian family, four subjects with adult (30–46 years) onset back and neck Zortea et al. (2002) pain related to disk herniation and spastic paraplegia; surgical correction of disk herniation ameliorated pain, and reduced spastic paraplegia. Peripheral neuropathy also present B4GALNT1 Complicated: child-to-adolescent ¼ onset, progressive spastic paraparesis with dysarthria Wilkinson et al. (2005); Boukhris and distal amyotrophy in both upper and lower limbs. May include intellectual disability, et al. (2013) peripheral neuropathy, ataxia, and extrapyramidal disturbance Unknown Complicated or uncomplicated HSP. Two families described. In one family (7 affected Meijer et al. (2004); Ribai et al. subjects), uncomplicated spastic paraplegia began between ages 25 and 45 years. In the (2006) second family (three subjects described), the disorder began in childhood and included spastic paraplegia, ataxia, dysarthria; mental retardation, sensorimotor polyneuropathy, facial dysmorphism, and short stature DDHD1 Uncomplicated: pure spastic paraplegia, onset in infancy, childhood, or adolescence, either Bouslam et al. (2005); Tesson et al. as an uncomplicated spastic paraplegia syndrome; or variable associated with axonal (2012) neuropathy, distal sensory loss, and cerebellar eye movement disturbance Unknown Mild mental retardation, brainstem generalize, clinically asymptomatic cerebellar atrophy Stevanin et al. (2007) Fatty acid 2-hydroxylase Childhood onset (6–11 years), spastic paraplegia with extrapyramidal features, progressive Kruer et al. (2010); Dick et al. (2008, (FA2H) dysarthria, dementia, seizures. Brain white matter abnormalities and brain iron 2010) accumulation; an Omani and Pakistani kindred reported Neuropathy target Complicated: spastic paraplegia associated with wasting of distal upper and lower extremity Rainier et al. (2008) esterase (NTE) muscles

SPG43 615043 SPG44 613206

SPG45 613162 (SPG45 is the same as SPG65) SPG46 614409

C19orf12

Two sisters from Mali, symptom onset 7 and 12 years, progressive spastic paraplegia with Meilleur et al. (2010) atrophy of intrinsic hand muscles and dysarthria (one sister) Allelic with “Pelizeaus-Merzbacher-like disease” (PMLD, early onset demyelinating Gap junction protein, Orthmann-Murphy et al. (2009) disorder with nystagmus, psychomotor delay, progressive spasticity, ataxia). GJA/GJC2 GJA12/GJC2, also mutation I33M causes a milder phenotype: late-onset (first and second decades), known as connexin47 cognitive impairment, slowly progressive, spastic paraplegia, dysarthria, and upper (Cx47) extremity involvement. MRI and MR spectroscopy imaging consistent with a hypomyelinating leukoencephalopathy NT5C2 See description for SPG65 below Dursun et al. (2009)

GBA2

SPG47 614066

AP4B1

SPG48 613647

AP5Z1

SPG49 615031

TECPR2

Childhood-onset, progressive spastic paraplegia complicated by ataxia, cognitive impairment, and variable cataracts and thin corpus callosum Two affected siblings from consanguineous Arabic family with early childhood onset slowly progressive spastic paraparesis, mental retardation, and seizures; one subject had ventriculomegaly; the other subject had thin corpus callosum and periventricular white matter abnormalities Comment: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1), and SPG52 (AP4S1) are due mutations in subunits of the adapter protein 4 (AP-4) that functions in trafficking of transmembrane proteins from the trans-Golgi network to early and late endosomes. Mutation in any of these subunits leads to loss of AP4 function and similar neurologic syndromes characterized by developmental delay, moderate-to-marked intellectual impairment, impaired speech acquisition (many subjects are nonverbal), accompanied by seizures in
50% of subjects AP5Z mutations are associated with diverse phenotypes including adult-onset progressive spastic paraplegia (variably accompanied by spinal cord MRI hyperintensities, upper extremity dysmetria; thin corpus callosum); adult-onset spastic paraplegia, ataxia, retinopathy, neuropathy, and parkinsonism; and infantile-onset, psychomotor delay, intellectual impairment, spastic paraplegia, thin corpus callosum, and periventricular white matter hyperintensities. It is noted that adult-onset spastic paraplegia has been reported in subjects with homozygous and heterozygous AP5Z1 mutations Five subjects from three apparently unrelated families (Jewish Bukharin ancestry) had infantile-onset hypotonia, developmental delay with severe cognitive impairment, dysmorphic features (short stature, brady-microcephaly, oral, facial, dental, nuchal abnormalities). Spastic, ataxic, rigid gait developed in childhood; additional features included gastroesophageal reflux, recurrent apneic episodes, and mild dysmorphic features. Two subjects had epilepsy and the MRI of two subjects showed a thin corpus callosum and cerebellar atrophy. In addition to progressive spastic, 3 additional subjects had intellectual impairment, autonomic-sensory neuropathy, paroxysmal autonomic events, and chronic respiratory disease

Boukhris et al. (2010); Martin et al. (2013) Blumkin et al. (2011); EbrahimiFakhari et al. (1993); Behne et al. (2020)

Slabicki et al. (2010); Hirst et al. (2015)

Oz-Levi et al. (2012); Heimer et al. (2016)

Continued

Table 3.1 Continued Autosomal recessive HSP Spastic gait (SPG) locus and OMIM numbera Protein SPG50 612936

AP4M1

SPG51 613744

AP4E1

SPG52 614067

AP4S1

SPG53 614898

VPS37A

SPG54 615033

DDHD2

SPG55 615035

C12ORF65

SPG56 615030

CYP2U1

Clinical syndrome

References

Five subjects from one consanguineous Moroccan family exhibited infantile onset, nonprogressive spastic quadriplegic with severe cognitive impairment; variably associated with adducted thumbs. Ventriculomegaly, white matter abnormalities, and variable cerebellar atrophy noted on neuroimaging. Neuroaxonal abnormalities, gliosis, and reduced myelin noted on postmortem examination. See comment above for SPG47 Two siblings from a consanguineous Palestinian Jordanian family and two siblings from a consanguineous Syrian family exhibited microcephaly, hypotonia, psychomotor delay, spastic tetraplegia, marked cognitive impairment with severe language impairment, facial dysmorphic features, and abnormal brain MRI showed (including atrophy and diffuse white matter loss). Seizures were variably present. See comment above for SPG47 Five subjects from consanguineous Syrian kindred exhibited delayed motor development, and severe cognitive impairment. Neonatal hypotonia was followed by progressive spastic gait with contractures. Dysmorphic features included short stature, microcephaly, and facial abnormalities. See comment above for SPG47 A total of nine subjects from two Arab Moslem families exhibited developmental delay, progressive lower extremity spasticity, and subsequently progressive upper extremity involvement; associated with skeletal dysmorphism (kyphosis and pectus carinatum); mild-to-moderate cognitive impairment; and variable hypertrichosis and impaired vibration sensation Affected subjects reported from four unrelated families exhibited psychomotor delay, cognitive impairment, progressive spasticity (onset before age 2 years), thin corpus callosum, periventricular white matter abnormalities. Additional clinical features include foot contractures, dysarthria, dysphagia, strabismus, and optic hypoplasia Two Japanese brothers from consanguineous parents exhibited early-onset spastic paraplegia variably associated with reduced visual acuity (with central scotoma and optic atrophy), reduced upper extremity strength and dexterity, lower extremity muscle atrophy, and motor sensory neuropathy Five unrelated families were reported with early-childhood onset spastic paraplegia, variable upper extremity involvement, upper extremity dystonia, cognitive impairment, thin corpus callosum, brain white matter disturbance, axonal neuropathy, and basal ganglia calcifications

Verkerk et al. (2009); Najmabadi et al. (2011)

Najmabadi et al. (2011); Moreno-De-Luca et al. (2011); Abou-áJamra et al. (2011)

Abou-áJamra et al. (2011); Abou Jamra et al. (2011); Dell’Angelica et al. (1999); Hirst et al. (1999) Zivony-Elboum et al. (2012)

Al-Yahyaee et al. (2006); Schuurs-Hoeijmakers et al. (2012)

Shimazaki et al. (2012); Antonicka et al. (2010)

Tesson et al. (2012)

SPG57 602490

Trk-fused gene (TFG)

SPG59 603158

USP8

SPG60 612167 SPG61 616685

WDR48

SPG62

ERLIN1

SPG63 615686

AMPD2

SPG64 615683

ENTPD1

SPG65 (same disorder is SPG45)

NT5C2

SPG66 610009

ARSI

SPG67 611655

PGAP1

SPG68 604806

FLRT1

ARL6IP1

Early-childhood onset spastic paraplegia, optic atrophy (at age 2.5 years), and wasting of hand and leg muscles due to axonal-demyelinating sensorimotor neuropathy; and normal intelligence. Patients with TFG mutations may be similar to those with neuroaxonal dystrophy (NAD). This is notable because NAD is most frequently due to PLAG6 mutations, which may also present as complicated hereditary spastic paraplegia Uncomplicated spastic gait reported in two subjects from one consanguineous family. Toe-walking noted at age 20 months. When examined in late childhood, subjects were ambulatory with spastic gait Early-childhood onset gait impairment associated with increased lower extremity muscle tone and reflexes, nystagmus, peripheral neuropathy, and mild learning disability Two affected subjects are reported from one consanguineous family, with onset at age 14 months. Subjects were non-ambulatory at ages 11 and 12 years. Examination demonstrated increased patellar and absent ankle deep tendon reflexes; diffuse motor and sensory neuropathy with loss of digits and acromutilation; and normal intelligence Two affected subjects from one consanguineous family are reported. Symptom onset (toe-walking) at ages 2 and 3 years; spastic gait described at ages16 and 20 years. Subjects were ambulatory despite having flexion contractures at the knees. Cognition was normal cognition. One subject had absent lower extremity reflexes Two affected subjects from one consanguineous family are reported: delayed walking milestone, ambulatory with scissoring gait, and normal. One subject had periventricular white matter and corpus callosum abnormalities Two affected subjects from one consanguineous family are reported with childhood-onset complicated spastic paraplegia. Symptom onset between ages 3 and 4 years; examination showed lower extremity spasticity, hyperreflexia, amyotrophy (one subject), microcephaly, aggressiveness, and delayed puberty Consanguineous kindred from Turkey with five subjects described: affected subjects had mental retardation, infantile onset lower extremity spasticity and contractures, one subject with optic atrophy, two subjects with pendular nystagmus; MRI in one subject was normal. Four additional families reported with infantile onset spasticity, thin or dysplastic corpus callosum, and learning difficulty One affected subject from a consanguineous family is described with early childhood-onset of abnormal gait. At 3.5 years, the subject was not ambulatory, had lower extremity spasticity but was areflexic; and had severe sensorimotor polyneuropathy, corpus callosum and cerebellar hypoplasia, colpocephaly, and borderline intelligence Two affected subjects from one consanguineous family are described. Onset in infancy with global delay, abnormal hand movements, spasticity, and borderline intelligence (one subject). The MRI scan was abnormal, showing prominent cortical sulci in one subject and corpus callosum agenesis, vermis hypoplasia, and defective myelination in the other subject Two affected subjects from one consanguineous family are described: early childhood onset gait impairment with hyperreflexia (patellar clonus) but no spasticity; nystagmus, optic atrophy, foot drop, peripheral neuropathy, normal brain MRI, and normal intelligence

Beetz et al. (2013); Koh et al. (2019a, b); Catania et al. (2018)

Novarino et al. (2014)

Novarino et al. (2014) Novarino et al. (2014); Darvish et al. (2017)

Novarino et al. (2014)

Novarino et al. (2014)

Novarino et al. (2014)

Novarino et al. (2014); Dursun et al., (2009); Nizon et al. (2018)

Novarino et al. (2014)

Novarino et al. (2014)

Novarino et al. (2014)

Continued

Table 3.1 Continued Autosomal recessive HSP Spastic gait (SPG) locus and OMIM numbera Protein SPG69

RAB3GAP2

SPG70 156560 SPG71 615635

MARS1

SPG72 615625

REEP2

SPG74 616451

IBA57

SPG76 616907 SPG77 617046

CAPN1

SPG78 617225

ATP13A2

SPG79 (AR) 615491

UCHL1

ZFR

FARS2

Clinical syndrome

References

One subject from a consanguineous family is described: infantile-onset, global developmental delay, lower extremity spasticity, dysarthria, deafness, cataract, and intellectual impairment Four subjects from one consanguineous family are described: infantile onset, delayed motor milestones, lower extremity spasticity, amyotrophy, and borderline intelligence One affected subject from a consanguineous family is described with symptom onset at age 1 year. At age 3 years, the subject had lower extremity spasticity and flexion contractures at the knees. The brain MRI showed thin corpus callosum. Normal intelligence Uncomplicated spastic paraplegia manifesting as childhood onset (infancy to age 8 years), toe walking or progressive spastic gait. Two of ten subjects had upper extremity spasticity Cognition, speech, and vision were normal. REEP2 mutations may cause both autosomal dominant HSP (due to heterozygous mutation); or autosomal recessive HSP due to compound heterozygote mutations Ten members of a consanguineous family had childhood onset, spastic paraplegia, optic atrophy, and peripheral neuropathy (SPOAN syndrome). SPOAN syndrome is genetically heterogeneous. KLC2 mutations also cause SPOAN syndrome Adolescent to adult-onset progressive spastic paraplegia, variably associated with dysarthria and ataxia Four subjects from a consanguineous family had early childhood onset, uncomplicated spastic paraplegia (Yang et al., 2016). FARS2 mutations have also been associated with early-onset epileptic encephalopathy, liver disease, lactic acidosis, and epilepsy Complicated HSP syndrome with variable presentations including adolescent onset progressive spastic quadriparesis with dementia, ataxia, nystagmus and impaired up-gaze; adult-onset progressive spastic paraparesis associated with oculomotor disturbance, ataxia, axonal motor-sensory neuropathy; variably associated with dementia and supranuclear gaze paresis, and auditory hallucinations One adult subject had marked spasticity particularly in the legs and rapidly progressive parkinsonism, supranuclear gaze palsy, perioral myokymia, and dementia Early childhood-onset progressive spastic paraparesis followed by upper extremity involvement (tetraparesis); optic atrophy leading to visual failure in childhood; variably associated with intellectual impairment and ataxia The naturally occurring mutant mouse “gracile axonal dystrophy” due to UCHL1 mutation exhibits autosomal recessive sensory-motor ataxia and “dying-back” axonal degeneration with formation of spheroid bodies in nerve terminals

Novarino et al. (2014)

Novarino et al. (2014) Novarino et al. (2014)

Esteves et al. (2014)

Lossos et al. (2015)

Gan-Or et al. (2016); Mereaux et al. (2021) Yang et al. (2016,c); Vernon et al. (2015); Almalki et al. (2014); Elo et al. (2012); Vantroys et al. (2017) Kara et al. (2016); Estrada-Cuzcano et al. (2017)

Bilguvar et al. (2013); Rydning et al. (2017); Saigoh et al. (1999); Yamazaki et al. (1988)

SPG81 618768

SELENOI

SPG82 618770

PCYT2

SPG83 619027

HPDL

603513

GAD1

609541

KLC2

256840

Epsilon subunit of the cytosolic chaperonincontaining t-complex peptide-1 (Cct5) ACO2 Two affected siblings in a consanguineous Arab-Bedouin family had intellectual disability Bouwkamp et al. (2018); Spiegel (moderate to severe), microcephaly, childhood seizures, progressive lower extremity et al. (2012) spasticity, lower extremity weakness; and involvement of upper extremities. In one subject, episodes of encephalopathy were followed by progressive decline in psychomotor abilities. Mutations in this gene are associated with infantile cerebellar retinal degeneration (ICRD; OMIM 614559) and isolated optic atrophy (OPA9; OMIM 616289) VPS53 Homozygous, probably pathogenic mutations in VPS53, were identified in two siblings Hausman-Kedem et al. (2019); from a nonconsanguineous Moroccan-Jewish family who demonstrated intellectual Feinstein et al. (2014) disability, childhood onset progressive lower extremity spasticity, and variable seizures. Mutations in this gene also cause autosomal recessive, pontocerebellar hypoplasia, type 2E (615851)

614559a 616289a

615851a

Complicated, spastic paraplegia, described in five subjects from two consanguineous Ahmed et al. (2017); Kara et al. families. Four subjects in one family had childhood-to-adult onset progressive spastic (2016) paraparesis with intellectual impairment, dysarthria, seizures, pigmentary retinopathy, and visual impairment. Brain imaging showed increased T2-weighted signals in periventricular white matter and subcortical frontal regions. One child from another family had infantile seizures, neurodevelopmental arrest, and spastic quadriparesis; the brain MRI showed brain hypomyelination, progressive cerebral, cerebellar, and brainstem atrophy, myelin loss, optic nerve hypoplasia, and thin corpus callosum Complicated spastic paraplegia syndrome beginning in infancy with delayed motor Estrada-Cuzcano et al. (2017) development and progressive spasticity, intellectual impairment, seizures; variably associated with nystagmus, hearing, and vision impairment, and dysarthria. Progressive cerebral and cerebellar atrophy and white matter hyperintensities evident on MRI. Five subjects reported from four unrelated families (three consanguineous) Childhood-to-adult-onset progressive spastic paraplegia (Hussain et al., 2020) variably Losekoot et al. (1990); Ghosh et al. complicated by upper extremity involvement(Wiessner et al., 2021) and cognitive (2021); Bilguvar et al. (2013); impairment(Losekoot et al., 1990; Ghosh et al., 2021) Rydning et al. (2017); Saigoh et al. (1999) Four siblings in a consanguineous Pakistani family with spastic cerebral palsy, and Mitchell and Bundey (1997); moderate-to-severe mental retardation McHale et al. (1999); Lynex et al. (2004) Complicated spastic paraplegia associated with optic atrophy, and neuropathy (SPOAN). Macedo-Souza et al. (2005); Lossos Note that mutations in a separate gene (IBA57) are also associated with the SPOAN et al. (2015); Melo et al. (2015) syndrome Complicated spastic paraplegia associated with mutilating sensory neuropathy Bouhouche et al. (2006a,b)

Continued

Table 3.1 Continued Autosomal recessive HSP Spastic gait (SPG) locus and OMIM numbera Protein 613115a

FAM134B

617114a

KY

614739a

SERAC1

No MIM number

KLC4

611105a

DARS2

616281a

GPT2

607694a 264090a

POLR3A

Clinical syndrome

References

FAM134B mutations cause hereditary sensory neuropathy type IIB (OMIM: 613115) and that may be associated with lower extremity spasticity and childhood onset-spastic gait A total of 12 members of a consanguineous Bedouin kindred are described with infantile-toearly childhood-onset spastic paraplegia associated with tongue atrophy and variably associated with intellectual disability. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers. KY mutations cause myofibrillar myopathy type 7 (OMIM: 617114) SERAC1 mutations are implicated in ‘Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like’ syndrome (MEGDEL syndrome, OMIM: 614739) may also manifest as intellectual disability associated with adolescent-onset progressive spastic paraplegia that may progress to tetraplegia; and may include generalized dystonia, dysphagia, and axonal-demyelinating motor sensory neuropathy. MRI abnormalities (“putaminal eye”) involving basal ganglia were noted Three affected subjects in one family exhibited cognitive impairment, progressive spastic gait beginning at age 3 years, associated with progressive hearing and vision impairment, retinitis pigmentosa, ataxia, demyelinating peripheral neuropathy, cerebellar abnormalities on brain MRI; and variably associated with prominent muscle atrophy in both upper and lower extremities and upper extremity flexion contractures One individual described with adolescent onset, insidiously progressive spastic paraplegia with marked dorsal column impairment. MRI scan showed T2 hyperintensities in cerebrum, cerebellum, brainstem, and spinal cord. Although DARS2 mutations are known to cause the complex neurodegenerative syndrome Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM: 611105), this patient illustrates that the spectrum of DARS2 mutation-associated syndromes includes isolated, progressive spastic paraplegia, dorsal column impairment, and white matter abnormalities; and further illustrates the spectrum of neurologic involvement from mitochondrial disturbance Five subjects reported from two consanguineous families had infantile onset severe psychomotor delay and hypotonia, that progressed to spasticity, facial dysmorphism, and variable seizures. One subject showed progressive spastic gait. GPT2 mutations cause autosomal recessive mental retardation (OMIM: 616281) Adolescent to adult (age 51) onset of progressive spastic ataxia, dysarthria, and dentition abnormality. POLR3A mutations also cause leukodystrophy, hypomyelinating,(Filla et al., 1992) with or without oligodontia and/or hypogonadotropic hypogonadism (MIM: 607694), and Wiedemann-Rautenstrauch syndrome (WDRTS, MIM: 264090)

Wakil et al. (2018); Ilgaz et al. (2014); Kurth et al. (2009) Yogev et al. (2017)

Tort et al. (2013); Roeben et al. (2018)

Bayrakli et al. (2015)

Lan et al. (2017)

Hengel et al. (2018)

Minnerop et al. (2017)

256600a 612953a

PLA2G6

Mental retardation associated with infantile or childhood onset spastic paraplegia and Koh et al. (2019c,d); Chen et al. ataxia. The brain MRI showed cerebellar atrophy and variable hypodensity of the globus (2018); Ozes et al. (2017) pallidus PLA2G6 mutations are associated with autosomal recessive neurodegenerative disorders associated with brain iron accumulation. Variable and overlapping syndromes associated with PLA2G6 mutation include infantile neuroaxonal dystrophy (MIM: 256600), parkinsonism (PARK14, MIM: 612953), and hereditary spastic paraplegia complicated by ataxia

SPG1 303350

L1 cell adhesion molecule (L1CAM)

SPG2 300401

Proteolipid protein

SPG16 300266

Unknown

SPG22 300523

Monocarboxylate transport 8 (MCT8) Unknown

Complicated: associated with mental retardation, and variably, hydrocephalus, aphasia, and Jouet et al. (1994) adducted thumbs. (L1CAM mutations cause overlapping syndromes: MASA syndrome, CRASH syndrome, and X-linked hydrocephalus) Complicated: variably associated with MRI evidence of CNS white matter abnormality; and Kobayashi et al. (1994); Hudson may have peripheral neuropathy (2003); Saugier-Veber et al. (1994); Cambi et al. (1996) Uncomplicated; or complicated: associated with motor aphasia, reduced vision, nystagmus, Steinmuller et al. (1997); Tamagaki mild mental retardation, and dysfunction of the bowel and bladder et al. (2000) Complicated (Allan-Herndon-Dudley syndrome): congenital onset, neck muscle hypotonia Marx (1991); Allan et al. (1944); in infancy, mental retardation, dysarthria, ataxia, spastic paraplegia, and abnormal facies Bialer et al. (1992) Uncomplicated, onset: 12–25 years Macedo-Souza et al. (2008)

X-linked HSP

SPG34 300750 225750a

RNASEH2B

Single individual described with childhood onset, non-progressive spastic gait, and Spagnoli et al. (2018); Rice et al. homozygous mutations in RNAseH. Mutations in this gene are associated with Aicardi(2007) Goutières syndrome (MIM: 225750)

Maternal (mitochondrial) inheritance HSP 516060a 500006a

Mitochondrial ATP6 gene

616539a

Mitochondrial TRMT5

a

Adult onset, progressive spastic paraplegia, mild-to-severe symptoms, variably associated Verny et al. (2011) with axonal neuropathy, late-onset dementia, and cardiomyopathy. Mitochondrial ATP6 (MTATP6) mutations cause myopathy, lactic acidosis, sideroblastic anemia (OMIM: 516060), and infantile cardiomyopathy (500006) Progressive weakness and spasticity in adulthood (may begin in adulthood or occur after Tarnopolsky et al. (2017) infantile onset intellectual impairment and spastic diplegic cerebral palsy-like syndrome); associated with exercise intolerance, dyspnea, and neuropathy. The syndrome is variable and lactic acidosis and stroke-like episodes may occur. Mutations in TRMT5 cause combined oxidative phosphorylation deficiency 26 (OMIM: 616539)

Online Mendelian Inheritance in Man (OMIM) number to allelic disorder(s) is given when there is no OMIM phenotype number for the HSP syndrome.

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DEFINITIONS The term “hereditary spastic paraplegia” (HSP) refers to the inherited syndrome in which lower extremity spasticity and weakness (each of variable degree) are either the primary clinical features or, when accompanied by other neurologic impairments, major aspects of the clinical presentation. When the family history of the disorder is present, the syndromic designation HSP may be refined by the apparent pattern of inheritance (AD, AR, X-linked (XL), or maternally transmitted HSP). When a causative gene mutation is identified (e.g., mutation in the SPG4 Spastin gene), a more precise disease designation may be used (e.g., SPG4 HSP). For many individuals, despite genetic testing, the molecular basis is unknown and only a syndromic diagnosis (“HSP syndrome”) is possible.

CLASSIFICATION HSP is classified according to the mode of inheritance (AD, AR, XL, and maternal [mitochondrial]) and according to the clinical manifestations. HSP has been classified as “uncomplicated” when the syndrome consists of spastic paraparesis (or paraplegia) typically accompanied by urinary urgency (Harding, 1982). This is frequently accompanied by mild dorsal column impairment in the feet. This indicates that even uncomplicated HSP is usually not an exclusively upper motor neuron disorder but rather a central nervous system (CNS) motor-sensory disorder, in which symptoms of upper motor neuron (UMN) impairment predominate. HSP is classified as “complicated” when, in addition to spastic paraparesis (or paraplegia), the inherited syndrome includes one or more additional neurologic or systemic abnormalities such as cerebellar ataxia, peripheral neuropathy, epilepsy, developmental disability, intellectual impairment, dementia, muscle wasting, spasticity and weakness involving the upper extremities, dysarthria, dysphagia, cataracts, retinopathy, or ichthyosis. Many genetic types of HSP usually (but not always) present as either “uncomplicated” or “complicated” syndromes. For example, although SPG3A and SPG4 HSP almost always present as “uncomplicated HSP,” there are exceptions in which individuals have more extensive neurologic involvement (for example, having upper extremity, speech, and swallowing impairment). Conversely, although subjects with SPG7 HSP frequently manifest as “complicated” HSP, having additional neurologic impairments (particularly cerebellar ataxia and peripheral neuropathy), it is not uncommon for SPG7 to present as “uncomplicated” HSP. Recognizing the imperfect correlation between genetic type and clinical presentation, it is prudent to describe a genetic type of HSP that “usually” (rather than “always”)

manifests as uncomplicated HSP or “usually” (rather than “always”) manifests as complicated HSP.

EPIDEMIOLOGY HSP has been described in males and females of all ages from around the world. Many rare forms of HSP have been described thus far in only a few families from specific populations (Table 3.1). Estimates of HSP prevalence, ranging from 1.27 to 9.6 per 100,000 (Polo et al., 1991; Filla et al., 1992; Ruano et al., 2014) are somewhat greater than that of amyotrophic lateral sclerosis (ALS,
1.6 per 100,000 (Hirtz et al., 2007)), and AD and AR cerebellar ataxia (1.5–4.0 per 100,000 and 1.8–4.9 per 100,000, respectively) (Ruano et al., 2014).

SIMPLEX CASES Despite the term “hereditary,” HSP is not always ascertained as a “familial” disorder in which multiple relatives share the same syndrome. The absence of family history of similar symptoms certainly does not exclude the diagnosis of HSP. Such “simplex” cases (without affected relatives), in which HSP diagnosis has been confirmed by discovery of a pathogenic mutation in an HSP gene, are not uncommon. Genetic testing of relatives may give insight into the cause of “apparently sporadic” HSP (simplex cases), for example, due to incomplete genetic penetrance of an AD disorder, de novo gene mutation, AR or XL transmission (with unaffected parental carriers), or variable age-of-symptom onset (in which case firstdegree asymptomatic subjects are still at risk of developing symptoms), or nonpaternity. Family members must be informed and provide consent to genetic testing that could reveal nonpaternity or that although unaffected, they may be at risk of developing the disorder.

CLINICAL PRESENTATION There may be marked clinical variability both within a genetic type of HSP and between the more than 90 different genetic types of HSP. There may also be significant clinical variation in both the nature of neurologic impairments and their severity between affected subjects in the same family who share the same HSP gene mutation. Some forms of HSP (described below and summarized in the Table 3.1) manifest as a relatively isolated, spastic gait that is either progressive (when symptoms begin after infancy) or nonprogressive (when symptoms begin in infancy). In other forms of HSP, progressive spastic paraplegia evolves into a complex neurodegenerative syndrome. Still other forms manifest as developmental delay, intellectual impairment, and often complex neurologic syndromes that include

THE HEREDITARY SPASTIC PARAPLEGIAS (but often are not limited to) upper motor neuron impairment in the legs. The following descriptions illustrate seven increasingly complex HSP syndrome presentations.

Illustrative cases UNCOMPLICATED SPASTIC PARAPLEGIA Insidiously progressive spastic gait A 35-year-old individual has a very slowly progressive gait impairment over 5 years. There is urinary urgency but no other symptoms. This is a typical presentation of “uncomplicated” progressive spastic paraplegia. This presentation is characteristic (but not pathognomonic) of a number of types of HSP, including SPG4 HSP (the single most common dominantly inherited form of HSP), as well as SPG6, SPG8, and many other forms (Table 3.1). Note in this example that spastic gait began after early childhood and was progressive. This differs from the next example in which spastic gait begins in infancy and is nonprogressive (resembling spastic diplegic cerebral palsy).

CEREBRAL PALSY PHENOTYPE Infantile-onset, nonprogressive spastic gait An individual, previously diagnosed as having spastic diplegic cerebral palsy, has two children, each of whom have similar, infantile-onset, spastic gait symptoms. The proband and children were each the product of full-term, uncomplicated gestation and delivery. There are no neuroimaging abnormalities or other neurologic impairments. For each individual, “toe walking” in early childhood was followed by increased spasticity limited to the legs. Functional ability to walk has not declined over several decades. This pattern, resembling spastic diplegic cerebral palsy, is the most common presentation of autosomal dominant SPG3A HSP and may also occur in AD SPG4 and other forms of HSP. In this example, AD inheritance clearly distinguishes infantile-onset HSP from sporadically occurring spastic diplegic cerebral palsy. However, when it occurs without a family history (e.g., from de novo mutation) (Rainier et al., 2006), infantile onset forms of HSP may not be clinically distinguishable from spastic diplegic cerebral palsy. In these circumstances, the diagnosis of HSP vs cerebral palsy may only be made through genetic testing.

Primary lateral sclerosis phenotype Adolescent onset, progressive spastic paraplegia, followed by involvement of the upper extremities, speech, swallowing, and dementia

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A 14-year-old has an insidiously progressive spastic gait. By age 18, there is progressive spastic dysarthria and dysphagia and impaired use of the upper extremities. By age 30, the subject is nonambulatory, can no longer use their hands, and has progressive cognitive impairment, marked dysarthria, and dysphagia requiring a feeding tube. This vignette describes a progressive “complicated” spastic paraplegia syndrome. This syndrome is not uncommon in subjects with SPG11 HSP (recognizing that some SPG11 subjects have an “uncomplicated” spastic paraplegia syndrome) and many other forms of HSP (Table 3.1). It also illustrates two important points. First, “a lower extremity-predominant, upper motor neuron syndrome” may be a phase of the disorder, replaced by “generalized spastic quadriparesis” as the condition advances; and second, the occurrence of other symptoms (e.g., dementia and dysphagia) may become the primary or most important clinical features (rather than gait disturbance) as the disorder evolves. Except for the occurrence of dementia, this presentation of HSP resembles the typical presentation of primary lateral sclerosis (PLS), in which an insidiously progressive lower extremity spasticity and weakness become later associated with the involvement of upper extremities, speech, and swallowing (Barohn et al., 2020; Turner et al., 2020). Juvenile primary lateral sclerosis due to ALS2 mutations may resemble HSP (Eymard-Pierre et al., 2006). In addition, occasionally, subjects with adult-onset PLS are discovered to have gene mutations causative of HSP (Yang et al., 2016; Liu et al., 2019).

Spastic ataxia phenotype Progressive spastic paraplegia with cerebellar ataxia and peripheral motor-sensory neuropathy This pattern is very common in subjects with SPG7 HSP (recognizing that some subjects with SPG7 HSP also have an uncomplicated spastic paraplegia syndrome). This manifestation of HSP overlaps that of many forms of spinocerebellar ataxia (SCA) that include UMN impairment (“spastic ataxias”). These include spinocerebellar ataxia 3 (Machado-Joseph disease), Charlevoix-Saguenay, Friedreich’s ataxia (some presentations), and others (reviewed in Ref. Bereznyakova and Dupr
e, 2018). Understanding the clinical overlaps between some forms of HSP and some forms of SCA underscores the value of extending genetic testing if the analysis of an HSP gene panel does not identify a causative mutation. Note that trinucleotide repeat expansions, causative of many spinocerebellar ataxias, may not be detected in next-generation sequencing (NGS) of HSP gene panels.

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Spastic paraplegia with distal muscle wasting Initially reported in AR Troyer syndrome (SPG20 HSP), distal muscle wasting is recognized as a feature of a number of types of HSP, including AR SPG39 HSP autosomal dominant “Silver syndrome” (SPG17 HSP). In addition to these HSP syndromes recognizable by characteristic distal wasting, varying degrees of muscle atrophy may be a feature of many forms of HSP (Table 3.1). For example, muscle atrophy may be present in subjects with SPG11 HSP, one of the most common autosomal recessive forms of HSP. In 20% of subjects with SPG11, the distribution of lower motor neuron (LMN) involvement meets the El Escorial criteria for amyotrophic lateral sclerosis (ALS) (Orlacchio et al., 2010).

Developmental delay, intellectual impairment, dysarthria, spastic paraparesis or quadriparesis Mutations in many genes (Table 3.1) cause complex neurodevelopmental disorders that include UMN impairment which may be progressive, predominant in the legs, and which are included among the HSPs. For example, KIF1A mutations are associated with a wide variety of neurodevelopmental and neurodegenerative disorders including AR hereditary sensory and autonomic neuropathy (HSAN) type 2; AR SPG30 HSP; and AD mental retardation type 9 (reviewed in Ref. Nicita et al., 2021).

Complex neurodegenerative disorders that include spastic paraparesis It is useful to consider variant presentations of HSP when evaluating subjects with complex neurodegenerative disorders of uncertain etiology. Mutations in a number of genes (Table 3.1) that typically are associated with other, often complex neurodegenerative disorders sometimes present with relatively uncomplicated spastic paraplegia. For example, TUBB4A mutations that cause hypomyelinating leukodystrophy and AD torsion dystonia, and SPG77/FARS2 mutations that cause epileptic encephalopathy, may each manifest as HSP (see Table 3.1). In other instances, progressive spastic paraparesis is an early presentation (transiently recognizable as HSP syndrome) through which the neurodegenerative disorder evolves (e.g., ALS and sometimes Alzheimer’s disease due to presenilin 1 or 2 mutation).

CLINICAL ASPECTS AND DISEASE COURSE For most HSP syndromes, particularly those that are “uncomplicated,” the initial symptoms are impaired walking (or impaired acquisition of standing and walking

milestones) and balance. Urinary urgency is occasionally and may precede gait disturbance. As noted above, when HSP symptoms begin in very early childhood (e.g., before age 2 years), symptoms may be nonprogressive even over decades. This form of HSP is typical of SPG3A HSP (which represents
10% of AD HSP) and may also occur in SPG4 and other forms. When symptoms begin after early childhood, they typically progress insidiously. Indeed, the onset of HSP is so slow that family members may observe gait disturbance for many years before the subject experiences functional impairment. Dating the onset of symptoms to a particular year, month, or season, is so atypical in HSP as to support the possibility of an alternate disorder. HSP symptoms that begin after early childhood progress steadily without exacerbations or remissions. After a number of years of steady progression, the rate of functional decline appears to become slower for many but not all subjects. The extent to which the reduced rate of functional decline in many (not all) subjects represents reduced disease progression vs the effect of neurologic compensation is not known.

Neurologic findings in subjects with “uncomplicated” HSP Subjects with uncomplicated HSP exhibit deficits referable to UMNs subserving bilateral lower extremities relatively symmetrically, often accompanied by mild deficits referable to dorsal columns serving distal lower extremities (fasciculus gracilis fibers). This includes varying degrees of weakness (from full strength to marked weakness), spasticity (varying from subtle to severe), and impaired speed of activation (e.g., reduced foot-tapping speed).

Weakness In “uncomplicated” HSP, weakness (of variable degree) does not affect all lower extremity muscles uniformly. When it occurs, weakness is most notable in the iliopsoas, hamstrings, gluteus medius, and tibialis anterior muscles. Quadriceps strength is almost always preserved.

Spasticity Spasticity (of variable degree) is present in adductors, hamstrings, quadriceps, and gastrocnemius-soleus muscles. In an estimated 5%–10% of subjects, bedside examination will demonstrate only minimal spasticity despite the appearance of a frankly “spastic gait” pattern. These subjects appear to have spasticity that is increased by activity and reduced at rest.

THE HEREDITARY SPASTIC PARAPLEGIAS

Mild impairment of distal vibration perception In uncomplicated HSP, light touch, temperature, and pain perception are usually preserved except in the many types of HSP associated with peripheral neuropathy HSP (e.g., SPG2, 3A, 4, 5, 6, 7, 10, 25, 27, 30, and others (see Table 3.1). Peripheral neuropathy may be present in some types of HSP that typically manifest as uncomplicated HSP. For example, approximately 17% of subjects with SPG3A HSP have motor-sensory axonal peripheral neuropathy (Ivanova et al., 2007). Mildly reduced vibration perception in the toes is commonly observed in subjects with uncomplicated HSP. This finding, which correlates with the postmortem observation of mild degeneration of fasciculus gracilis fibers, may contribute to balance impairment. It is emphasized that the degree of vibration perception impairment in uncomplicated HSP is only very mild. In the absence of peripheral neuropathy, the occurrence of marked vibration impairment would suggest alternate diagnoses including vitamin B12 deficiency, Friedreich’s ataxia, copper deficiency, or nitrous oxide-related myelopathy.

Hyperreflexia Deep tendon reflexes are brisk (at least 3+) in the lower extremities and plantar responses are often (not always) extensor. Deep tendon reflexes (and spasticity) may diminish in subjects who also have advancing neuropathy. Deep tendon reflexes in the legs are typically absent in subjects receiving intrathecal baclofen.

Reduced speed of muscle activation Subjects with uncomplicated HSP typically show slowing of foot tapping and repetitive knee lifting that is not attributable to weakness or spasticity. Often, gait evaluation shows the appearance of very slightly delayed knee extension and hip flexion. In the author’s opinion, this apparently reduces the rate of lower extremity muscle activation contributing to functional balance impairment; and informs proactive physical therapies focusing on agility, balance, and speed exercises.

Gait Subjects with uncomplicated HSP manifest various degrees of gait disturbance typical of chronic upper motor neuron deficit. Although widely used, the term “spastic gait” does not describe all the elements of this abnormal gait pattern, which includes spasticity (variable in its distribution and severity between subjects), balance impairment, weakness (variably affecting different

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muscles), and delayed speed and reduced precision of muscle activation (reduced “precision” referring to the impaired ability to specifically isolate contraction to only one or a few muscles and selectively inhibit other muscle contraction). Rather than stating “the subject has spastic gait,” it is recommended that each of these factors (tone, strength, speed of activation, balance, precision) be considered separately in order to develop a patient-specific rehabilitation strategy.

Stance Narrow-based stance with varying degrees of circumduction is common. Alternately, subjects with balance impairment (either from dorsal column involvement alone or the occurrence of peripheral neuropathy or cerebellar ataxia) exhibit a wide-based gait.

Forward-shifted foot strike and toe walking The subtlest evidence of UMN impairment affecting gait is the forward shifting of the foot strike from near the heel to the mid-foot. With moderate to severe disturbance, this becomes “toe walking.” Dorsiflexion is reduced (to a similar degree as the forward-shifted foot strike) and may cause toe dragging or stumbling over the toes. Subjects often demonstrate the abnormal pattern of wear on the toes of their shoes.

Hip flexion is often reduced (or slightly delayed) To compensate, subjects may develop the habit of tilting the trunk laterally or accentuating lordosis with each step, tipping the pelvis (laterally or posteriorly) in an apparent attempt to compensate for impaired knee lifting and reduced foot dorsiflexion and thus reduce toe dragging. Over time, these compensatory maneuvers are often associated with chronic low back pain.

Knee adduction and incomplete extension Many subjects, particularly those with moderate to marked spasticity in adductors and hamstrings, exhibit varying degrees of knee adduction and incomplete knee extension when walking. This observation signals the need for additional spasticity-reducing approaches including stretching and medication (including botulinum toxin [Botox] administration).

Upper extremities Examination of the upper extremities in subjects with “uncomplicated” HSP syndromes often demonstrates brisk deep tendon reflexes (though less hyperactive than those in the legs). However, spasticity, weakness, or

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reduced dexterity in the upper extremities is not a feature of uncomplicated HSP. The occurrence of brisk upper extremity reflexes, without other signs of UMN impairment, in the arms does not indicate that the upper extremity function will decline. Rather, this frequent finding indicates a relative gradient of mild (asymptomatic) UMN impairment in the arms and marked (symptomatic) UMN involvement in the legs. Indeed, neuropathologic studies (discussed below) have shown that corticospinal tract (CST) axon degeneration is not isolated to fibers serving the legs (terminating in the thoracic spinal cord) but also involves fibers terminating in the cervical region (serving the arms), albeit to a much lesser (asymptomatic) extent.

DIAGNOSIS HSP is diagnosed by the occurrence of typical signs and symptoms (discussed above); the exclusion of alternate disorders; supported by the presence of family history of similar disorder; and confirmed by the discovery of a pathogenic mutation in an identified HSP gene. Acute or subacute onset in HSP is highly atypical. Exacerbations and remissions have not been reported in HSP. Neurologic findings may be asymmetrical, particularly in the first few years, but have not been reported to be unilateral. The syndrome of “insidiously progressive spastic paraparesis” may be a phase of many neurologic disorders including UMN-predominant ALS, PLS, and some forms of early-onset Alzheimer’s disease. Exclusion of these and other disorders requires serial analysis. For example, repeat electromyography for at least the first 3 years is recommended to exclude UMNpredominant ALS.

Differential diagnosis The differential diagnosis of “uncomplicated” HSP manifesting as a progressive spastic gait is listed in Table 3.2. Considering that HSP represents an extremely large number (>90) of separate disorders that may have widely different clinical presentations, it is useful to consider more focused differential diagnoses for the various HSP presentations, including (1) a nonprogressive, infantile onset spastic gait (resembling cerebral palsy), (2) a relatively isolated, progressive spastic paraparesis, and (3) complex neurodevelopmental (nonprogressive) and neurodegenerative (progressive) syndromes that include spastic paraparesis together with other neurologic impairments. For example, genetic testing for spinocerebellar ataxias would be more appropriate for some subjects than others.

Table 3.2 Differential diagnosis of hereditary spastic paraplegia (Fink, 2019) Structural abnormality of the brain and spinal cord Tethered cord syndrome Spinal cord compression from degenerative spondylosis or neoplasm CNS predominant leukodystrophy Vitamin B12 deficiency Multiple sclerosis Adrenomyeloneuropathy, Adrenoleukodystrophy Krabbe disease Metachromatic leukodystrophy Mitochondrial disorder CNS infection Tropical spastic paraplegia due toHTLV1 infection (which may be familial) Pachymeningitis from tertiary syphilis Motor neuron disorders and other degenerative neurologic disorders whose presentations include lower extremity spasticity and weakness Amyotrophic lateral sclerosis Primary lateral sclerosis Alzheimer’s disease due to APP, PS1, or PS2 gene mutation Spinal cord arteriovenous malformation Spinocerebellar ataxias Friedreich’s ataxia SCA3 type III (Machado-Joseph disease) Charlevoix-Saguenay ataxia Dopa-responsive dystonia Toxins Lathyrism Konzo Nitrous oxide toxicity Organophosphate toxicity Metabolic disorders Mitochondrial myelopathy Hypocupremia Vitamin E deficiency Vitamin B12 deficiency Folate deficiency Partial hexosaminidase deficiency Glutaric acidemia Cerebral folate deficiency Biotinidase deficiency 5MTHFR deficiency Hyperornithinemia–hyperammonemia Homocitrullinuria Type III 3-methylglutaconic aciduria Coenzyme Q10 deficiency GM2 gangliosidosis

Diagnostic evaluation Advances in gene and genome sequencing have transformed our knowledge of HSP including its numerous molecular causes and our ability to add molecular precision to a clinical diagnosis. Nonetheless, gene testing is

THE HEREDITARY SPASTIC PARAPLEGIAS not the first diagnostic test. Prior to ordering genetic tests, it is recommended that a clinical (syndromic) diagnosis be established on the basis of family history, signs, symptoms, and course; and that other disorders are excluded by brain and spinal cord MRI, clinical laboratory testing.

Routine laboratory testing The routine laboratory evaluation of subjects with an insidiously progressive spastic gait should include levels of vitamin B12, folate, urine (Sudheer et al., 2022; Wang et al., 2022), and plasma amino acids, serum copper, vitamin E, very long-chain fatty acids (VLCFAs), urine organic acids, and cerebrospinal fluid (CSF) analysis (the latter as clinically indicated). Neurophysiologic studies including needle electromyography (EMG) and nerve conduction studies (NCS) are recommended. Visual, brainstem, and somatosensory evoked potentials (VEP, BAEP, and SSEP) are performed as clinically indicated.

NEUROIMAGING It is important that subjects with spastic paraplegia be evaluated by brain and spinal cord magnetic resonance imaging (MRI) in order to exclude alternate disorders including structural abnormalities and leukodystrophy. Routine clinical MRI of the brain and spinal cord is usually normal in subjects with uncomplicated HSP (e.g., due to SPG3A or SPG4 HSP). Research studies of these subjects have shown a reduced anterior-posterior diameter of the thoracic spinal cord, consistent with the atrophy of distal CST axons, as well as the more widespread fiber loss evident on diffusion tensor imaging (DTI) studies (Hedera et al., 2005). A number of different MRI abnormalities are associated with various “complicated” HSP syndromes. For example, a thin corpus callosum is a common feature of SPG11 and SPG15 and has also been present in many other types of HSP (including SPG3A, SPG4, SPG7, SPG15, SPG21, SPG32, SPG47, PG49, SPG54, and SPG56) (Fink, 2016, 2019). Cerebellar atrophy is often noted in SPG7 HSP. Cerebral white matter abnormality is noted in a number of complicated HSPs including SPG5/CYPB7, SPG7/Paraplegin, SPG21/Maspardin, and SPG35/FA2H gene mutations (Fink, 2016, 2019).

NEUROPHYSIOLOGY Subjects with uncomplicated HSP usually have normal findings on EMG and NCS. For example, though formerly considered to represent “uncomplicated” HSP, approximately 17% of subjects with SPG3A HSP have motor-sensory axonal peripheral neuropathy (Ivanova et al., 2007). Peripheral neuropathy has been described as either a rare or common feature in more than a dozen genetic types of HSP (Table 3.1). As noted above, peripheral neuropathy is a feature of many types of

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HSP (e.g., SPG7 and SPG11) including typically forms that are usually “uncomplicated” (e.g., SPG3A and SPG4 HSP). Peripheral motor neuropathy may be present in subjects with distal atrophy (e.g., SPG39, SPG20, and SPG17, see Table 3.1). In uncomplicated HSP, SSEPs recorded from the legs often show slowed central conduction velocity and reduced amplitude. SSEPs recorded from the upper extremities are usually normal. These findings correlate with distal atrophy of dorsal columns predominantly affecting the longer fibers from the legs (fasciculus gracilis) more than those from the arms (fasciculus cuneatus). Spinal cord conduction velocity recorded in the legs in uncomplicated HSP subjects often shows slowing, reduced amplitude, and increased signal dispersion. In contrast, spinal cord conduction velocity recorded in the arms is usually normal. This correlates with lengthdependent CST axon degeneration particularly affecting longer CST fibers terminating in the thoracic spinal cord compared to the relatively shorter CST that terminates in the cervical spinal cord.

GENETIC TESTING Genetic testing begins after alternate disorders have been excluded by history, examination, and routine neuroimaging, neurophysiologic, and clinical laboratory studies. When a causative mutation has been identified in other family members, it may be most appropriate to analyze that specific gene. Alternatively, particularly for subjects with an uncomplicated HSP and obvious family history, genetic analysis usually begins with evaluation of HSP gene panels (which should include specific analysis of exon and gene deletions). Whole exome sequencing (WES), whole genome sequencing (WGS), mitochondrial genome analysis, and chromosome microarray analysis are often used as the primary methods for subjects with more complicated presentations. It is noted that testing for genetic mitochondrial disorders includes analysis of both the mitochondrial genome as well as those nuclear-encoded (autosomal genes) whose proteins function in mitochondria. Analysis of these latter genes is available either in gene panels or through WES. Despite advances in our knowledge of the genetic causes of HSP, gene testing including whole exome analysis either does not identify a causative pathogenic mutation or only identifies gene variants of uncertain significance in an estimated 35% of subjects, including those with a family history of similar disorder. This may reflect the occurrence of mutations in nonanalyzed regions (e.g., gene promoter and other regulatory elements) that might be identified in whole genome analysis as well as gene copy number variation (for which chromosome microarray analysis may be more sensitive than currently available NGS).

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GENETIC COUNSELING Genetic counseling in HSP is based on both family history (pedigree analysis) and results of gene testing (when a causative mutation is identified). Genetic penetrance in AD HSP is age-dependent and is very high (estimates exceed 95%), although instances of incomplete genetic penetrance have been observed (Hedera et al., 1999). A number of different types of HSP (SPG7, SPG9A, SPG9B, SPG18, SPG30, SPG58, and SPG72) manifest as both AD and AR disorders (see Table 3.1). The extent to which variable modes of inheritance are associated with specific mutant alleles (genotype-phenotype correlation) is not yet known. It is possible that some subjects for whom NGS identified only a heterozygous mutation have a second “cryptic” mutation involving a noncoding regulatory region and therefore actually have autosomal recessive disease. Genetic counseling of such subjects is difficult and must be individualized.

NEUROPATHOLOGY (Schwarz, 1952; Schwarz and Liu, 1956; Behan and Maia, 1974; Sack et al., 1978; Buge et al., 1979; Harding, 1993; White et al., 2000; Deluca et al., 2004) Studies of uncomplicated HSP have shown axon degeneration primarily affecting the distal ends of CST (in the thoracic region) and distal ends of fasciculus gracilis fibers (in the cervicomedullary region) (Schwarz and Liu, 1956; Behan and Maia, 1974; Sack et al., 1978; Buge et al., 1979; Harding, 1993; Fink, 2003; Deluca et al., 2004). Demyelination of degenerating fibers and gliosis in uncomplicated HSP have been attributed to the consequences of axon degeneration rather than primary demyelination. The finding of a decrease in the number of cortical motor neurons and anterior horn cells (AHCs) (Behan and Maia, 1974; Harding, 1993) needs additional study. Some studies (reviewed in Ref. Fink, 2013) have demonstrated AHC abnormalities (hyaline inclusions, altered mitochondrial distribution, and altered immunostaining) for cytoskeletal proteins [nonphosphorylated neurofilament protein and b-tubulin] in postmortem studies in SPG4 HSP (Wharton et al., 2003) (the single most common form of dominantly inherited HSP, which usually manifests as an uncomplicated spastic paraplegia syndrome). These observations form the basis for the “central dogma” of the HSPs, that is, they represent the consequences of motor-sensory axon degeneration (rather than primary demyelination or neuronal cell death) that principally affect the distal ends of the longest motor nerves (CST) and sensory nerves (fasciculus gracilis fibers) in the CNS. As such, many HSPs are thought to represent central nervous system-predominant, motor-sensory distal

axonopathies and considered analogous to CharcotMarie-Tooth (CMT) type 2, a group of inherited disorders in which motor-sensory axonal degeneration is length-dependent and limited to the peripheral nervous system (PNS). Unfortunately, this generalization about HSP neuropathology is based on very few autopsies, many of which were performed on subjects who did not have genetic testing. Indeed, Postmortem analysis has not been performed for the vast majority of HSP genetic types. The extent to which findings from relatively few autopsies can be generalized to all or most types of HSP is not known. The theory (“central dogma”) that HSP represents “CNS-specific, length-dependent axon degeneration” does not explain either the occurrence of HSP as a developmental rather than degenerative disorder; or the extent of additional neurologic involvement in many forms of HSP. SPG1, due to X-linked L1CAM mutation, is an example of disturbed UMN development (axon pathfinding) rather than axon degeneration (Wang et al., 2008). As noted above, the occurrence of peripheral neuropathy in many forms of HSP indicates that axon degeneration is not always “CNS-specific.” Moreover, the occurrence of cerebellar ataxia (e.g., in SPG7 and in many other forms), dementia (e.g., in SPG11 and in many other forms), or retinopathy (e.g., SPG11 and SPG48, Table 3.1) may not be best explained by length-dependent axon degeneration, selectively affecting the longest CNS axons. Furthermore, although the postmortem findings of spinal cord demyelination may be the consequence of axon degeneration, it is well recognized that cerebral white matter abnormalities are present in many forms of complicated HSP (e.g., SPG5/CYPB7, SPG7/Paraplegin, SPG21/Maspardin, and SPG35/FA2H gene mutations, see Table 3.1) (DeMichele et al., 1998; Simpson et al., 2003; Zhao et al., 2008; Dick et al., 2010; Kruer et al., 2010; Warnecke et al., 2010). The extent to which this represents a primary demyelinating process or is secondary to axon degeneration is not clear. Finally, for nearly all of the more than 90 types of HSP, it is not known if axon degeneration represents a mutation-induced, intrinsic axon abnormality; or if axon degeneration represents the consequences of primary disturbance in glia. SPG2 HSP (due to PLP1 gene mutation) represents a type of HSP (Wolf et al., 1993) in which axon degeneration appears to be not “neuron cell autonomous,” but appears to arise because of the intrinsic abnormality in glia (Inoue, 2005).

GENETIC BASIS There are more than 90 different genetic types of HSP, each due to mutation in a separate gene (Table 3.1).

THE HEREDITARY SPASTIC PARAPLEGIAS The finding that
35% of subjects show signs and symptoms of HSP (and for whom alternate disorders are excluded) indicates the need for discovery of additional HSP genes, as well as additional mechanisms for identified genes. These mechanisms may include somatic mutation, gene silencing (epigenetic regulation), lowlevel mosaicism, and mutations involving gene regulatory regions.

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Presently, only symptomatic treatments for HSP are available. These include reducing spasticity, treating urinary (and sometimes fecal) urgency, improving balance, reducing weakness, and addressing secondary orthopedic complications from chronic gait disturbance. HSP is a large group of disorders, some of which include difficulty swallowing (for which parenteral feeding is required) and other neurologic impairments (e.g., seizures or parkinsonism) for which specific interventions are required.

of intrathecal baclofen. The outcome of intrathecal baclofen trials is judged not simply on whether reduced lower extremity spasticity was achieved, but importantly whether gait was improved. It is recommended that an intrathecal baclofen pump be placed only if there was clear evidence that trial injections improved walking. In addition to placement of an intrathecal baclofen pump, surgical approaches to reduce spasticity include selective dorsal rhizotomy and percutaneous tendon lengthening have had benefited, although outcomes of large cohorts of HSP subjects have not been reported. In general, such approaches are considered for subjects in whom spasticity (rather than weakness) is the primary, function-limiting factor, and after nonsurgical approaches have been tried. Weakness, rather than spasticity, is an important, function-limiting factor for many individuals with many types of HSP. In particular, weakness of hip flexion may be most problematic, limiting the ability to stand from sitting and walk even with a walker. Presently, only gradually progressive resistance exercises are known to maintain and hopefully improve strength.

Spasticity treatment

Orthotics

The goal of spasticity treatment is to maintain a range of motion and prevent tendon contracture, which is important for essentially all HSP subjects, particularly those with childhood onset symptoms. Spasticity treatment begins with physical therapy including stretching, focusing on the muscles that are particularly tight (e.g., hamstrings and gastrocnemius-soleus muscles), which can be variable between individuals. It is recommended that stretching be performed for short intervals (3–5 min) and repeated several times a day, supplemented by longer periods of stretching (e.g., yoga exercises) multiple times a week.

Ankle-foot-orthotic (AFO) devices are often helpful in reducing toe dragging. Reducing spasticity (e.g., with Baclofen and Botox) in gastrocnemius-soleus muscles is often needed to make AFOs tolerable and achieve full benefit. Devices that deliver transcutaneous electrical nerve stimulation to achieve foot dorsiflexion (e.g., “Bioness” device and others) may also be helpful. Above the knee braces may be required for individuals with quadriceps hyperextension (“back-kneeing”).

TREATMENT AND PROGNOSIS

Medication The medications used to reduce spasticity include Lioresal (Baclofen), Tizanidine (Zanaflex), and Dantrolene (Dantrium). The use of Dantrolene must include pretreatment and on-treatment monitoring of liver enzymes. In addition to oral medication, botulinum toxin (Botox) injection may be helpful when functionally impairing spasticity particularly involves specific muscles (e.g., gastrocnemius-soleus and adductors). Intrathecal baclofen has been useful to reduce spasticity. This approach is considered when subjects have demonstrated benefit from oral baclofen, but cannot tolerate high oral doses because of fatigue. Intrathecal baclofen is less useful when subjects have marked weakness. In these circumstances, reducing spasticity may limit the ability to stand and transfer. It is important that subjects considering placement of an intrathecal baclofen pump undergo one or more trial injections

Physical therapy Physical therapy for individuals with HSP is considered a cornerstone of maintaining and improving gait, balance, and cardiovascular, orthopedic, and mental health. Surprisingly, despite its enthusiastic adherents and proponents, there is very little objective data showing the effects of physical therapy in subjects with HSP. Recommendations for physical therapy in HSP come mainly from a large amount of anecdotal experience and from studies showing the benefits of physical therapies in other neurodegenerative disorders including Parkinson’s disease and ataxia (Kalyani et al., 2019, 2020; Radder et al., 2020). It is recommended that individuals with HSP participate in daily physical exercise that is individualized, monitored, advanced slowly (over months and years), and becoming increasingly complex. Working with a Physical Medicine and Rehabilitation physician and trained physical therapist, an “exercise prescription” is given and outcomes monitored. Individuals should be told

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to being exercising slowly, increase gradually, and avoid injury. In addition to isolated muscle strengthening and stretching, it is recommended that individuals with HSP participate in complex exercises focusing on agility, speed, gestures, and balance. These include exoskeleton-assisted walking, water aerobics, swimming, dancing, therapeutic horseback riding, and computer-assisted (virtual) exercise games.

Prognosis Only a few generalizations may be made regarding prognosis because HSP is highly variable between genetic types, within a given genetic type, and even between affected individuals in the same family who share the same gene mutation. When HSP begins in very early childhood, there is often no significant functional worsening even over several decades. When HSP begins after early childhood, symptoms typically tend to worsen slowly for a number of years. For many (but not all) subjects, after a number of years of worsening, the rate of functional decline seems to slow. Thereafter, allowing for the effects of age and deconditioning from reduced walking, many of these individuals seem to maintain a relatively similar degree of functional impairment over many years. In general, prognosis is based more on the patient’s demonstrated course and neurologic involvement rather than entirely based on the genetic type of HSP. This recommendation reflects the wide clinical variability between and within genetic types of HSP and the fact that little is known about genotype-phenotype correlation for most types of HSP. Moreover, for the majority of types of HSP, only a small number of families have been described. For these types of HSP in particular, the full spectrum of symptoms and their severity is not known. Therefore, although the general course may be surmised, rather than predicting the development of specific neurologic features or their severity based on the type of HSP, a cautious “wait and see” attitude is recommended.

CONCLUSIONS The HSPs are an extremely large group of disorders in which lower extremity spasticity and weakness (of varying proportion and degree) are either the primary features or important elements in the clinical presentation. Symptoms range from infantile-onset, essentially nonprogressive spastic diplegia, to slowly progressive, relatively isolated spastic gait; and include many other complex neurodevelopmental and neurodegenerative syndromes in which lower extremity spasticity is accompanied by additional neurologic impairments. The differential diagnosis of HSP includes treatable disorders (e.g., including

vitamin B12 deficiency, 5MTHFR deficiency, copper deficiency, and dopa-responsive dystonia); as well as disorders with a significantly different prognosis (e.g., ALS, PLS, and early-onset Alzheimer’s disease due to PS1 or PS2 gene mutation). Though relatively limited, neuropathology studies have shown degeneration that is maximal at the distal ends of the longest motor fibers (CST) and sensory fibers (fasciculus gracilis) in the CNS. These observations give rise to the generalization that at least some of the HSPs represent CNS-predominant leukodystrophy, length-dependent, motor-sensory axonopathy. More than 90 genes have been identified as causing various HSP syndromes.

FUTURE DIRECTIONS The functions of HSP genes (discussed in Refs. Engelen et al., 2012; Fink, 2013; Elsayed et al., 2021; Martinuzzi et al., 2021) implicate a number of different molecular processes including axon transport, cytoskeleton and microtubule stability, endoplasmic reticulum development, vesicle sorting, mitochondrial function, lipid metabolism, and cell signaling. Genetic testing is currently able to provide diagnostic confirmation for many but not all subjects. When a causative mutation is identified, this information can be used for prenatal testing, including preimplantation genetic testing. Future developments identifying causative gene mutations and development of clinically available biochemical analysis for gene variants of uncertain significance will target those subjects that present diagnostic dilemmas. Treatment for HSP is limited to symptom reduction to ameliorate spasticity and urinary urgency, as well as individualized physiotherapy to improve mobility through stretching, strengthening, agility, and balance. Preclinical and experimental animal studies are needed to accelerate pharmacological testing to screen potentially attractive compounds for clinical trials to treat refractory and progressive cases of HSP.

ACKNOWLEDGMENTS This research is supported by grants from the Spastic Paraplegia Foundation and generous support from the Paul and Lois Katzman Family, the Susan Parkinson Foundation, and the Annette Lockwood Family. I am grateful for the support and participation of HSP patients and their family members from whom I have learned about HSP and without whom our investigations would not have been possible.

ABBREVIATIONS AB4B1, adaptor-related protein complex 4, beta-1 subunit; ACO2, aconitase, mitochondrial; ALS, amyotrophic lateral sclerosis; AMPD2, adenosine monophosphate

THE HEREDITARY SPASTIC PARAPLEGIAS deaminase 2; AP4E1, adaptor-related protein complex 4, E1 subunit; AP4M1, adaptor-related protein complex 4, M1 subunit; AP4S1, adaptor-related protein complex 4, S1 subunit; AP5Z, adaptor-related protein complex 5, zeta-1 subunit; ARL6IP1, ADP-ribosylation factor-like GTPase 6-interacting protein 1; ARSI, arylsulfatase I; ATP13A2, ATPase 13A2; B4GALNT1, beta-1,4-N-acetylgalactosaminyltransferase 1; C12ORF 65, chromosome 12 open reading frame 65; C19orf12, chromosome 19 open reading frame 12; CAPN1, calpain 1; CNS, central nervous system; CRASH, corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus; CYP2U1, cytochrome P450, family 2, subfamily U, polypeptide 1; CYP7B1, cytochrome P450 family 7 subfamily B member 1; DARS2, aspartyl-tRNA synthetase 2; DDHD1, aspartate ( D) aspartate (D) histidine (H) aspartate (D) domain containing protein 1; DDHD2, aspartate (D) aspartate (D) histidine (H) aspartate (D) domain Containing protein 2; DSTYK, dual serine/ threonine and tyrosine protein kinase; ENTPD1, ectonucleoside triphosphate diphosphohydrolase; ERLIN1, endoplasmic reticulum lipid raft-associated protein 1; FAM134B, family with sequence similarity 134, member B; FARS2, phenylalanyl-tRNA synthetase 2, mitochondrial; FLRT1, fibronectin-like domaincontaining leucine-rich transmembrane protein 1; GAD1, glutamate decarboxylase 1; GBA2, glucosidase, beta, acid 2; Gba2; GJA/GJC2, gap junction protein A, gap junction protein C2; GPT2, glutamate pyruvate transaminase 2; HPDL, 4-hydroxyphenylpyruvate dioxygenase-like; HSP, hereditary spastic paraplegia; IBA57, iron-sulfur cluster assembly factor Iba57; ICRD, infantile cerebellar retinal degeneration and isolated optic atrophy (Opa9; 616289); KIAA1840, Kazusa Cdna project identified cDNA (KIAA) 1840; KLC2, kinesin light chain 2; KLC4, kinesin light chain 4; KY, kyphoscoliosis peptidase; L1CAM, L1 cell adhesion molecule; LBSL, leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation; MARS1, methionyl-tRNA synthetase 1; MASA, mental retardation, aphasia, shuffling gait, and adducted thumbs; Mitochondrial ATP6, ATP synthase 6; Mitochondrial TRMT5, tRNA methyltransferase 5; MRI, magnetic resonance imaging; NT5C2, 5-prime-nucleotidase, cytosolic II; OMIM, on line mendelian inheritance in man; OPA9, optic atrophy, type 9; PARK14, Parkinson’s disease 4; PCYT2, phosphate cytidylyltransferase 2, ethanolamine; PGAP1, post-GPI attachment to proteins 1; PLA2G6, phospholipase A2, group Vi; PMLD, Pelizaeus-Merzbacher like disease; POLR3A, polymerase Iii, RNA, subunit A; RAB3GAP2, Rab3 GTPase-activating protein, noncatalytic subunit; REEP2, receptor expression-enhancing

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protein 2; RNASEH2B, ribonuclease H2, subunit B; SELENOI, selenoprotein I; SERAC1, serine active site-containing protein 1; SPOAN, spastic paraplegia associated with optic atrophy, neuropathy; TECPR2, tectonin beta-propeller repeat-containing protein 2; UCHL1, ubiquitin carboxyl-terminal esterase L1; USP8, ubiquitin-specific protease 8; VPS53, vacuolar protein sorting 53; VSP37A, vacuolar protein sorting 37; WDR48, tryptophan (W)-aspartic acid (D) repeat containing protein 48; ZFR, zinc finger RNA-binding protein; ZFYVE26, zinc finger Fyve-type containing 26.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00021-1 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 4

Primary lateral sclerosis SINA MARZOUGHI1, GERALD PFEFFER2, AND NEIL CASHMAN1⁎ 1

Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada 2

Department of Neurosciences, Division of Neurology, University of Calgary, Calgary, AB, Canada

Abstract Like motor neuron diseases (MNDs) refer to a constellation of primarily sporadic neurodegenerative diseases characterized by a progressive loss of upper and/or lower motor neurons. Primary lateral sclerosis (PLS) is considered a neurodegenerative disorder that is characterized by a gradually progressive course affecting the central motor systems, designated by the phrase “upper motor neurons.” Despite significant development in neuroimaging, neurophysiology, and molecular biology, there is a growing consensus that PLS is of unknown etiology. Currently there is no disease-modifying treatment for PLS, or prospective randomized trials being carried out, partly due to the rarity of the disease and lack of significant understanding of the underlying pathophysiology. Consequently, the approach to treatment remains largely symptomatic. In this chapter we provide an overview of primary lateral sclerosis including clinical and electrodiagnostic considerations, differential diagnosis, updates in genetics and pathophysiology, and future directions for research.

INTRODUCTION The term motor neuron diseases (MNDs) refer to a constellation of primarily sporadic neurodegenerative diseases characterized by a gradual loss of upper and/or lower motor neurons. MNDs are generally classified into three phenotypes based on their clinical features including most common amyotrophic lateral sclerosis (ALS) which involves a combination of upper and lower motor neuron features, progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). Charcot first described amyotrophic lateral sclerosis (ALS) in 1865 but it was not until later (1875) when Erb described a phenotype characterized by pure involvement of the corticospinal tracts named “spastic spinal paralysis” (Eisen, 2007). However, the description of the first case of ALS by Charcot may have been a description of primary lateral sclerosis (PLS). The PLS is considered a neurodegenerative disorder characterized by a

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gradually progressive course affecting the central motor systems. The PLS is considered a rare disorder, although recently the prevalence is estimated to be around 0.046 and 1.896 in two Spanish regions (Catalonia and Valencia) and incidence of 0.202 per 100,000 personyears (Barceló et al., 2021). The clinical course of PLS is classically described by progressive muscle stiffness that progresses to compromise mobility and typically involves corticobulbar dysfunction. Although it may share clinical features with ALS, there is a lack of a development of lower motor neuron features throughout the clinical course. Interestingly, similar to PLS, ALS phenotypes that are more upper motor neuron (UMN) predominantly tend to progress at a slower rate compared with more typical forms of ALS, with prolonged survival (Chiò et al., 2011). Consequently, the most recent criteria for a definitive diagnosis of PLS require a minimum duration of symptoms of 3–5 years (Turner et al., 2020).

Correspondence to: Neil Cashman, MD, FRCPC, DMCBH Koerner Labs, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. Tel: +1-604-822-2135, Fax: +1-604-822-7299, E-mail: [email protected]

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Based on the most recent consensus diagnostic criteria (Turner et al., 2020) for PLS, there is a requirement for both “core criteria” including age equal to or greater than 25 years, symptoms of progressive UMN dysfunction for at least 2 years, signs of UMN dysfunction in at least two of three regions (lower extremity, upper extremity, bulbar), without sensory symptoms (unexplained by a comorbid condition), active LMN degeneration, or an alternative diagnosis. The criteria for a diagnosis of PLS have evolved over the years with the original 1945 Pringle criteria suggesting a 3-year minimum duration of symptoms (Pringle et al., 1992). In 2006, Gordon et al. proposed a duration of 4 years of symptoms to confirm a diagnosis. The most recent criteria from 2020 have introduced the entity “probable PLS” for patients presenting with an isolated UMN symptoms for 2–4 years. The differential diagnosis for PLS is difficult because several conditions mimic some aspects of the disease. The greatest phenotypic overlap exists with hereditary spastic paraparesis (HSP) particularly in the early phase of lower extremity onset PLS (Fink, 2001). Clinically differentiating PLS from HSP can be very challenging, especially when HSP presents in later adulthood, most commonly seen with spastic paraplegia types 4 and 7 (Almomen et al., 2019). However, over the course of clinical follow-up HSP can generally be distinguished because of its slow progression, absence of bulbar involvement, and single gene mutations on panel testing. Other mimics of PLS can be subdivided into: (1) neurodegenerative disorders (e.g., UMN-variant ALS, HSP), (2) neuroinflammatory diseases (e.g., primary progressive multiple sclerosis, antiamphiphysin paraneoplastic syndrome), (3) metabolic disorders (adrenomyeloneuropathy), (4) infections such as human T-cell leukemia virus type 1 and 2 (HTLV1, 2) and neurosyphilis, in addition to other brain and spine structural abnormalities, most of which are relatively easily “ruled out” by brain and spine imaging as well as cerebrospinal fluid analysis. Despite significant improvements and development in neuroimaging, neurophysiology, and molecular biology, there is ongoing consensus that PLS represents a distinct clinical entity of unknown etiology. Although one study has outlined a Canadian pedigree of a phenotypically consistent familial UMN syndrome (Dupr
e et al., 2007), there have been no other specific genes associated with PLS or any recognized environmental risk factors (Turner and Talbot, 2020). In this chapter, we aim to review the main clinical description of PLS, biochemical and imaging investigations to consider current understanding of potential processes that contribute to neurodegeneration in motor neuron disease in addition to symptomatic management of the condition.

CLINICAL DESCRIPTION Considering motor neuron disease as a whole, there are a variety of recognized phenotypes of ALS, clinically speaking, that can be differentiated based on the original site of onset (i.e., bulbar, spinal, respiratory), and the involvement of cognitive symptoms (i.e., ALS with frontotemporal dementia or ALS-FTD) (Al-Chalabi et al., 2016). In a recent study analyzing the incidence and prevalence of MND including ALS, PLS, and PMA, ALS has been found to be the most frequent, making up 85.5%–96.7% of all MND patients. Although there have been no major large-scale epidemiological studies on PLS, the incidence was recently estimated to be 0.2–0.6 per 100,000, suggesting a higher incidence than the previous studies have reported (Turner and Talbot, 2020). PLS is classically considered an adult-onset disease with a mean age of onset of about 50 years, which is approximately 10 years younger than those with typical ALS (Turner and Talbot, 2020). It can present with insidious symptomatology, with the deficits only noticeable once spasticity has a profound effect on ambulation and functional status. Most symptoms begin in the lower extremities with initial imbalance and falls sometimes reported. Infrequently, there can be a corticobulbar presentation with spastic dysarthria and pseudobulbar affect. In a large cohort of 41 PLS patients, only 6 patients did not have any dysarthria or dysphagia (Mitsumoto et al., 2015). There is typically spastic tone with increased reflexes on the examination and quite often can be symmetric involving the lower extremities. The condition progresses gradually over time, although patients with PLS and isolated UMN involvement have slow progression and do not convert to ALS, even after extended disease duration (Hassan et al., 2021). Unlike ALS, a presentation involving a unilateral upper limb as onset of symptoms is atypical in PLS (Zhai et al., 2003). An extremely rare variant of ALS known as the “Mills hemiplegic variant” can present with bulbar systems and subsequently followed by a gradually ascending or descending hemiplegic pattern. Although there is motor weakness, the main functional deficits result from significant spasticity in dexterity and gait. Patients with PLS rarely get muscle atrophy and if at all, it is typically a late feature. Some have reported characteristics of atypical Parkinson disease (PD) in patients diagnosed with PLS (Norlinah et al., 2007; Wolf Gilbert et al., 2010). Although uncommon, in a large prospective study analyzing a cohort of 41 patients diagnosed with clinically typical PLS, mutations in the PARK2 gene (p.Arg275Trp) was found, which has previously been described in relation to familial PD (Mitsumoto et al., 2015). The same

PRIMARY LATERAL SCLEROSIS study also identified another pathogenic mutation of the DCTN1 gene (Vilariño-G€ uell et al., 2009), which has previously been reported in a sporadic case of ALS (Mitsumoto et al., 2015). Frontotemporal dementia (FTD) has also been reported coincident with PLS (de Vries et al., 2017). This is noteworthy because of FTD’s place in the disease spectrum with ALS, although the coexistence of FTD with PLS is much less frequent than with ALS (de Vries et al., 2017). There do however appear to be patterns of cognitive involvement that suggest similarities with ALS-FTD, albeit with much slower progression. The extent of cognitive changes described in recent studies of PLS patients suggests that PLS should not be considered a single system pyramidal disorder (Finegan et al., 2021). In addition to the typical progressive motor symptoms with lack of sensory symptoms or findings, increased urinary frequency and retention may also be seen in PLS. Unlike ALS, respiratory symptoms are not typically observed in PLS, and forced vital capacity (FVC) is not reduced (Gordon et al., 2009).

NEUROPATHOLOGY Given the rarity of the disease, few reports of the neuropathological characteristics of PLS exist, with the majority being prior to the existence of modern diagnostic methods (Mackenzie, 2021). Most case series on postmortem/autopsies in PLS describe loss of Betz cells and chronic neurodegenerative changes in the primary motor cortex (PMC), corticospinal tract (CST) with relative sparing of the LMN. Although some cases have not shown changes in the primary motor cortex, most have shown involvement of the CST and corresponding pathology extending into the upper brainstem and internal capsule. Based on a most recent review on PLS neuropathology, it appears that the majority of cases are significant for a cortical TDP-43 ubiquitin immunoreactive (-ir) pathology as the substrate for the UMN degeneration and symptoms (Mackenzie, 2021). Interestingly, nearly half also show TDP-43-ir neuronal cytoplasmic inclusion bodies (NCI) in LMNs, which may suggest a neuropathological overlap with classical ALS. However, rather than suggesting that ALS and PLS are on a disease continuum, this may suggest that PLS is a forme fruste of ALS. In cases of more early onset ALS with LMN features, neuropathological findings show advanced LMN pathology at the time of LMN symptoms (Mackenzie, 2021). Since the recognition that TDP-43 pathology occurs in PLS, several autopsy case reports have been published on clinically definite PLS. One case reported had a disease duration of 9 years with

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pathology finding of PMC and CST degeneration but preservation of LMN without Bunina bodies or TDP43-ir-inclusions (Murray et al., 2011).

ELECTROPHYSIOLOGY Given the possibility of a late onset of LMN dysfunction in some cases of ALS, numerous diagnostic criteria have been proposed for electromyography of PLS (Turner et al., 2020). In addition, several cases of PLS have demonstrated minimal and nonprogressive electromyographic (EMG) changes suggestive of muscle denervation (Pringle et al., 1992; Kuipers-Upmeijer et al., 2001; Le Forestier et al., 2001). As such, EMG abnormalities seen in PLS have ranged from “at most, occasional fibrillation and increased insertional activity in a few muscles” (Pringle et al., 1992) to subdividing PLS patients into categories based on the presence or absence of EMG findings (Singer et al., 2007). However, a consensus exists that patients with only minor denervation in a single muscle should continue to be classified as a pure UMN syndrome. Generally, the findings are minor and nonprogressive which can be observed with follow-up neurophysiology studies (Silva et al., 2021). A case series of 25 patients with PLS found abnormal nerve conduction studies (NCS) in only one patient with evidence of diabetic polyneuropathy, and two patients with median nerve mononeuropathy (Singer et al., 2005). In addition, 10 patients showed evidence of mild active denervation on needle EMG with rare fibrillation potentials and/or positive sharp waves. None of the patients satisfied the El Escorial World Federation of Neurology electrophysiological criteria for ALS.

NEUROIMAGING MRI Although most MND MRI studies are focused on ALS, many of the same techniques and methodological characteristics of those studies can inform imaging features of PLS (Pioro et al., 2020). In addition, several dedicated imaging studies have investigated changes seen in structural, functional, and metabolic profiles in PLS. Specifically, several case reports and a small case series have shown atrophy of the precentral gyri in PLS with a “knife edge” appearance of adjacent gyri (Singer et al., 2007). In addition, a significant degree of atrophy has been observed in PLS with involvement of the underlying white matter, which can also extend more anteriorly in the frontal lobe (Kuipers-Upmeijer et al., 2001). Other MRI features have included T2/FLAIR hyperintensities in the brain and spinal cord with a “funnel-like” appearance when viewed from a sagittal perspective.

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In contrast with MRI changes of the corticospinal tracts, there is no consensus on reported PLS imaging abnormalities in subcortical and lentiform nuclei. Given predominant white matter changes in PLS, a host of studies have looked at diffusion tensor imaging protocols which have consistently shown CST pathology in addition to cerebellar and corpus callosum involvement (Iwata et al., 2011; Tzarouchi et al., 2011; Chipika et al., 2019). Other studies looking at subcortical gray matter involvement have shown that there is more amygdala involvement in ALS as compared with PLS (Chipika et al., 2019). Although small in number, several studies have used MR spectroscopy and functional MRI to demonstrate reduced N-acetylaspartate (NAA)/creatine (Cr) ratios and increased myo-inositol/Cr ratios which are suggestive of neuronal dysfunction and gliosis, respectively (Zhai et al., 2003; Van Der Graaff et al., 2010). Interestingly, a greater degree of network functional connectivity is seen in both PLS and ALS in functional MRI (fMRI) studies, which is believed to be secondary to an adaptive/ compensatory process (Agosta et al., 2014; Abidi et al., 2020). It is important to note that spinal cord hyperintensities along the pyramidal tracts is very rare in PLS and should raise concern for an alternate etiology such as primary progressive MS (PPMS). There are currently no prospective spinal cord imaging studies on PLS (Pioro et al., 2020).

Positron emission tomography In contrast to ALS, there are relatively few PET studies published on PLS. One method using [18F]-fluoro-2-deoxy-D-glucose PET ([18F]-FDGPET) assess glucose metabolism of neurons and glial cells. In addition, other PET ligands including [11C]flumazenil can be used to illustrate cortical neuronal dysfunction (Claassen et al., 2010) and specifically to demonstrate upper motor neuron degeneration in PLS patients in areas including the pericentral cortex and PMC. Some reports of a restricted hypometabolism pattern to the PMC in patients with different degree of lower and upper limb spasticity (Claassen et al., 2010). In one study, a group of 70 ALS patients were compared with a smaller group of PLS patients (7) and ALS patients were found more likely to have hypometabolism in the prefrontal cortex and posterior cingulate (Van Laere et al., 2014). In the same study, using a posteriori corrected discriminant analysis, 95% of ALS cases were correctly identified using PET imaging as compared with 71% of PLS cases. Although other case reports have illustrated severe bilateral hypometabolism in the primary motor cortex (Cosgrove et al., 2015), this pattern does not appear to

be specific to PLS and may also be seen in ALS (Claassen et al., 2010; Van Laere et al., 2014). Given the clinical ambiguity that can exist in differentiating pure PLS from other motor neuron disease syndromes including ALS and the group of HSPs, PET may be one tool that we may be able to use in the future for diagnostic clarity. However, given similar patterns that may also be observed in other neurodegenerative processes, ultimate diagnosis should be based on the clinical presentation, disease course, and a combination of biochemical and imaging investigations to rule out other PLS mimics.

DIFFERENTIAL DIAGNOSIS PLS remains a clinical diagnosis and primarily a diagnosis of exclusion. In addition, throughout the disease course, there is always the possibility of conversion to ALS that can occur several years after the onset of symptoms. The main considerations for a differential diagnosis of PLS including primary progressive multiple sclerosis (PPMS), infectious etiologies including HTLV-1 and HTLV-2 myelopathy, genetic causes such as the hereditary spastic paraplegias and some genetic forms of ALS, in addition to spondylotic compressive myelopathy and vascular malformation of the spinal cord. A common mimic of PLS is cervical spondylosis as its presentation can represent early manifestations of PLS resulting in a spastic myelopathy with spasticity and hyperreflexia in the lower extremities. In addition, given the prevalence of MRI changes in the spine in the age group of PLS, it can be difficult to determine the relevance of radiological findings. The primary progressive form of multiple sclerosis can likewise present with a spastic paraparesis but may also include cerebellar dysfunction, hemiplegia, brainstem syndromes, visual loss, and cognitive decline (Montalban, 2005). Brain and spine MRI can typically differentiate PLS from demyelinating etiologies given prominent T2/FLAIR hyperintensities. Infectious etiologies such as HTLV-1 and HTLV-2 myelopathy can result in spastic paraparesis which may clinically present similarly to PLS. Typically this is a chronic progressive myelopathy resulting in spastic paraparesis in addition to sphincter dysfunction and paresthesia. HTLV myelopathy can be confirmed with serologic testing with reactive ELISA tests for HTLV-1 or HTLV-2 and confirmed by positive western blot assays. Inherited etiologies include a large group of disorders known collectively as the hereditary spastic paraplegias (HSPs) covered in Chapter 3. These are generally classified by the mode of inheritance, the locus of the HSP, or whether it is isolated or part of a neurological syndrome

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Table 4.1 The differential diagnosis of primary lateral sclerosis Etiology

Disease type

Clinical and investigative features

Structural and compressive Compressive myelopathy etiologies Foramen Magnum compression (tumor, Chiari malformation, basilar invagination) Spinal cord compression (spondylosis, intervertebral disc herniation, syringomyelia, tumor) Brain involvement Traumatic brain injury Parasagittal Meningioma Vascular Spinal Arteriovenous Malformation Spinal dural arteriovenous fistula Spinal epidural hemorrhage Spinal infarction Infectious Tropical Spastic Paraparesis (Human T-cell lymphotropic virus, HTLV-1 & HTLV-2) HIV Neurosyphilis Genetic Metabolic disorders Adrenomyeloneuropathy and rarely, late-onset presentations of inborn errors of metabolism Degenerative disorders Hereditary Spastic Paraparesis (most commonly type 4 or 7 for late-onset presentations) Spastic ataxias (e.g., autosomal recessive spastic ataxia of Charlevoix-Saguenay) Friedreich ataxia Adult-onset Alexander Disease or other late-onset leukodystrophy presentations Neuroinflammatory Primary Progressive Multiple Sclerosis Paraneoplastic syndromes Mixed connective tissue disease

Spine and Brain MRI Imaging

Step-wise decline Spine MRI imaging

Serology testing

Brain MRI white matter abnormalities Elevated serum levels of long chain fatty acids Pathogenic variant of ABCD1

Demyelinating changes on spine MRI Positive antiamphiphysin antibodies

Metabolic/nutritional/toxic Vitamin B12 deficiency Nitrous oxide toxicity Cu deficiency

(Fink, 2006). Clinically, they present predominantly with signs and symptoms of hereditary spastic paraplegia with bilateral lower extremity weakness and spasticity (Hedera, 2021) although there is considerable variability in the degree of weakness and spasticity in each patient. Patients often have lower extremity hyperreflexia and extensor plantar responses on exam. Genetic causes of HSP include autosomal dominant HSP which affects most patients. In contrast, autosomal recessive HSP is quite rare and more likely seen in higher consanguinity families. Other etiologies to consider include structural lesions such as foramen magnum region lesions, parasagittal meningiomas, and vascular etiologies, including a spinal arteriovenous malformation that often presents in a step-

wise decline fashion (Turner and Talbot, 2020). A comprehensive list of the differential diagnosis for PLS can be found in Table 4.1.

NEURODEGENERATION AND RELATION TO MOTOR NEURON DISEASE Although a variety of risk factors have been identified in ALS, the same have not been associated with PLS in studies although this may be due to the rare nature of the condition. The risk factors include smoking (Weisskopf et al., 2009), agricultural chemicals (Ward et al., 2014), heavy metals (Kamel et al., 2002), low frequency electromagnetic waves (Zhou et al., 2012), as well as extreme athletics (Zhang et al., 2014). The etiology

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of the neurodegenerative process behind PLS and other motor neuron diseases including ALS is unknown. However, a wide variety of mechanisms including abnormal processing of RNA, protein quality control disorders, excitotoxicity, cytoskeletal derangements, mitochondrial dysfunction, viral infections, and inflammatory responses have been proposed as potentially contributing to the pathophysiology (Peters et al., 2015). Excess glutamate may have neurotoxic effects with accumulation at the synapses which may contribute to neurodegeneration in both ALS and other motor neuron diseases such as PLS (Rojas et al., 2020). In patients with motor neuron disease of different types as well as a superoxide dismutase 1 (SOD1) transgenic mouse model, a reduction in glutamate receptors (GluRs) has been reported in astrocytes resulting in the accumulation of glutamate at the synapse, overstimulation of GluRs, and excitotoxicity-induced apoptosis (Pratt et al., 2012). There has been an increasing amount of evidence that alterations in the processing and aggregation of abnormal proteins through altered RNA processing may have a major role in the pathogenesis of MND, specifically ALS (Ito and Suzuki, 2011; Verma and Tandan, 2013). A variety of RNA binding proteins are coded by variants in several genes including TDP-43 and FUS. Of note, studies have suggested that these proteins can behave in a “prion-like” manner with an intrinsic ability to selfaggregate and spread (Polymenidou and Cleveland, 2011). Furthermore, it is thought that they contain prion like domains which can promote inclusion of proteins into granules that can be difficult to degrade and ultimately lead to the formation of cytoplasmic inclusions and neurodegenerative disease. TDP-43 inclusions have been observed in motor cortical neurons in PLS, as an exemplar of such proteinopathy. However, we should note that these mechanisms have all been studied in the context of ALS. Whether or not PLS follows these same mechanistic features and how it differs are not known. A common disturbance in motor neuron disease includes mitochondrial dysfunction such as fragmentation and aggregation (Cozzolino and Carrì, 2012) with an increase in the misfolded non-SOD1 (including SOD2) mitochondrial enzyme in the spinal cord in animal models. In addition, both retrograde and anterograde axonal transport can be impaired in ALS patients including in mutant SOD1 mice, evident from the excess altered structures including mitochondria, neurofilaments, and autophagosomes seen on pathology (Zarei et al., 2015). Accumulation of abnormal proteins are thought to also contribute to the pathogenesis of motor neuron disease (Blokhuis et al., 2013). The ubiquitinproteasome (UP) complex, involved in the repair and

removal of proteins, may have an important role given the finding of ubiquitin reactive inclusions being characteristic in the pathology (Pratt et al., 2012). Specifically, inclusions of TDP-43 and p62 have been indicative of this pathology (Williams et al., 2016). Interestingly, in the discussion of neurodegeneration regarding motor neuron disease, Bak et al. described the systematic nature of spread in MND with respect to the anatomically and functionally related neurons in the nervous system (Bak, 2012). It is suspected that MND may start focally in the nervous system and spread elsewhere through nearby anatomically and functionally connected neurons (Shaw, 2005). Overall, the mechanisms that underlie MND are most likely multifactorial and the exact mechanism that triggers and mediates cell death is still unknown, including in PLS. There is likely a significant relationship between genetic factors, oxidative stress, excitotoxicity, protein aggregation, and damage to cellular processes and other mechanisms mentioned here that contributes to neurodegeneration in MND.

GENETICS OF PRIMARY LATERAL SCLEROSIS Although PLS has been considered an exclusively sporadic motor neuron disease, there have been some identification of PLS cases within pedigrees with familial forms of amyotrophic lateral sclerosis (Silani et al., 2021). This combined with the clinical and neuropathological overlap with neurodegenerative conditions such as ALS and HSP suggest that there may potentially be a genetic component in PLS. Interestingly, there has been an observance of the occurrence of ALS and PLS phenotypes within the same family pedigrees. Although rare, there have been genetic studies illustrating a minimal amount of genetic overlap (Silani et al., 2021). Although many ALS-associated genes exist including SOD1, TARDBP, FUS, and C9orf72, only the (G4C2)n hexanucleotide repeat expansion in C9orf72 has been reported in PLS patients (Van Rheenen et al., 2012; Mitsumoto et al., 2015). It is possible that other genetic conditions are underreported as causes of PLS-like syndromes, due to PLS clinical criteria that previously required sporadic disease without family history (Pringle et al., 1992). As previously mentioned, the HSPs are a collection of heterogeneous genetic neurodegenerative diseases that clinically are characterized by progressive spasticity of the lower extremities with associated corticospinal tract dysfunction and degeneration. They are distinguished from PLS by the lack of involvement of the upper limbs and bulbar regions but still do have considerable overlap with the PLS syndrome (Silani et al., 2021). There have been more than 70 loci and genes that have now been

PRIMARY LATERAL SCLEROSIS linked with HSP which have a phenotype similar to many neurodegenerative diseases including motor neuron disease (Parodi et al., 2018). In addition, in-depth analysis of these studies suggest a significant degree of overlap between the genetic characteristics of HSP and ALS (Novarino et al., 2014). Although a study looking at a small cohort of 8 PLS patients in the UK did not find any mutations in the SPAST and SPG7 genes (associated with HSP) (McDermott et al., 2009), a sequencing study on 41 patients was able to identify a p.A510V heterozygous mutation in SPG7 in a patient with clinically definitive PLS (Mitsumoto et al., 2015). Adult-onset familial PLS appears to have some connection with the SPG7 mutation as some exome sequencing studies have illustrated compound heterozygous missense variants p.L695P and p.I743T in SPG7 in a PLS family with five affected siblings (Yang et al., 2016). Another small study identified mutations in SPG7 or SPAST in two patients previously diagnosed with PLS, emphasizing the challenges of distinguishing PLS from late-onset HSP (Almomen et al., 2019). Among causes of HSP, the most common genetic diseases (types 4 and 7, respectively, due to mutations in SPAST and SPG7) are also most likely to have very late-onset clinical presentations (Sch€ule et al., 2016). The extent of the association between HSP-related genetic mutations causing a PLS phenotype is considered to be quite rare but may be underreported. It is also important to consider that many cases of HSP do not have identified gene mutations, and may present in a disease spectrum with PLS that shares many similarities in terms of onset age and symptom progression (Brugman et al., 2009). Additional research is necessary to better understand the distinctions between these sporadic upper motor neuron syndromes. Given the rarity of the disease, very few have systematically studied a large cohort of patients with PLS using modern next-generation sequencing technologies. One particular study has found a pathogenic mutation in C9orf72 and SPG7 genes in two sporadic patients in addition to other variants of interest including p. T1249I in DCTN1 (Mitsumoto et al., 2015), which has been described in sporadic ALS (M€ unch et al., 2004). Although PLS is historically believed to be an adultonset sporadic disease, there have been reports of an isolated upper motor neuron (UMN) syndrome in children within certain pedigrees that have been consistent with an autosomal recessive inheritance (Grunnet et al., 1989; Lerman-Sagie et al., 1996; Gascón et al., 2008). The phenotype of these conditions has been reported to present with progressive degeneration of the corticospinal and corticobulbar tracts starting in the first two decades with progression to a spastic tetraparesis with involvement of the bulbar region and spared

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cognition. However, a gaze paresis has been shown in juvenile PLS (JPLS) patients (Gascon et al., 1995; Mintchev et al., 2009). Another gene implicated in JPLS has been the ALS2 syndrome associated with tripletrepeat expansions in the protein Alsin (Panzeri et al., 2006; Mintchev et al., 2009). In addition, disruption of both allele copies of Alsin is causative for ALS2; a juvenile-onset ALS phenotype which is a combination of upper and lower motor neuron degeneration (Silani et al., 2021). Due to a multitude of factors including the rarity of the disease, previous diagnostic criteria that required the absence of family history for motor neuron disorders (Pringle et al., 1992), genetic screening has not traditionally been routinely done and studies are lacking using next-generation sequencing methods in PLS (Silani et al., 2021). However, with new sequencing methods and ongoing developments in genetic diagnostic methods alongside greater international collaborative efforts will lead to greater insights into the genetics of the condition and possible overlap between the HSPs and other motor neuron disease syndromes.

TREATMENT Currently there are no disease-modifying treatments for PLS or prospective randomized trials being carried out, partly due to the rarity of the disease and lack of significant understanding of the underlying pathophysiology. Consequently, the approach to treatment remains patient-based and largely symptomatic. Generally, several features of the condition require symptomatic treatment including fatigue, spasticity, pseudobulbar palsy, pain, depression, bladder and bowl dysfunction, and sexual dysfunction. Similar to the approach of ALS treatment, a multimodal and multidisciplinary approach should be taken toward patient care, involving professionals in specialties including psychiatry, physiatry, and other professionals as needed depending on the patient’s needs. Evidence from patients with ALS indicates that multidisciplinary care improves quality of life and survival (Rooney et al., 2015; Paipa et al., 2019), and it stands to reason this may also be true for other motor neuron disorders. Treatment of spasticity includes using a variety of pharmacological interventions including baclofen, diazepam, gabapentin, and dantrolene. In related conditions that cause spasticity due to neurodegenerative processes such as HSP, there have been studies investigating the role of dalfampridine (4-aminopyridine) in an open label trial which has demonstrated some benefits (B
ereau et al., 2015). For very severe spasticity, intrathecal baclofen can be considered to reduce significantly high tone

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and associated pain and functional decline. In addition, botulin toxin injections may be effective for patients with a significant degree of focal spasticity in a particular muscle group. In a study with botulinum toxin injections in patients with SPG4, SPG3A, and SPG8, efficacy was shown in improvement with respect to gait velocity, reduced spasticity while preserving strength and balance function (De Niet et al., 2015). Bilateral upper motor neuron (UMN) of the corticobulbar tract lesions and dysfunction can result in pseudobulbar palsy which is commonly encountered in PLS and characterized by dysarthria, dysphagia, facial weakness, and emotional lability (Saleem and Munakomi, 2022). There are a variety of therapies targeted at different features of pseudobulbar palsy including physiotherapy, swallowing function training, and pharmacological therapy including with nifedipine and metoclopramide. For emotional incontinence, a combination of dextromethorphan and quinidine has been shown to be effective with respect to reducing the frequency and severity of laughing and crying behavior. Agents such as oxybutynin can be helpful in treating urinary urgency and frequency. Finally, communication devices that augment patient’s ability to communicate using computer interfaces and communication boards are often helpful in PLS as well. Currently there are no disease-modifying therapies for PLS, and there are special challenges with PLS that will complicate clinical trial design. Some of these include the rarity of PLS, the very slow progression, heterogeneity between patients, and incomplete knowledge regarding natural history of the disease. The possibility of overlap with other disorders such as undiagnosed HSP may be a concern at centers where genetic testing is not readily available. The lack of biomarkers for this condition is a major limitation, although as discussed above, progress is being made in neuroimaging and with potential biofluid markers. It is also uncertain which rating scale may be preferred as the clinical metric although the recently developed PLS functional rating scale (PLS-FRS) may be preferred (Mitsumoto et al., 2015). Recommendations for clinical trial design focused on PLS have recently been published (Floeter et al., 2020).

CONCLUSIONS Primary lateral sclerosis remains a fascinating but rare neurological disease entity for which the pathophysiology has not yet been delineated. Although there are a select group of conditions that can mimic this disease, most can be differentiated based on imaging and other basic investigations such as cerebrospinal fluid analysis. Many factors about the condition have resulted in

research being difficult including the rarity of the disease and recent advances in the field of genetics which have historically not been applied to PLS, given the belief that it is largely a sporadic condition. However, at this point (in time), exciting developments in the field of genetic sequencing have led to the collection of a large cohort of PLS patients and DNA and biosamples for more advanced genetic analysis (Silani et al., 2021). These large databases will require international collaboration and the use of the most recent next-generation sequence-based strategies to search for disease-associated variants. In addition, other advances within the domain of neurodegeneration and motor neuron disease such as ALS will undoubtedly also be applied to PLS. In the meantime, a patient-centered and multidisciplinary model of care is required for symptomatic treatment of patients with PLS.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00020-X Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 5

Transverse myelitis in children and adults ELEONORA AGATA GRASSO, VALERIA POZZILLI, AND VALENTINA TOMASSINI* Department of Neurosciences, Imaging and Clinical Sciences, Institute of Advanced Biomedical Technologies (ITAB), University G. d’Annunzio of Chieti-Pescara, Chieti, Italy

Abstract Transverse myelitis is a noncompressive myelopathy of inflammatory origin. The causes are broad, ranging from infective or toxic to immuno-mediated etiology. They can be manifestations of systemic diseases, such as sarcoidosis and systemic lupus erythematous, or phenotypes of neuroinflammation; in a portion of cases, the etiology remains unknown, leading to the designation idiopathic. The clinical presentation of transverse myelitis depends on the level of spinal cord damage and may include sensorimotor deficits and autonomic dysfunction. The age of onset of the disorder can impact the symptoms and outcomes of affected patients, with differences in manifestation and prognosis between children and adults. Spinal cord magnetic resonance imaging and cerebrospinal fluid examination are the main diagnostic tools that can guide clinicians in the diagnostic process, even though the search for antibodies that target the structural components of the neural tissue (anti-aquaporin4 antibodies and anti-myelin-oligodendrocyte antibodies) helps in the distinction among the immune-mediated phenotypes. Management and outcomes depend on the underlying cause, with different probabilities of relapse according to the phenotypes. Hence, immunosuppression is often recommended for the immune-mediated diseases that may have a higher risk of recurrence. Age at onset has implications for the choice of treatment.

INTRODUCTION Myelopathies can be broadly divided into compressive and noncompressive (Fig. 5.1). Compressive myelopathies may be secondary to trauma, disc herniation, or extraspinal tumors. Noncompressive myelopathies include a variety of spinal cord conditions with vascular, metabolic, neurodegenerative, infectious, and immunemediated etiologies. Transverse myelitis (TM) is a subtype of noncompressive myelopathy of inflammatory origin. It presents with a variety of symptoms including motor and sensory deficits and autonomic dysfunction. Spinal cord magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination are the main tools that guide clinicians in the diagnostic process (Borchers and Gershwin, 2012). This chapter reviews myelitis of infectious and noninfectious etiology in adults and

children with an emphasis on diagnosis, characterization of the proximate cause, and treatment.

INFECTIOUS MYELITIS Infectious pathogens affect the spinal cord through both a direct pathogenic effect and an immune-mediated mechanism, which usually occurs with symptoms manifesting weeks after the infection. Infectious myelitis is suspected when the onset of symptoms develops in hours to days. Symptoms include systemic illness (i.e., fever, gastrointestinal, or respiratory involvement) that precede or accompany specific spinal cord dysfunction (Román and Kerr, 2003). Compared to immune-mediated myelitis, infectious myelitis is usually monophasic, with low risk of occurrence. MRI with gadolinium is necessary

*Correspondence to: Prof. Valentina Tomassini, MD, PhD, Institute of Advanced Biomedical Technologies (ITAB), Department of Neurosciences, Imaging and Clinical Sciences, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy. Tel: +39-0871-3556926, Fax: +39-0871-358102, E-mail: [email protected]

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Fig. 5.1. Diagnostic flow-chart following clinical suspicion of acute myelopathy. The flow-chart shows an etiological classification of myelopathies, indicating in red myelopathies of recognized or hypothesized inflammatory origin. ADEM, acute disseminated encephalomyelitis; CSF, cerebrospinal fluid; MOGAD, myelin oligodendrocyte glycoprotein antibody-associated disease; MRI, magnetic resonance imaging; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorders; SLE, systemic lupus erythematosus.

for the diagnosis. MRI patterns are variable (segmental, transverse, ventral horn, mass-like) and the type of pattern may guide toward the likely etiology (e.g., poliomyelitis that involves the anterior gray matter horns). All patients should be evaluated with blood tests and lumbar puncture, which typically shows pleocytosis, usually with lymphocytic predominance. Cultures and polymerase chain reaction (PCR) on CSF are necessary to confirm etiology. Infectious myelitis include bacterial, viral, fungal, and parasitic causes (Asundi et al., 2019). The most frequent causes of infectious myelitis are listed in Table 5.1.

Bacterial myelitis Myelitis of bacterial etiology may be the consequence of hematogenous spread from other systems, of propagation from a contiguous infection site (e.g., vertebral osteomyelitis, discitis), or of local invasion (e.g., trauma, surgery, or spinal procedures). Myelitis can take the form of abscess or localized areas of spinal cord inflammation. Abscesses can develop within the spinal cord following bacterial infiltration of the epidural space or, more rarely, of the spinal cord parenchyma (Montalvo and Cho, 2018). A high risk of developing epidural abscesses is related to intravenous (IV) administration of medications, alcohol abuse, diabetes mellitus, cancer, and

hemodialysis, whereas intramedullary abscesses have been found more frequently in patients affected by immunodeficiency (Zimmerli, 2010; Montalvo and Cho, 2018). Spinal abscesses occur rarely and usually locate posteriorly in the thoracic and lumbar regions. They may cause myelopathy through compression of the spinal cord, disruption of the arterial blood flow, thrombosis/thrombophlebitis, or by the induction of an inflammatory response in the surrounding tissue (Montalvo and Cho, 2018). Patients initially complain of back pain and fever. Elevated serological inflammatory indices can reveal the diagnosis. MRI findings include edema, early diffuse enhancement, late ring, and/or central diffusion restriction (Mihai and Jubelt, 2012). The treatment regimen is optimized after culture. Decompressive surgery and drainage may be required. Several bacteria are known as iatrogenic causes of myelitis (Saini et al., 2014; Montalvo and Cho, 2018; Yeh et al., 2022). However, Staphylococcus pneumoniae and Streptococcus aureus are the most common causes of spinal abscesses (Asundi et al., 2019). Mycoplasma pneumoniae is a common etiological agent for respiratory tract infections, but may also cause encephalomyelitis (Mihai and Jubelt, 2012; Asundi et al., 2019). Mycoplasma-related TM is usually preceded by a respiratory tract infection 1–4 weeks before the onset of myelitis. Diagnosis requires signs of TM on MRI, pleocytosis

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Table 5.1 Infectious causes of transverse myelitis Bacteria

Viruses

Fungi

Parasites

Staphylococcus pneumoniae Streptococcus aureus Mycoplasma pneumoniae Treponema pallidum Borrelia burgdorferi Mycobacterium tuberculosis Actinomyces Clostridium tetani Bordetella pertussis Corynebacterium diphtheriae Brucella melitensis Chlamydia psittaci

Herpes viruses (HSV-1, HSV-2, VZV) Poliovirus 1,2,3 Enterovirus D-68 West Nile virus Zika virus HIV HTLV-1 SARS CoV-2 Echovirus Epstein Barr virus Citomegalovirus Influenza virus

Histoplasma capsulatum Cryptococcus neoformans Coccidioides Aspergillus Cysticercus Blastomyces Cladophialophora bantiana

Schistosoma haematobium Schistosoma mansoni Taenia solium Toxocara canis Strongyloides stercoralis Ascaris suum Toxoplasma gondii Trypanosoma brucei

HIV, human immunodeficiency virus; HSV, Herpes Simplex virus; HTLV-1, Human T-lymphotropic virus 1; VZV, Varicella Zoster virus.

and elevated protein on CSF analysis and serological positivity for cold hemagglutinins and antibodies, with a high immunoglobulin M (IgM) titer in the acute phase (Mihai and Jubelt, 2012). Treatment usually consists of intravenous immune globulin (IVIg) and macrolide antibiotics (e.g., clarithromycin). The prognosis is favorable with appropriate treatment. Spirochete was the most common cause of myelitis before the introduction of antibiotics (Asundi et al., 2019). Neurosyphilis caused by Treponema pallidum can develop any time after the primary infection (Mihai and Jubelt, 2012). Tabes dorsalis is the typical spinal manifestation and consists of dorsal roots and posterior column degeneration at the lumbosacral or lower thoracic level. Patients typically complain of paresthesia and acute radicular pain in the lower extremities; some may also develop abdominal pain, urinary incontinence, sensory ataxia, diminished reflexes, and impaired proprioception (Mihai and Jubelt, 2012). Spinal cord damage may also result from vascular inflammatory alteration, which may lead to thrombosis and infarction (Montalvo and Cho, 2018). Moreover, spinal cord gummas may cause mechanical compression. MRI typically shows a swollen cord with patchy or nodular appearance (Nabatame et al., 1992); a typical sign is the guttered candle appearance with a flip-flop sign (Asundi et al., 2019). Diagnosis consists of a positive Venereal Disease Research Laboratory (VDRL) test, later confirmed by a treponemal test, such as fluorescent treponemal antibody absorption test. CSF VDRL antibodies and CSF fluorescent treponemal antibody test are also useful to diagnose neurosyphilis (Montalvo and Cho, 2018). Management requires the administration of antibiotics (beta-lactam antibiotics such as

penicillin for 10–14 days) to stop progression, although this does not ensure recovery. Corticosteroids help to prevent the paradoxical worsening of symptoms at the start of antibiotics that happens as a consequence of spirochetal lysis (Montalvo and Cho, 2018). Borreliosis or Lyme disease is caused by Borrelia burgdorferi, inoculated in humans through a tick bite. A rash appears around the Ixodes bite and is usually associated with flu-like symptoms. Neuroborreliosis manifests in the second phase of the disease. However, myelitis is rare compared to encephalitis, meningoradiculitis, and cranial nerve involvement (Mihai and Jubelt, 2012). The cervical cord is usually affected in the rare cases of TM (Asundi et al., 2019). Diagnosis is made with a Lyme antibody test and, if negative, with a PCR on CSF. CSF analysis shows lymphocytic pleocytosis, elevated protein, and Immunoglobulin G (IgG) index. Cephalosporin antibiotics (e.g., ceftriaxone) or tetracycline antibiotics (e.g., doxycycline) are the standard treatment. Tuberculosis of the spinal cord caused by Mycobacterium tuberculosis may be secondary to the downward extension of tuberculous meningitis or osteitis and it is usually described as Pott’s disease, which consist of vertebral collapse first, spinal cord and tuberculous arachnoiditis later (Hernandez-Albujar et al., 2000; Mihai and Jubelt, 2012). However, the tuberculous exudate may trigger an inflammatory reaction that may also lead to myelitis, intramedullary or intradural tuberculomas, radiculomyelitis, syringomyelia and, less frequently, abscesses. The inflammatory process may alter the spinal vascular system, leading to thrombosis or vasculitis of the spinal cord (Montalvo and Cho, 2018). TM usually follows or goes along respiratory symptoms, but cases of isolated radiculomyelitis have been reported

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(Feng et al., 2011; Anand et al., 2021). Signs on MRI may appear as cord edema, T2-hyperintensity, or T1-hypointensity, or enhancing lesions with nodular ring-enhanced pattern (Mihai and Jubelt, 2012; Montalvo and Cho, 2018; Asundi et al., 2019). The necrotic material at the center of the tuberculoma may also cause restricted diffusion (Marais et al., 2018). CSF analysis usually detects lymphocytic pleocytosis, decreased glucose levels, and elevated proteins. Mycobacteria are also recognized with acid fast stain, culture, and PCR analysis. Treatment regimen includes a combination of antibiotics (typically rifampicin, isoniazid, pyrazinamide, and ethambutol) for 2 months, followed by another combination of antibiotics (typically rifampicin and isoniazid) administered for 7–10 months. The use of corticosteroids is also recommended.

Viral myelitis Agents responsible for acute viral myelitis include herpes viruses, picornaviruses, flaviviruses, human immunodeficiency virus (HIV)-associated myelopathy, human T-cell lymphotropic virus type 1 (HTLV-1), and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Herpes simplex virus-1 (HSV-1) is associated with oral ulcerations and is rarely a cause of myelitis in immunocompetent hosts (Figueroa et al., 2016). Herpes simplex virus-2 (HSV-2) myelitis is due to a reactivation of the infection in the sacral dorsal root ganglia with secondary spread to the spinal cord. Types of HSV-2 myelitis include ascending myelitis, radiculomyelitis, and necrotizing myelitis. Patients may present with sensory, motor, and autonomic disturbances. Demonstration of HSV-2 by PCR in CSF is diagnostic. MRI shows T2 hyperintense spinal cord lesions with edema and eventually necrosis (Nardone et al., 2017). Treatment includes antiviral medication (typically acyclovir); corticosteroids can be associated (Nakajima et al., 1998). Myelitis is a rare complication of Varicella-zoster virus (VZV) infection and usually occurs in immunocompromised patients. Similar to HSV, VZV remains latent in the dorsal root ganglia after the first infection. VZV may also cause spinal cord infarction through vasculopathy as a distinct type of damage. Neurological manifestations include progressive asymmetric weakness, associated with the typical herpes zoster or shingles characterized by painful and burning sensations. Spinal cord damage, however, may occur without shingles (zoster sine herpete) (Hung et al., 2012). The CSF detection of VZV PCR and/or IgM anti-VZV is diagnostic. MRI may show longitudinal serpiginous lesions. Antiviral treatment (typically acyclovir) and high doses of

corticosteroids are used and may be helpful in preventing the clinical manifestation of postherpetic neuralgia (Ong et al., 2010). Among the picornaviruses, poliovirus, enterovirus, and coxsackievirus are most commonly associated with myelitis. Symptoms include acute flaccid myelitis secondary to the involvement of the anterior horn of the spinal cord. Poliovirus serotypes 1, 2, and 3 were the predominant etiologies of viral myelitis until polio was eradicated in Europe and in North America. However, they are still present in low-income countries. Poliomyelitis is characterized by acute motor weakness occurring during febrile illness. Neurological examination shows signs of involvement of the second motoneuron and thus weak or absent deep tendon reflexes, fasciculations, and muscle atrophy (Bitnun and Yeh, 2018). In recent years, new viruses have shown similar clinical manifestations, such as enteroviruses A71 and D68. Enterovirus A71 is associated with hand-footand-mouth disease. MRI shows anterior horn and ventral root lesions corresponding to a clinical segmental level (Huang et al., 1999). The Enterovirus D68 outbreak, seen in America in 2014, is associated with respiratory symptoms, and longitudinally extensive lesions, followed by anterior horn damage on MRI. Corticosteroids and IVIg may be beneficial (Jeha et al., 2003). Within the family of Flaviviridae, West Nile virus and Zika virus have been involved in spinal cord damage. West Nile virus can cause meningitis, encephalitis, and myeloradiculitis. Fever, rash, and back pain may precede the acute motor deficits that occur secondary to an involvement of the anterior horns of the spinal cord. Symptoms develop 24–48 h from infection and can progress to quadriparesis and respiratory involvement. The CSF usually shows high protein levels and lymphocytosis. Treatment is mainly supportive (Wuliji et al., 2019). Zika virus has been associated with a wide spectrum of neurological manifestations including myelitis and it should be suspected in individuals who live in or come from endemic areas (Palacios et al., 2019). Myelitis associated with HIV may be secondary to the virus itself or due to the opportunistic infections that arise because of the immunocompromised state (e.g., toxoplasmosis). Patients with advanced acquired immunodeficiency syndrome (AIDS) may also develop a vascular myelopathy, although antiretroviral therapy has reduced its incidence (Wuliji et al., 2019). About 1/10 of patients may show on MRI spinal cord atrophy, which determines lower limb weakness, gait impairment, and sphincter dysfunction (Harrop et al., 2010). HTLV-1 is endemic in Japan, the Caribbean, South America, and Africa and is transmitted through blood, sexual intercourse, and breastfeeding. It is more common in women and usually presents around 40–50 years of

TRANSVERSE MYELITIS IN CHILDREN AND ADULTS age. Symptoms include lower extremity weakness, increased deep tendon reflexes, urinary disturbance, and sensory disturbance. Usually, the upper limbs are spared (Gessain and Cassar, 2012). MRI shows white matter lesions and some degree of atrophy in the spinal cord (Taniguchi et al., 2017). Antiretroviral treatments have shown efficacy in vitro against HTLV-1; corticosteroids may be helpful during flares (Lezin et al., 2005). SARS-CoV-2 causes mainly an upper respiratory illness. However, neurological manifestations have been described, including Guillain Barr
e syndrome (GBS), encephalitis, stroke, and myelitis. Myelitis has been reported as both para- and postinfectious. Symptoms are variable and include motor and sensory deficits, with frequent involvement of the bladder and bowel. Descriptions are heterogeneous in the clinical setting. However, typically neurological deficits have been described as occurring about 1–2 weeks after the first respiratory symptoms (Schulte et al., 2021). CSF usually shows lymphocytic pleocytosis and elevation of proteins, while SARS-CoV-2 RNA is found only in a small minority of cases (Virhammar et al., 2020). MRI typically shows central longitudinal changes, but dorsal and lateral involvement has also been described (Huang et al., 2021). In most of the reported cases, immune therapy was administered (Schulte et al., 2021).

Fungal myelitis Fungal infections are rare within the central nervous system (CNS) and usually described in immunocompromised patients (Nathan et al., 2021). Histoplasmosis is a rare, disseminated disease that may affect immunocompromised patients (Mihai and Jubelt, 2012; Araúz and Papineni, 2021). Diagnosis is made through histoplasma antigens or antibodies in the CSF, serum antibodies, or urinary antigens. Treatment requires antifungal treatment (typically, an amphotericin B course for 4–6 weeks followed by itraconazole for at least 1 year) (Araúz and Papineni, 2021). Cryptococcus neoformans is the cause of cryptococcosis, which may manifest with meningitis in immunocompromised patients; rarely it may also cause incomplete TM (Brown et al., 2012; Mihai and Jubelt, 2012). Diagnosis requires dosing the fungal antigen or culture from serum or CSF. Treatment includes antifungal treatment (typically amphotericin B and flucytosine for 4–6 weeks) (Brown et al., 2012; Nathan et al., 2021). Coccidioidomycosis, an endemic infection of the South-west of the United States and Northern Mexico, may occur in immunocompetent patients (Mitchell et al., 1995; Nathan et al., 2021). The infection may spread to the vertebrae and dissemination within the spinal cord may subsequently follow. The diagnosis requires detection of antibodies, antigens, or DNA by

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PCR in the CSF. Patients are treated with antifungal treatment (typically fluconazole) (Shao et al., 2006; Brown et al., 2012).

Parasitic Schistosomiasis is caused by Schistosoma haematobium and Schistosoma mansoni, parasites endemic in Africa, Middle East, Central, and South America. Spinal cord involvement is possible, with acute or subacute TM, typically presenting with lower extremities’ pain followed by lower limb weakness, paresthesia, and bladder dysfunction. The CNS infection follows the migration of the eggs from the portal system to the epidural veins. Eggs and granulomas may cause myelitis and myeloradiculitis. CSF analysis may show increased protein, lymphocytic pleocytosis, and sometimes eosinophils. MRI features are a T2-hyperintense signal in the conus medullaris, edema of the spinal cord, enhancement of the cord and nerve roots; intramedullary granulomas appear as patchy enhancing lesions or heterogeneous and hyperintense (Montalvo and Cho, 2018). Diagnosis can be also made with fecal sample examination or rectal biopsy. Treatment requires anthelmintics (praziquantel) and corticosteroids. Neurocysticercosis is a CNS infection caused by the tapeworm Taenia solium. In only 3% of cases, it causes myelopathy. The parasite spreads from the intracranial subarachnoid space to the spinal subarachnoid space, where it deposits eggs within the lumbosacral region. This may cause radiculopathy and, rarely, the parasite may invade the spinal parenchyma. The CSF shows high protein and eosinophilia, whereas the MRI detects leptomeningeal or intramedullary cysts. Patients receive anthelmintics (albendazole) and corticosteroids, but surgical decompression may be needed in some cases (Montalvo and Cho, 2018).

NONINFECTIOUS MYELITIS Noninfectious myelitis includes a variety of immunemediated conditions, implicating differential diagnosis among multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD), acute disseminated encephalomyelitis (ADEM), myelin oligodendrocyte glycoproteinantibody-associated diseases (MOGAD), and idiopathic transverse myelitis. Systemic autoimmune inflammatory diseases, such as systemic lupus erythematosus (SLE), sarcoidosis, and paraneoplastic syndromes may also cause or manifest through TM. Clinical, blood-, or CSF-related and MRI manifestations are crucial for diagnosis and may show differences according to the age of onset (Table 5.2 and Fig. 5.2) and to the portion of the

Table 5.2 Similarities and differences of inflammatory demyelinating syndromes among children and adults Children

Epidemiology Age Sex prevalence Clinical features MRI features

Multiple sclerosis 2%–10% of all MS cases (including adult onset) 13–15 years old, only 10% under 10 years old More frequent in females Polyfocal symptoms, encephalopathy under 10 years old Larger and less defined lesions, more often located in the brainstem and cerebellum

CSF, antibodies OCB often negative under 11 years old MOG-ab and AQP4-ab negative Treatment CS, Immunomodulatory medications or immunosuppressants Idiopathic transverse myelitis Epidemiology 20% of cases are in children, approximately 0.2 per 100,000.00 children per year Age Bimodal distribution: below 5 and over 10 years old Sex prevalence Male prevalence (1.1–1.6:1) Clinical Neck, head, or lower back pain, followed by motor and features sensory deficits; in younger children, irritability, reduced movement, and urinary output. Asymptomatic lesions are reported in 40% of children. Acute flaccid myelitis is common MRI features Same as adults, but more extended, with lesions that may be contiguous or patchy CSF, antibodies CSF may be normal or may find increased protein and lymphocytic pleocytosis Treatment IVIGs, PLEX, immunosuppressants MOGAD Epidemiology Incidence of 1.6–3.4 per 100,000.00 More frequent in children (more than half of the cases) Age 13–15, rarely 1–2-cm) white matter lesions, rare T1-hypointense demarcated white matter lesions, deep gray matter lesions (e.g., basal ganglia, thalamus, or spinal cord) CSF, antibodies Pleocytosis and/or increased protein OCBs in CSF in 1–2 cm) hyperintense lesions on T2 and fluid attenuated inversion recovery (FLAIR) sequences, which involve predominantly the cerebral white matter, despite deep gray matter lesions that can be present (Krupp et al., 2013). Lesion enhancement after gadolinium is reported in 14%–30% of cases (Nakajima et al., 1998; Ong et al., 2010; Hung et al., 2012; Nardone et al., 2017), whereas hypointense lesions on T1-weighted images are rare. Spinal involvement is reported in only 11%–28% of the cases (Tenembaum et al., 2002). Similarly to brain lesions, spinal involvement is characterized by large and swollen lesions, with variable contrast enhancement (Tenembaum et al., 2002); extensive lesions have also been reported (Tenembaum et al., 2002; Anlar et al., 2003; Mikaeloff et al., 2007; Rostásy et al., 2009). Treatment for ADEM consists of high dose corticosteroids and alternatively IVIg (Kahn, 2020). Prognosis is overall favorable, in the majority of patients, despite mortality being estimated to be 10%–20% in the initial phase and sequelae may follow, with deficits in attention, executive functions, and behavior as the most frequently reported (Cañellas et al., 2007; DeSanto and Ross, 2011; Sarbu et al., 2016).

Myelin oligodendrocyte glycoproteinantibody-associated disease Myelin oligodendrocyte glycoprotein is expressed exclusively on the outer surface of the myelin sheath and plasma membrane of oligodendrocytes. Although it represents only a minor component of myelin (0.5%), it is a target for autoantibodies (Hacohen and Banwell, 2019). A growing interest on antibodies toward MOG has progressively risen, leading to the identification of a new clinical phenotype of inflammatory demyelination distinct from MS and NMOSD, defined as MOGAD (Reindl and Rostasy, 2015). Despite patients often meeting the diagnostic criteria for MS at the beginning, the clinical course in MOGAD is not typical of MS. Moreover, in cases initially suggestive of NMOSD, patients positive for MOG antibodies have fewer relapses, better clinical outcome, and a wider range of MRI features compared to patients positive for AQP4 antibodies (Reindl and Rostasy, 2015; Hacohen and Banwell, 2019). MOGAD has higher incidence in pediatric patients, with 0.3 cases over 100,000.00 children, compared to the ratio of 0.13:100,000 reported in adults. Indeed, 30%–50% of children are positive for MOG antibodies at the first demyelinating event, which may consist of

ADEM, ON, and rarely TM (Duignan et al., 2018; Hacohen and Banwell, 2019). Boys and girls are equally affected, with a slight prevalence for females at an older age (Hacohen and Banwell, 2019). MOG-antibody (Ab) autoimmunity typically demonstrates age-dependent phenotypes, with a predominant ADEM-like brain involvement among younger children, whereas optic nerve and spinal cord disease resembling NMOSD is more frequent in older children (Shahriari et al., 2021). Indeed, the clinical manifestations of MOGAD are extremely heterogeneous and patients may develop ADEM, MDEM, ADEM-ON, AQP4negative NMOSD, brain or brainstem syndromes, e.g., area postrema syndrome, manifesting with intractable nausea, vomiting and/or unexplained hiccups, and acute diencephalic syndrome, which is characterized by hypothermia, hypotension, bradycardia, and hyponatremia (Fujihara and Cook, 2020). Among these, brainstem syndrome is reported in one third of patients with MOGAD, although rarely in children, and it may present with cranial deficits, ataxia, or respiratory insufficiency (Banks et al., 2021). Although many patients report prodromal illnesses, no specific viruses have been linked to MOG-related inflammatory demyelination. Clinical course can be monophasic or relapsing and patients may turn seronegative after the first detection of antibodies. Persistence of seropositivity and high titers of antibodies has been linked to a relapsing course (Hacohen and Banwell, 2019; Shahriari et al., 2021). The diagnostic criteria proposed for MOGAD include the presence of (a) serum positivity for MOG-IgG by a cell-based assay; (b) clinical presentation consistent with any of the CNS syndromes (e.g., ADEM, optic neuritis, TM, and brain or brainstem demyelinating syndrome), including any combination of these; and (c) exclusion of an alternative diagnosis (López-Chiriboga et al., 2018). Patients with MOG-Ab may exhibit different MRI patterns notably: (1) multifocal hazy/poorly marginated lesions, involving both gray matter and white matter, the latter typically involving the middle cerebellar peduncles; (2) spinal cord and/or optic nerve involvement with normal intracranial appearance, or nonspecific white matter lesions; (3) extensive and periventricular white matter lesions, resembling a “leukodystrophylike” pattern; and (4) cortical encephalitis with leptomeningeal enhancement (Hacohen and Banwell, 2019; Baumann et al., 2020). Spinal involvement in MOGAD can be observed as an abnormal hyperintense T2-signal, lesions localized centrally within the cord and involving both gray and white matter, cord swelling or spinal involvement greater than 50% of the axial section of the cord (Shahriari et al., 2021). LETM is reported in two-thirds of children with MOG-related myelitis, but

TRANSVERSE MYELITIS IN CHILDREN AND ADULTS short lesions have also been reported (Cobo-Calvo et al., 2017; Shahriari et al., 2021). Compared to MS, conus medullaris and meningeal enhancement is also common, whereas contrast enhancement during acute relapses is more typical of MS (Shahriari et al., 2021). Acute management relies on high-dose corticosteroids followed by a taper with prednisone. IVIg and PLEX can be used if remission is not achieved with corticosteroids. Monthly IVIg administrations is also an option in cases with a relapsing course. An alternative for the maintenance regimen is monoclonal antibodies (rituximab), which has proven to be highly effective and safe (Hacohen and Banwell, 2019; Bruijstens et al., 2020; Ghezzi et al., 2021).

IDIOPATHIC MYELITIS Some cases of acute TM have no known etiology. These cases have been referred to as “idiopathic” and are defined by rigorous criteria: development of sensory motor and autonomic dysfunction attributable to the spinal cord, bilateral signs and symptoms, a clearly defined sensory level, inflammation demonstrated by CSF, and progression to nadir between 4 h and 21 days (Transverse Myelitis Consortium Working Group, 2002). Conditions that need to be excluded are a compressive etiology, history of radiation of the spine, history of ON, serological evidence of an infection or a connective tissue disorder, and brain abnormalities suggesting MS. The cases that fulfill all the criteria except for inflammation within the spinal cord or in CSF can be defined as “possible” idiopathic TM (Transverse Myelitis Consortium Working Group, 2002). Twenty percent of TM cases manifest in the pediatric age (Wolf et al., 2012), with 2 new cases per million children (Banwell et al., 2009). TM may represent the first manifestation of a pediatric acquired demyelinating disease, preceding the onset of a relapsing inflammatory disease such as MS or NMOSD (Banwell et al., 2009). ON is usually the most common clinically isolated presentation in children, followed by TM and, later, by brainstem symptoms (Trabatti et al., 2016; Padilha et al., 2020). Pediatric TM is usually reported in two age spans: from birth to 2 years old and from 5 to 17 years of age (Pidcock et al., 2007), and is slightly more prevalent in males, whereas females are more frequently affected at the pubertal age, reflecting a trend also typical for pediatric onset MS (Banwell et al., 2009; Absoud et al., 2013). In most pediatric cases of TM, a mild illness is reported in the 3 weeks prior the onset of the spinal symptoms, although specific viruses or bacteria are rarely identified. Many cases of pediatric TM have also been reported after the SARS-CoV-2 pandemic (Kaur et al., 2020; Nejad Biglari et al., 2020; Pagenkopf and

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S€udmeyer, 2021; Siracusa et al., 2021; Poyrazoglu et al., 2022). Children manifest the peak of the symptoms within 2–4 days, usually with sensory deficits, limb weakness, and urinary dysfunction. In younger children, unable to verbally express sensory impairment, irritability may be the main complaint. Clues in the clinical diagnosis is the observation of reduced movements and of decreased urinary output, whereas less dramatic signs of weakness may be overlooked (Wolf et al., 2012). In childhood cases of idiopathic TM, lesions usually locate at the cervical or cervicothoracic level. LETM is more frequent in children with idiopathic TM compared to adults, where the diagnosis of NMOSD is more likely. CSF analysis is normal in a large proportion of children, even if increased protein and lymphocytic pleocytosis are also reported. The outcome is variable, but children usually improve within the first 2 weeks. Risk factors for a worse prognosis consist of young age at the onset of symptoms, severe motor weakness at nadir, lack of increased deep tendon reflexes at onset, need for ventilator support, elevated CSF white blood cell count, LETM, and longer time to diagnosis. Overall, idiopathic TM and NMOSD have worse outcome compared to children with ADEM or MS. Acute flaccid myelitis is a variant of myelitis that is common in children, characterized by an asymmetric onset of flaccid limb weakness, commonly starting in an arm, associated with pain or paresthesia in the affected limb, without an apparent sensory deficit. Patients may also develop facial droop, diplopia, dysphagia, or dysarthria, whereas bowel and bladder dysfunction are less commonly seen. The inflammatory process typically involves the motoneurons of the spinal cord, similar to the myelitis caused by the poliovirus. Acute flaccid myelitis has lately been associated also with enterovirus EV68, West Nile virus and adenovirus. However, the spinal damage seems to be mediated by a direct infection of the motoneurons rather than by a dysimmune response that is typical of TM.

TRANSVERSE MYELITIS AND VACCINES Vaccines are a powerful trigger for the immune system, as they can induce or exacerbate autoimmune disorders in genetically or immunologically predisposed patients (Vadalà et al., 2017). However, a cause-effect relationship between autoimmune conditions and vaccination has yet to be determined, and the benefit of vaccination still outweighs the risk of an adverse event. TM rarely follows the administration of a vaccine (Shah et al., 2018). Although an etiological link between TM and vaccines has not been found, the antigens of the vaccine may trigger molecular mimicry with CNS self-antigens,

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may accelerate an ongoing dysimmune process through epitope spreading, and may induce polyclonal or bystander activation of lymphocytes (Lehmann et al., 1992; Murali-Krishna et al., 1998; Blank et al., 2007; Agmon-Levin et al., 2009). Moreover, the adjuvants and preservatives contained in the vaccines may have a role in the development of dysimmunity (AgmonLevin et al., 2009). Cases of myelitis postvaccination have been reported, with symptoms reported usually 1 month after the administration of the vaccine (West et al., 2012). The vaccines more often associated with myelitis are the ones against Hepatitis B virus (HBV), measles, mumps and rubella, diphtheria, tetanus, rabies, polio, and influenza; rarely, it may also follow typhoid fever, pertussis, and Japanese encephalitis vaccine (Agmon-Levin et al., 2009). Several reports have been published about cases of myelitis following anti-SARSCoV-2 vaccination (Hsiao et al., 2021; Nistri et al., 2021; Pagenkopf and S€ udmeyer, 2021; Khan et al., 2022). Among the cases of spinal cord inflammatory damage that follows vaccination, several vaccines have been associated with ADEM, such as measles, rabies, diphtheria-tetanus-polio, smallpox, rubella, Japanese B encephalitis, pertussis, influenza, HBV, and human papilloma virus (Huynh et al., 2008; Wildemann et al., 2009; Denholm et al., 2010). Both in TM and in ADEM, the association of high dose corticosteroids may improve the clinical course, with IVIg and/or PLEX recommended in patients who do not adequately respond to corticosteroids. It is also suggested to avoid the administration of vaccines in the 6 months following the diagnosis of ADEM, since it may trigger the development of multiphasic ADEM (Booss and Davis, 2003).

SYSTEMIC DISORDERS Sarcoidosis Neurological involvement occurs in approximately 5% of cases of sarcoidosis and may cause damage to the spinal cord, the meninges, the hypothalamus, the pituitary glands, the brain parenchyma, and the peripheral nerves (Kidd, 2018). Hypotheses regarding the pathophysiology of the CNS involvement include a leptomeningeal inflammation along the perivascular spaces that surround small- and medium-sized arteries and veins. Since its etiology is unknown and neurological manifestations are variable, diagnosis of neurosarcoidosis is based on clinical neurological findings in a patient with proven systemic sarcoidosis (Krumholz and Stern, 2014). A diagnosis of definite neurosarcoidosis can be made only with a positive neural biopsy (Owen et al., 2018). The clinical presentation of spinal sarcoidosis varies depending on extradural, intradural, or intramedullary involvement. Cervical and thoracic segments are most

often affected (Terushkin et al., 2010). Sarcoidosisassociated myelitis is a diagnostic challenge, as clinical and radiological characteristics may overlap with other inflammatory conditions such as NMOSD. Sarcoidosisassociated myelitis typically has a chronic temporal evolution with a predominance of sensory symptoms, due to dorsal medullary inflammation. Symptoms may nonetheless vary, ranging from radiculopathy to autonomic dysfunction and paraparesis. The CSF shows nonspecific markers of inflammation such as pleocytosis and elevated proteins. Oligoclonal bands can be found in a small number of patients. The classical MRI finding is a longitudinal extensive myelitis (>3 segments) with predominantly dorsal subpial and meningeal enhancement (Murphy et al., 2020). Another typical MRI finding is the “trident head sign,” which is a central canal enhancement in combination with dorsal-subpial enhancement. Other MRI patterns of spinal sarcoidosis include short tumefactive myelitis, spinal meningitis/meningoradiculitis, and anterior myelitis with disc degeneration (Zalewski et al., 2016). Initial therapy consists of high-dose corticosteroid preparations, followed by a corticosteroid-sparing immunosuppressive agent such as methotrexate, mycophenolate mofetil or azathioprine. The subsequent therapeutic option includes antitumor necrosis factor (TNF)-a inhibitors such as infliximab (Voortman et al., 2019).

Systemic lupus erythematosus Among the neurological manifestations of systemic lupus erythematosus (SLE), myelitis can occur in 1%–2% of cases (Kovacs, 2000; D’Cruz et al., 2004; West et al., 2012) and it may also represent the first manifestation of the disease (West et al., 2012). In 40%–64% of cases, myelitis occurs in the presence of active disease (Kampylafka et al., 2013; Li et al., 2017). The diagnosis of SLE-associated myelitis is clear in patients with a history of SLE. However, TM may be the first manifestation of the disease, the differential diagnosis of which is extensive (Table 5.2). Both MS and NMOSD can be comorbidities of SLE; for NMOSD, the inflammatory process of SLE may cause the exposure to antigens that leads to the formation of AQP4 antibodies (Wingerchuk and Weinshenker, 2012; Kampylafka et al., 2013; Fanouriakis et al., 2014). Spinal cord damage is thought to be the result of SLE pathological mechanisms, with a combination of vasculopathy, cytokine and chemokine release, oxidative stress, and autoantibody production (Li et al., 2017). Autoptic studies report the presence of ischemic necrosis, infarction, or vasculitis in the majority of the cases, with lymphocytic infiltration, connective tissue proliferation, and thrombosis of the small vessels (Andrianakos

TRANSVERSE MYELITIS IN CHILDREN AND ADULTS 1975; Li et al., 2017; Provenzale and Bouldin, 1992). The prevalence of longitudinal or extensive myelitis as seen on MRI is higher when compared to cases of short lesions (Li et al., 2017). Among the laboratory findings, serum levels of ANA and antidouble-stranded (ds)DNA antibodies are found in patients with SLE-related TM (Beh et al., 2013) and anticardiolipin antibodies (aPLs) are linked to a high risk of TM in SLE patients. Therefore, antibody titers may be useful to quantify the thrombotic risk, which has been linked to the onset of myelopathy. The management of SLE-associated myelitis relies on the treatment of SLE and is based on the use of high-dose corticosteroids in association with immunosuppression (cyclophosphamide), which can improve patient outcome (Barile-Fabris, 2005; Li et al., 2017). In nonresponders, PLEX and monoclonal antibodies (rituximab) should be considered. Maintenance therapy should follow an induction lasting for at least 3 years, with the administration of immunosuppressants (azathioprine, methotrexate, mycophenolate, or cyclophosphamide) (Li et al., 2017). Antiplatelet and/or anticoagulation may be indicated in aPLs-positive patients, especially in cases of refractory TM. The prognosis of SLEassociated-TM is not favorable and depends on the severity of the symptoms at the onset. The risk of recurrence is estimated to be between 20% and 55%; complete recovery is reported in 7%–28% of cases (Kovacs, 2000; Saison et al., 2015).

Paraneoplastic myelitis Neoplastic diseases may cause myelopathy in different ways, such as intramedullary metastases, intramedullary tumors (e.g., ependymoma), intravascular lymphoma, and paraneoplastic syndromes that are often the consequence of the production of antineuronal antibodies, which mediate an attack toward components of the CNS. Among these, paraneoplastic TM are rare and rapidly progressive diseases, usually linked to lung and breast carcinoma or ovarian teratomas (Beh et al., 2013). Among antineuronal antibodies, collapsing response-mediator protein-5 (CRMP-5) antibodies are the most frequently identified, with small cell lung carcinoma as the most common diagnosis (Keegan et al., 2008). Moreover, CRMP-5 antibodies have also been associated with clinical features that may simulate MS or NMOSD. Other antibodies, such as voltage-gated calcium channel antibodies, antiganglionic acetylcholine receptor antibodies, antiamphiphysin antibodies, usually related to breast cancer, and anti-Ri antineuronal nuclear antibody type 2 (ANNA-2), usually related to lung or breast carcinoma, have been associated with

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paraneoplastic TM (Pittock et al., 2005; Leypoldt, 2006; Chamard et al., 2011). In paraneoplastic myelitis, CSF analysis shows increased protein levels, and IgG index, and mild pleocytosis (Flanagan et al., 2011; Beh et al., 2013). Typical MRI features include T2-hyperintense lesions with contrast enhancement, with LETM being present in 40% of cases (Keegan et al., 2008; Flanagan et al., 2011; Jain et al., 2015). Management of paraneoplastic TM relies on the treatment of the underlying tumor. However, since the tumor is not detected in many cases, immunosuppression based on corticosteroids and PLEX is administered (Leypoldt, 2006; Flabeau et al., 2022). The overall prognosis is not favorable, with persistence of severe disability despite treatment (Flanagan et al., 2011).

Radiation therapy-related myelitis Radiation-induced myelitis is a rare complication of radiation exposure and is often a diagnosis of exclusion. The pathophysiology of the damage is not well defined; but, it has been postulated that early transient changes are due to demyelination, caused by the radiation-related inhibition of oligodendroglia, which produce myelin within the spinal cord, while more permanent changes are due to small-vessel ischemia (Abuzneid et al., 2021). Diagnosis may be difficult because symptoms vary and onset may range from months to years following the radiation exposure. MRI images typical of this condition include spinal cord swelling, atrophy, hyperintense signal changes on T2-weighted sequences, and contrast enhancement. These findings, however, vary according to the timing of imaging from the exposure of radiations. Radiation-induced myelitis may be a progressive disorder, but some patients report improvement on follow-up. Most patients are treated with steroids at presentation, but Ig, PLEX, and monoclonal antibodies (bevacizumab) may be used in addition to corticosteroids (Khan et al., 2018).

Toxic-metabolic vascular mimickers Within the differential diagnosis of TM, special attention should be made to myelopathies of other origin that clinically may mimic TM. Metabolic causes of myelopathies include deficiency of vitamin B12 (cobalamin), folic acid, copper, and vitamin E. Vitamin B12 deficiency may occur in the absence of hematological abnormalities and presents as weakness and paresthesia, due to subacute combined degeneration (i.e., involvement of the lateral corticospinal and posterior columns of the spinal cord) and cognitive impairment. Subacute combined degeneration has been reported also in folate deficiency (Senol et al., 2008). Treatment consists of supplementation. Toxic causes of myelopathy include nitrous oxide

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exposure, heroin abuse, konzo, and neurolathyrism. Nitrous oxide exposure may result from repeated anesthetic or recreational exposure, and can inactivate vitamin B12 (Pema et al., 1998). Therefore, toxicity has been associated with myelopathy, peripheral neuropathy, and cognitive changes (similarly to vitamin B12 deficiency). No effective treatment exists. Management is supportive and consists of gait aids, medications, and physical therapy for spasticity (Goodman, 2015). Vascular myelopathies are frequently misdiagnosed as TM. Different vascular mechanisms can cause myelopathies, including arterial ischemia, hematomyelia, venous congestion or ischemia, and epidural hematoma (Barreras et al., 2018). Management is multidisciplinary and involves neurologists, neuroradiologists, and vascular neurosurgeons (Zalewski, 2021).

CONCLUSIONS TM comprises pathobiologically heterogeneous syndromes with immune-mediated, inflammatory damage of the spinal cord predominating. A detailed history and thorough physical examination are indispensable in arriving at a presumptive diagnosis. However, the most important investigation to undertake is an MRI of the entire spinal axis and the brain because the location and length of the lesion are important discriminators with etiologic and prognostic significance. Whereas acute partial transverse myelitis may be attributable to MS longitudinally extensive transverse myelitis are more characteristic of NMO but may occur in other diseases as well. Whereas brain MRI and CSF OCBs are powerful predictors of conversion to MS, AQP4 seropositivity has a high specificity for NMO. The epidemiologic, clinical, radiologic, and longitudinal data seen in pediatric TM suggests that the pathobiological underpinnings are distinct from TM in the adult population. It remains possible that idiopathic TM represents a unique category of disorders; however, longitudinal studies are needed to elucidate the nature of its recurrence.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00016-8 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 6

Multiple sclerosis: Motor dysfunction DAVID S. YOUNGER1,2* 1

Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States

2

Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States

Abstract Multiple sclerosis is a chronic neurological disease characterized by inflammation and degeneration within the central nervous system. Over the course of the disease, most MS patients successively accumulate inflammatory lesions, axonal damage, and diffuse CNS pathology, along with an increasing degree of motor disability. While the pharmacological approach to MS targets inflammation to decrease relapse rates and relieve symptoms, disease-modifying therapy and immunosuppressive medications may not prevent the accumulation of pathology in most patients leading to long-term motor disability. This has been met with recent interest in promoting plasticity-guided concepts, enhanced by neurophysiological and neuroimaging approaches to address the preservation of motor function.

INTRODUCTION Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system (CNS) characterized pathologically by plaques of inflammation, demyelination, gliosis, disseminated in time (DIT) and disseminated in space (DIS). The signs and symptoms depend on the location of the lesions within the brain and spinal cord. Motor dysfunction, which includes spasticity, weakness, tremor, ataxia, and visuomotor deficits, is the most common disabling aspect of MS and contributes to balance, gait, and falls. Multiple sclerosis and related inflammatory demyelinating disorders have recently been reviewed (Thompson et al., 2018b). It is the most common nontraumatic cause of disability among young adults. Cases of MS have been described since the first clinical pathologic correlations of the disease by Jean-Martin Charcot described characteristic spinal, cerebral, and mixed cerebrospinal presentations and provided a clinical description for the diagnosis. Although Charcot’s diagnostic triad of nystagmus, intention tremor, and scanning speech did not directly encompass problems with gait, balance,

or falls, there was early recognition that MS affects walking. The past decade has witnessed a tremendous expansion of research and understanding of the motor impairment and challenges associated with MS and its related variants.

EPIDEMIOLOGY AND ETIOPATHOGENIC FACTORS Cotsapas et al. (2018) have recently reviewed the genetic aspects of MS. The prevalence of MS is estimated to be 2 persons per 100,000 in Japan to 100 or more persons per 100,000 in Northern Europe and North America (Baum and Rothschild, 1981; Rosati, 1994) with the disease twice as common in temperate regions than in the tropics. Women are affected twice as often as men, and whites have a much higher incidence rate than other races. The incidence of MS peaks in the fourth decade of life, but the disease commonly presents between ages 15 and 60. Childhood onset occurs but is uncommon. Overall, MS is the third commonest cause of disability

*Correspondence to: David S. Younger, MD, DrPH, MPH, MS, 333 East 34th Street, Suite 1J, New York, NY 10016, United States. Tel: +1-212-213-3778, Fax: +1-212-213-3779, E-mail: [email protected]

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in the United States in 15- to 50-year-old individuals after trauma and musculoskeletal disease (Smith and Scheinberg, 1985). Although the etiology is unknown, three factors enhance the occurrence of MS. The first is genetic vulnerability, the second is yet-to-be identified environmental exposures, and the last is the host immune system, which damages the CNS. Genetic predisposition is an important risk factor in MS with siblings of affected patients having a 2%–5% lifetime risk and parents and children of MS patients having a 1% lifetime risk. Monozygotic twins have a 30% risk, whereas dizygotic twins have a risk similar to that of another sibling (McFarland et al., 1984; Ebers et al., 1986). Early attempts to identify nonhuman leukocyte antigen (HLA), MS risk alleles focused on testing specific genes including T-cell receptor-a and b loci, the immunoglobulin (Ig) heavy-chain genes, and the gene for myelin basic protein (MBP), thought to play a role in MS pathogenesis. However, candidate gene studies typically investigated a few hundred individuals for a handful of variants and produced inconsistent findings (Dyment et al., 1997) due to inadequate sample sizes and limited knowledge of the mechanisms underlying disease, as most of these genes do not harbor disease risk variants (Altshuler et al., 2008). Genetic linkage studies relying primarily on microsatellite markers implicating the major histocompatibility complex (MHC) and other immunoregulatory genes as important determinants of this hereditary risk (Hillert, 1994) led to several genome-wide linkage screens of consanguineous multiple kinships replicating HLA risk alleles but not significant linkage to regions outside MHC (Modin et al., 2003). The International Multiple Sclerosis Genetics Consortium (IMSGC), organized as a multinational collaboration, pooled resources and samples, and was able to type 4506 single-nucleotide polymorphisms in 730 multiplex families (Sawcer et al., 2005). Similar to the previous linkage studies, this also confirmed significant linkage in the HLA region and identified a number of suggestive linkage peaks in other regions of the human genome. More recently, genome-wide association studies (GWAS) examining allele frequency differences across the whole genome between cases and controls, with significant differences implying risk alleles for disease, have proven remarkably successful in MS. However, functional interpretation of these results continues to be a challenge, and translation to an understanding of pathobiology is a major target for the immediate future (Cotsapas and Mitrovic, 2018). A critical barrier to large-scale genetic mapping for differences in secondary clinical characteristics is the absence of data and limitations to aggregating endophenotypes for individual patients or clinical trials. Notably, the first GWAS

performed in 1540 MS parent-affected offspring trios identified a set of single-nucleotide polymorphisms (SNPs) located outside the MHC region associated with MS, most significantly among them SNPs in the genes encoding the interleukin-2 receptor (IL2RA) and the interleukin-7 receptor (IL7RA) already implicated in the pathogenesis of type 1 diabetes and Graves’ disease, adding to the evidence from pathological and immunological studies that MS is a heritable autoimmune inflammatory disorder (International Multiple Sclerosis Genetics C et al., 2007). Specifically, their findings support the idea that polymorphisms within genes related to the regulation of the immune response are important factors in MS. A common variant hypothesis of human diseases (Pritchard and Cox, 2002), wherein genetic disease risk is due to a moderate number of common variants, explains a small fraction of the risk in a population. Migration studies suggest that a critical environmental exposure occurs before age 15 (Kurtzke et al., 1979; Kurtzke et al., 1985). Patients who reside further from the equator and are exposed to less sunlight have lower vitamin D levels, placing them at increased risk of MS (Cantorna, 2008). The association of MS with latent Epstein-Barr virus (EBV) infection is more controversial, with evidence of immune activation of latent EBV in active MS lesions of some patients (Tzartos et al., 2012) and the 32-fold increased risk of MS caused by EBV in a longitudinal cohort analysis of more than 10 million young adults on active US military duty, 955 of whom were diagnosed with MS during their period of service (Bjornevik et al., 2022). Nevertheless, EBV is not a characteristic feature of MS brains or detected in the cerebrospinal fluid (CSF) of affected cases (Willis et al., 2009; Sargsyan et al., 2010). Beyond case-control associations, many aspects of the epidemiology remain unexplained. The largest single risk factor for MS is biological sex with >75% of patients being female; however, the cause for this discrepancy in incidence is not known. Approximately 95% of MS cases follow a relapsing-remitting pattern (RRMS), with approximately 50% of these converting to a secondary progressive form (SPMS) over time. The remaining 5% of all MS cases are of a more aggressive, primary progressive form (PPMS). Yet the determinants of either PPMS or the risk factors for conversion from RRMS to SPMS are not well understood. MS is also remarkably heterogeneous with some patients declining rapidly and others showing few or no symptoms for decades.

Clinical motor dysfunction Motor dysfunction is manifested by clinical spasticity, weakness, tremor, and ataxia. Spasticity, defined as a

MULTIPLE SCLEROSIS: MOTOR DYSFUNCTION velocity-dependent increase in muscular tone, is caused by the loss of inhibitory inputs from the corticospinal tract (CST) and other descending motor pathways to g-motor neurons and interneuron networks that participate in spinal cord reflex arcs, as are hyperreflexia, muscle spasms, and upper motor neuron (UMN) Hoffman and Babinski signs. Weakness affecting up to 89% of MS patients at some point in the disease course (Swingler and Compston, 1992) may be focal due to involvement of CTSs and thus accompanied by a UMN syndrome, with impairment of fine motor control being due more specifically to interruption of input to a-MNs and chronic disuse of limb muscles rather than frank lower motor neuron (LMN) involvement. Tremor and ataxia are related to lesions of the cerebellum and cerebellar pathways through the brain stem, red nucleus, thalamus, and basal ganglia, specifically in the Mollaret triangle, comprising the dentate nucleus of the cerebellum, inferior olive, and red nucleus. In some patients, proprioceptive loss may be the primary cause for impairment. The neural circuitry involved in the pathogenesis of tremor is complex and variable, as evidenced by the mixed results of ablative procedures such as thalamotomy (Whittle and Haddow, 1995). Fatigue, defined as a loss of force-generating capacity during sustained motor activity, contributes to motor dysfunction and disability in patients without other signs of motor dysfunction. Paroxysmal tonic “seizures” characterized clinically as involuntary contractions of the limbs, and sometimes rhythmic, may be seen in association with spinal cord and brain stem lesions and disseminated MS (Matthews, 1958). These tonic spasms, precipitated by movements or hyperventilation, may be confined to one side of the body and last 30 s to a minute, singly or multiply (often >15) times a day, preceded by sensory symptoms on the opposite side of the body. Electroencephalogram (EEG) recordings during ictal events are invariably normal. Symptoms and signs in MS reflect the location of demyelinating CNS lesions. Affected patients commonly present with afferent pupillary defect, visual loss, and diplopia related to optic neuritis; internuclear ophthalmoplegia, facial weakness and numbness, and vertigo resulting from brain stem lesions; ataxia resulting from cerebellar lesions; bowel and bladder urgency, frequency, and retention resulting from autonomic lesions; and paresthesia and hyperesthesia resulting from sensory tract lesions. MS patients also describe being off-balance, unsteady, or uncoordinated and may present difficulty in localization. A cerebellar origin is suggested by concomitant tremor, dysmetria, dysdiadochokinesia, gait ataxia, and eye movement abnormalities. Cognitive deficits, including slowed information processing, loss of executive function, and impaired short-term memory, appear to be related to the overall burden of subcortical

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white-matter lesions. Seizures that occur in up to 5% of patients, coincide with active lesions near the cerebral cortex. Spastic paraparesis is the commonest UMN abnormality, associated with stiffness, cramps, weakness, and motor fatigability, and flexor, extensor, and painful adductor spasms provoked by active or passive movements. Motor deficits may also be quite asymmetric, with isolated monoparesis and hemiparesis related to focal demyelinating lesions. The cutaneous reflexes such as the superficial abdominal may be absent as an early sign of spinal cord involvement, with loss of tendon stretch reflexes later in the course as a correlate of demyelination at the dorsal root entry zone. Gait difficulty, postural instability, and frequent falls are common disabling consequences of the motor dysfunction in MS. Patients have measurable deficits in walking speed and endurance; among a cohort of 237 ambulatory MS patients, 44 (78%) took more than 5 s to walk 8 m (range, 2.6–185.1 s) compared to healthy control subjects, with one-half unable to walk 100–500 m despite support. An Expanded Disability Status Scale (EDSS) based on ambulatory impairment (Kurtzke, 1983) classically rates disability status in MS. Motor function worsens with exercise, fever, sun exposure, and hot baths, so characteristically that the latter is considered a diagnostic inference of MS, the underlying mechanism of which presumably involves worsening of the conduction block in partially demyelinated pathways. Whereas early prognostic features of the later course of MS include sensory symptoms at the onset that correlate with an ultimately benign course, motor and cerebellar signs, early relapse, and age at onset >40 years predict a more aggressive and rapid course (Detels et al., 1982; Poser et al., 1989; Runmarker and Andersen, 1993). Men presenting after age 40 with progressive myelopathy exhibit a steadily worsening paraparesis with variable involvement of the arms and few deficits related to the cerebral subcortical white matter.

DIAGNOSIS The diagnosis of MS requires clinical symptoms of a CNS lesion and CNS signs, symptoms, or lesions on magnetic resonance imaging (MRI) DIT and DIS (i.e., more than once and in more than one location). The course varies among individuals and over time (Fig. 6.1). Most people with MS start with a relapsingremitting course characterized by relapses defined by new symptoms developing over 24 hours or more and lasting about 1–2 months, then gradually resolving completely or almost completely. MS relapses are separated by periods of months to years of stability known as remissions. Over years, the frequency of

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Fig. 6.1. Multiple sclerosis disease course: relapsing-remitting, secondary progressive, and primary progressive. Reproduced from Cameron MH, Nilsagard Y (2018). Balance, gait, and falls in multiple sclerosis. Handb Clin Neurol 159:237–250 with permission of the publisher.

relapses declines and, after 10–15 years, on average, relapses stop occurring, evolving into a progressive course without relapses but with gradual progression of the severity of neurologic symptoms, especially in gait and cognitive dysfunction, as well as fatigue known as SPMS. A minority of people with MS never have relapses and have a progressive course from onset, known as PPMS. The negative symptoms relating to reduced function including motor dysfunction and weakness are caused by altered CNS nerve conductions due to demyelination and axonal damage, which initially slow conduction resulting in impaired function and, with more severe demyelination or axonal loss, with complete blocking of impulse conduction, resulting in greater impairment or complete loss of function. Demyelination also underlies positive symptoms relating to increased function such as painful spasms due to spontaneous excitation of a nerve, excessive discharges in response to mechanical stimulation, and pathological impulse transmission from one demyelinated nerve fiber to another conducted along short and long myelinated fiber tracts. Both the negative and positive symptoms of MS ultimately contribute to inexorable or stepwise progressive worsening of motor function (Cameron and Nilsagard, 2018). Filippi et al. (2016) have reviewed brain MRI in the laboratory diagnosis of MS. The characterization of

lesion features suggestive of MS on conventional MR scans is central in the diagnostic workup of patients suspected of having this condition. Brain MS lesions are frequently located, asymmetrically between the two hemispheres, in the periventricular and juxtacortical white matter, the corpus callosum (CC) (where the so-called “Dawson’s fingers” can be seen) and infratentorial areas (with the pons and cerebellum more frequently affected than the medulla and midbrain). Such lesions can have oval or elliptic shapes. Consensus has also been reached on criteria useful to identify T2-hyperintense (Filippi et al., 1998) and T1-enhancing lesions (Barkhof et al., 1997). Conventional MR sequences employing dual-echo, fluid-attenuated inversion recovery (FLAIR), and T1-weighted, both with and without gadolinium contrast agent administration, provide important pieces of information for diagnosing MS, understanding its natural history, and assessing treatment efficacy, both with a high sensitivity in detecting MS lesions that appear as hyperintense focal areas on these scans (Fig. 6.2). However, they lack specificity to the heterogeneous pathologic substrates of individual lesions. Gadolinium-enhanced T1-weighted images allow active lesions to be distinguished from inactive lesions, since enhancement occurs as a result of increased blood–brain barrier permeability and corresponds to areas with ongoing inflammation. Finally, lesions that persistently

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Fig. 6.2. Brain MRI imaging infratentorial regions, periventricular and juxtacortical white-matter lesions in a 28-year-old patient with RRMS. Axial T2-weighted (A) and postcontrast T1-weighted (B) spin-echo magnetic resonance images. In (A), multiple hyperintense lesions are visible, which suggest multifocal white-matter pathology, involving infratentorial regions, periventricular and juxtacortical white matter. In (B), several of these lesions (white arrows) are clearly contrast-enhanced, which indicates the presence of a local disruption of the blood–brain barrier, while others are hypointense, representing regions with irreversible axonal loss, demyelination, and gliosis (arrowhead). Reproduced from Filippi M, Preziosa P, Rocca MA (2016). Multiple sclerosis. Handb Clin Neurol 135:399–423 with permission of the publisher.

appear dark on postcontrast T1-weighted images are associated with more severe tissue damage (both demyelination and axonal loss) compared to lesions that do not appear dark on such images. However, the strength of the correlation between conventional MRI findings and the clinical manifestations of the disease remains modest in patients with MS, likely due to the relative lack of specificity of conventional MRI in the evaluation of the heterogeneous pathologic substrates of the disease, its inability to provide accurate estimates of damage outside focal lesions, and the fact that it cannot provide information on CNS functional reorganization after tissue injury has occurred. The most compelling reason for measuring atrophy in RRMS and SPMS is that it provides a measure of axonal loss, which, if progressive, is likely to result in irreversible disability. There is a large range of techniques available for the measurement of tissue volumes. Many methods satisfy the essential requirements of being reproducible, sensitive to change, and stable over time (Fig. 6.3). Accuracy is less easy to evaluate as there is no gold standard; the experience of markedly different

absolute changes in brain volumes using different acquisition and segmentation methods indicates that not all methods are accurate RRMS and SPMS (Miller et al., 2002). A large-scale, 14-month follow-up study (De Stefano et al., 2010) of untreated MS patients with different disease subtypes showed that brain atrophy proceeded relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume. Initial criteria defined the certainty of MS for the purposes of epidemiologic studies and clinical trials (Poser et al., 1983). The McDonald criteria of the International Panel on Diagnosis of MS (McDonald et al., 2001; Polman et al., 2005) emphasized that although the diagnosis could be made on clinical grounds alone, MRI of the CNS could support, supplement, or even replace some clinical criteria, resulting in earlier detection of MS with a high degree of specificity and sensitivity, especially in clinically isolated syndromes (Dalton et al., 2002), in early conversion to clinically definite MS (CHAMPS Study Group, 2002), in predicting response to immunotherapy including interferon b-1a

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Fig. 6.3. Brain atrophy in a 42-year-old patient with RMMS. 3D T1-weighted magnetic resonance images acquired at two different times, at time 0 (A) and (B) after 5 years of follow-up, reveal significant diffuse atrophy that is evident after 5 years, with a brain volume decrease of 15.6%. Reproduced from Filippi M, Preziosa P, Rocca MA (2016). Multiple sclerosis. Handb Clin Neurol 135:399–423 with permission of the publisher.

(Barkhof et al., 2003) and in documenting the first demyelinating episode (Tintore et al., 2003). Revisions to the McDonald criteria (Polman et al., 2011) incorporated criteria for demonstration of DIS (Swanton et al., 2006; Swanton et al., 2007) and DIT (Montalban et al., 2010). Recognizing the special diagnostic needs of PPMS, the 2010 McDonald criteria (McDonald et al., 2001; Polman et al., 2005) maintained two of three MRI or CSF findings for PPMS, replacing previous brain imaging criteria for DIS (Swanton et al., 2007). The final criteria for PPMS was 1 year of retrospective or prospective disease progression, plus two of the three following criteria: one or more T2 lesions in at least one area characteristic for MS (periventricular, juxtacortical, or infratentorial), two or more T2 lesions in the cord, or positive CSF [isoelectric focusing evidence of oligoclonal bands (OCBs) and/or an elevated IgG index]. Gadolinium enhancement of lesions was not required. Sagittal MRI from the spinal cord in different clinical phenotypes is shown in Fig. 6.4. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions and the resulting 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome (CIS), defining what is needed to fulfill dissemination in time and space of lesions in the CNS, stressing the

need for no better explanation for the presentation (Thompson et al., 2018a). In applying the 2017 McDonald criteria, MS can be diagnosed more frequently at the time of the first clinical event as compared to earlier McDonald criteria. Those most impacted by the updated criteria include affected patients with a typical clinically isolated syndrome or CIS, which refers to a first episode of inflammatory demyelination in the CNS (Fig. 6.5) as might occur in optic neuritis (ON). Two important changes of the new criteria are the implementation of CSF OCBs as a substitute for DIT; and the inclusion of symptomatic and asymptomatic MRI lesions in the determination of DIS and DIT, with cortical lesions being equivalent to juxtacortical lesions (Fig. 6.6). Thus, the early diagnosis of MS can be ascertained with a single attack and clinical evidence of two or more lesions that meet DIT criteria by manifesting CSF OCBs; and in others with a single attack and clinical evidence of one CNS lesion who concomitantly meet DIS and DIT, respectively, with either an additional attack and CSF OCBs, or 1 or more typical T2 lesions in two or more areas of the CNS (periventricular, cortical, juxtacortical, infracortical, or spinal cord) and the simultaneous presence of enhancing and nonenhancing or a new T2 or enhancing MRI lesion compared to baseline. Affected patients with 1 year of retrospective or prospective steady disease progression may meet DIS with 1 or

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Fig. 6.4. Sagittal MRI of the spinal cord in different clinical MS phenotypes. (A) In a clinically isolated syndrome (CIS) patient, a focal, oval-shape lesion, hyperintense on a T2-weighted scan and enhancing after gadolinium administration (white arrow) is visible at C3–C4. (B) In relapsing-remitting MS (RRMS), several oval-shape T2-hyperintense cervical cord lesions are visible. In both secondary progressive (SPMS: C) and primary progressive MS (PPMS: E), several T2 hyperintense lesions are evident, which are associated with some degree of spinal cord atrophy. In a patient with benign MS (BMS: D), no focal T2-hyperintense lesions are detectable. Reproduced from Filippi M, Preziosa P, Rocca MA (2016). Multiple sclerosis. Handb Clin Neurol 135:399–423 with permission of the publisher.

Fig. 6.5. Axial T2-weighted MRI in a patient with left optic neuritis. (A) T2-weighted with fat suppression (B) spin-echo and postcontrast T1-weighted (C) magnetic resonance images of the brain from a 25-year-old patient at presentation with a clinically isolated syndrome suggestive of multiple sclerosis, characterized by left optic neuritis. In (A) and (B), a hyperintensity in the intraorbitary part of the left optic nerve is visible (white arrow). In (B), this portion of the optic nerve is contrast-enhanced (white arrow). Reproduced from Filippi M, Preziosa P, Rocca MA (2016). Multiple sclerosis. Handb Clin Neurol 135:399–423 with permission of the publisher.

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Fig. 6.6. Brain MRI imaging cortical lesions in a 44-year-old patient with RRMS. Axial proton density-weighted (A), T2-weighted (B), T1-weighted (C) spin-echo, and double-inversion recovery (D) magnetic resonance images of the brain. One cortical lesion (white arrow), hypointense on a T1-weighted sequence and more visible on a double-inversion recovery sequence, is evident. Reproduced from Filippi M, Preziosa P, Rocca MA (2016). Multiple sclerosis. Handb Clin Neurol 135:399–423 with permission of the publisher.

more typical T2 brain lesions or two or more T2 spinal cord lesions, and CSF OCBs. Careful differential diagnosis is still essential in patients with atypical clinical manifestations to avoid misdiagnoses. However, research to further refine the criteria should focus on optic nerve involvement, validation of the criteria in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers. Magnetic resonance spectroscopy (MRS) has been studied extensively in MS and differs from MRI because the signal does not derive from protons in water but instead from organic molecules contained in living tissue (Inglese et al., 2005). These imaging metrics may assist in making other clinical measures more robust through integration such as assessing neurodegeneration, neuronal integrity and repair based on measurements of the neuro-axonal marker N-acetylaspartate (NAA) or one

of the many nonneuronal metabolites choline, myoinositol, glutamate and g-aminobutyric acid (GABA) in whole-brain or head proton 3 T MRS (Kirov et al., 2017) or in voxels of interest (De Stefano et al., 2007). Lymphocytic CSF pleocytosis of 5–50 cells/mm3 is noted in up to two-thirds of MS patients, and OCB in >90% of patients (Thompson et al., 1979) and may not appear until several years after onset of MS, persisting thereafter. It is not indicative of active disease and can be encountered in other neuroinflammatory disorders including encephalitis, meningitis, Guillain-Barr
e syndrome, and even cerebral infarction (Kostulas et al., 1987). Two noninvasive investigative modalities, transcranial magnetic stimulation (TMS) and functional MRI (fMRI), have revealed insights into synaptic transmission and mediating the response of the brain to injury in MS.

MULTIPLE SCLEROSIS: MOTOR DYSFUNCTION There are fMRI navigated TMS systems to precisely localize the cerebral site of TMS stimulation with respect to the underlying brain function or anatomy (Rossini and Rossi, 2007). An evoked brief and intense magnetic field, created by a strong electric current circulating within a coil resting on the scalp, penetrates human tissue painlessly and, if the current amplitude, duration, and direction are appropriate, induces in the brain (or in spinal roots, or in nerves) electric currents that can depolarize neurons or their axons. When TMS is delivered over the primary motor cortex (M1) with adequate intensity, it induces efferent volleys along CST. Several measures of distinct physiologic importance can be recorded and measured besides the “classic” electromyography (EMG) motor evoked potentials (MEPs) from the muscles contralateral to the stimulated motor cortex including the resting and active motor threshold (RMT, AMT), central conduction time (CCT), cortical silent period (CSP), intracortical inhibition and facilitation (ICI, ICF). These different measures allow a comprehensive evaluation of the functional state of the CST pathway useful for investigating both physiologic and pathologic conditions. Brain plasticity may be revealed with TMS where the area of maximal excitability, also called the “hot spot,” migrates outside the usual boundaries in association with a pathological insult such as the demyelinating brain lesion. Such “migration” may be due to the activation of a secondary hot spot previously hidden by the predominant one or to the recruitment of silent but already existing synapses or even to the creation of new synaptic connections and neural networks. Moreover, interhemispheric differences in the output maps, which are otherwise symmetric in normal subjects, can emerge due to monohemispheric lesions such as in MS wherein the hand motor cortical area of the affected hemisphere is significantly larger in nearly three-fifths of cases, in parallel with clinical improvement (Rossini et al., 2003). Various MEP parameters and transcallosal connections, as well as intracortical excitability that undergoes “plastic” changes weeks to months after injury, may provide insight into neural plasticity and clues for targeted rehabilitation. Recently, fMRI allows investigation of dynamic changes in brain tissue and in brain network connectivity in the resting and task-based states in response to simple motor tasks (Stampanoni Bassi et al., 2017). A study that compared fMRI with T2 lesion volume and severity of MS pathology in lesions and normal-appearing brain tissue in nondisabled RRMS patients compared to controls found increased cortical activation over a distributed network in response to simple motor tasks (contralateral primary sensorimotor cortex, bilaterally in the supplementary motor area, bilaterally in the cingulate motor area, in the contralateral ascending bank of the Sylvian fissure, and in the contralateral intraparietal

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sulcus) that may contribute to the limitation of the functional impact of white-matter MS injury (Rocca et al., 2002). Similar cortical plasticity occurred in patients with SPMS where fMRI studies show increased adaptive cortical changes in highly specialized areas (ipsilateral inferior frontal gyrus, middle frontal gyrus, bilaterally, and contralateral intraparietal sulcus) during the performance of simple motor tasks compared to volunteers, where it may also have a role in limiting the clinical impact of MS-related damage (Rocca et al., 2003). Evoked responses are useful in detecting subclinical lesions and in confirming the relation of questionable symptoms and signs to a CNS process (Hume and Waxman, 1988). Trimodal evoked responses are commonly employed in clinical practice for the detection of clinical and subclinical demyelinating lesions. Visual evoked responses (VER) evidencing prolongation of the P100 latency and an inter-eye latency difference greater than 12 ms, with preserved amplitude, likely have prechiasmal optic nerve conduction block due to focal demyelination, as noted in 80%–95% of patients with optic neuritis, while others have less specific reduced amplitude. Brain stem auditory evoked responses (BAER) show prolonged interpeak latencies in up to two-thirds of patients with clinically definite lesions, mainly wave III to IV, and disappearance of wave V. By comparison, somatosensory evoked responses (SSER), recording from the tibial and median mixed nerve, show a sensitivity of 86% in clinically definite MS, due to the increased length of CNS long tracts that can be studied, from the lumbar or cervical enlargement to the sensory cortex. Patients with spinal cord MS lesions can have significantly delayed motor evoked responses after transcutaneous magnetic stimulation of the brain (Ingram et al., 1988), although the overall utility of this technique for detecting subclinical motor deficits is low compared with trimodal evoked responses. Insidious progression is common in elderly patients with MS; however, it is rare for an MS patient to present with a first clinical attack (relapse) after age 60 (Kis et al., 2008). In that instance, other potential causes, especially vascular disease, should be considered especially with abnormally enhancing lesions on MRI, which necessitate exclusion of infection, metastases, lymphoma, and paraneoplasia. By comparison, with the notable exception of recurrent isolated optic neuritis, it is extremely unusual for MS to be present with completely normal MRI of the neuroaxis, assuming neuroimaging is of adequate quality.

MS VARIANTS: AQP4, NMOSD, AND MOGAD Neuromyelitis optica (NMO) is an antibody-mediated inflammatory disease of the CNS with a predilection

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Fig. 6.7. Chiasmal lesion in aquaporin-4 antibody-positive neuromyelitis optica (NMO) (A) with gadolinium enhancement (arrow) and (B) T2-hyperintensity (arrow). Reproduced from Hinson SR, Lennon VA, Pittock SJ (2016). Autoimmune AQP4 channelopathies and neuromyelitis optica spectrum disorders. Handb Clin Neurol 133:377–403 with permission of the publisher.

for the optic nerves, spinal cord, and certain brain regions. While NMO has previously been considered a variant of MS, it is now known to have distinct clinical, pathological, and immunological features. The identification of the pathogenic antibody against aquaporin-4 (AQP4) delineates NMO from MS. The antibody specificity has allowed an expanded view of the clinical presentations of NMO-spectrum disorders (NMOSD), without requiring all the clinical features that were previously essential to make a clinical diagnosis. Early, accurate diagnosis of patients with NMOSD permits treatment with appropriate acute and long-term immunosuppressive agents that are critical to mitigate the risk of disability associated with this disease. Subsets of patients with the NMOSD phenotype have autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG), which has a different pathogenesis and expected outcome. NMOSD must be distinguished from MOGIgG-antibody disease (MODAD) that features perivenous inflammation and white-matter demyelination. With a worldwide prevalence of NMOSD among Whites of 1/100,000, and an annual incidence of less than 1/million, the annual incidence of MOGAD in adults is estimated to be 1.3/million, and 3.1/million in children (Hor et al., 2020). A better understanding of the distinct pathophysiology of these disorders is laying the foundation for targeted efforts to develop novel, disease-specific treatments. Children and adults with NMOSD (Rubiera et al., 2006) present with recurrent attacks of ON and longitudinally extensive transverse myelitis (TM) that is distinct from MS. Magnetic resonance imaging is the first-line test in aiding the diagnosis of NMOSD. Optic nerve, spinal cord, and brain lesions are often distinctive. Imaging of the optic nerve distinguishes NMOSD from MS

(Tackley et al., 2014). Optic nerve MRI abnormalities in NMOSD are commonly extensive (Fig. 6.7A and B) with more posterior involvement and enhancement of the chiasm. While the frequency and severity or types of signal alterations and contrast enhancement do not appear to differ between NMOSD and MS (Khanna et al., 2012), chiasmal enhancement is not typical of MS and the visual pathway tends to be more inflamed in NMOSD than in MS. Spinal cord lesions are predominantly central and extend longitudinally to three or more vertebral segments (Fig. 6.8A–C). Lesions may be spotty with central necrosis and cavitation. In a study of 137 cases reported by Jarius et al. (2012), the initial spinal cord MRI had at least one cord lesion extending over three or more vertebral segments in 127 cases (92.7%), with a median extension of six segments with a trend of longer lesions in APQP4-IgG seropositive cases. The total lesion load at the first MRI correlated with the EDSS at the last follow-up in patients with a disease duration
100 months. Lesions often occupy more than half of the spinal cord in cross section (Nakamura et al., 2008) and may have a patchy or continuous in-distribution appearance with diffuse swelling in the cervical, thoracic or both locations (Asgari et al., 2013). Although commonly long, 17% of seropositive patients can present with short TM lesions (Flanagan et al., 2015). Brain MRI lesions were detected in 60% of NMOSD cases and were often nonspecific at first relapse, increasing with disease progression (Pittock et al., 2006). Most brain MRI lesions are read as nonspecific, but approximately 10% are MS-like however asymptomatic. NMO-typical brain lesions localize at AQP4-enriched regions, namely astroglial foot processes in subpial and subependymal zones around the lateral, third, and fourth ventricles characterized by fenestrated capillaries and

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Fig. 6.8. Sagittal T2- (A, B) and PD- (C) weighted images of neuromyelitis optica. In both sequences, a long hyperintense lesion, involving the entire cervical portion of the cord as well as part of the dorsal portion is visible. Reproduced from Hinson SR, Lennon VA, Pittock SJ (2016). Autoimmune AQP4 channelopathies and neuromyelitis optica spectrum disorders. Handb Clin Neurol 133:377–403 with permission of the publisher.

loosely apposed astrocytic processes that can facilitate IgG access to the CNS; they may produce symptoms of inappropriate antidiuresis (SIAD) and endocrinopathies. NMO-IgG determination is crucial in detecting patients who will develop NMO; however, its value as a routine test in patients with symptoms of a CIS of the type seen in MS is low. Aquaporin-4 antibody positive NMOSD may be regarded as an immune astrocytopathy. The incorporation of clinical features like area postrema syndrome, brain stem syndrome, diencephalic syndrome, and cortical manifestations as core clinical characteristics into evolving diagnostic criteria has widened the clinical spectrum of NMOSD. Newer therapeutic agents are being introduced for NMOSD disease; however, challenges remain in treating seronegative disease because of the limited treatment options. Clinically, NMOSD may now be classified into AQP4-antibody seropositive and seronegative diseases, detecting more patients earlier than before. Seronegative NMOSD includes cases of MOG-antibody-seropositive disease with its unique clinical spectrum somewhat different from AQP4-antibody-seropositive NMOSD. Pathologically, NMOSD includes AQP4-antibodyseropositive autoimmune astrocytopathic disease and MOG-antibody-seropositive inflammatory demyelinating disease. The double seronegative group needs further research. Therapeutic options of NMOSD have been shaped by randomized clinical trials (RCTs) of monoclonal

antibodies (Pittock et al., 2019; Yamamura et al., 2019). Unanswered questions remain, including the cause of AQP4-IgG-negative disease, how astrocyte-mediated damage leads to demyelination, the role of T-cells, why peripheral AQP4-expressing organs are undamaged, and how circulating AQP4-IgG enters NMO lesions. Myelin oligodendrocyte glycoprotein-IgG1-associated disorder (MOGAD) is a distinct nosological entity characterized by attacks of optic neuritis, myelitis, brain or brain stem inflammation, or combinations thereof (Wynford-Thomas et al., 2019). Seropositivity for MOG-IgG1 confirms the diagnosis with a compatible clinical and radiologic phenotype according to recent international recommendations (Jarius et al., 2018). Live cell-based assays yield the highest specificity for MOGAD. Indiscriminate testing for MOG-IgG1 may lead to false-positive results despite high specificity. Although no age group is exempt, the median age of onset is in the fourth decade of life, with ON and TM being frequent presenting phenotypes. Disease course can be monophasic or relapsing with subsequent relapses most commonly involving the optic nerve. MRI characteristics help differentiate MOG-AD from other neuroinflammatory disorders, including MS and NMOSD. Analogous to patients with AQP4-IgG seropositivity who are at higher risk for relapse after inflammatory demyelinating disease attacks of optic neuritis, transverse

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myelitis, and monophasic acute disseminated encephalomyelitis (ADEM), so too are those with persistent MOG-IgG1 seropositivity at risk for relapse (LopezChiriboga et al., 2018). Cerebrospinal fluid OCBs are uncommon. RCTs are limited in MOGAD. There is a role for high-dose corticosteroids and plasma exchange in the treatment of acute attacks, as well as oral immunosuppressants, and other immunotherapies that target various B-cell-related proteins (Graf et al., 2021a, 2021b). Residual motor disability culminates in flaccid paraplegia in the majority of cases, with TM at onset being the most significant predictor of long-term outcome.

Childhood MS Banwell (2014) has reviewed the clinical and laboratory aspects of childhood MS which has been described in retrospective case series, case reports, and in prospective series and cross-sectional database cohorts, often with considerable variability between reports (Gall Jr. et al., 1958; Sevon, 2001; Boiko et al., 2002; Ruggieri et al., 2004; Alroughani and Boyko, 2018).

CLINICAL FEATURES The International Pediatrics Multiple Sclerosis Study Group (IPMSSG) consensus definitions for pediatric ADEM, pediatric CIS, pediatric NMO, and pediatric MS were published in 2007 (Krupp et al., 2007) and revised in 2013 (Krupp et al., 2013). A long-term follow-up analysis of the criteria (Peche et al., 2013) showed that children with initial clinically isolated syndrome were more likely to develop future MS compared to those with ADEM initial diagnosis; in addition, female gender, brain stem or hemispheric involvement, and Callen MRI criteria (Callen et al., 2009) predict the eventual diagnosis of MS. Overall, most children present with focal or multifocal neurologic syndromes similar to those seen in adults with MS, although certain agespecific features seem to stand out. For example, ataxia and brain stem syndromes are particularly prominent in children presenting under the age of 10 years, although some series have found brain stem symptoms to be the most frequent initial localization in both young and adolescent MS patients (Ruggieri et al., 2004). Optic neuritis seems to be a more common presentation in adolescents than in younger children (Sindern et al., 1992) and is especially prominent in the childhood MS reported from Japan (Shiraishi et al., 2005). Encephalopathy, fever, seizures, and multifocal onset indistinguishable at presentation from current clinical definitions of ADEM (Mikaeloff et al., 2004b) occur as the first manifestation of MS more frequently in children than in adults (Ghezzi et al., 2002). Very young children may present with acute, severe encephalopathy, which may

be fatal, and in survivors it is often associated with significant residual cognitive deficits (demyelinating encephalopathy) and motor sequelae (Ruggieri et al., 1999). Childhood and adolescent-onset MS is characterized by a shorter interval between the first and second demyelinating event, and by a higher relapse frequency compared to adult-onset MS with >95% of childhoodonset MS cases having a relapsing-remitting MS course at onset (Boiko et al., 2002). Primary progressive MS, by contrast, was exceptionally rare, occurring in 100 mL PVR volume was set to secure the high specificity of a clinically established diagnosis of MSA. Objective evidence of a neurogenic etiology of orthostatic hypotension can be obtained with active standing with a 20 mmHg systolic blood pressure (SBP) drop usually accompanied by a diastolic BP (DBP) drop of 10 mmHg and a D heart rate (HR)/DSBP ratio < 0.5 beats per min (bpm)/mmHg within 3 min of standing (Norcliffe-Kaufmann et al., 2018). Due to its increased sensitivity in the diagnosis of MSA, the 20/10 mmHg BP drop replaced the 30/15 mmHg BP drop criterion of the 2008 criteria. Delayed neurogenic OH (i.e., between 3 and 10 min) was also included as a feature of clinically probable MSA. Both clinically established and clinically probable MSA require supportive motor or nonmotor features (previously termed “red flags”) and the absence of exclusion criteria. The most exciting but challenging part of the 2022 diagnostic criteria is the introduction of possible

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Table 9.2 Revised consensus criteria for multiple system atrophy A sporadic, progressive adult (>30 years) onset disease Essential features Core clinical features

Supportive featuresa MRI marker Exclusion criteriab

Clinically established MSA

Clinically probable MSA

Possible prodromal MSA

1. Autonomic dysfunction (at least one required) o Unexplained voiding difficulties with PVR 100 mL o Unexplained urinary urge incontinence o Neurogenic OH (20/10) within 3 min of standing or head-up tilt test and at least one 2. Poorly L-dopa-responsive parkinsonism 3. Cerebellar syndrome

At least two of:> 1. Autonomic dysfunction defined as (at least one is required): o Unexplained voiding difficulties with PVR o Unexplained urinary urge incontinence o Neurogenic OH (20/10) within 10 min of standing or head-up tilt test 2. Parkinsonism 3. Cerebellar syndrome

At least one of the following: 1. RBD (polysomnography) 2. Neurogenic OH (20/10) within 10 min of standing or head-up tilt 3. Urogenital failure (ED in males < 60 years + at least one of unexplained voiding difficulties with PVR > 100 mL or unexplained urinary urge incontinence) and at least one

At least two

At least one

NA

At least one Absence

Not required Absence

Not required Absence

1. Subtle parkinsonism 2. Subtle cerebellar signs

aa

Supportive clinical features: Rapid progression within 3 years of motor onset, moderate-to-severe postural instability within 3 years of motor onset, craniocervical dystonia induced or exacerbated by L-dopa in the absence of limb dyskinesia, severe speech impairment within 3 years of motor onset, severe dysphagia within 3 years of motor onset, unexplained Babinski sign, jerky myoclonic postural or kinetic tremor, postural deformities, stridor, inspiratory sighs, cold discolored hands and feet, erectile dysfunction (below age of 60 years for clinically probable MSA), pathologic laughter or crying. b Exclusion criteria: Substantial and persistent beneficial response to dopaminergic medications, unexplained anosmia on olfactory testing, fluctuating cognition with pronounced variation in attention and alertness and early decline in visuoperceptual abilities, recurrent visual hallucinations not induced by drugs within 3 years of disease onset, dementia according to DSM-V within 3 years of disease onset, downgaze supranuclear palsy or slowing of vertical saccades, brain MRI findings suggestive of an alternative diagnosis (e.g., PSP, multiple sclerosis, vascular parkinsonism, symptomatic cerebellar disease, etc.), documentation of an alternative condition (MSA look-alike, including genetic or symptomatic ataxia and parkinsonism) known to produce autonomic failure, ataxia, or parkinsonism and plausibly connected to the patient’s symptoms.

prodromal MSA as a research category (Table 9.2). The essential features are either polysomnography-proven rapid eye movement sleep behavior disorder (RBD), or isolated autonomic failure, defined as at least one of urogenital failure with PVR > 00 mL or urinary urge incontinence, or neurogenic OH within 10 min of standing or HUT, as well as the presence of subtle parkinsonian motor signs or cerebellar signs. This category has limited specificity, especially without other imaging or laboratory biomarkers, and should be used with caution and mainly for research purposes at this time.

MOTOR FEATURES The motor features of MSA include parkinsonism, myoclonus, dystonia, cerebellar signs and pyramidal signs (Fanciulli and Wenning, 2015). Bradykinesia is the most common presenting feature, but the akinetic-rigid

syndrome is often symmetric in MSA and the classical “pill-rolling” resting tremor seen in PD rarely occurs in MSA-P. When ataxic limb movements, wide-based gait, and nystagmus dominate the clinical picture, the phenotype is referred to as MSA-C. With the progression of the disease, parkinsonism and cerebellar features overlap. Postural tremor is seen in as many as 50% of patients with MSA with evidence of minipolymyoclonus on neurophysiologic examination. Imbalance and loss of postural reflexes associated with falls are common early in the course of MSA contrary to PD. As the disease advances, dysarthria may progress to anarthria. Swallowing is also often impaired with dysphagia. Transient response to levodopa may be observed in approximately 40% of patients during early disease stages (Martin et al., 2021). The use of levodopa in MSA may be associated with drug-induced involuntary movements, such as head and neck dystonia or lower face dyskinesias. Dystonia

SYNUCLEINOPATHIES may be prominent and 15% of patients develop a “disproportionate” antecollis in the later stages of the disease. Pyramidal signs are seen in about 60% of patients with hyperreflexia and extensor plantar responses. An increase in tone due to rigidity from parkinsonism may contribute to difficulty identifying spasticity in patients with MSA. Frequently, especially late in the disease, motor features of parkinsonism, ataxia, and pyramidal findings overlap (Fanciulli and Wenning, 2015).

NONMOTOR FEATURES Several nonmotor features are seen in MSA including autonomic failure with cardiovascular and urogenital manifestations, sleep and respiratory disturbances, anhidrosis, cognitive impairment, and pain. Autonomic symptoms are early manifestations of MSA. These symptoms tend to be severe and widespread and precede motor symptoms by a median of 4 years in 75% of patients (Coon et al., 2015). Over time, nearly all patients with MSA develop clear symptoms and signs of progressive autonomic failure. Similar to patients with PAF, manifestations of adrenergic failure in MSA include orthostatic intolerance, blurred or dim vision, neck and shoulder ache (coat hanger phenomenon), and syncope. Postprandial hypotension and supine hypertension can be severe in MSA. Erectile dysfunction is usually seen at disease onset in men whereas genital hyposensitivity during intercourse and impairment in desire, arousal, and lubrication are reported in women (Raccagni et al., 2021). Urinary dysfunction is frequent and the usual sequence of events is the initial development of neurogenic bladder with frequency and urgency that progress to incontinence and incomplete bladder emptying with urinary retention requiring catheterization (Fanciulli and Wenning, 2015). Sleep disorders are common in MSA. Rapid eye movement sleep behavior disorder is present in close to 90% of patients with MSA and more than half report symptoms of REM sleep behavior disorder before the onset of motor deficits (Palma et al., 2015). Approximately half of all patients develop diurnal or nocturnal inspiratory laryngeal stridor; nocturnal stridor may occur in association with sleep apneas (K€ ollensperger et al., 2008). Severe stridor may be associated with a shortened lifespan possibly due to sudden death. Cognitive involvement in patients with MSA is being increasingly recognized and frontal-lobe dysfunction with attention deficits is most frequently reported followed by memory and visuospatial dysfunction (Stankovic et al., 2014). Emotional lability and incontinence with pathologic laughter and crying, consistent with pseudobulbar affect, occasionally are evident. Mood disorders such as depression and apathy, as well as anxiety, are likely underrecognized.

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SURVIVAL MSA is a progressive neurodegenerative disorder with a median time from onset of symptoms to death of approximately 8 years in prospective cohort studies with few patients surviving beyond 15 years (Fanciulli and Wenning, 2015). The most common causes of death include bronchopneumonia, urosepsis, or sudden death which may be a result of acute disruption of the brainstem cardiorespiratory drive or related to vocal cord dysfunction. Several risk factors have been associated with shorter survival in patients with MSA including older age at onset, hypometabolism of the left insula, early requirement of bladder catheterization, generalized autonomic failure, and low vitamin B12 levels (Wenning et al., 1994; McCarter et al., 2020; Grimaldi et al., 2021).

Paraclinical testing AUTONOMIC CARDIOVASCULAR DOMAIN Autonomic function testing in MSA reveals evidence of central autonomic dysfunction. Cardiovascular adrenergic failure is usually severe and frequently the most pronounced finding. Relative preservation of cardiovagal function has been reported in patients with MSA compared to other synucleinopathies (Goldstein et al., 2000; Norcliffe-Kaufmann et al., 2018).

PLASMA CATECHOLAMINES Analysis of supine and standing plasma norepinephrine levels and its metabolites can be helpful in the diagnosis of MSA and risk stratification of patients with isolated orthostatic hypotension. Supine and standing plasma norepinephrine levels are usually normal in MSA but do not increase appropriately with standing (100 mL), absence of detrusor-sphincter

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coordination, and atonic bladder with low urethral pressure (Shin et al., 2019). Measurement of rectal sphincter tone and rectal manometry demonstrate loss of analsphincter relaxation and decreased anal tone in MSA, whereas electromyogram of the urethral and anal sphincters shows evidence of denervation and reinnervation. Polysomnography is recommended for the diagnosis of REM sleep behavior disorder, and screening for nocturnal stridor. Laryngoscopy is suggested in patients with MSA to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions.

shows different a-synuclein seeding activity in MSA compared to the Lewy-body synucleinopathies and allows for faithful differentiation of MSA from PD/DLB (Rossi et al., 2020; Shahnawaz et al., 2020b; Singer et al., 2020) (Fig. 9.3). While less specific and also elevated in other neurologic disorders associated with rapid progression or considerable neuronal injury, NfL in spinal fluid has been found to be markedly elevated even in early MSA in contrast to PD/DLB, so high levels of NfL can differentiate MSA from these other synucleinopathies (Singer et al., 2020).

BRAIN IMAGING Brain MRI may vary based on the clinical subtype. In MSA-P, the brain MRI frequently reveals atrophy of the putamen with a hyperintense T2 border of the lateral putamen and T2 hypointensity of the body of the putamen. Atrophy of the middle cerebellar peduncle, pons, or cerebellum can be seen in MSA-P and MSA-C. The hot cross bun sign is the classic sign in patients with MSA-C and refers to cruciform T2 hyperintensities of the pons (Palma et al., 2018). Hypometabolism of the putamen, brainstem, or cerebellum on fluorodeoxyglucose positron emission tomography is seen in MSA. Imaging of presynaptic dopaminergic transporter reveals evidence of denervation in all cases of MSA-P, whereas relative preservation of dopaminergic terminals is observed in MSA with cerebellar features (Pirker et al., 2000).

CARDIAC SYMPATHETIC NEUROIMAGING Cardiac noradrenergic denervation can be visualized with 123I-metaiodobenzyl guanidine scintigraphy or 6-18F-dopamine PET scan. Most MSA patients have biomarkers of intact cardiac sympathetic innervation; however, rare cases of MSA with neuroimaging evidence of cardiac noradrenergic deficiency have been reported (Goldstein et al., 1997; Cook et al., 2014; Lamotte et al., 2020).

SKIN BIOPSY Skin biopsy has been utilized to confirm a diagnosis of synucleinopathy (Gibbons et al., 2020); however, described methodologies differ and while commercial testing is available, confirmatory studies are currently lacking to corroborate test performance. Routine available testing does not distinguish between the different synucleinopathies (see Skin biopsy section in PAF).

ANALYSIS OF CEREBROSPINAL FLUID As discussed in the Cerebrospinal fluid section of Pure Autonomic Failure, cerebrospinal fluid can be assayed for a-synuclein seeding activity using PMCA, which

Treatment MULTIDISCIPLINARY APPROACH Even more important for patients with PAF is a multidisciplinary and individualized care model that is necessary to optimally address the various symptoms and complications of MSA. Optimal care of patients with MSA requires the involvement of the patient’s primary care physician and multiple specialties including movement and autonomic disorders, urology, sleep medicine, physical medicine and rehabilitation, speech pathology, otorhinolaryngology, social work, and palliative medicine, among others. More recently, specialized MSA clinics have been implemented at a number of institutions to address this unmet need.

SYMPTOM MANAGEMENT Motor symptoms No DMT for MSA is currently available in MSA. In MSA-P, Levodopa should be trialed for the treatment of parkinsonism if symptoms are bothersome to the patient and impact quality of life (QoL). Transient response to levodopa is observed in 40% of patients with improvement of akinesia and rigidity (Martin et al., 2021). Levodopa should be used cautiously to minimize and monitor potential side effects such as hypotension or dyskinesias. In cases where levodopa cannot be tolerated dopamine agonists may be tried, however, they are less likely to provide a motor benefit. Botulinum toxin injections can be helpful for disabling hand, foot, or axial dystonia. No treatments have proven effective for cerebellar features of MSA. Rehabilitation approaches may be helpful to optimize gait aid use, prevent falls, and provide adaptive mechanisms. Rehabilitation programs (including home visits) with occupational, physical, and speech therapy can be helpful for patients with MSA in preventing falls and developing general coping and communication abilities. Clonazepam may help myoclonus or action tremor, whereas spasticity rarely requires treatment with baclofen or botulinum toxin injections (Fanciulli and Wenning, 2015).

SYNUCLEINOPATHIES Nonmotor symptoms The management of orthostatic hypotension, constipation, thermoregulatory disturbances, and erectile dysfunction in MSA is similar to the one in PAF. Patients with MSA and neurogenic bladder symptoms should be screened regularly for urinary tract infections. Detrusor overactivity can be treated with antimuscarinic agents; however, anticholinergic side effects must be monitored and botulinum toxin injections in the detrusor muscle may be beneficial in some patients, particularly early in the disease when there is no evidence of significant retention. Clean intermittent self-catheterization is the first-line therapy for urinary retention with postvoid residual volumes above 100 mL. Unfortunately, lack of manual dexterity may make this impossible and there is a risk of urethral ulceration long term such that chronic indwelling catheterization or suprapubic indwelling catheterization may be required. Nocturia can be alleviated with controlling supine hypertension at night; intranasal desmopressin at bedtime can be helpful. Severe dysphagia and its complications should be anticipated by alteration of the diet. Surgical intervention with gastrostomy is rarely indicated given the overall prognosis

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of the disease, and involvement of palliative care medicine can be extremely helpful for patients and caregivers. The management of inspiratory stridor in MSA is challenging and continuous positive airway pressure and tracheostomy are both suggested as symptomatic treatment of stridor, but whether they improve survival is uncertain. Treatment of obstructive sleep apnea is recommended after evaluation by a sleep specialist. Patients should be encouraged to remain physically active and exercise regularly, which can help prevent deconditioning and cardiovascular complications, and may positively influence prognosis. Recumbent exercise may be preferable when orthostatic hypotension is present. Disease-modifying approaches (Fig. 9.4) There is currently no DMT available for MSA and many clinical trials have yielded negative results. Identification of imaging and nonimaging biomarkers should be a priority to select patients who would benefit from a neuroprotective treatment. To date, only one controlled study reported positive effects on the progression of MSA using placebocontrolled intravenous and intra-arterial injections of

Fig. 9.4. Pathophysiology and disease-modifying strategies in multiple system atrophy. Neuron-derived a-synuclein aggregates in the extracellular space are taken up by neighboring glial cells. Microglia and astrocytes, which secrete inflammatory molecules, are activated. Oligodendrocytes undergo demyelination, exposing neuronal axons that may retract or be degenerated by the hostile external environment, causing neurodegeneration. Disease-modifying strategies include anti-a-synuclein therapies, antiinflammatory therapies, cell replacement therapies, and therapies targeting neurodegeneration.

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mesenchymal stem cells; however, the single-center design, safety concerns with ischemic lesions detected on MRI in one-third of participants, and the exclusive recruitment of patients with MSA-C limit the generalizability of the findings (Lee et al., 2012). Intrathecal mesenchymal stem cells administration was also studied in a phase I/II study in 24 patients. In this study, the treatment was demonstrated to be overall safe and well tolerated, but an implantation response associated with thickening/enhancement of lumbar nerve roots was seen at high doses. There was a dose-dependent efficacy signal compared to a historical cohort of patients with MSA (Singer et al., 2019). Because of its possible role in the pathogenesis of MSA, a-synuclein has been proposed as a target for the development of possible neuroprotective strategies. The results of a 52-week, randomized, double-blind, placebo-controlled trial targeting a-synuclein aggregation in patients with probable MSA with polyphenol epigallocatechin gallate were published in 2019. The mean change from baseline in motor examination scores of the Unified Multiple System Atrophy Rating Scale (UMSARS) at week 52 did not differ significantly between the treatment and placebo groups and epigallocatechin gallate was associated with hepatotoxicity in some patients (Levin et al., 2019). The MRI substudy of 32 patients suggested reduced brain atrophy in the treatment group. Future studies will explore different strategies of targeting a-synuclein through inhibition of cleavage, inhibition of oligomer formation, immunotherapy, and increasing clearance through enhancing autophagy. In another recent study (NCT03952806), the use of a myeloperoxidase inhibitor failed to show any benefit in patients with MSA. There is also an urgent need for studies investigating symptomatic treatments for nonmotor symptoms as well as nonpharmacological strategies including different rehabilitation programs until a disease-modifying approach becomes available.

LEWY BODY DISORDERS—PARKINSON DISEASE AND DEMENTIA WITH LEWY BODIES Pathophysiology The pathophysiology of Lewy body disorders is complex and not fully understood. In both DLB and PD, dopamine depletion from the basal ganglia leads to parkinsonian signs such as bradykinesia. Different models of basal ganglia dysfunction have been proposed and may be useful for conceptualizing how the motor symptoms of PD and DLB arise; however, these models do not consider the complex interaction between different pathophysiological processes. The neuropathologist Heiko Braak

has proposed that the pathologic changes of PD start in the medulla of the brainstem and the olfactory bulb, progressing rostrally over many years to the cerebral cortex in a predictable six-stage process (Braak et al., 2004). The validity and predictive utility of Braak staging has been challenged and many patients with PD or DLB do not follow the proposed staging system (Jellinger, 2008). Horsager and colleagues proposed a “brain-first” versus “body-first” classification of PD (Horsager et al., 2020). In the “brain-first” (top-down) subtype, a-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system in the “body-first” (bottom-up) type, the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. This “brain-first”/“body-first” division is supported by animal models demonstrating the bidirectional connection between the gut and the brain of a-synuclein pathology along sympathetic and parasympathetic pathways (Arotcarena et al., 2020). Nevertheless, some evidence would argue against REM sleep behavior representing a “body” onset before parkinsonism. For example, autopsy data demonstrate a-synuclein deposition and neuronal loss in brain and brainstem regions in patients with isolated REM sleep behavior disorder (Gagnon et al., 2006), and REM sleep behavior disorder has been associated with other pathologies such as tau, b-amyloid, or TDP-43 (Keir and Breen, 2020). Identifying different subtypes of PD has been an active area of research with promising prospects to improve the understanding of disease mechanisms, predict prognosis, and ultimately develop personalized DMT. Subtypes of PD have been defined according to clinical symptoms and demographic characteristics; however, data-driven clinical subtyping has failed to predict patterns of aggregation of a-synuclein (De Pablo-Fernandez et al., 2019; Espay and Marras, 2019). Therefore, an alternative to subtyping PD patients based on cooccurring clinical symptoms is to identify biological-based subtypes, or biotypes, based on shared and distinguishable neuroanatomical signatures (Sturchio et al., 2020). Irrespective of the initial trigger of the neuronal degeneration in PD and DLB, the pathogenesis of neurodegeneration probably involves either apoptosis or necrosis. One of the pathophysiological hallmarks of PD and DLB is the highly selective degeneration of catecholaminergic neurons. Potential mechanisms of neurodegeneration in PD include a-synuclein misfolding, aggregation, toxicity, defective proteolysis and autophagy, mitochondrial dysfunction, abnormal lysosomes or vesicle transport, oxidative stress, abnormality of iron metabolism, and immunologic mechanisms leading to neuroinflammation (Schapira, 2006). A possible link between a-synuclein pathology and catecholaminergic neurodegeneration is supported by the

SYNUCLEINOPATHIES catecholaldehyde hypothesis and the potential role of the autotoxic intra-neuronal metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL) (Goldstein, 2020b). Studies have found that DOPAL potently oligomerizes and quinonizes a-synuclein (Burke et al., 2008; Jinsmaa et al., 2018); DOPAL-induced synuclein oligomers impede vesicular functions of catecholaminergic neurons (Goldstein, 2020b). Nevertheless, the exact role of a-synuclein oligomers in synucleinopathies is far from being elucidated.

Pathology Dementia with Lewy bodies and PD are characterized by neuronal a-synuclein inclusions in the form of Lewy bodies and Lewy neurites. Pathologically, three types of DLB are recognized: brain stem predominant, limbic (transitional), and neocortical (McKeith et al., 1996). It has long been thought that the different distribution of a-synuclein explains the clinical heterogeneity between patients with Lewy body disorders, however, the data to support this assumption is scarce. For example, the association between cortical Lewy bodies and dementia in patients with PD or LDB has not been clearly defined and all PD brains, from demented cases or not, may have cortical Lewy bodies (Hughes et al., 1992). In DLB, no correlation has been found between regional cortical Lewy body density and clinical symptoms (Gómez-Tortosa et al., 1999). Furthermore, a-synuclein, b-amyloid, and tau aggregation are frequent “copathologies” in neurodegenerative disorders such as PD and DLB that can be found in the brain of individuals without dementia or parkinsonism (Irwin et al., 2017). Indirect evidence from human studies suggests that protein aggregation may be protective (Espay et al., 2019). Further research is needed to investigate the role of protein aggregation in Lewy body disorders. The predominant pathology of the autonomic nervous system in Lewy body disorder is peripheral, although central involvement of autonomic structures likely contributes to orthostatic hypotension in both PD and DLB. Central autonomic structures involved in PD include the insular cortex, which has been associated with nonmotor symptoms, including autonomic dysfunction and impaired arousal (Papapetropoulos and Mash, 2007; Christopher et al., 2015), the hypothalamus (Langston and Forno, 1978; Swinn et al., 2003), the dorsal motor nucleus of the vagus, and to a lesser extent the rostral ventrolateral medulla. Involvement of the enteric nervous system and ganglionic and postganglionic sympathetic and parasympathetic neurons is common in Lewy body disorders. a-Synuclein pathology has been demonstrated in the submandibular gland, lower esophagus, stomach, small bowel, colon, and rectum; however, the presence of synuclein pathology in the enteric nervous system is not

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necessarily associated with neuronal loss (Dickson, 2012; Lamotte et al., 2020). A typical finding in PD is cardiac sympathetic noradrenergic deficiency with severe myocardial norepinephrine depletion (Goldstein and Sharabi, 2019). Postmortem studies show a significant reduction of fibers immunoreactive for tyrosine hydroxylase (a marker of noradrenergic axons) in both the myocardium and epicardium in pathologically confirmed PD compared to age-matched controls (Orimo et al., 2007; Fujishiro et al., 2008; Serrano et al., 2020). Lewy bodies have been found in unmyelinated nerve cell processes in sympathetic ganglia in PD (Forno and Norville, 1976; Orimo et al., 2005). Orimo and collaborators reported that Lewy bodies were present in sympathetic ganglia early in the disease process in PD and preceded neuronal loss (Orimo et al., 2005). In the heart of PD patients, Lewy bodies are found in the atrial ganglia, the nerve fibers around the coronary arteries, and the myocardium (Wakabayashi and Takahashi, 1997). Accumulation of a-synuclein in the distal axons of the cardiac sympathetic neurons seems to precede that in neuronal somata or neurites in the paravertebral sympathetic ganglia and suggests a centripetal degeneration of the cardiac sympathetic nerves in PD (Orimo et al., 2008).

Genetics The majority of cases of PD appear to be sporadic but there is increasing evidence that genetic factors play a role in the pathogenesis of PD (Blauwendraat et al., 2020). Mutations in more than 20 genes have been associated with PD, however, the age of onset, clinical presentation, and progression can differ, even among those with the same variant and within families suggesting the influence of additional genetic or environmental factors (Blauwendraat et al., 2020). Genome-wide association studies have also revealed that a large proportion of PD cases are affected by genetic risk factors (Blauwendraat et al., 2020). The genetic basis of DLB is not well understood. Whole-genome sequencing in large cohorts of DLB cases and healthy controls identified five independent risk loci (GBA, BIN1, TREM175, NCA, APOE), whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. This study demonstrated that DLB shares risk profiles and pathways with Alzheimer disease and PD (Chia et al., 2021).

Epidemiology Parkinson disease is the most common of the synucleinopathies with a mean incidence of 33.3 per 100,000 person-years, with incidence increasing with age, affecting 2%–3% of the population over the age of 65 (Savica et al., 2016). The global prevalence is expected to double

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from 6.2 million cases in 2015 to 12.9 million cases by 2040 (Dorsey and Bloem, 2018). The prevalence of PD increases with age, reaching a prevalence of 2.6% in people aged 85–89 years (Pringsheim et al., 2014). Dementia with Lewy bodies is the second most common form of dementia (accounting for as much as 30% of all dementia cases), with an incidence of 3.5 cases per 100,000 person-years (Savica et al., 2013). Similar to PD, the prevalence of DLB increases with age (Wakisaka et al., 2003), with an average age at presentation of 75 years.

Clinical features DIAGNOSTIC CRITERIA Dementia with Lewy bodies is characterized by progressive and severe cognitive decline, with disproportionate attentional and executive dysfunction with visual processing deficits (McKeith et al., 2017). Core clinical features include fluctuating cognition, recurrent visual hallucinations, and REM sleep behavior disorder with at least one cardinal feature of parkinsonism (bradykinesia, resting tremor, or rigidity). Along with autonomic dysfunction, neuroleptic sensitivity, postural instability with repeated falls, and neuropsychiatric manifestations are supportive clinical features (McKeith et al., 2017). Parkinson disease is characterized by motor features of parkinsonism, which is based on three cardinal motor manifestations. Parkinsonism is defined as bradykinesia, in combination with rest tremor, rigidity, or both. These features must be demonstrable and not attributable to confounding factors (Postuma et al., 2015). Various levels of certainty are established using the current Movement Disorder Society’s Clinical Diagnostic Criteria for Parkinson’s Disease, including clinically established and clinically probable (Postuma et al., 2015). Limb bradykinesia must be documented to establish a diagnosis of PD. Supportive criteria include a clear and dramatic beneficial response to dopaminergic therapy, the presence of levodopa-induced dyskinesia, a resting tremor, olfactory loss, and cardiac sympathetic denervation on MIBG scintigraphy (Postuma et al., 2015). The presence of exclusion criteria and red flags for the diagnosis of PD should be carefully assessed for each patient. Of note, severe autonomic failure in the first 5 years of disease with an orthostatic decrease of blood pressure within 3 min of standing by at least 30 mmHg systolic or 15 mmHg diastolic, in the absence of dehydration, medication, or other diseases is listed as a red flag for a clinical diagnosis of PD while studies have documented that orthostatic hypotension may appear early in the course of PD (Strano et al., 2016; Kim et al., 2016b).

NONMOTOR FEATURES Approximately 90% of patients with PD will develop at least one nonmotor symptom (Shulman et al., 2001). Autonomic symptoms are common nonmotor symptoms in PD. The most commonly reported symptoms of autonomic dysfunction in patients with PD include constipation (33%
48% of patients), urinary problems (37%
63% of patients), orthostatic lightheadedness or prior history of fainting (29%
36% of patients), dysphagia (30% of patients), and hypersialorrhea (33%
46% of patients) (Rodriguez-Blazquez et al., 2021). The prevalence of orthostatic hypotension in PD increases with age and disease duration (Strano et al., 2016; Kim et al., 2016b). Anosmia is frequent in Lewy body disorders, but the patients may not be aware of the deficit. The presence of orthostatic hypotension in PD has been associated with more rapid disease progression, shorter survival time, cognitive impairment, and falls (Rascol et al., 2015; De Pablo-Fernandez et al., 2017; Fanciulli et al., 2020). The prevalence of orthostatic hypotension in PD increases with age and disease duration; however, multiple studies have documented that orthostatic hypotension may appear early in the course of PD (Strano et al., 2016; Kim et al., 2016b). The reported estimated prevalence of orthostatic hypotension in PD ranges from 30% to 65% (Velseboer et al., 2011; Hiorth et al., 2019). Several mechanisms may contribute to the pathophysiology of neurogenic orthostatic hypotension in PD including baroreflex-cardiovagal and baroreflexsympathoneural failure, cardiac sympathetic noradrenergic denervation, and central autonomic dysfunction (Goldstein, 2003). Patients with DLB frequently have orthostatic symptoms, and neurogenic orthostatic hypotension is detected in 50% of patients (Thaisetthawatkul et al., 2004). Constipation and genitourinary failure are less commonly reported in DLB than in PD and MSA (Thaisetthawatkul et al., 2004). Constipation may precede the onset of motor symptoms in PD by over two decades (Savica et al., 2009). Patients with PD and DLB typically have mild dysphagia that occurs late in the disease course (Suttrup and Warnecke, 2016; Calandra-Buonaura et al., 2021). Esophageal abnormalities in patients with PD may include incomplete relaxation of the upper portion of the lower esophageal sphincter, esophageal spasms, and reduced esophageal peristalsis (Suttrup et al., 2017). Clinical manifestations include early satiety with anorexia, nausea, vomiting, abdominal fullness, and bloating. Symptoms may be exacerbated by the effect of levodopa on dopaminergic enteric neurons which additionally slows gastric motility and gastric emptying (Bestetti et al., 2017). Urinary symptoms are frequent in PD and DLB and include increased urinary frequency, urinary urgency, and

SYNUCLEINOPATHIES nocturia, whereas urinary retention is less frequently seen (Sakakibara et al., 2005). Erectile dysfunction is reported in up to 79% of males with PD. Women report sexual dysfunction including vaginal dryness, decreased libido, and difficulty reaching orgasm (Coon et al., 2019b). The spectrum of thermoregulatory symptoms includes heat or cold intolerance, intermittent hyperhidrosis episodes such as night sweats, and hyperhidrosis or hypohidrosis. A low degree of anhidrosis is typically seen in patients with PD, whereas a moderate degree of anhidrosis can be seen in patients with DLB (Coon, 2020). Medication effects may contribute to thermoregulatory symptoms. For example, hyperhidrosis episodes are more frequently reported by patients with PD during off periods or times of motor fluctuations.

Paraclinical testing IMAGING TECHNIQUES The diagnosis of PD and DLB remains clinical. Paraclinical testing is recommended to look for a treatable cause of cognitive impairment in patients with LBD (e.g., vitamin B12 deficiency, hypothyroidism). Brain MRI may be useful in patients with PD and DLB. The MRI may assess for atypical parkinsonism such as MSA in patients with PD with significant autonomic features. Brain MRI is useful to assess concomitant cerebrovascular pathology and the impact of white matter disease and cerebral microbleeds in the pathogenesis and clinical trajectory of Lewy body disorders is an active area of research. There are no easily identifiable MRI features to specifically support the diagnosis of DLB; however, the mesial temporal lobe and hippocampi remain relatively normal in size, helping to distinguish DLB from Alzheimer disease (Whitwell et al., 2007). Imaging findings on MRI in patients with DLB include atrophy of the frontal lobes and parietotemporal regions, enlargement of the lateral ventricles, and absent swallow-tail sign in the substantia nigra pars compacta (also seen in PD) (Whitwell et al., 2007; Shams et al., 2017). Nuclear imaging modalities such as single-photon emission computed tomography and positron emission tomography are well-established, reliable imaging methods to assess molecular changes in PD and DLB. Imaging of presynaptic dopaminergic transporter with 123 FP-CIT (DaTSCAN) reveals evidence of denervation and can assist in making a correct diagnosis in patients with suspected parkinsonian syndromes (Bega et al., 2021); however, when there is clinical evidence of parkinsonism, the utility of the DaTSCAN is limited. The effectiveness of DaTSCAN in the distinction between DLB and Alzheimer disease was confirmed in an autopsy study with 88% sensitivity and 100% specificity (Walker et al., 2007). Perfusion studies have demonstrated a

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distinctive pattern of occipital hypoperfusion in DLB when compared to AD, affecting both the primary visual cortex and visual association areas, and including the precuneus (Lobotesis et al., 2001). Amyloid imaging studies in DLB have yielded variable results. Some studies have reported similar amyloid-b deposition in DLB and Alzheimer disease, whereas most studies report lower mean cortical amyloid-b ligand binding in patients with DLB (Donaghy et al., 2015). The cingulate island sign may be demonstrated on fluorodeoxyglucose positron emission tomography corresponding to preserved posterior cingulate cortex metabolism. Neuroimaging evidence of cardiac sympathetic denervation in PD was first reported by Goldstein and collaborators using 18-fluorodopamine cardiac PET imaging (Goldstein et al., 1997) (Fig. 9.5). Numerous studies have confirmed these findings using 123I-metaiodobenzylguanidine scanning (Suzuki et al., 2006; Treglia et al., 2011, 2012). Loss of cardiac sympathetic innervation progresses over time and decreases by a median of 4% per year in PD (Lamotte et al., 2019). Peripheral noradrenergic deficiency in Lewy body synucleinopathies is cardioselective based on in vivo sympathetic neuroimaging and postmortem neurochemistry in cardiac and extracardiac organs (Lamotte et al., 2020). Evidence of cardiac sympathetic denervation by imaging has also been studied as a diagnostic tool in patients with dementia to distinguish between DLB and Alzheimer disease. Several studies have reported a high correlation between abnormal cardiac sympathetic activity evaluated with MIBG myocardial scintigraphy and a clinical diagnosis of DLB (Estorch et al., 2008; Kim et al., 2015). Reduced MIBG uptake on myocardial scintigraphy is a proposed biomarker in the new research criteria for the diagnosis of prodromal DLB (McKeith et al., 2020). The clinical implication of cardiac noradrenergic deficiency in Lewy body disorders is not fully understood (Lamotte and Benarroch, 2021). Transcranial ultrasound of the substantia nigra may reveal the presence of hyperechogenicity in PD, whereas normal echogenicity predicts atypical parkinsonism and poorer treatment response. Limitations of this technique include the requirements for an experienced examiner and a sufficient bone window (Saeed et al., 2020).

AUTONOMIC TESTING Evaluation of autonomic function in patients with PD may include evaluation for orthostatic hypotension, which can be done at the bedside or with autonomic function testing or ambulatory blood pressure monitoring. The ambulatory blood pressure monitoring can be useful to detect autonomic failure or when suspicion exists that medication effect, such as levodopa, is contributing to orthostatic hypotension. The degree of orthostatic

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Control

Parkinson disease

Fig. 9.5. Illustrative examples of cardiac 18-fluorodopamine PET scanning in a patient with Parkinson disease and control. Analysis of tissue norepinephrine content demonstrates profound myocardial norepinephrine depletion in Lewy body (LB) disorders compared with controls (non-LB) (97% reduction).

hypotension in PD tends to be less severe than that found in DLB or MSA. Analysis of postganglionic sympathetic sudomotor function often reveals a distal or lengthdependent impairment (Coon, 2020). Urodynamic studies in patients with PD frequently reveal a high prevalence of detrusor overactivity (McDonald et al., 2017).

DLB/PD from MSA; NfL in cerebrospinal fluid is normal or only modestly elevated in DLB which can help in differentiating DLB from MSA (see Analysis of cerebrospinal fluid section in PAF and MSA).

PLASMA CATECHOLAMINES

Polysomnography may be helpful for the detection of REM sleep behavior disorder. Quantitative olfactory testing provides a supportive criterion to establish a diagnosis of PD. Finally, neurophysiological analysis of tremors may aid in the differential diagnosis (e.g., functional parkinsonism vs PD). Detection of a-synuclein in plasma-derived extracellular vesicles may serve as a potential diagnostic biomarker for PD. In one study, a-synuclein concentration in plasma extracellular vesicles provided discrimination among PD, DLB, PSP, and healthy controls, with an area under the curve of 0.804 (PD vs DLB), 0.815 (PD vs PSP), and 0.769 (PD vs. healthy controls) (Stuendl et al., 2021). Analysis of exosomal a-synuclein in the blood may also differentiate between PD and MSA (Dutta et al., 2021).

Low supine plasma norepinephrine with inappropriate increase with standing characterizes postganglionic efferent autonomic failure; however, normal supine plasma norepinephrine levels can be seen in PD and DLB. Plasma dihydroxyphenylglycol (DHPG)—the main neuronal metabolite of norepinephrine—can provide a neurochemical clue to the diagnosis. Plasma DHPG level is low in PD reflecting decreased norepinephrine stores in sympathetic terminals (Goldstein et al., 2003).

SKIN BIOPSY Skin biopsy has been utilized to confirm a diagnosis of synucleinopathy (Gibbons et al., 2020); however, described methodologies differ and while commercial testing is available, confirmatory studies are currently lacking to corroborate test performance. Routine available testing does not distinguish between the different synucleinopathies (see Skin biopsy section in PAF).

ANALYSIS OF CEREBROSPINAL FLUID a-synuclein seeding activity in RT-QuIC and PMCA assays of cerebrospinal fluid can confirm the presence of a synucleinopathy, and PMCA can further differentiate

OTHERS

Treatment Parkinson disease and DLB have no cure. Dopaminergic agents are the mainstay of treatment of parkinsonism in both PD and DLB. The decision to initiate symptomatic medical therapy in patients with PD is determined by the degree to which symptoms interfere with functioning or impair quality of life. There is no evidence that delaying the start of levodopa prevents the development of motor fluctuations and dyskinesias, and the development of motor fluctuations over time is most likely due to

SYNUCLEINOPATHIES progressive degeneration of nigrostriatal dopamine terminals. The LEAP study used a delayed start design in which people with PD either received levodopa immediately or after a placebo period of 9 months. This study showed no evidence of levodopa toxicity or neuroprotective effects (Verschuur et al., 2019). Starting levodopa early is associated with fewer motor symptoms and better quality of life in PD. The main classes of drugs that have been studied in the symptomatic treatment of the parkinsonian features in PD include monoamine oxidase type B (MAO B) inhibitors, amantadine, dopamine agonists, anticholinergic drugs, and levodopa. Important factors to consider when prescribing medications for PD include the patient’s age, antiparkinsonian potency of each drug (levodopa being the most effective agent), potential side effects, and the patient’s preferences. Treatment strategy must be individualized. Newer modes of delivery of levodopa have been approved for the treatment of motor complications in patients with PD including inhaled levodopa that can be used as a rescue medication, enteral suspension of levodopa delivered as a continuous infusion in the jejunum bypassing the stomach, and extended-release formulation of levodopa. The medical management of motor fluctuations often requires dose and interval adjustment of levodopa and other options available include the addition of MAO B inhibitors, catechol-O-methyl transferase (COMT) inhibitors, dopamine agonists, istradefylline, an oral adenosine A2A receptor antagonist. The presence of bothersome dyskinesias often requires a reduction in levodopa or adjunctive therapies such as amantadine. Levodopa has little or no effect on certain motor features of PD (e.g., gait and balance dysfunction) (Bloem et al., 2021). Many people with PD have debilitating response fluctuations with the progression of the disease. Deep brain stimulation of the subthalamic nucleus and globus pallidus internus is an effective therapy for patients with PD. Deep brain stimulation is often used bilaterally, but people with asymmetric symptoms might only require unilateral surgery (Bloem et al., 2021). The long-term benefit of deep brain stimulation has been demonstrated. In a study of 51 patients with 17.06  2.18 years of deep brain stimulation of the subthalamic nucleus follow-up for PD, there was a significant improvement in motor complications, stable reduction of dopaminergic drugs, and improvement in QoL (Bove et al., 2021). Unilateral focused ultrasound delivered at high frequencies is a newer FDA-approved lesion technique that can be applied to the thalamus to treat tremor dominant PD. The treatment of nonmotor symptoms in PD is crucial. Some nonmotor symptoms (e.g., sialorrhea, pain, depression, anxiety) may fluctuate between on and off states, similar to motor symptoms, so dopaminergic

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drugs can be considered as treatment. Orthostatic hypotension has been documented as a potential side effect of levodopa in different studies (Senard et al., 1997; Bouhaddi et al., 2004). As a result, clinicians may be reluctant to prescribe levodopa in patients with PD with autonomic failure, which may lead to suboptimal management of motor symptoms. On the other hand, several studies failed to show any clear relationship between levodopa and orthostatic hypotension in patients with PD (Goldstein et al., 2005; Perez-Lloret et al., 2012; Jost et al., 2020). Important limitations of previous studies include the lack of detailed investigation of baroreflex cardiovagal and sympathetic noradrenergic functions and the fact that the same patients were not tested on and off levodopa (Senard et al., 1997; Bouhaddi et al., 2004; Goldstein et al., 2005; Perez-Lloret et al., 2012; Jost et al., 2020). A multidisciplinary approach and the use of both pharmacological and nonpharmacological interventions are important for optimal management of nonmotor symptoms in PD and DLB. Similar to patients with PAF and MSA, bladder symptoms of neurogenic detrusor overactivity may be managed with antimuscarinic agents as well as the b3-adrenergic agonist mirabegron. Cognitive and neuropsychiatric symptoms in PD and DLB may respond to the cholinesterase inhibitors rivastigmine and donepezil. The oral 5-HT2A inverse agonist and antagonist pimavanserin on psychosis can also be used in patients with DLB and PD with psychosis (Tariot et al., 2021); however, its use was associated with an increased risk of 30-day hospitalization and higher 90-, 180-, and 365-day mortality in patients with PD (Hwang et al., 2021). Exercise should be part of the treatment of patients with Lewy body disorders. Aerobic and resistance exercise training may slow the progression of the disease with benefits on motor and nonmotor symptoms (Corcos et al., 2013; David et al., 2015; Schenkman et al., 2018).

CONCLUSIONS The different synucleinopathies differ in the cellular location and pattern of a-synuclein deposition in the central and peripheral nervous systems. Research has improved our understanding of the pathophysiology of these disorders but the function of a-synuclein remains unknown and the pathophysiological relevance of a-synuclein aggregates is unknown. Over the past two decades, there have been significant advances in the symptomatic treatment of motor and nonmotor symptoms in synucleinopathies with alternative routes of delivery of levodopa, surgical treatments, and medications with new mechanisms of action. A multidisciplinary and individualized care model is recommended to optimally address the various symptoms.

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There is no DMT available. There is an urgent need for studies investigating disease mechanisms, biomarkers, potential DMTs, and symptomatic treatments for motor and nonmotor symptoms as well as nonpharmacological strategies. Autonomic dysfunction is characteristic of the synucleinopathies with peripheral or postganglionic involvement prominent in the Lewy body disorders of PD, DLB, and PAF, and central or preganglionic involvement in MSA. The severity of autonomic dysfunction has implications on prognosis and survival. Various forms of autonomic failure influence the quality of life in patients with synucleinopathies. Future research will focus on the identification of subjects at risk for developing synucleinopathies (e.g., patients with isolated REM sleep behavior disorder). Further research is also needed to validate biomarkers of different synucleinopathies and the analysis of the pattern of a-synuclein aggregation in cerebrospinal fluid or skin biopsy is promising in that regard.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00031-4 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 10

Amyotrophic lateral sclerosis DAVID S. YOUNGER1,2⁎ AND ROBERT H. BROWN JR.3 1

Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States

2

Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States 3

Department of Neurology, UMass Chan Medical School, Donna M. and Robert J. Manning Chair in Neurosciences and Director in Neurotherapeutics, Worcester, MA, United States

Abstract The scientific landscape surrounding amyotrophic lateral sclerosis has shifted immensely with a number of well-defined ALS disease-causing genes, each with related phenotypical and cellular motor neuron processes that have come to light. Yet in spite of decades of research and clinical investigation, there is still no etiology for sporadic amyotrophic lateral sclerosis, and treatment options even for those with well-defined familial syndromes are still limited. This chapter provides a comprehensive review of the genetic basis of amyotrophic lateral sclerosis, highlighting factors that contribute to its heritability and phenotypic manifestations, and an overview of past, present, and upcoming therapeutic strategies.

INTRODUCTION Amyotrophic lateral sclerosis (ALS) is the prototypical adult-onset motor neuron disease (MND) that results from motor neuron degeneration in the motor cortex, brainstem, and spinal cord that culminates in death typically from respiratory failure within 3–5 years. Luys (1860) demonstrated atrophy and loss of anterior horn cells (AHC), followed by Charcot and Marie (1885) who characterized spinal cord and corticospinal motor neuron degeneration. For the next 100 years, prominent investigators (too numerous to recount) have devoted their careers to understanding sporadic and familial ALS and related MNDs. At the turn of the 20th century, Rowland (2000) was asked to identify the most important themes in ALS research to which he responded: the use of transgenic mice (Gurney et al., 1994) carrying the mutant human gene for superoxide dismutase-1 (SOD1) associated with FALS (Rosen et al., 1993) in evaluating potential therapies and toxicity in the pathogenesis of ALS; and the future of gene therapy. Two decades later, advances in ⁎

the genetics of ALS in a vast number of well-defined ALS disease-causing genes, each with related phenotypical and cellular motor neuron processes, have opened the therapeutic landscape to innovative treatment approaches beyond riluzole (Bensimon et al., 1994) and edaravone (The Writing Group and Edaravone (Mci-186) ALS 19 Study Group, 2017), to the possibilities of delivering diverse cargoes including missing or therapeutic genes and gene-silencing elements. There are excellent reviews of this topic (Taylor et al., 2016; Goutman et al., 2018).

Epidemiology The global incidence of ALS is approximately 1–2.6 cases per 100,000 persons annually, with an overall prevalence of approximately 6 cases per 100,000 (Talbott et al., 2016) that varies with age. A population-based study of urban London, similar to the United States, found 1–2 new ALS cases per year per 100,000 persons (Johnston et al., 2006). Between October 19, 2010, and December 31, 2011, there were an estimated 12,187 prevalent cases diagnosed with definite ALS in the

Correspondence to: David S. Younger, MD, DrPH, MPH, MS, 333 East 34th Street, Suite 1J, New York, NY 10016, United States. Tel: +1-212-213-3778, Fax: +1-212-213-3779, E-mail: [email protected]

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United States. Moreover, with a cumulative lifetime risk of ALS of about 1 in 400 persons in the United States alone, 800,000 persons who are now alive are expected to die from ALS. The average age of onset of ALS is currently 58–60 years and the average survival from onset to death is 3–4 years. Sporadic ALS in an estimated 90% of cases constitutes the large majority of affected patients. The remaining 10%, considered familial (FALS), are most apparent in families with one or more first- or second-degree relatives or carrying a known mutation in a disease-causing gene that comigrates in the family pedigree. However, advances in genetic analysis of individuals with sporadic disease suggest that genetic variants in established ALS genes are not infrequent and may enhance susceptibility or modify the clinical phenotype of ALS even if they do not cause the disease. This may occur by influencing genetic susceptibility to a putative environmental risk factor for ALS, or in reducing or enhancing expression of a second disease-causing gene that respectively improves or worsens the overall survival in an affected patient. Recent advances in the genotype–phenotype expression of FALS have aligned with clinical, pathological, and genetic observations in families revealing several patterns of presentations, all generally associated with autosomal dominant (AD) in transmission (Horton et al., 1976). The first so noted, was the rapid clinical decline in 10–20 years. Those with associated frontotemporal dementia (FTD) (FTD-ALS) had multisystem manifestations; so-called ALS-plus syndromes (Mccluskey et al., 2014) with clinical features extending beyond the motor system including cognitive and neurobehavioral impairments, notwithstanding bulbar-onset and pathogenic gene expansion or mutations twice as often; and commonly shorter survival compared to non-ALS-plus cases. Rarely and devastatingly, some patients with FALS showed onset in early teens.

NEUROPATHOLOGY Postmortem neuropathologic findings of ALS seen in up to 90% of cases of ALS (presumed to be sporadic) include selective loss and death of large motor neurons in the motor cortex and anterior horns of the spinal cord (Fig. 10.1A), with degeneration of CST axons (Fig. 10.2) visible on myelin stains that cause thinning and scarring of the lateral funiculi. With loss of brainstem and

spinal motor neurons, there is thinning of the ventral roots and denervation atrophy (amyotrophy) of the lingual, oropharyngeal, and limb musculature. Histochemical and electrophysiological studies suggest that in the early phases of motor neuron degeneration, denervated muscle is reinnervated, leading to recognizable myofiber changes indicative of sprouting of nearby distal motor nerve terminals. However, reinnervation is less effective than in peripheral motor neuropathy or poliomyelitis. Failing to reinnervate over a prolonged period in recovering from poliomyelitis leads to MND-like features in postpolio muscular atrophy (Klingman et al., 1988; Pezeshkpour and Dalakas, 1988). Degeneration of motor neurons is accompanied by proliferation of astroglia, microglia, and oligodendroglial cells (Kang et al., 2013b; Philips and Rothstein, 2014). Atrophic dark neurons, especially those laden with lipofuscin pigment, and chromatolytic neurons (Fig. 10.1A), and a few normallooking neurons and their processes, appear atrophic with chromatolytic cytoplasm containing bundles of neurofilaments mixed with lipofuscin and rough endoplasmic reticulum (ER). Other characteristic pathological features include aggregates of hyperphosphorylated nuclear TAR DNAbinding protein 43 (TDP-43), which in most cases is cleaved (Neumann et al., 2006), and mislocalized to the cytoplasm of motor neurons and glial cells, and correlates with cell loss, disseminating in a sequential pattern along the motor pathways, as suggested by the hypothesis of corticofugal (prion-like) propagation of misfolded proteins in ALS (Yoshida, 2019). TDP-43 is the major protein of ubiquitinated inclusions in ALSTDP, the neuropathology of which consists of abnormal cytoplasmic accumulation of TDP-43 in neurons and glia of brainstem motor nuclei, spinal cord anterior horns, and associated white matter tracts. Cells that contain cytoplasmic TDP-43 aggregates appear to have lost normal nuclear-associated immunoreactivity (ir), with large neurons of the primary motor cortex affected in the same way. Aggregates of ubiquilin 1 can be observed (Deng et al., 2011b) in cases of dominant X-linked (XL) juvenile and adult-onset ALS and ALS/dementia. Several other neuronal cytoplasmic inclusions (NCIs) and histopathological findings can be seen that support the postmortem diagnosis of ALS. One such finding is Bunina bodies (Mizuno et al., 2006, 2011), which are typically negative for TDP-43; however, these aggregates may be an important diagnostic feature in sporadic ALS and a minority of FALS with TDP-43 gene mutations. Two other inclusions are round hyaline inclusions (Kato et al., 1989) and skein-like inclusions (Sasaki and Maruyama, 1992) (Fig. 10.1B–G). Finally, there can be an accumulation of neurofilaments. The latter consists of argyrophilic round structures or spheroids, with a

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Fig. 10.1. (A–I) Lumbar anterior horn cells in classical sporadic ALS. (A) A chromatolytic but relatively atrophic neuron is occasionally seen in the LMN nuclei (H&E stain). (B) The remaining neurons are also atrophic (wide black arrow) and sometimes contain a round hyaline inclusion. A large spheroid, presumed to have arisen from a proximal segment of the axon, is also seen (white broad arrow) (H&E stain). (C) An anticystatin C antibody depicts Bunina bodies (anticystatin C antibody stain). (D) Ultrastructurally, the Bunina body is composed of electron-dense amorphous material studded with many vacuoles and tubules, making a conspicuous structure as a whole. (E) Round hyaline inclusions are immunopositive for ubiquitin as well as for TDP-43 (anti-TDP-43 antibody stain). (F) Round hyaline inclusions are immunopositive for optineurin (antioptineurin antibody stain). (G) Ultrastructurally, round inclusions are a collection of crisscrossing filaments 15–25 nm in diameter and of various lengths, without a limiting membrane. The filaments are coated with electron-dense granules. The nucleus is seen at the bottom of the figure. (H and I) Skein-like inclusions are distinctly depicted by antiubiquitin antibodies as well as by anti-TDP-43 and antioptineurin antibodies (anti-TDP-43 and antioptineurin antibody stains). Bar ¼ 10 mm.

diameter greater than 20 mm derived from the accumulation of phosphorylated neurofilaments found in the proximal portion of LMN axons that correspond to chromatolysis cytoplasmic changes (Fig. 10.1H). There may be different pathological changes associated with specific genes, for example, Lewy body-like hyaline inclusions with a core and halo that immunostain positive for SOD-1 and ubiquitin (Fig. 10.3A–C) or a

conglomerate of neurofilaments (Fig. 10.3D); and others with intranuclear RNA foci (Dejesus-Hernandez et al., 2011) and p62 positive, TDP-43 negative cerebellar and hippocampal nuclear cytoplasmic inclusions (AlSarraj et al., 2011) virtually pathognomonic of an expansion in the noncoding GGGGCC hexanucleotide repeat of the C9ORF72 gene; however, the latter inclusions are now known to contain sequestosome-1 or ubiquitin-binding

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Fig. 10.2. Lateral corticospinal tract pallor in ALS (Weigert myelin stain). Reproduced from Tyler H, Shefner J (1991). Amyotrophic lateral sclerosis. Handb Clin Neurol 169–215 with permission.

Fig. 10.3. (A–D) Familial ALS with SOD-1 mutations. (A) A patient with SOD-1 mutation (A4V) and Lewy body-like hyaline inclusions that have a core and halo (H&E stain). (B) Lewy body-like hyaline inclusions are immunopositive for SOD-1 (antiSOD-1 antibody stain). (C) Lewy body-like hyaline inclusions are immunopositive for ubiquitin (antiubiquitin antibody stain). (D) A patient with a different SOD-1 mutation (I113T) that shows an inclusion containing a conglomerate of neurofilaments in a large neuron in a lumbar anterior horn (H&E stain). Bar ¼ 10 mm.

protein p62, encoded by the sequestosome 1 (SQSTM1) gene. Cases of ALS caused by mutations in the genes SOD1 or fused in sarcoma (FUS) are pathologically distinct in part because they exhibit inclusions of abnormal SOD1 or FUS proteins, respectively, rather than those of TDP-43. Finally, the histopathological changes in nonmotor neuron cell types mentioned earlier, for example, astrogliosis and microgliosis, may adversely influence progression of ALS.

CLINICAL PRESENTATION Meaningful clues in any given patient with ALS, whether sporadic or familial, can be gleaned from careful inspection, keeping in mind the basic clinical construct that the varied clinical phenotypes fall into a spectrum of a heterogeneous disease manifesting the combination of LMN and upper motor neuron (UMN) signs, respectively, corresponding to the innervation of limb and bulbar musculature, which if interrupted leads to characteristic

AMYOTROPHIC LATERAL SCLEROSIS weakness, wasting and fasciculation; and hyperreflexia, Hoffman, Babinski signs and clonus (Younger et al., 1991). Clinical subsets of ALS lie in a spectrum depending on the involvement of different sets of motor neurons and affected body regions, from progressive muscular atrophy (PMA) (Younger and Qian, 2015) which classically affects spinal motor neurons alone, to primary lateral sclerosis (PLS) (Younger et al., 1988) with isolated involvement of corticospinal motor neurons. Cases of ALS with FTD-ALS occur with other multisystem manifestations; rarely “ALS-plus” syndromes (Mccluskey et al., 2014) of cases with clinical features extending beyond the CST and LMN with cognitive impairment, bulbar-onset and pathogenic gene expansion or mutations twice as commonly, with shorter survival compared to non-ALS-plus cases. The manifestations of ALS can be somewhat variable depending on whether corticospinal neurons or brainstem or spinal cord motor neurons are more prominently involved. When spinal cord neurons are involved early, there is insidiously progressing asymmetrical weakness and wasting, with focal fasciculation first evident distally in the arm or leg, with cramping in other muscles and limbs soon to be involved on volitional movements such as stretching in bed at night or on awakening. Regardless of whether the initial disease involves UMN or LMN motor neurons, both will eventually become implicated on examination. However, even in later stages, sensory, bowel, bladder, visual, and even cognitive functioning may remain relatively intact except in cases of FTD characterized by early behavioral features indicative of frontal lobe involvement.

DIAGNOSIS The diagnosis of ALS in any given patient relies on an integrative approach combining a clinical history and symptom evolution, detailed neurological and neuromuscular examination including strength testing, deep tendon and pathological reflexes, and confirmatory neurophysiological studies encompassing nerve conduction studies and needle electromyography. Genetic testing is gaining traction but not without caveats. Although the bedside or office diagnosis remains suboptimal, there is an expanding toolbox of available methods and novel biomarkers. However, most of these approaches are only used in the research setting and have generally not been validated for clinical use (Goutman et al., 2022). Formal diagnostic criteria have a role in establishing relative certainty in the diagnosis. The first diagnostic criteria for ALS that were proposed in 1994 by the World Federation of Neurology in El Escorial, Spain, were developed as the standard for diagnosing ALS in clinical work (Brooks, 1994). Using these criteria, a diagnosis of

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ALS was defined by evidence of LMN impairment, with symptoms and signs obtained through clinical examination and electrophysiological or neuropathological tests, accompanied by clinically demonstrated impairment of UMNs, and followed by the chronic and progressive development of these symptoms and signs. Nevertheless, it remains necessary to eliminate other diseases that might explain the degeneration of motor neurons, using their electrophysiological, neuroimaging, and pathological characteristics. However, most investigators involved in ALS research have reached the consensus that the aforementioned clinical appearances and electrophysiological findings leave space for doubt when making the diagnosis in some specific situations; notwithstanding, the uncertainty of the validity of achieving an early diagnosis of ALS. El Escorial Revisited, published online, refined the diagnosis of ALS (Brooks et al., 2000), which in the new version added new methods, including electrophysiology, neuroimaging, immunohistochemistry, genome analysis, and cerebrospinal fluid (CSF) disease biomarkers such as neurofilament light chains, phosphorylated neurofilament heavy chains, and the inflammatory marker monocyte chemoattractant protein 1, which are available at academic centers and important as endpoints in clinical trials. The usefulness of formal diagnostic criteria (Brooks et al., 2000) is debated, as most ALS patients would probably go undiagnosed, for example, if the El Escorial Revisited was used in the early diagnosis of ALS (Belsh, 2000; Traynor et al., 2000), since the majority of ALS patients present with clinical signs or symptoms in one or two regions, or with pure muscle atrophy or only a lateral funiculus lesion. Moreover, ALS must be distinguished from a range of ALS-mimicking syndromes that have similar clinical manifestations to ALS in the early period (Johnsen et al., 2019). Although the error rate of the absolute clinical diagnosis of ALS is probably 10 years (Cudkowicz et al., 1997). The shorter survival in SOD1 subjects is associated with the stability of the SOD1 protein, and the propensity to aggregate SOD1 mutations decreases the protein structural stability, acting as a trigger for protein misfolding as well as the appearance of toxic species. Almost all of these mutations are missense changes, scattered across

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the coding sequence without focal mutation hotspots; however none are predicted to eliminate production of the protein. This strongly suggests that the mutant protein must be present to initiate motor neuron death. Deleterious mutations modify SOD1 activity, which leads to the accumulation of highly toxic hydroxyl radicals. Accumulation of these free radicals causes degradation of both nuclear and mitochondrial DNA and protein misfolding, features which can be used as pathological indicators associated with ALS. Since pathogenicity of mutant SOD1 is proportional to the dose of the toxic protein, a rational approach to treating SOD1-related ALS is to reduce levels of the toxic SOD1 species. This strategy obviates intervening in multiple downstream pathological cascades. In recent years, several strategies to silence gene expression have been developed. Although mutations in SOD1 account for a minority of ALS cases, the discovery of this gene influenced ALS research leading to the first mouse model of the disease (Gurney et al., 1994) and numerous pathophysiologic and therapeutic investigations.

cases and other genetic mutations (Chiò et al., 2012). Additionally, one-half of patients with C9ORF72 mutations can show executive dysfunction, and an earlier age at onset as in other FALS cases, contrasting with the later age of sporadic ALS patients, as well as a median survival that is shortened for both familial and sporadic C9ORF72 ALS cases compared to non-C9ORF72 carriers (Cooper-Knock et al., 2012). The pathologic features of C9ORF72 ALS are also typical, with Bunina bodies, degeneration of CSTs, and ubiquitinated neuronal and glial cytoplasmic inclusions that stain positive for ALS-associated pathologic proteins in motor neurons, notably in the hippocampus and cerebellum. A mouse model expressing (G4C2)66 throughout the murine CNS using somatic brain transgenesis mediated by adeno-associated virus mimics the neuropathological and clinical FTD-ALS phenotype caused by C9ORF72 mutations including hyperactivity, anxiety, antisocial behavior, and motor neuron deficits (Chew et al., 2015). Nonetheless, the molecular mechanisms underlying neurodegeneration in C9orf72-related diseases are still debated.

C9ORF72

TARDBP

Heterozygous hexanucleotide repeat expansion (HRE) of GGGGCC in a noncoding region of the C9orf 72 gene on chromosome 9p21 causes FTD and/or ALS (FTDALS). It is the most prevalent disease-causing ALS gene. Unaffected individuals have 2–19 repeats, whereas affected individuals have 250 to over 2000 repeats. However, some individuals can show symptoms with as few as 20–22 repeats (Reddy et al., 2013). The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA/DNA hybrids. The structural polymorphism causes a repeat length-dependent accumulation of transcripts aborted in the HRE region that bind to ribonucleoproteins in a conformationdependent manner. Nucleolin, an abundantly expressed acidic phosphoprotein of exponentially growing cells located mainly in dense fibrillar regions of the nucleolus where it is involved in the control of transcription of ribosomal RNA genes, binds the HRE G-quadruplex, causing nucleolar stress and incipient neurodegeneration. Patients with the repeat expansion likely share a common Finnish founder risk haplotype (Majounie et al., 2012). Penetrance increases over time with persons < age 35 unlikely to manifest disease compared to 100% penetrance for those >80 years, whereas penetrance approaches 100% for those >age 80 (Cooper-Knock et al., 2014). C9ORF72 mutation carriers resemble the typical phenotypes of ALS, with disease onset beginning in the arms or legs and prototypical features of combined UMN and LMN signs. Such patients also have a higher proportion of bulbar-onset disease and FTD compared to sporadic

The TARDBP gene encoding TARDBP is a predominantly nuclear RNA/DNA-binding protein that functions in RNA processing and metabolism, including RNA transcription, splicing surveillance, transport, and stability. Following cell stress, TARDBP localizes to cytoplasmic stress granules and plays a role in stress granule formation (Xia et al., 2016). Pathogenic mutations at the 1p36.22 locus can be detected in patients with FTLD, FTD, and TDP43positive inclusions with or without signs of MND (Arai et al., 2006; Neumann et al., 2006), and others with sporadic and FALS (Kabashi et al., 2008; Sreedharan et al., 2008; Yokoseki et al., 2008). Nuclear-to-cytoplasmic mislocalization of TDP-43 induces toxicity through both loss-of-function (LOF) and GOF mechanisms. Classic roles for TDP-43 pertain to mRNA maturation in the nucleus, specifically acting as a repressor of alternate splicing, cryptic exon splicing, and alternate polyadenylation (Polymenidou et al., 2011). TDP-43 is involved in mRNA transport, a mechanism that is dysregulated within ALS, as well as local translational regulation. Disruption of either of these mechanisms may effectively trap TDP-43 in the cytoplasm, inhibiting its normal functions. This hypothesis is substantiated by transcriptomic evidence showing that diseased neurons and mouse models of ALS demonstrate increases in alternative splicing events, cryptic exon inclusion, and alternate polyadenylated sequences (Suk and Rousseaux, 2020). Not only does aggregation sequester the normal function of TDP-43, but the aggregates actively block normal cellular processes inevitably leading to cellular demise in

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a short time span. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. These pathological findings, and the coexistence of AD ALS and FTD in some patients, underscore that the two diseases are in a clinicopathological spectrum. In 2008, TARDBP mutations were identified in both FALS and sporadic ALS cases (Sreedharan et al., 2008). All such mutations identified to date map to exon 6, except Asp169Gly in exon 4 encoding a highly conserved region of the C-terminal domain of TDP-43 protein. This domain is involved in the inhibition of the splicing of the cystic fibrosis transmembrane conductance regulator mRNA (Buratti et al., 2005). This C-terminal domain has been observed in a phosphorylated form in the neuronal cytosolic ubiquitinated inclusions of ALS and FTD patients, together with a TDP-43 nuclear loss, suggesting that cleavage, phosphorylation, and cytoplasmic accumulation of this C-terminal fragment underlie the neurodegenerative process involved in ALS and FTD. The frequency of TARDBP mutations in ALS dramatically varies among different studies; the highest frequencies are estimated to be about 5%–6% of FALS and SALS cohorts. One study (Corcia et al., 2012) investigated the phenotypes of 28 patients with TARDBP mutations (9 were sporadic ALS) and reviewed the phenotypes of 117 patients with TARDBP mutations reported in the literature (21 were sporadic ALS). In that report (Corcia et al., 2012), individuals with TARDBP mutations had an earlier onset and longer survival than SALS patients without TARDBP mutations. Moreover, the site of onset in this group was predominantly the arm. Additionally, the G298S mutation was associated with shorter survival. Given that ALS and FTD coexist in some individuals, and that there are cytosolic ubiquitinated TDP43 inclusions in both diseases, it is reasonable to anticipate that TARDBP mutations could also account for FTD cases without MND. In fact, one TARDBP mutation (N267S) was reported in a single patient with FTD without MND (Borroni et al., 2009). A more common observation is that TARDBP mutations may cause both ALS and FTD in the same individual (Benajiba et al., 2009). Among a cohort of sporadic ALS patients in which disease duration exceeded 10 years, particularly among those exposed to chronic artificial respiratory support (Nishihira et al., 2008), there was widespread occurrence of TDP-43 in nuclear and glial cytoplasmic inclusions (GCIs) not only in motor neuron systems, but in other portions of the brain including the globus pallidus, thalamus, inferior olivary nucleus, brain reticular formation, amygdala, frontal and temporal cortices, and the hippocampus. The demonstration of UI, SLI, and RIs in hippocampal dentate granule cells differentiates the

type-2 distribution of TDP-43-ir NCI, which is highly predictive of dementia. A subset of patients with the pure UMN syndrome PLS (Konagaya et al., 1998) and FTLD (Kwong et al., 2007; Nishii et al., 2009) demonstrated aggregates of LMN TDP-43 protein without other apparent pathology, as did those with PSMA (Geser et al., 2011), implying a relation to TDP-43 proteinopathy. It is estimated that 15% of patients with FTLD develop ALS, whereas about 50% of patients with ALS develop various degrees of cognitive impairment. Such patients may be considered to have TDP-43 proteinopathy since TDP-43 is found in clinically affected patients with FTLD with or without frank dementia (Dickson et al., 2007).

Fused in sarcoma Mutations in FUS at the 16p11.2 chromosome locus cause FALS and SALS, but rarely FTD (Rademakers et al., 2010). Products of the FUS, EWS RNA-binding protein 1 (EWS) and the TAF15 RNA polymerase II, TATA Box-binding protein-associated factor, 68-kDa (TAF15) genes are structurally similar multifunctional proteins first discovered upon characterization of fusion oncogenes in human sarcomas and leukemias. The proteins belong to the FET (previously TET) family of RNA-binding proteins and are implicated in central cellular processes such as regulation of gene expression, maintenance of genomic integrity, RNA metabolism, mRNA/microRNA processing including mRNA splicing (Law et al., 2006). However, the impact of ALS-causative mutations on splicing has not been fully characterized, as most disease models have been based on overexpressing mutant FUS, which alters RNA processing due to FUS autoregulation. FUS-ALS mutations induce widespread LOF on expression and splicing (Humphrey et al., 2020). Specifically, mutations in FUS directly alter intron retention levels in RNA-binding proteins and identify an intron retention event in FUS itself that is associated with its autoregulation. The highest levels of FUS are found in the nucleus, driven by a highly conserved carboxyl (C) terminal PY nuclear localization signal (PY-NLS). FUS is found in the cytoplasm at lower levels and can shuttle rapidly between the nucleus and the cytoplasm (Zinszner et al., 1997). However, the majority of disease-linked FUS mutations cluster in the C-terminus and disrupt nuclear import, but the precise pathogenic mechanism of FUS mutations is currently unknown.

Optineurin Mutations in the OPTN gene have been implicated in both FALS (ALS12) with or without frontotemporal dementia due to homozygous or heterozygous mutation on chromosome 10p13. Both AD and AR inheritance patterns have been reported as well as SALS occurrences

AMYOTROPHIC LATERAL SCLEROSIS (Feng et al., 2019). Optineurin was first identified as a binding partner of an adenoviral E3 14.7 kDa protein and named “FIP-2” (for E3-14.7K-interacting protein) but afterward renamed “optineurin” (for optic neuropathy inducing), since mutations in the OPTN gene had been identified in patients with primary open-angle glaucoma. Later, OPTN mutations were also identified in other human pathologies including Paget’s disease of the bone, ALS, and FTD (Maruyama et al., 2010). Optineurin has been characterized as a multifunctional protein regulating multiple cellular processes such as vesicular trafficking, cell division, inflammatory and antiviral signaling, antibacterial responses, and autophagy. OPTN can bind multiple partners; hence, disease-causing mutations may alter these interactions disturbing normal signaling. The clinical phenotypes in OPTN mutated ALS have not been homogeneous, with some individuals showing a relatively slow progression and a long duration and others an aggressive progression and a short survival. OPTN-immunoreactive, skein-like inclusions were found in AHC neurons and neurites in spinal cord sections from a cohort of 32 patients with SALS and in all 8 patients with FALS who did not have mutations in the SOD1 gene (Deng et al., 2011a). OPTN immunoreactivity was absent in all 6 patients with FALS due to SOD1 mutations and in tissue from 2 mouse models of ALS due to Sod1 mutations. The findings suggested that OPTN may play a role in the pathogenesis of non-SOD1 ALS, and that SOD1-linked ALS has a distinct disease pathogenesis. ALS-associated OPTN mutations include deletions, missense, frameshift, and nonsense mutations. Functional studies identified three major neuroprotective mechanisms of optineurin: regulation of autophagy, mitigation of inflammatory signaling, and blockade of necroptosis. Deletions, nonsense, and frameshift mutations in OPTN are detected in either homozygous or heterozygous states, suggesting that complete LOF or haploinsufficiency of optineurin may be sufficient to cause or contribute to ALS. Most ALS-linked missense optineurin mutations are disproportionately enriched in the C-terminus coiled coil domain, ubiquitin-binding domain, and zinc finger domain. The strongest evidences for pathogenicity exists for the heterozygous missense mutation p.E478G in the ubiquitin-binding domain of OPTN, suggesting that it causes disease by gain-of-function or haploinsufficiency (Markovinovic et al., 2017). Optineurin is an adaptor protein that interacts with numerous proteins and is involved in regulating many cellular functions, including vesicular trafficking from the Golgi to plasma membrane, endocytic trafficking, and signaling leading to NF-kappa-B activation (Vaibhava et al., 2012). OPTN is phosphorylated by, and binds to, the

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threonine kinase TBK1 (itself an ALS gene) while the OPTN-TBK1 complex mediates recycling of damaged mitochondria via mitophagy and influences mitochondrial quality control (He et al., 2017; Chua et al., 2022). OPTN actively suppresses receptor-interacting kinase-1 (RIPK1; 603453)-dependent signaling by regulating its turnover (Ito et al., 2016). Loss of OPTN leads to progressive demyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1 (G93A) transgenic mice and pathological samples from human ALS patients.

Valsolin-containing protein VCP encodes valsolin-containing protein, a ubiquitously expressed multifunctional protein that is a member of the AAA+ (ATPase associated with various activities) protein family and implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin-dependent protein degradation (Weihl et al., 2009; Chua et al., 2022). Mutations in VCP cause inclusion body myopathy (IBM) associated with Paget’s disease of the bone (PDB) and FTD (IBMPFD1). In some families with a VCP mutation, family members may have ALS, FTD, or IBMPFD. Patients with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6) present with AD inheritance of and highly variable manifestations including the behavioral variant of FTD, characterized by reduced empathy, impulsive behavior, personality changes, and reduced verbal output; and others with features of UMN and LMN features of ALS. In both ALS and FTD, there are ubiquitinpositive inclusions within surviving neurons as well as deposition of pathologic TDP43 and pathologic tau aggregates. The primary finding in a cohort of 231 patients was a general lack of genotype–phenotype correlations because of the enormous phenotypic heterogeneity within and between families. Among 36 families of European, Brazilian, Hispanic/Apache, and an African-American ethnicity carrying 15 different heterozygous VCP mutations (AlObeidi et al., 2018), 187 were clinically symptomatic and 44 were presymptomatic carriers. Most (90%) of the symptomatic patients presented with myopathy (90%), while others presented with Paget disease (42%), dementia (30%), and ALS (8%) associated with UMN and LMN degeneration. Others were diagnosed with Parkinson disease (PD) (4%) and AD (2%). Autopsy data available on one individual with ALS revealed loss of brainstem and spinal cord motor neurons with Bunina bodies in surviving AHCs and TDP-43 immunostaining, consistent with the diagnosis of ALS. There are 17 exons

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in the VCP gene and mutations have been reported in 11 of them—the vast majority occurring in exon 5. The mutations associated with IBMPFD and/or familial ALS are all exonic missense mutations. In particular, the R155 locus is a mutation hotspot. Transgenic mice with the VCP D395G mutation (601023.0014) do not spontaneously develop a neurodegenerative phenotype and their brains do not show abnormal tau accumulation (Darwich et al., 2020). However, when stimulated with pathologic tau derived from patients with AD, transgenic mice developed pathologic tau aggregation in several brain regions. The findings suggested that neurons with this VCP mutation have increased susceptibility to pathologic tau aggregation under certain circumstances, resulting in downstream neurodegeneration.

Dynactin Regulation of microtubule dynamics in neurons is critical, as defects in the microtubule-based transport of axonal organelles lead to neurodegenerative disease. The microtubule motor cytoplasmic dynein and its partner complex dynactin drive retrograde transport from the distal axon. The DCTN1 gene encodes p150(Glued), the large, heteromultimeric polypeptide of the dynactin complex that binds directly to microtubules and to cytoplasmic dynein, a microtubule-based biologic motor protein (Holzbaur and Tokito, 1996). The dynactin complex is required for dynein-mediated retrograde fast axonal transport of vesicles and organelles along microtubules. The complex provides a link between specific cargos, the microtubule and cytoplasmic dynein during vesicle transport. Overexpression of the dynamitin (p50) subunit of dynactin causes a dissociation of dynactin at the junction of p150Glued and the Arp1 filament that effectively renders dynactin nonfunctional (Echeverri et al., 1996) and disrupts the complex and produces a late-onset progressive motor neuron disease in transgenic mice (Lamonte et al., 2002). Dynamitin overexpression is a powerful tool in dissecting the roles of dynein and dynactin in the cell. A GWAS showed linkage of the DCTN1 gene to chromosome 2q13 between the flanking markers D2S291 and D2S2114 in a family with adult-onset progressive AD LMN MND characterized by onset of breathing difficulty due to vocal fold paralysis followed by facial and limb weakness sparing sensation (Puls et al., 2003). Mutation analysis showed a single base-pair change resulting in an amino acid substitution of serine for glycine at position 59 (G59S) in all affected family members. Modeling of the G59S substitution, which occurs in a highly conserved CAP-Gly motif of the p150Glued subunit of dynactin, was postulated to reduce the affinity

of DCTN1 for microtubules and cause steric hindrance introduced by the larger side chain of serine that distorts its folding compared to the wild-type, which distorts the folding of the microtubule-binding domain. A mutation that severely inhibits the ability of dynactin to bind to microtubules would probably result in a more pronounced degeneration of motor neurons, as is predicted by the transgenic mouse model in which dynamitin is overexpressed (Lamonte et al., 2002). There is heterogeneity of clinical phenotypes associated with mutations in the dynactin gene, reportedly ranging from distal hereditary motor neuropathy to a variant form of Parkinsonism (Mishima et al., 2017).

Senataxin Heterozygous mutations in the SEXT gene located at the 9q34.13 chromosomal locus cause juvenile-onset ALS (ALS4), an AD disorder characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs, with onset of symptoms before the age of 25 years, a slow rate of progression, and a normal life span. The function of the senataxin protein is incompletely understood. Suraweera et al. (2009) identified novel senataxininteracting proteins, the majority of which were involved in transcription and RNA processing, including RNA polymerase II. Binding of RNA polymerase II to candidate genes was significantly reduced in senataxindeficient cells, accompanied by decreased transcription of these genes, suggesting a role for senataxin in the regulation/modulation of transcription. RNA polymerase II-dependent transcription termination was defective in cells depleted of senataxin, in keeping with the observed interaction of senataxin with poly(A) binding proteins 1 (PABP1) and 2 (PABP2). Splicing efficiency of specific mRNAs and alternate splice site selection of both endogenous genes and artificial minigenes were altered in senataxin-depleted cells. It has been suggested that senataxin may play a role in coordinating transcriptional events. Also suggested is an adverse impact of SEXT gene mutations on the formation of R-loops, structures at sites of focal opening of the DNA helix that permit binding to mRNA. This interaction suppresses local DNA methylation, enhancing gene expression. Mutations in SEXT are reported to decrease the number of R-loops, potentially impacting expression levels of 100s of gene (Grunseich et al., 2018, 2020).

GLE1, RNA export mediator The GLE1, RNA export mediator (GLE1) is an evolutionarily conserved protein and an essential multifunctional modulator of DEAD-box RNA helicases with a critical role in the nuclear export of mRNA, as well as in the initiation and termination of translation

AMYOTROPHIC LATERAL SCLEROSIS (Folkmann et al., 2013). Lethal congenital contracture syndrome 1 and lethal arthrogryposis are both AR fetal MNDs caused by mutations in GLE1 encoding the global RNA-processing protein, hGle1. Kaneb et al. (2015) reported the identification of heterozygous mutations in GLE1 associated with ALS in 3 rare variations (two deleterious and one missense) that were absent from controls in Sanger sequencing and whole exome sequencing, as well as from 285 additional controls screened via Sanger sequencing specifically for these variations, and in available data from the Exome Variant Server (EVS). An investigation of 2 deleterious mutations, c.209C > A and c.1965-2A > C, suggest that they operate via a haploinsufficiency mechanism. Specifically, the c.209C > A nonsense mutation results in degradation of c.209C > A mRNA by the nonsense-mediated decay (NMD) pathway reducing the levels of hGle1 both at the nuclear pore complex (NPC) (Isoform B) and in the cytoplasm (Isoform A). A second report from China ascribed adult ALS to mutations in the GLE1 gene; these mutations were rare, occurring in 7/628 ALS cases (Li et al., 2021). It is intriguing that hGle1, like TDP-43 and FUS, plays roles at multiple stages of the mRNA life cycle and that all three are linked to motor neuron pathologies. While there are no apparent functional links between hGle1 and either TDP-43 or FUS, hGle1 could be required for the nuclear export of the same mRNAs that need TDP-43 and FUS function.

UBQLN2, PFN1, and VAPB Mutations in the ubiquilin 2 (UBQLN2) gene cause X-linked dominant ALS and ALS/FTD, with an age of onset from the teenage years to the early 70s (Deng et al., 2011b). Males tend to have an earlier onset of disease, although the disease duration is about the same. UBQLN2 accumulates in skein-like inclusions seen in X-linked and other forms of ALS. In one Italian cohort, evaluation of the UBQLN2 gene indicated that FALS patients carrying this mutation had a younger disease onset compared to SALS (Gellera et al., 2013) and more UMN-predominant symptoms. This gene, which likely encodes a proteasomal adaptor protein, suggests a role for protein degradation in ALS. The mechanism whereby UBQLN2 mutations impair neuronal viability have not been fully delineated but likely involve impaired formation of stress granules, and cytosolic condensates of ribonuclear proteins that withdraw RNA from protein synthesis at times of cellular stress (Riley et al., 2021; Peng et al., 2022). Mutations in profilin-1 (PFN1) cause an AD limbonset ALS (Wu et al., 2012). Screening for this mutation in many other cohorts has shown only a few positive patients, thus suggesting that this gene is a rare cause of ALS. Profilin is a ubiquitous 12- to 15-kDa protein

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that binds monomeric (G) actin and regulates the extension of (F)-actin, inhibiting actin polymerization. The actual mechanism by which profilin lowers the critical concentration of ATP-actin is still a mystery (Theriot and Mitchison, 1993). One factor is that mutations in PFN1 destabilize the profiiln-1 protein (Boopathy et al., 2015). Mutations in VAPB cause an AD form of ALS with two unique phenotypes (Nishimura et al., 2004). The first phenotype includes a typical ALS disease course. The second, an atypical ALS, shows features of bulbar dysfunction, CST signs, and essential tremor. Mutations in this gene were initially described in a cohort of Portuguese-Brazilian patients, and have not been found in other cohorts, suggesting that this type of ALS is the result of a rare founder mutation (Landers et al., 2008). It is reported that VAPB mutations perturb the interface between the ER and mitochondria (GomezSuaga et al., 2022).

DISEASE PATHOGENESIS One can loosely ascribe the genetic causes of ALS to three pathogenic mechanisms to specific disease-causing mutations. In the first group, the primary disturbance is inherited instability of the mutant proteins, with subsequent perturbations in protein degradation (SOD1, ubiquilin-1 and 2). In the second group, the causative mutant genes disrupt RNA processing, transport, and metabolism (C9orf72, TARDBP, FUS), or result in aberrant cytosolic protein misfolding, aggregation, and ubiquitinated deposition (SOD1, OPTN, VCP) toxic to motor neurons. In the third group of ALS genes, the primary disturbance lies in defective axonal cytoskeletal and transport (DCTN1, PFN1). Beyond the upstream of these primary genetic causes, there may be other underlying putative gene-related mechanisms (Fig. 10.5), and contributing factors related to defective autophagy (SOD1), ER stress and impaired degradation (SOD1, OPTN), and prion-like mechanisms (SOD1, TARDBP, PFN1, VAPB).

Instability of mutant proteins SOD1 SOD1 is an example where studies of gene mutations have implicated protein misfolding, insolubility, and altered degradation in disease (Bruijn et al., 1998). Initially, oxidative stress and excitotoxicity in motor neurons were linked to the reduction in SOD1 enzymatic dismutase activity; however, investigators (Lobsiger et al., 2009; Prudencio et al., 2009; Turner et al., 2010) later proposed that degeneration could be due to noxious mutant SOD1 protein aggregates independent of dismutase activity (Caughey and Lansbury, 2003). Kepp (2015) analyzed

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Fig. 10.5. Implicated mechanisms of disease in ALS. (A) Familial ALS-associated mutations frequently affect genes that are components of the cellular protein quality control system. Other mutations, such as those in SOD1, affect protein folding. (B) Hyperactivation of microglia produces extracellular superoxide, which triggers inflammation and degeneration in motor neurons. (C) A reduction in the levels of the lactate transporter MCT 1 diminishes energy supplied by oligodendrocytes to motor neurons. (D) A failure of astrocytes to clear synaptic glutamate via the transporter EAAT2 triggers repetitive firing of motor neurons and excitotoxicity. (E) Disruption of the cytoskeleton and impaired axonal transport limits the exchange of essential macromolecules and organelles between the neuronal cell body and distal compartments. (F) Disturbances in aspects of RNA metabolism, including RNA processing, transport, and utilization, are largely the result of impaired hnRNP function. Reproduced from Taylor JP, Brown RH, Jr., Cleveland DW (2016). Decoding ALS: from genes to mechanism. Nature 539: 197–206 with permission.

30 different SOD1 mutations and found a convincing correlation between loss of SOD1 protein stability and diminished survival, which was exacerbated by altering the charge of the mutant protein. They hypothesized that the Achilles heel in SOD1-ALS is the energetic cost of accelerated protein turnover. Heat shock proteins experimentally bind to mutant SOD1 in neuroblastoma cell extracts; however, that binding makes them unavailable for their antiapoptotic functions promoting motor neuron death (Okado-Matsumoto and Fridovich, 2002).

TARDBP In sporadic ALS, non-SOD1 FALS, and some FTDs, TDP-43 is a principal component of the hallmark cytoplasmic ubiquitinated inclusions (Liu-Yesucevitz et al.,

2010). TDP-43 aggregates are seen in FALS cases where TARDBP is not the mutated gene (Narayanan et al., 2013). TDP-43 normally shuttles from the nucleus into the cytoplasm and back, and reversibly redistributes and preferentially stays in the cytoplasm during neuronal injury. However, a key question in understanding ALSlinked AD mutations in TDP-43 cause cellular toxicity is whether, and if so, point mutations alter the normal function of TDP-43. The C-terminal domain of TDP-43 is critical for spontaneous aggregation. Several ALS-linked TDP-43 mutations within this domain increase the number of TDP-43 aggregates and promote toxicity in vivo. Importantly, mutations that promote toxicity in vivo also accelerate aggregation of pure TDP-43 in vitro. Most forms of TDP-43 have a propensity for self-assembly, due in part to the relatively unstructured glycine rich

AMYOTROPHIC LATERAL SCLEROSIS C-terminal. Thus, TDP-43 is intrinsically aggregationprone, and its propensity for toxic misfolding trajectories is accentuated by specific ALS-linked mutations (Johnson et al., 2009). In contrast to SOD1, where ALS-linked mutations destabilize the mutant protein (Borchelt et al., 1994), ALS-linked TDP-43 mutations exhibit longer protein half-lives compared with wild-type protein, suggesting that abnormal stability may be a common feature for ALS-linked TDP-43 mutations (Ling et al., 2010). Further, under pathologic conditions, TDP-43 and FUS, which associate with and reversibly redistribute to the cytoplasm, can interact with other proteins that regulate RNA metabolism, leading to abnormal phosphorylation, ubiquitination, aggregation, and aberrations in their normal cellular functions. As noted above, TDP43 suppresses mis-splicing of 100s of genes. When TDP43 is mutated, or otherwise pathological as in sporadic ALS, mis-splicing of several critical genes likely impairs motor neuron viability. Representative examples are stathmin2 (Klim et al., 2019; Melamed et al., 2019) and UNC13A (Ma et al., 2022).

Disrupted RNA metabolism In this category of disease mechanisms, the primary pathology resides in one or more disturbances in the genesis and function of various categories of RNAs. This is well exemplified by mutant C9ORF72, whose molecular pathology results from expansion of the intronic hexanucleotide repeat (-GGGGCC-) beyond the upper normal of 30 repeats to hundreds or even thousands of repeats. These disrupt RNA metabolism in at least three ways as discussed below. TARDBP and FUS both encode multifunctional proteins that bind RNA and DNA and shuttle between the nucleus and the cytoplasm, playing multiple roles in the control of cell proliferation, DNA repair and transcription, and gene translation in the cytoplasm and locally in dendritic spines in response to electrical activation. How mutations in FUS/TLS provoke motor neuron cell death is unclear, although it may represent LOF of FUS/TLS in the nucleus or an acquired toxic function of the mutant protein in the cytosol. Similar disease mechanisms for disrupted RNA metabolism may be postulated in the intronic GGCCTG hexanucleotide repeats in a form of hereditary ataxia (SCA36) with ALS manifestations.

C9ORF72 The function of endogenous C9orf72 protein is not fully characterized, although it has been identified as a guanine exchange factor (GEF), with both Rho and Rab-GTPase GEF activity (Iyer et al., 2018). It has also been shown that the C9orf72 protein interacts with the Rab1a and Unc-51like kinase 1 (ULK1) autophagy initiation complex, with the C9orf72 protein regulating the trafficking of the ULK1

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complex to the phagophore (Webster et al., 2016). As such, a reduction in the C9orf72 protein would lead to reduced autophagy and accumulation of p62-positive aggregates, similar to those seen upon neuropathological examination of patients. How the repeat expansion causes disease remains unclear (Sareen et al., 2013). However, three potentially overlapping mechanisms. Because the hexanucleotide expansion is in the promotor of the major isoform of C9orf72, it is not surprising that this leads to haploinsufficiency of endogenous C9orf72 protein (Xi et al., 2013). At the same time, the expansions are adverse (toxic GOF) because they form RNA foci that sequester transcription factors. Additionally, the expanded tracts of RNA migrate to the cytoplasm, engage ribosomes, and form dipeptide repeat (DPR) protein inclusions (Morris et al., 2012; Walker et al., 2017). Altered protein homeostasis may result from impaired autophagy or accumulation of dipeptide repeat proteins after non-ATG mediated translation (Lehmer et al., 2017). Finally, dipeptide repeat proteins are shown to interfere with nucleocytoplasmic transport (Zhang et al., 2015), and there may be a contribution of haploinsufficiency prompted by reduced gene activity through the accumulation of glutamate receptors and excitotoxicity in response to glutamate; or induced motor neuron hypersensitivity by impairing their clearance (Shi et al., 2018). The gold standard for detecting the C9orf72 repeat expansion is Southern blotting, as PCR-based techniques are still failure-prone.

SCA36 Two unrelated patients with hereditary ataxia who showed ataxia as the first symptom later resembling ALS (Ohta et al., 2007) were postulated to have noncoding repeat expansion associated with RNA toxicity in SCA36. A genome-wide linkage analysis and subsequent mapping of 5 unrelated Japanese families of SCA36 characterized the onset of cerebellar truncal and gait ataxia, dysarthria, and limb incoordination at a mean age of 53 years, with lingual atrophy, fasciculation, skeletal muscle atrophy and fasciculation, and hyperactive reflexes (Kobayashi et al., 2011). SCA36 was indeed caused by hexanucleotide repeat expansions through RNA GOF due to heterozygous expansion of an intronic GGCCTG hexanucleotide repeat in the NOP56 gene. Unaffected individuals carry 3–8 repeats, whereas affected patients carry 1500–2000 repeats. The NOP56 gene functions in an early to middle step in pre-rRNA processing.

Defective axonal cytoskeletal and transport DCTN1 Neurons possess a striking asymmetric morphology in which elongated axonal processes extend from the cell

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body. The growth and maintenance of the axon, as well as the movement of materials between the cell body and the distal tip of the axon, rely on the mechanisms of fast axonal and retrograde transport. Impairment of axonal transport in motor neurons is a mechanism for neuronal degeneration in MND. Cytoplasmic dynein is necessary but not sufficient for retrograde transport directed from the synapse to the cell body. The p150(Glued) subunit of dynactin promotes the initiation of dynein-driven cargo motility from the microtubule plus-end. As plus end-localized microtubule-associated proteins like p150(Glued) also modulate the dynamics of microtubules, it has been hypothesized that p150(Glued) might promote cargo initiation by stabilizing the microtubule track (Lazarus et al., 2013). In vitro assembly assays and total internal reflection fluorescence microscopy in primary neurons using live-cell imaging found that p150(Glued) was a potent anticatastrophe factor for microtubules by binding both to microtubules and to tubulin dimers. Depletion of p150(Glued) in neurons leads to a dramatic increase in microtubule catastrophe due to absence of anticatastrophe activity. Moreover, disruption of the two functions of dynactin in neurons, in activating dynein-mediated retrograde axonal transport and enhancing microtubule stability through a novel anticatastrophe mechanism regulated by tissue-specific p150(Glued), or both, can contribute to susceptibility of FALS.

PROFILIN-1 PFN1 is a small actin-binding protein that promotes actin polymerization and regulates numerous cellular functions, but how mutations in PFN1 lead to ALS is unclear. It is striking that forced expression of mutant PFN1 in mice produces an adult-onset motor neuron disorder (Yang et al., 2016; Fil et al., 2017). Mutant, but not wild-type, PFN1 forms insoluble aggregates, disrupts cytoskeletal structure, and elevates ubiquitin and p62/ SQSTM levels in motor neurons. Unexpectedly, the acceleration of motor neuron degeneration precedes the accumulation of mutant PFN1 aggregates. These results suggest that although mutant PFN1 aggregation may contribute to neurodegeneration, it does not trigger its onset.

Other putative disease mechanisms DEFECTIVE AUTOPHAGY The highly regulated processes of autophagy that culminates in lysosomal degradation of diverse intracellular substances, from organelles to protein aggregates, can be disturbed leading to death of the cell. Mutant SOD1 impairs autophagy by interfering with dynein, leading

to a feedback loop allowing more accumulation of SOD1 aggregates (Zhang et al., 2007). Surprisingly, while an induction of autophagy may be associated with disease acceleration in ALS mice (Zhang et al., 2011), inhibition of the ubiquitin-protease system in a neuronal ALS model was associated with improved survival likely through enhanced TDP-43 turnover (Barmada et al., 2014). Dysfunction of several ALS genes has been implicated in disturbances of autophagy in ALS (Chua et al., 2022).

ER STRESS AND IMPAIRED DEGRADATION (SOD1, OPTN) Initial evidence of ER stress arose in studies of mutant SOD1 in which mutant SOD1 specifically interacted with Derlin-1, a component of the ER-associated degradation (ERAD) pathway for extraction and degradation of misfolded ER proteins, and activated the apoptosis signal-regulating kinase 1 (ASK1)-dependent cell death pathway (Nishitoh et al., 2008). In three mouse models of familial ALS, the ER stress-protective agent salubrinal attenuated disease and delayed progression in vivo in vulnerable motor neurons selectively prone to ER stress from birth, whereas chronic enhancement of ER stress promoted disease (Saxena et al., 2009). Disruption of two main protein clearance pathways, the ubiquitinproteasome system and autophagy, may be central components of the disease mechanism in ALS. Mutations in the OPTN gene (Maruyama et al., 2010) may also have a role in ERAD and sorting endosomal proteins. As recently reviewed, it is likely that ER stress may be implicated by multiple ALS genes (Jeon et al., 2023).

PRION-LIKE SPREAD It is remarkable that several mutant proteins (e.g., TDP34, FUS) that initiate ALS have domains predicted to be relatively unstructured. Such domains predispose the proteins both to self-assembly and to interaction with other proteins, thereby leading to the formation of protein aggregates. The capacity of these proteins to selfassemble suggests they can propagate protein misfolding in a prion-like manner. Prion-like templated conversion of a natively folded protein into a misfolded version of itself is a prominent feature of cell-to-cell spread of protein aggregates in neurodegenerative diseases (Jucker and Walker, 2013). Misfolded SOD1 can propagate aggregation of wild-type SOD1, hastening onset of the ALS in mutant SOD1 transgenic mouse models (Deng et al., 2006). This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are cross-linked through intermolecular disulfide bonds via oxidation of cysteine residues in the SOD1 protein. After injection into the sciatic nerve, some preparations of

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mutant SOD1 accelerated spread of motor neuron death in transgenic ALS mice; the efficacy of seeding of disease varied with different SOD1 proteins (Ayers et al., 2021). Prion-like domain-containing proteins are particularly important in the formation of stress granules, a defense mechanism that enables cells to sequester pretranslation mRNA during physiological perturbations. After the disruption has resolved, these ribonucleoprotein granules dissociate, freeing up mRNA for translation and disaggregating DNA/RNA-binding proteins like TDP-43 and FUS; mutation forms thereof, however, may incorporate into stress granules that are unable to dissociate, rendering them persistent and pathological (Colombrita et al., 2009; Bosco et al., 2010). However, it is not known whether TDP-43 also exhibits templated misfolding that can spread from cell to cell.

microglial function contributes to neurodegeneration in C9orf72 expansion carriers in several ways, including by enhancing synaptic loss (Lall and Baloh, 2017; Lall et al., 2021). Two independent mouse lines lacking the C9ORF72 ortholog (3110043O21Rik) in all tissues develop normally and age without MND (O’rourke et al., 2016). but nonetheless develop splenomegaly, neutrophilia, thrombocytopenia, increased expression of inflammatory cytokines, and severe autoimmunity, ultimately leading to a high mortality rate. Transplantation of mutant mouse bone marrow into wild-type recipients recapitulates the phenotypes observed in the knock-out animals, including autoimmunity and premature mortality (Burberry et al., 2016).

A ROLE FOR GLIA IN ALS

The ways that a given gene defect ultimately leads to clinical disease is still incompletely understood in many inherited neurologic motor system disorders. However, neurogenetics is revolutionizing the development of validated, qualified, and standardized genetic biomarkers of a disease. This is much needed in CNS neurodegenerative disorders such as ALS, tauopathies, synucleinopathies, and Alzheimer disease to facilitate early presymptomatic diagnosis and improve therapeutic clinical trial designs to select likely responders, predict disease progression, reflect target patient engagement, and ascertain treatment effects. There are currently no validated biomarkers for ALS; however, recent studies suggest that markers of inflammation and NF concentration in blood and CSF reliably occur in the course of motor neuron dysfunction and axonal injury (Bowser et al., 2011; Poesen and Van Damme, 2018). Vascular endothelial growth factor (VEGF) gene expression appears to be deficient in ALS patient fibroblasts and lower CSF VEGF levels are associated with disease progression (Raman et al., 2015; Guo et al., 2017). Importantly, neurofilament levels rise in the year prior to symptom onset in presymptomatic people carrying a mutation in the SOD1 gene (Benatar et al., 2019) suggesting this as a potential presymptomatic indicator of disease onset. Elevated phosphorylated neurofilament heavy chain (pNf ) levels in particular correlate with patient survival, prompting investigations into their use for stratifying patients with ALS into prognostic subsets (Poesen et al., 2017). Nonclinical studies of transgenic rodents and clinical studies of patients with FALS implicate neuroinflammation and immune dysregulation in pathogenesis and heterogeneity (Beers and Appel, 2019; Chipika et al., 2019). There is an early contribution of a neuroinflammatory response for UMN degeneration with respect to TDP-43 pathology, and MCP-1-CCR2 signaling that is important for

Resident microglia can become activated in all types of ALS and the synthesis of mutant SOD1 by microglia is an important determinant of the rate of disease progression; selectively silencing of the mutant SOD1 gene in microglia prolongs survival in SOD1-G93A ALS mice. Diminishing the mutant levels of microglia had little effect on the early disease phase but sharply slowed later disease progression (Boill
ee et al., 2006). Bone marrow transplants in mutant SOD1 mice replacing microglia expressing mutant SOD1 with wild-type donor-derived microglia slowed motor neuron loss and prolonged disease duration and survival compared to mice receiving mutant expressing cells (Beers et al., 2006), confirming that lack of mutant SOD1 expression contributed to motor neuron protection. Consistent with these findings, selective inhibition of nuclear factor-kappa B (NF-kB), a master regulator of inflammation, and upregulated in the spinal cords of ALS patients and SOD1 mice, rescued motor neurons from microglial-mediated death in vitro and extended survival in ALS mice by impairing proinflammatory microglial activation. Conversely, constitutive activation of NF-kB selectively in wild-type microglia induced gliosis and motor neuron death in vitro and in vivo. Disturbances in microglial function have also emerged as a potential contributor to ALS that is associated with mutations in C9orf72. The impact of SOD1 mutations is not confined only to microglia. A very substantial increase in survival in SOD1-G93A ALS mice achieved by eliminating the SOD1 protein from oligodendroglia (Kang et al., 2013a). C9ORF72 is abundant in, and required for, the normal function of myeloid cells (Rizzu et al., 2016). In mice, genetic knock-out of C9orf72 enhances type 1 interferon activation of microglia, due to reduced degradation of the stimulator of interferon gene (STING) protein. Activated

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the recognition of diseased UMNs by infiltrating monocytes. Activated astrocytes, microglia, and MCP1CCR2-mediated infiltration of monocytes are detected in the motor cortex of ALS patients and TDP-43 mouse models and these findings are conserved among species and observed in both ALS and FTD-ALS patients (Jara et al., 2019). Higher levels of CK, ferritin, TNF-a, interleukins (ILs), and C-reactive protein (CRP) are all found in patients with ALS and correlate with a more rapid disease progression (Lu et al., 2016; Lunetta et al., 2017). Mutations in the triggering receptor expressed on the myeloid cells 2 (TREM2) gene that encodes a receptor of the innate immune system expressed on microglia, macrophages, dendritic cells, and osteoclasts are associated with ALS, Alzheimer disease, and FTD. Moreover, soluble TREM2 (sTREM2), a proteolytic product of TREM2, may indicate activated myeloid cells in both the CNS and PNS (Bekris et al., 2018). One longitudinal study of 108 patients with ALS and 41 controls without neurological disease (Huang et al., 2020), included 17 with FALS of whom 10 had C9orf72 mutation cases, stratified into fast- and slowprogression subgroups using the ALS Functional Rating Scale-Revised change rate for a comparison of cytokines/chemokines and NF levels between cases and controls, among progression subgroups, and in those with C9orf72 mutations. The investigators found significant elevations of cytokines, including MCP-1, IL-18, and NFs in the cases vs controls. Among cases, these cytokines and NFs were significantly higher in fast-progression and C9orf72 mutation subgroups vs slow progressors. Analyte levels were generally stable over time, a key feature for monitoring treatment effects. Moreover, CSF/plasma neurofilament light chain (NFL) levels predicted disease progression.

PARANEOPLASTIC MECHANISMS Autoantibody-mediated Paraneoplastic neurologic syndromes may include aspects of LMN disease alone or in combination with UMN signs clinically and histopathologically. These are immunemediated neurological syndromes associated with systemic cancers that result from tissue damage remote from the site of a malignant neoplasm or its metastases. The malignancy must not invade, compress, or metastasize to the nervous system. Two years before Guichard et al. (1956) introduced the term “paraneoplastiques” in an account of three patients with systemic carcinomas and subacute sensorimotor neuropathy, Henson et al. (1954) described a patient with subacute cerebellar degeneration and concomitant features of subacute motor neuronopathy associated with occult breast carcinoma. Postmortem examination showed spinal cord AHC loss accompanied

by focal lymphocytic inflammation, crescentic anterolateral cord demyelination sparing CSTs, and Wallerian motor nerve degeneration in the legs. Such disorders are virtually always immune-mediated according to a mechanism that begins with the ectopic expression of an antigen by the occult tumor that is normally expressed exclusively in the nervous system. The tumor antigen is identical to the neural antigen (Carpentier et al., 1998); however, for unknown reasons, the immune system identifies it as foreign and mounts an immune attack against it that may inhibit the growth of the tumor and in a few instances obliterate it. The secreted antibodies and onconeural antigenspecific cytotoxic T-cells are insufficient to cause the neurologic disease unless it crosses the blood–brain barrier (BBB) and reacts with neurons expressing it. In such syndromes affecting the brain, relatively high titers of the putative autoantibody in the CSF compared to total IgG indicate that the antibody is synthesized in the CNS presumably by specific B-cells that have crossed the BBB (Furneaux et al., 1990).

ANTI-HU/HUD Dalmau et al. (1991) investigated the causal role of antiHu IgG using immunohistochemical studies of the brain and small cell lung cancer (SCLC) tumors of affected patients, demonstrating IgG bound to the nuclei of neurons and the cytoplasm of glial cells, with neuropil deposits of IgG, compared to control brains that failed to show anti-Hu IgG. Classical ALS is not a presenting syndrome of type 1 antineuronal nuclear antibody (ANNA-1)/anti-Hu-associated paraneoplastic encephalomyelitis (PEM), but up to 20% of patients exhibit signs and symptoms of LMN involvement (Dalmau et al., 1992). Human and experimental animal models suggest that the PNSs cannot be attributed to the infrequency of expression of the relevant encoded tumor antigens or to mutations in the genes encoding these antigens. Molecular analysis of the HuD gene encoding the PEM antigen in human lung cancer cell lines (Carpentier et al., 1998) shows that it is not mutated and that its expression highly correlates with tumor cell types displaying neuroendocrine features. This suggests that HuD is not involved in the etiology of lung cancer, but may be involved in determining neuroendocrine cell development and differentiation in the tumor cell lines that express it. Yet it is still not known why a small number of SCLC patients mount a profound immune response to the HuD product, while almost all SCLCs express HuD. The hypothesis that a mutated form of the HuD gene induces these immune reactions was considered by Dalmau et al. (1992) who detected aberrantly spliced HuD mRNA (lacking 13 amino acids) in the tumor cells of an affected case. In Hu-D, it is believed that sequestration of the

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onconeural antigen from immune surveillance in the CNS results in a lack of immune tolerance to these proteins when they are ectopically expressed in tumor cells.

ANTI-RI/NOVA1 The antineuronal antibody, Ri or ANNA-2, in association with known breast cancer or other gynecologic cancers typically identifies a subset of patients with paraneoplastic opsoclonus-myoclonus ataxia (POMA) syndrome, a disorder of motor control (Luque et al., 1991). It recognizes the tumor nuclei and a neuronal protein of 55 kDa in an animal model of ventral motor system disease and human paraneoplastic MND. The nova alternative splicing regulator 1 (Nova1) gene encodes a highly conserved protein homologous to the RNA-binding protein (hnRNP K) that is inhibited by the Ri antibodies. Northern blot analysis detects Nova1 transcripts only in the brain, and in E18 experimental mice in the developing ventral brainstem and spinal cord (Buckanovich et al., 1993). Using antisera from patients with POMA, neuronal-specific RNA-binding protein Nova-1 binds to mRNA with high affinity in the subcortical nervous system (Buckanovich et al., 1996). Younger et al. (2013) described a 49-year-old woman with elevated serum and CSF Ri antibodies associated with malignant breast cancer who, after curative surgery, radiation therapy, and chemotherapy, developed MND with LMN and UMN signs. Nova was present in the patient’s tumor cells and reactive with mouse cerebellar neurons, staining the developing mouse spinal cord, as did a 1:100 dilution of CSF (Fig. 10.6). Moreover, patient antisera reacted to 55 kDa antigen present in tumor nuclei and Nova1 and Nova2 antigens. In the same way that the production of Ri antibodies that inhibit Nova-1-RNA interactions appear to be the cause of POMA, these same antibodies present in serum and CSF were the likely cause of paraneoplastic MND. The patient improved with 3 months of immune modulatory therapy of intravenous immune globulin and plasma exchange.

LYMPHOMA-MEDIATED Patients with occult Hodgkin and non-Hodgkin lymphoma (HL,NHL) present additional challenges to the nomenclature and influenced concepts of cancer-related MND, motor neuropathy, and neuronopathy (Schold et al., 1979; Younger, 2000), all with uncertain epidemiology. Rowland and Schneck (1963) described 2 young women with progressive limb weakness and wasting, and generally absent tendon reflexes, without fasciculation, Babinski signs, or sensory loss. One died after removal of HL tumor, and the other of progressive neurologic disease. At postmortem examination, there was AHC loss, gliosis, astrocytosis, and perivascular

Fig. 10.6. (A) Immunoreactivity of patient tumor with antiNova (anti-Ri) antisera, stained with rabbit anti-Nova antisera (a), mouse anti-Elavl (Hu) antisera, or DAPI to visualize nuclei (data not shown). Nova was present in tumor cells in a speckled nuclear pattern with no Hu reactivity. Both Nova and Hu were reactive with mouse cerebellar neurons, and neither was reactive with spleen (data not shown). (B) Embryonic day 11.5 mouse spinal cord was stained with patient cerebrospinal fluid (CSF), anti-HuC/D monoclonal antibody, or DAPI (40 ,6-diamidine-2-phenylidole-dihydrochloride) as indicated. Patient CSF at 1:100 dilution reacted in a restricted manner with central nervous system (CNS) spinal cord neurons. This is evident by comparison with Hu reactivity, which reacted with both CNS and dorsal root ganglia neurons, and DAPI uniquely stained mitotic progenitors in the central cord. Normal CSF at 1:100 dilution showed no reactivity (data not shown). (C) Extracts from WT, Nova1, Nova2, or Nova1 + Nova2 (DKO) mouse brains (as indicated) were probed with the indicated antibodies (Ri+, patient, and negative control samples of CSF were diluted respectively 1:250, 1:100, and 1:1000; Hu +was a 1:1000 dilution of patient antisera). Patient antisera reacted with both Nova1 and Nova2 antigens.

lymphocytic infiltration, with variably severe demyelination of the posterior roots and columns. In addition, the peripheral nerves of the first case were normal at postmortem examination, but variable demyelination and Schwann cell proliferation without axonal loss were found in the second case. Younger et al. (1991) broadened the concept of lymphoma-associated MND, demonstrating a greater heterogeneity than previously suspected. MND syndromes, including classical ALS, that occurred in both HL and NHL, before and after treatment of the underlying malignancy. No specific clinical syndrome implied concomitant lymphoma, monoclonal paraproteinemia, an increased CSF protein concentration and oligoclonal bands increased the likelihood of detecting a lymphoma, even in those with classic ALS. Postmortem studies of peripheral nerves and roots in several patients have showed foci of demyelination, IgG and C3 complement

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deposits, and inflammatory cell infiltrates exceeding the minor abnormalities in ALS without lymphoma.

TREATMENT Antisense oligonucleotides and microRNA Despite substantial advances in defining molecular pathologies in ALS, therapy development has been challenging. There currently are five FDA-approved ALS drugs, including riluzole, edaravone, two combination formulations (dextromethorphan combined with quinidine-sulfate and sodium phenylbutyrate with taurursodiol) and tofersen. Regrettably, these have at most modest benefits. It is therefore exciting that new molecular therapies are emerging that offer precision targeting of well-defined triggers of ALS (reviewed in Meijboom and Brown, 2022). An important recent development in ALS therapy has been the “platform trial,” a design that allows parallel testing of multiple drugs with shared controls, thereby reducing costs, improving speed of trial enrollment, and increasing likelihood of receiving drug vs placebo (Paganoni et al., 2022). Two approaches to treatment of ALS involve antisense oligonucleotides (ASOs), which in GOF disorders can silence the mutated gene, while in LOF disorders they normalize the function of the mutated protein (Southwell et al., 2012). Smith et al. (2006) developed ASOs targeting either rat or human SOD1 that in healthy rats and nonhuman primates that resulted in therapeutic doses of ASO throughout the CNS; 28-day intracerebroventicular (ICV) infusion of the most potent human SOD1 ASO to presymptomatic G93A SOD1 rats significantly reduced muSOD1 mRNA levels and protein. While this therapy did not delay symptom onset, it did achieve a 37% increase in survival after motor onset. A Phase I, safety, tolerability and pharmacokinetics study of single doses of ISIS 333611 administered into the spinal canal at four very low dose levels (0.15, 0.5, 1.5 and 3 mg) were evaluated sequentially in a cohort of 8 patients, of whom 6 were randomized to active drug (ISIS 333611; clinicaltrials.gov, NCT01041222; Miller et al., 2013). After that, ASO proved to be safe, the same investigators (Mccampbell et al., 2018) developed next-generation SOD1 ASOs that more potently reduces SOD1 mRNA and protein and extends survival in SOD1G93A rats and mice. Further, the initial loss of compound muscle action potentials in SOD1G93A mice was reversed after a single dose of SOD1 ASO. Encouraged by these data, this team next conducted two human trials of this ASO (now designated Tofersen). The first study, a phase1-2 trial of ascending doses of Tofersen clearly showed a dose-dependent reduction in CSF. SOD1 and plasma neurofilament levels (Miller et al., 2020). In a small cohort to the fastest progressors, there was clinical benefit as well. The second study was a phase 3 efficacy trial of Tofersen at 100 mg. This again

revealed significant reductions in CSF SOD1 and plasma neurofilament levels (Miller et al., 2022). At 6 months, functional benefit was suggested by slower declines in the ALSFRS-R (functional rating scale), vital capacity; after another 6 months of open label extension, these trends were more pronounced. Tofersen has received provisional approval from the FDA. Other ASO trials are in progress (Boros et al., 2022). An ASO that suppresses the isoforms of C9orf72 harboring the hexanucleotide repeat has been shown to reduce levels of polydipeptides in CSF in a single case following intrathecal delivery (Tran et al., 2022). In a single case, an ASO has been reported to significantly reduce tissue levels of the FUS gene, with some evidence of transient clinical benefit. This initial pilot study has led to a follow-up trial of the same anti-FuS ASO in a cohort of FUS cases. A disadvantage of ASO therapy is that it must be delivered repeatedly. An alternative approach is to employ a viral delivery system, such as adeno-associated virus (AAV), that in theory, can produce the gene suppressing reagent continuously for years (so-called one and done therapy). One set of cargos that should be ideal for AAV delivery are microRNAs (miR) and small interfering RNAs (siRNA). Like ASOs, miR and siRNA suppress target genes but via a different mechanism than ASO. Gene suppression by ASOs occurs in both the nucleus and cytoplasm; ASOs act by binding their target RNA and activating RNAseH to digest the hybrid nucleic acid molecule. MiRs and siRNA, on the other hand, act in the cytoplasm to bind and direct their target RNA to the RISC complex for degradation. There are more than 1000 naturally occurring miRs. However, one can fabricate synthetic RNAs to target ALS genes and deliver these miR to the cell or tissue using viruses like AAV. In fact, miR and siRNA strategies to silence SOD1 have been studied extensively, both in vitro (Ding et al., 2003) and in vivo in ALS mice (Ralph et al., 2005; Miller et al., 2005; Foust et al., 2013), often with substantial clinical benefit. In a pilot human study, AAVrh10 delivery of a synthetic miR targeting SOD1 suppressed spinal cord levels of the SOD1 protein in a single case. While there was a suggestion of transient clinical benefit, that individual developed an intense T-cell reaction to the virus with associated liver dysfunction. In a second case, treatment with immunosuppressive therapy appeared to blunt the adverse immunoreactivity.

Pluripotent stem cell therapy Induced pluripotent stem cell (iPSC) technology has advanced our approach to the genetics of ALS with the ability to directly create cell lines from patients with ALS-associated mutations, and in creating models of disease that incorporate entire genomes rather than specific genes (Goutman et al., 2015). iPSC neurons derived

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from C9ORF72 subjects show RNA foci, altered gene expression, sequestration of RNA-binding proteins, and glutamate excitotoxicity (Donnelly et al., 2013). Patient-specific iPS cells obtained by both integration and transgene-free delivery methods of reprogramming transcription factors have the properties of pluripotent cells and are capable of direct differentiation into motor neurons targeting SOD1-associated ALS (Chestkov et al., 2014). Motor neurons induced from IPSCs from FALS patients carrying mutations in TARDBP provide a useful tool for elucidating ALS disease pathogenesis and for screening drug candidates (Egawa et al., 2012). Mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF) represent a novel autologous cell-therapy capable of targeting multiple pathways that may slow disease progression of ALS. A randomized, double-blind, placebo-controlled trial (RCT) that enrolled ALS participants with a 25 points on the revised ALS Functional Rating Scale (ALSFRS-R) and a 3 points decline prior to randomization, received 3 IT treatments of MSC-NTF or placebo with a primary endpoint defined as a change in the disease progression posttreatment of 1.25 points on the (ALSFRS-R). Although none of the subjects met the primary endpoints, there were significant improvements in CSF biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support: vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), and neurofilament light chains (NfL) in the treated subjects, but not controls. A subgroup of MSC-NTF participants with less severe disease may have retained more function compared to placebo (Cudkowicz et al., 2022).

related MNDs. There is little doubt that the pace of future discoveries will continue to accelerate in many directions toward effective therapy. To accomplish these goals, research programs already in place, and others convening will be primed to collect and sequence the whole genome from patients and carriers. Additional disease-causing genes and significant variants in noncoding DNA likely to be discovered both through conventional genetics and enhanced genome associated studies, will be compared with quantifiable clinical parameters to develop even more precise genotype–phenotype correlations. With continued understanding of FALS, there may be better understanding of SALS and meaningful epigenetic and environmental influences that trigger motor neuron degeneration. With more careful and precise neurodiagnostics and outreach, long-awaited effective therapeutics on the horizon will be available for the neediest cases at risk for the inexorably lethal course that characterizes most cases today.

CONCLUSIONS

Abel O, Powell JF, Andersen PM et al. (2012). ALSoD: a userfriendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Hum Mutat 33: 1345–1351. Al-Obeidi E, Al-Tahan S, Surampalli A et al. (2018). Genotypephenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy. Clin Genet 93: 119–125. Al-Sarraj S, King A, Troakes C et al. (2011). p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol 122: 691–702. Arai T, Hasegawa M, Akiyama H et al. (2006). TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351: 602–611. Ayers JI et al. (2021). Variation in the vulnerability of mice expressing human superoxide dismutase 1 to prion-like seeding: a study of the influence of primary amino acid sequence. Acta Neuropathol Commun 9: 92. Barmada SJ, Serio A, Arjun A et al. (2014). Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol 10: 677–685.

ALS and other motor neuron disorders were described more than a century ago, yet the first disease-associated gene was discovered only 3 decades ago. Despite the discovery of more than 50 ALS genes, and a compelling overlap between molecular events in both FALS and SALS, the etiopathogenesis of ALS is still not fully understood. Treatment options are severely limited to only 4 approved drugs with marginal life-extending benefit. Progress in ALS and other MNDs will require even greater insights into the neurobiology of the diseasecausing genes inherent in disease susceptibility in both FALS and SALS forms of this disease. Moreover, improving the outcome of potentially effective cutting-edge therapies on the horizon will require directing our focus in the direction of improved technological assessment, rigorous RCTs, and innovative treatment approaches.

FUTURE DIRECTIONS There is dramatic progress toward defining the genetic landscape and molecular neurobiology of ALS and

ACKNOWLEDGMENTS The authors acknowledge the memory of Lewis P. “Bud” Rowland, MD, Chair of neurology at Columbia Vagelos Physicians and Surgeons Medical School, and Director of the Neurological Institute of New York for 25 years. He was an inspiring leader of American neurology for many more years and focused much of his career on ALS, imparting to his trainees the importance of translating research for the care of patients.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00018-1 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 11

Paraneoplastic motor disorders DAVID S. YOUNGER1,2* 1

Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States

2

Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States

Abstract Paraneoplastic neurological disorders (PNDs) are heterogeneous clinicopathologic syndromes that occur throughout the neuraxis resulting from damage to organs or tissues remote from the site of a malignant neoplasm or its metastases. The discordance between severe neurological disability and even an indolent malignancy suggests an underlying neuroimmunologic host immune response that inflicts nervous tissue damage while inhibiting malignant tumor growth. Motor system involvement, like other symptoms and signs, is associated with focal or diffuse involvement of the brain, spinal cord, peripheral nerve, neuromuscular junction or muscle, alone or in combination due to an underlying neuroimmune and neuroinflammatory process targeting neural-specific antigens. Unrecognized and therefore untreated, PNDs are often lethal making early detection and aggressive treatment of paramount importance. While the combination of clinical symptoms and signs, and analysis of detailed body and neuroimaging, clinical neurophysiology and electrodiagnostic studies, and tumor and nervous system tissue biopsies are all vitally important, the certain diagnosis of a PND rests with the discovery of a corresponding neural-specific paraneoplastic autoantibody in the blood and/or spinal cerebrospinal fluid.

INTRODUCTION Paraneoplastic neurologic disorders (PNDs) are immunemediated neurological syndromes associated with systemic cancers that result from tissue damage remote from the site of a malignant neoplasm or its metastases. The malignancy must not invade, compress, or metastasize to the nervous system. Such disorders may affect any portion of the neuraxis including a single cell type, for example, Purkinje cells of the cerebellum resulting in the relatively isolated disorder paraneoplastic cerebellar degeneration (PCD). In other instances, there can be more complex symptomatology such as that seen in paraneoplastic encephalomyelitis (PEM) with multiple levels of involvement of the neuraxis. Motor system involvement in PND is highly variable leading to a variety of motor phenomena ranging from movement disorders to fluctuating or progressive weakness depending on the

target of the associated neural-specific autoantibody and neuroimmunological response (Table 11.1). While motor dysfunction may be a frequent component of PNDs, it is rarely the only symptom. As motor dysfunction may have many etiologies and occurs frequently in the absence of cancer, it is often difficult to exclude that motor dysfunction in such patients is merely coincidental. This chapter reviews historical, epidemiologic, clinical and laboratory assessment, immunopathogenesis, and treatment of PNDs with an emphasis on motor involvement.

GENERAL CONSIDERATIONS Examples of paraneoplastic disorders outside the nervous system such as cancer-related anorexia (Inui, 2002), hypercalcemia (Luh et al., 2002), Cushing syndrome (Mansi et al., 1997), and carcinoid tumors

*Correspondence to: David S. Younger, MD, DrPH, MPH, MS, 333 East 34th Street, Suite 1J, New York, NY 10016, United States. Tel: +1-212-213-3778, Fax: +1-212-213-3779, E-mail: [email protected]

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Table 11.1 Paraneoplastic neurologic disorders with motor system involvement Dominant paraneoplastic syndrome

Abnormal movement

Common antibody association

PCDa

Ataxia, oscillopsia, tremor

Yo

PEM

PCD, MND, myelopathy Prominent chorea

Brainstem encephalitis

Hypokinesis, rigidity, gaze paralysis, orofacial dyskinesias, trismus

Tr, mGluR1 VGCCb Hu CRMP5 Amphiphysin Ma2

NMDA receptor encephalitis Stiff-person syndrome and PERM MND Myelopathy

POM

PSN Subacute and chronic sensorimotor neuropathy Neuromyotonia Morvan syndrome LEMS

a

Trismus, laryngospasm Orofacial dyskinesias, chorea, dystonia, choreoathetoid movements Axial rigidity and muscle spasms; progressive encephalomyelitis with myoclonus UMN LMN Isolated syndrome rare, more commonly associated with encephalomyelitis or PCD Predominant opsoclonus myoclonus (children) With additional brainstem and cerebellar dysfunction (adults) Sensory ataxia, pseudoathetoid movements Distal polyneuropathy

Muscle cramps, stiffness, delayed muscle relaxation  CNS involvement Proximal weakness that improves with exercise, muscle aches and stiffness

Ri Antibodies to the NR1 subunit of NMDAR Amphiphysinc GAD, GlyR

Common tumor association Breast, ovary, and other gynecological tumors HL SCLC SCLC SCLC, thymoma SCLC Germ-cell tumor of testis in young men, non-SCLC in older men or women Breast, ovary, SCLC Teratoma of the ovary

SCLC, thymoma, breast, HL Rarely paraneoplastic

None None Amphiphysin, CRMP5

Breast HL and NHL, SCLC Lung, breast

Not characterized

Neuroblastoma

Ri

Breast ovary, SCLC

Hu

SCLC

CRMP5, Hu None

Lung Plasma cell dyscrasias

Caspr2

Thymoma

VGCC, SOX1d

SCLC

These antibodies are typically found when PCD is the predominant syndrome although almost all known antibodies can associate with PCD. About one-half of patients with PCD and VGCC antibodies will also have LEMS. c Antibodies to glutamic acid decarboxylase are found in nonparaneoplastic stiff-person syndrome. d SOX1 antibodies are highly associated with the presence of an SCLC and are markers for paraneoplastic LEMS. Caspr2, contactin-associated protein-like 2; CRMP5, collapsin response-mediated protein 5; GAD, glutamic acid decarboxylase; GlyR, glycine receptor; HL, Hodgkin’s lymphoma; LEMS, Lambert–Eaton myasthenic syndrome; LMN, lower motor neuron; mGluR1, metabotropic glutamate receptor type 1; MND, motor neuron disease; MNDs, motor neuron disorders; NHL, non-Hodgkin’s lymphoma; NMDAR, N-methyl-D-aspartate receptor; PCD, paraneoplastic cerebellar degeneration; PEM, paraneoplastic encephalomyelitis; PERM, progressive encephalomyelitis with myoclonus; POM, paraneoplastic opsoclonus myoclonus; PSN, paraneoplastic sensory neuronopathy; SCLC, small cell lung cancer; UMN, upper motor neuron; VGCC, voltage-gated calcium channels. b

PARANEOPLASTIC MOTOR DISORDERS (Patchell and Posner, 1986) with associated cachexia, tetany or carpopedal spasm, myopathy, and generalized weakness are usually due to ectopic tumor secretion of substances that mimic normal hormones or that interfere with circulating proteins. Damage to the nervous system by cancer-induced coagulopathies or opportunistic infections is generally not considered to be a PND.

HISTORICAL PERSPECTIVE The historical achievements in cataloguing and understanding the PNDs span more than a century between continents and encompass diverse central, peripheral, and autonomic (CNS, PNS, ANS) disorders of the neuraxis. Auche (1890), Oppenheim (1911), Harris (1926), and Weber and Hill (1933) are generally credited with noting the remote effects of cancer on the nervous system. However, modern interest in the PNDs commenced in 1948 with early reports by Denny-Brown and Wyburn-Mason who described the same two cases of sensory neuropathy and bronchogenic lung carcinoma (Denny-Brown, 1948; Wyburn-Mason, 1948). DennyBrown (1948) postulated a relation between sensory neuropathy, muscular atrophy, and small cell lung cancer (SCLC). The cause of the muscular atrophy was not explained, but the pathologic finding of dorsal root ganglioneuritis was attributed to cancer, an observation that proved to be a unifying feature in subsequent pathologically defined cases of anti-Hu-associated PEM/sensory neuronopathy (SN) or type I antineuronal nuclear antibody (ANNA-1) (Dalmau et al., 1992). Other syndromes associated with PEM were elucidated by Dalmau and colleagues (Dalmau et al., 1999; Voltz et al., 1999) in their descriptions of anti-Ma1 and Ma2 and testicular cancer; and the collapsin response mediator protein-5 (CRMP5/Cv2) in association with thymoma (Antoine et al., 1995) manifesting symptoms and signs of limbic encephalitis (LE) and brainstem encephalitis and related motor features. Each with an intracellular target antigen target, the resultant histopathology of these antibodies generally consists of infiltrative cytotoxic (CD8+) T-cell destruction of neurons, with variable IgG and complement deposits in the CNS and dorsal root ganglia (DRG) (in the anti-Hu cases), and fewer helper (CD4+) T-cells, and generally absent CD20+ B-cells (Bernal et al., 2002). Two years before Guichard et al. (1956) introduced the term “paraneoplastiques” in an account of 3 patients with systemic carcinomas and subacute sensorimotor neuropathy, Henson et al. (1954) described a patient with subacute cerebellar degeneration and concomitant features of subacute motor neuronopathy (SMN) associated with occult breast carcinoma. Postmortem examination showed spinal cord anterior horn cell loss accompanied

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by focal lymphocytic inflammation, crescentic anterolateral cord demyelination sparing pyramidal tracts, and Wallerian motor nerve degeneration in the legs. In later studies of 8 women with ataxia, 6 also had eye movement abnormalities believed to be opsoclonus and myoclonus and found to harbor the antineuronal antibody, Ri or antineuronal nuclear antibody type 2 (ANNA-2) in association with known breast cancer or other gynecologic cancers (7 patients). The presence of the anti-Ri antibody, when present, identifies a subset of patients with paraneoplastic opsoclonus-myoclonus ataxia (POMA) syndrome most often associated with breast cancer (Luque et al., 1991). The clinicopathologic features of PCD displayed similar clinical heterogeneity and prominent motor features. The first cases reported in 1919 by Brouwer (1919) were mentioned in association with ovarian cancer but characterized clinically according to Brain et al. (1951) in a series of 12 literature and 4 cases of their own, manifesting subacute onset of ataxia, vertigo, dysarthria, and nystagmus prior to, during the course of, or after apparently successful cure of a known bronchial (three cases), ovarian (five cases), uterine (two cases), breast cancer (two cases). Pathological examination of affected brains uniformly revealed cerebellar atrophy with the destruction of Purkinje cells, variable loss of granule cells, and, in some cases, loss of basket cells (Henson and Urich, 1982). Several years later, Henson et al. (1954) described a 59-year-old woman with PCD and carcinomatous neuropathy and myopathy and concomitant features of SMN before the discovery of occult breast carcinoma. Postmortem examination showed spinal cord anterior horn cell loss accompanied by focal lymphocytic inflammation, crescentic anterolateral cord demyelination sparing pyramidal tracts, and Wallerian degeneration of motor nerves in the legs. Greenlee and Brashear (1983) and Giometto et al. (1997) described the Yo or anti-Purkinje cell cytoplasmic antibody 1 (PCA-1) as the cause of PCD demonstrating reactivity to both ovarian carcinoma nuclei and cerebellar Purkinje cell neurons. Although PCD is reported most frequently with carcinoma of the ovary and lung, additional cases occur with Hodgkin and non-Hodgkin lymphomas (HL, NHL), and carcinoma of the breast, uterus, stomach, colon, and larynx. These occurred as an isolated complication of malignancy or accompanied by other neural-specific autoantibodies and associated paraneoplastic syndromes outside the CNS such as Lambert–Eaton myasthenic syndrome (LEMS) (Takasugi et al., 2018; Wada et al., 2021). In 2000, Bien et al. (2000) and Mori et al. (2002) respectively described several patients with temporal lobe epilepsy (TLE) and amygdala-hippocampal mood disorders unrelated to neoplasm. The so-called

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nonparaneoplastic LE had already been recognized in patients with the motor disorder, stiff-person syndrome (SPS), associated with antibodies to glutamic acid decarboxylase (GAD) (Solimena et al., 1988). GAD65 was an important autoantigen in T1D, being highly expressed in the cytoplasm of pancreatic b cells. GAD-derived peptides were presentable by main histocompatibility complex (MHC) class I molecules and recognized by CD8+ cells on the surface of b cells (Panina-Bordignon et al., 1995). Activation of CD8+ GAD-specific T-cells further differentiated into memory cells suggesting a pathogenic role in T1D (Viglietta et al., 2002). However, only patients with very high titers of GAD were associated with LE (Malter et al., 2010), and they typically presented with recent-onset TLE and intrathecal secretion, defining a form of nonparaneoplastic LE. Other patients within the SPS spectrum harbored antibodies against other proteins of the GABAergic synapse, including amphiphysin and gephyrin, which were found to associate with lymphoma, a malignant cancer of the breast, colon, lung, and thymus (Murinson and Guarnaccia, 2008). Two groups of disorders emerged according to the location of the target antigen including neural-specific autoantibodies that recognized intracellular (IAg) and surface neuronal antigens (SAg). The former comprised predominantly onconeural antibodies Ri, Yo, Hu, Ma2, CRMP5/Cv2, and GAD useful in the designation of a specific PND, with the latter included voltage-gated potassium channel (VGKC) and N-methyl-D-aspartate (NMDA) (Graus et al., 2010a). Bien and colleagues (Bien et al., 2012) described qualitative and quantitative immunopathologic features of biopsy or postmortem brain tissue in 17 cases of autoimmune encephalitis (AE) associated with IAg vs SAgs noting higher CD8+/CD3+ ratio and more frequent appositions of granzyme-B-positive (GrB)(+) CD8+ cells to neurons, with associated cell loss in the IAg-onconeural group compared to those in the SAg group. The exceptions were GAD cases that had less intense inflammation and a relatively low CD8+/CD3+ ratio compared to IAg-onconeural cases. A role for T-cell-mediated neuronal cytotoxicity was found in LE associated with antibodies directed against IAg, whereas a complementmediated humoral immune mechanism was suggested in VGKC-complex encephalitis. There was an apparent absence of both mechanisms in NMDA receptor encephalitis. Bauer and Bien (2016) suggested that neurodegeneration in the brains of patients with antibodies against IAg was not simply induced by antibody reactivity with the target antigen, but rather by the inflammatory T-cells. To be pathogenic, the imputed antibody first had to transit the blood–brain barrier (BBB), then the target cell neuronal membrane to a location where it could bind the pathogenic intracellular antigen. Depending on

protein conformation and folding, the antigenic site might be readily accessible before inactivation and ensuing irreparable cell damage. It is difficult to imagine that an intracellular antibody could easily overcome each of these obstacles. Notwithstanding, in vivo studies revealed neuronal cell death due to infiltration with onconeural antibodies against putative IAg, while in vitro studies showed somewhat contradictory results, with earlier studies demonstrating accessed cultured neurons without damage (Hormigo and Lieberman, 1994) and later ones demonstrating induction of cell death after antibody uptake (Tanaka et al., 2004). A major concern in managing these disorders then, and now, has not only been the prompt treatment of the tumor, but the commencement of effective immunotherapy targeting mainly cytotoxic T-cells (Bataller and Dalmau, 2004). The earliest affected patients with VGKC-complex encephalitis were described by Brierley and colleagues in 1960. Three patients, all in the seventh decade of life, similar to the present patient, presented with focal temporal lobe seizures, neuropsychiatric, and memory disturbances, including one (Case 3) with neuropathic complaints. The patients progressed from stupor and coma to death over a mean of 8 months (range 3–14 months). Postmortem examination in all three showed an intense inflammatory reaction most severe in the medial parts of the temporal lobes without hemorrhage, necrosis or inclusion bodies. Although interpreted as a novel presentation of nonneoplastic subacute encephalitis, 2 patients were suggested to have a possible relation to cancer. Case 2 manifested had several enlarged mediastinal and hilar lymph nodes noted at postmortem examination which were infiltrated by oatshaped cells. The chest radiograph in Case 3 disclosed a shadow in the right hilum that was negative for cancer and at postmortem found to be fibrotic lymph nodes. Shortly afterward, Corsellis et al. (1968) coined the term LE noting a relation to bronchial cancer in 3 additional patients in the sixth to eighth decade of life, showing close clinicopathologic similarity to the cases described by Brierley et al. (1960). All 3 had subacute temporal lobe seizures, neuropsychiatric, and memory disturbances for 2 years before death, with resultant inflammatory lesions mainly in limbic gray matter sections of the brain, notably in medial temporal lobe structures of the uncus and amygdaloid nuclei, and in the hippocampal, cingulum, and dentate gyri. In addition, Case 2 had the removal of an undifferentiated nonmetastatic lung carcinoma 6 months after the onset of neurological symptoms, while 2 other patients had clinically unsuspected cancer at postmortem examination. Case 1 was found to have bronchial carcinoma restricted to a mediastinal lymph node without primary lesion, while Case 3 had an unsuspected oat cell

PARANEOPLASTIC MOTOR DISORDERS carcinoma infiltrating the main bronchi of both lungs and adjacent mediastinal nodes. More recently, the clinical phenotypes associated with autoantibodies to the VGKC-complex have been identified, ranging from peripheral nerve hyperexcitability (PNH) to Morvan syndrome (MoS), and LE and autoimmune epilepsy (Vincent et al., 2004; Irani et al., 2014). VGKC-complex antibodies were detected in a case of MoS (Liguori et al., 2001) and subsequently described in 2 patients with LE (Buckley et al., 2001). Both patients with LE were negative for typical paraneoplastic antibodies and had a near-complete recovery, including one with recurrent thymoma after plasma exchange, while the other patient recovered spontaneously without specific immunotherapy. Accordingly, the immunoprecipitation of VGKC-complexes links a number of clinical syndromes that might otherwise have remained separate. The past decade has witnessed the identification of antibodies to various CNS receptors-associated autoimmune neurological disorders directed at membrane SAgs. They include the NMDA receptor (NMDAR), the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), the metabotropic glutamate receptors (mGluRs), and type A and B g-aminobutyric acid (GABA) receptors (respectively GABAAR and GABABR). Although a minority of cases have been described with occult cancer, patients with receptor antibodies are often younger, they less frequently have malignancies, and in contrast to patients with classical paraneoplastic antibodies, the encephalitis of these patients improve with immunotherapy and, if present, treatment of the associated tumors. Many of the patients have LE with amnesia, disorientation, seizures, and psychological or psychiatric symptoms, however, those with NMDAR antibodies usually develop a more widespread form of encephalitis, often leading to a decrease in consciousness and requirement for long-term intensive care treatment. These autoantibodies bind directly to the synaptic or extrasynaptic receptors on the membrane surface and have direct effects on signal transduction in central synapses. These conditions are very important to recognize as the symptoms and complications can be fatal when not treated in time, whereas with immunotherapy many patients recover considerably. Serum autoantibodies to both NMDA and glycine receptors associated with clinicopathological syndromes of encephalitis in particular target synaptic-enriched regions of the hippocampus and cerebellum, sparing the cytoplasm and nuclei of neurons and neocortex can manifest treatment-responsive motor symptoms including rigidity, myoclonus, SPS, dyskinesia, autonomic instability, hypoventilation, and seizures respectively with a frequent underlying ovarian teratoma (Dalmau et al., 2008) or no underlying systemic neoplasm (Turner et al., 2011). Other

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treatment-responsive severe LEs manifest other novel neuropil antibodies, sparing the cytoplasm and nuclei of neurons, localized to neuronal and dendritic cell surface regions of high dendritic density or synaptic-enriched regions of the hippocampus or cerebellum (Ances et al., 2005).

EPIDEMIOLOGY Epidemiological trends of PNDs do not appear to be changing over time. Despite the elucidation of neuralspecific autoantibodies and their target antigens coupled with widely available commercial panels and the greater precision in tumor imaging (Scaravilli et al., 1999) symptomatic PNDs remain exceedingly rare, affecting less than 1% of patients with cancer with most of them targeting the central nervous system (CNS) (Darnell and Posner, 2003). However, there are several notable neuromuscular disorders with a motor expression that suggest an equally close relationship to cancer. Two neuromuscular junction (NMJ) disorders, the LEMS (Sculier et al., 1987) and myasthenia gravis (MG) (Lovelace and Younger, 1997) that respectively affect the presynaptic and postsynaptic NMJ, account for 3% of SCLC cases, and 15% of thymomas. The estimated frequency of thymoma in MG varies from 15% to 30%, increasing with age from 3% for individuals aged 20 years or younger, 12% for ages 21–45, and 35% for those aged 46 years or older. Although detection of thymoma most often follows the clinical diagnosis of MG, myasthenia may follow the detection and removal of the tumor in patients for up to 22 years. The often associated paradox of a severe clinical neurologic disability with a relatively indolent tumor especially over a long period suggests a host immune response that at the same time inflicts pervasive nervous tissue damage while inhibiting malignant tumor growth. Patients with both LEMS and thymoma have an increased tendency for associated autoimmune disorders including LE, neuromyotonia and peripheral neuropathy. Extrathymic neoplasms also occur with increased frequency including those of the breast, liver, lung, stomach, thyroid, lymphoproliferative cancers, and carcinoid tumors. Whereas LEMS and MG can occur separately with thymoma, and both LEMS and MG may at times occur together in the same patient, the presence of all three together has not been convincingly shown. Demyelinating peripheral neuropathy clinically affects up to 50% of patients in life with the osteosclerotic form of plasmacytoma manifesting polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes in POEMS syndrome (Brown and Ginsberg, 2019), and histopathologically at postmortem in lower motor neuron (LMN) forms of paraneoplastic motor neuron disease (MND) associated with HL and NHL. Patients with

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POEMS associated with osteosclerotic myeloma manifest hyperpathia and allodynia, however, atypical cases can present with prominent motor manifestations and acute ascending paralysis reminiscent of acute inflammatory demyelinating polyradiculoneuropathy due to motor conduction block (CB) (Guo et al., 2021). Patients with occult HL present challenges to nomenclature and etiopathogenesis and influence our concepts of cancer-related MND, motor neuropathy and neuronopathy (Schold et al., 1979; Younger, 2000) with uncertain epidemiology but a clear relationship to cancer. Rowland and Schneck (1963) described 2 young women with progressive limb weakness and wasting, and generally absent tendon reflexes, without fasciculation, Babinski signs, or sensory loss. One died after the removal of the HL tumor, and the other of progressive neurologic disease. At postmortem examination, there was anterior horn cell loss, gliosis, astrocytosis, and perivascular lymphocytic infiltration, with variably severe demyelination of the posterior roots and columns. In addition, the peripheral nerves of the first case were normal at postmortem examination, but variable demyelination and Schwann cell proliferation without axonal loss were found in the second case. Younger et al. (1991) broadened the concept of lymphoma-associated MND, demonstrating a greater heterogeneity than previously suspected. MND syndromes, including classic amyotrophic lateral sclerosis (ALS), occurred in both HL and NHL, before and after treatment of the underlying malignancy. While no specific clinical syndrome implies concomitant lymphoma, monoclonal paraproteinemia, increased protein concentration and oligoclonal bands in the cerebrospinal fluid (CSF) appear to increase the likelihood of detecting a lymphoma, even in those with classic ALS. Postmortem studies of peripheral nerves and roots in several patients so studied showed foci of demyelination, IgG and C3 complement deposits, and inflammatory cell infiltrates exceeding the minor abnormalities in ALS without lymphoma. Classical ALS is not a presenting syndrome of antiHu-associated PND, but up to 20% of patients exhibit signs and symptoms of LMN involvement (Dalmau et al., 1992). It is uncertain whether often disclosed electrophysiological and histopathological studies in patients with occult cancer, particularly SCLC (Elrington et al., 1991) represent true paraneoplastic manifestations. However one reported patient with wasting, weakness, and glove sensory loss to the wrists in the arms, pseudoathetosis, mild distal sensory loss in the feet and absent tendon reflexes was found to have epineurial and epimysial microvasculitis in the sural nerve and gastrocnemius muscle biopsy tissue (Younger et al., 1994) comprised of a predominance of T-cells and lesser number of B-cells.

An elevated serum anti-Hu IgG titer prompted the search for occult SCLC, which with successful treatment employing radiation therapy and chemotherapy led to a decline in the serum anti-Hu antibody titer that paralleled improvement and later remission of the PND (Dalmau et al., 1991).

CLINICAL SYNDROMES Paraneoplastic cerebellar degeneration This disorder is characterized by the subacute development of cerebellar dysfunction that initially manifests with dizziness, nausea, vomiting, dysarthria, oscillopsia, and diplopia. Within a few weeks or months, the patient is incapacitated with a pancerebellar syndrome often accompanied by a superimposed tremor of the head and extremities. The diagnosis of PCD should be suspected in any patient older than 50 years with subacute development of cerebellar dysfunction. The antibodies most typically associated with PCD include anti-Yo, anti-Tr, and voltage-gated calcium channel (VGCC) antibodies, although any of the well-characterized antibodies may be found (Shams’ili et al., 2003). Patients with Yo antibodies are typically postmenopausal women, of whom 75% have cancer of the ovary and 20% cancer of the breast (Peterson et al., 1992). Patients with Tr antibodies are usually young men with HL and rarely NHL, and symptoms may develop before the diagnosis of the lymphoma or when the tumor is in remission (Bernal et al., 2003). Patients with VGCC antibodies can harbor an occult SCLC, and about half of these patients will also have LEMS (Mason et al., 1997; Graus et al., 2002). Antibodies against mGluR1 have been identified in a few patients with idiopathic or paraneoplastic cerebellar ataxia associated with HL (Shams’ili et al., 2003). Autopsy studies of patients with PCD show complete or near-complete loss of Purkinje cells with relative preservation of other cerebellar neurons explaining why a response to therapy is most often minimal. However, some patients who receive antitumor treatment with or without immunosuppressive therapy may stabilize or improve, especially if treatment is started while symptoms are still progressing. Patients who undergo treatment for the underlying tumors live longer than those with untreated cancers. Some patients with Tr and mGluR1 antibodies will improve with immunotherapy.

Paraneoplastic encephalomyelitis Among 200 patients with anti-Hu-associated PEM described by Graus and colleagues (Graus et al., 2001), neurological dysfunction was confined to one area of the nervous system in 60 patients (30%), predominantly SN (48 patients) with isolated cases of cerebellar

PARANEOPLASTIC MOTOR DISORDERS ataxia, LE, brain stem encephalitis, myelopathy, intestinal pseudo-obstruction, and parietal encephalitis. The remaining 140 (70%) had multifocal involvement giving rise to several syndromes that can occur alone or in combination. Motor involvement in PEM is insidious, often in the absence of symptoms of CNS dysfunction, and overshadowed either by the severity of the associated DRG or ANS deficits so noted altogether in 16.5%. Paraneoplastic encephalomyelitis may be associated with virtually all types of tumors; however, in more than 75% of patients the underlying tumor is a SCLC; such patients usually have high titers of anti-Hu antibodies in serum and CSF (Graus et al., 2001). Less frequently, anti-CRMP5 antibodies with or without anti-Hu antibodies are found in association with SCLC, thymoma, renal, or lymphoma (Graus et al., 2001; Yu et al., 2001). Anti-amphiphysin antibodies, which often associate with the paraneoplastic SPS, also occur with PEM (Ishii et al., 2004). Motor neuron dysfunction is a predominant symptom in 20% of patients with anti-Hu-associated PEM and may be the presenting symptom (Dalmau et al., 1992). Symptoms usually start with a proximal loss of strength in the arms, sometimes in an asymmetric pattern. Weakness of neck extensor muscles has been reported in a few patients. Muscle wasting and fasciculation are common. Contemporaneous weakness and sensory neuronopathy may initially suggest Guillain–Barre syndrome (GBS), and when spinal cord involvement predominates, a diagnosis of atypical MND may be considered until other areas of the nervous system become involved (Forsyth et al., 1997). Patients with PEM and CRMP5 antibodies present with prominent choreic movements that may initially be asymmetric or unilateral (Vernino et al., 2002; Samii et al., 2003) with later cerebellar ataxia, uveitis, optic neuritis, and peripheral symptoms due to sensorimotor axonal neuropathy (Yu et al., 2001). Paraneoplastic encephalomyelitis is often refractory to treatment; however, there are patients who respond to treatment of the tumor, immunotherapy including corticosteroids, intravenous immunoglobulin (IVIg) therapy or rituximab, and often both, especially if treatment is instituted while symptoms are still progressing. Treatment responders should be considered for the maintenance of B-cell and T-cell immunosuppressive therapy.

Paraneoplastic limbic and brainstem encephalitis Patients with LE develop short-term memory loss with relative preservation of other cognitive functions. Antibodies usually found in paraneoplastic limbic encephalitis include anti-Hu, anti-Ma2, and anti-CRMP5 antibodies. In those with anti-Hu or CRMP5 autoantibodies, limbic encephalitis is a fragment of PEM with a presentation characteristic of that disorder. Detection of anti-Ma2

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antibodies in young men usually associates with testicular neoplasms while the commonest neoplasm of elderly men and women is non-SCLC (Mathew et al., 2007). Patients with anti-Ma2 antibodies often manifest brainstem encephalitis (Rosenfeld et al., 2001) with several types of motor disturbances, including Parkinsonism, severe hypokinesis, and gaze paralysis (Matsumoto et al., 2007). Upward and downward gaze can be affected early, along with forceful jaw opening and closing and involuntary masticatory movements that result in lip and tongue injuries (Dalmau et al., 2004). Involuntary tremor is uncommon, but hypokinesis, hypophonesis, and rigidity commonly occur. Brainstem symptoms may progress in a rostral-to-caudal direction involving cranial nerve nuclei and cerebellar and horizontal gaze neural pathways (Hoffmann et al., 2008). The disorder may be confused with Whipple’s disease and progressive supranuclear palsy (Castle et al., 2006). Prompt diagnosis of antiMa2 encephalitis is important because up to one-third of patients respond to immunotherapy and specific treatment of the tumor. CRMP5 antibodies were first designated anti-CV2 (Honnorat et al., 1996) based upon the staining properties of serum samples from patients with PNDs that labeled a particular subpopulation of glial cells in adult rat brain sections in particular the cytoplasm and processes of oligodendrocytes in the brain stem, spinal cord, and cerebellar white matter that were also negative for anti-Hu, anti-Ri, or anti-Yo antibodies. The antigen was later identified as CRMP5, a protein involved in neurite development (Hotta et al., 2005). Predominantly motor PNDs commonly associated with CRMP5 antibodies include LEMS, LE, EM, cerebellar ataxic syndrome and peripheral neuropathy. Underlying cancers are identified in three-quarters of cases of CRMP5 antibody-associated PND (Camdessanche et al., 2006).

NMDA receptor encephalitis Anti-NMDA receptor encephalitis most commonly occurs in young women and children (Florance et al., 2009; Dalmau et al., 2011). Patients initially develop psychiatric symptoms and memory loss that progresses to seizures, decreased consciousness, autonomic instability, and frequent hypoventilation necessitating intubation. Movement disorders occur in up to 80% of patients, including orofacial dyskinesia, choreoathetoid movements of the limbs, dystonia, rigidity, and opisthotonic postures (Kleinig et al., 2008; Dalmau et al., 2011). Such movements are described as kissing, pouting, and fish- and rabbit-like motions with tongue protrusion and rolling, which when synchronous with forceful jaw opening and closing frequently results in tongue injury. The limb movements present with a dancing, milking,

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bicycling, floating, flailing, or pill-rolling appearance, often accompanied by pelvic thrusting (Iizuka et al., 2008). Some of the movements may suggest a relation to seizures, but electroencephalography monitoring generally fails to confirm an epileptogenic basis. The pathogenic antibody is directed against cell surface epitopes of the NR1 subunit of the NMDA receptor regardless of the presence of an associated tumor. Whether the disorder is paraneoplastic depends on the age of the patient, with benign or malignant unilateral or bilateral ovarian teratomas found in more than one-half of women older than 18 years, but in less than 15% of women younger than 14 years (Dalmau et al., 2011). About 5% of men will have a tumor, usually a testicular germ-cell tumor. Prompt treatment with corticosteroids, IVIg, or plasma exchange (PE) alone or in combination with the removal of the tumor often results in substantial neurologic recovery (Dalmau et al., 2008). Patients refractory to these treatments may respond to second-line therapy with cyclophosphamide or rituximab (Ishiura et al., 2008). Relapses occur in one-quarter of patients, most often in patients without a tumor or whose tumor was not removed.

Paraneoplastic stiff-person syndrome SPS is characterized by progressive rigidity involving axial and proximal limb muscles with muscle ache and spasm triggered by sensory and emotional stimuli. The rigidity consists of a board-like contraction of the affected muscles that improves during sleep and with benzodiazepines. Nonparaneoplastic SPS may be associated with antibodies against GAD, while paraneoplastic SPS is often associated with antibodies to amphiphysin (De Camilli et al., 1993; Raju et al., 2005). The most common cancers are breast, lung, colon, and HL. Some patients with cancer, mostly SCLC, develop progressive encephalomyelitis with rigidity and spinal myoclonus (PERM) which is likely a variant of SPS (Meinck and Thompson, 2002) with additional brainstem dysfunction. Some patients with PERM have antibodies to the a-1 subunit of the glycine receptor (GlyR); however, none to date have had associated cancer (Mas et al., 2011). Paraneoplastic SPS may respond to immune therapy and treatment of the tumor and symptomatically to benzodiazepine medication and baclofen. IVIg is useful in patients with nonparaneoplastic SPS and is likely effective in the paraneoplastic form of the disorder.

Paraneoplastic myelopathy Paraneoplastic myelopathy usually occurs in association with neurologic dysfunction of other levels of the neuraxis. Isolated paraneoplastic myelopathy is rarely described in patients with lung or breast cancer. The more

commonly associated antibodies are antiamphiphysin, CRMP5, and Hu. Onset is insidious or subacute and usually precedes the detection of cancer. In one series, 23% of patients were initially diagnosed with primary progressive multiple sclerosis, in part due to the presence of CSF oligoclonal bands (Flanagan et al., 2011). This series found that the presence of symmetric longitudinally extensive tract or gray matter-specific changes on spinal magnetic resonance imaging was characteristic of paraneoplastic myelopathy. Systemic immunotherapy and specific treatment of the underlying tumor may provide mild improvement or stabilization, but the majority of patients fail to respond and become wheelchairdependent within 1 year of onset.

Paraneoplastic opsoclonus-myoclonus ataxia In children, POMA occurs in association with neuroblastoma with the neurological symptoms preceding the tumor diagnosis in 50% of cases. In adults, several underlying tumors have been reported, with SCLC and cancers of the breast and ovary most common. Most of the well-characterized paraneoplastic antibodies have been reported in isolated cases, but the majority of patients, both adults and children, are antibody negative (Flanagan et al., 2011). Some adult patients, in particular those with SCLC, and 5% of children with neuroblastoma have anti-Hu antibodies while a small subset of adults, predominantly those with breast and ovarian cancer, have anti-Ri antibodies (Casado et al., 1994). Such patients have additional motor symptoms and signs of the brainstem and cerebellar dysfunction, including truncal and gait ataxia, vertigo, nausea, dysphagia, ocular paresis, axial rigidity, trismus, laryngeal spasms (Pittock et al., 2003). Affected children with neuroblastoma have uncharacterized antibodies against postsynaptic or cell surface antigens located on cerebellar granular cells (Blaes et al., 2008). Children with neuroblastoma-associated POMA respond to tumor treatment along with immunomodulatory therapies such as prednisone, adrenocorticotropic hormone, IVIg, or rituximab. In many cases, the responses are partial and the children are left with residual behavioral, psychomotor, and sleep disorders. Adults with POMA are less responsive to immunotherapy, which nonetheless may be helpful, but improvement is mild or not sustained unless the tumor is treated (Erlich et al., 2004). Those whose tumors are treated promptly have better neurological outcomes than those whose tumors are not treated, in which case the disorder often progressed to severe encephalopathy and death (Bataller et al., 2001).

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Paraneoplastic motor neuron syndromes

Subacute motor neuronopathy

Simple paradigms for the early diagnosis and classification of clinical MND syndromes in life are based on the presence of LMN and upper motor neuron (UMN) signs and other qualifiers (Younger et al., 1990). Such paradigms have also been useful in highlighting the MND syndromes most associated with cancer for example, in those with essentially pure LMN disease and lymphoproliferative malignancies (Younger et al., 1991). A report of 26 patients with both MND and lymphoproliferative cancers are seen at a single institution between 1983 and 1995 with postmortem data, combining five series (Younger et al., 1991; Rowland et al., 1992, 1995; Louis et al., 1993; Sanders et al., 1993) comprised 23 patients with definite or probable UMN signs and 3 with LMN signs implying degeneration of the corticospinal tracts so noted in postmortem examination in association with Waldenstrom macroglobulinemia, multiple myeloma, chronic lymphocytic leukemia, follicular cell lymphoma, and HL. In all but one patient, the cause of disability or death was neurologic. Lymphoproliferative cancer was confined to bone marrow in 14 patients; 8 of 14 with monoclonal paraproteinemia. One patient had tumor discovered at autopsy. Treatment of cancer in 20 patients resulted in neurologic improvement in 1 patient and arrest of MND in another; both had LMN signs alone. The frequency of lymphoproliferative disease in MND has never been studied in a population or in a case–control analysis, but it seems to be 2.5%–5% which is much higher than the 0.5% in one autopsy series, which is undoubtedly an overestimate of that in the general population (Hashimoto et al., 1957). In contrast to the predominant LMN disorder observed in patients with lymphoma-associated MND, Forsyth and colleagues (Forsyth et al., 1997) identified a group of patients with the initial clinical diagnosis of primary lateral sclerosis (PLS) in association with breast cancer. Three of 5 patients developed concomitant involvement of LMNs, leading to the alternative diagnosis of ALS within a month (2 patients) to 2 years (1 patient) after onset, whereas 2 others remained with UMN involvement. The possibility that PLS could be a paraneoplastic disorder in either gender has not previously been considered. However, in retrospect, the observations of Younger et al. (1988) a decade earlier seemed relevant because among 3 men with autopsy-proven PLS (defined as the presence of isolated bilateral degeneration of corticospinal tracts), 1 had unsuspected metastatic adenocarcinoma of the lung at postmortem examination. Two of 13 living patients with PLS who were also studied and followed prospectively for up to 5 years were women, but none were screened for breast cancer.

Affected patients with PND harboring a specific antibody with an incongruous neurological disorder should prompt a laboratory investigation for an overlapping PND. This is exemplified in a personal anecdote of a 49-year-old woman referred to me with malignant breast cancer who while receiving curative surgery, radiation therapy, and chemotherapy was found to have nystagmus on bilateral gaze, saccadic eye movements, startle myoclonus, and cataplexy. An Ri (ANNA-2) antibody was identified in the serum and CSF without other paraneoplastic autoantibodies. This was followed by asymmetric lower limb weakness, wasting, fasciculation, brisk reflexes, ankle clonus, and Babinski signs indicative of both UMN and LMN signs. Electrodiagnostic studies showed normal motor and sensory conductions with active spontaneous activity in the legs but not in the arms. The patient’s serum and CSF bore the hallmark of specific tumor and CNS neuronal reactivity to Nova (Younger et al., 2013) reacting with mouse cerebellar neurons and staining embryonic mouse ventral spinal cord. A 1:100 dilution of CSF reacted in a restricted manner with CNS spinal cord neurons. Patient antisera reacted with the 55 kDa antigen present in tumor nuclei and to the Nova1 and Nova2 genes. The binding activity of the Nova (Ri) onconeural antigen to motor areas of the ventral brainstem and spinal cord has been studied in antisera from patients with POMA syndrome (Buckanovich et al., 1996) and in an experimental murine model (Buckanovich et al., 1993). In the same way that the production of Ri antibodies inhibits Nova1–RNA interactions and appears to be the cause of POMA, this same antibody present in the serum and CSF of this patient was the likely cause of paraneoplastic SMN. Moreover, the association between Ri and SMN suggested that SMN may lie in the spectrum of POMA. Since the classical descriptions of SMN with occult breast cancer by Henson et al. (1954); SMN in HL by Rowland and Schneck (1963), Walton et al. (1968), and Schold et al. (1979); and in NHL by Younger et al. (1991); additional patients with SMN and lymphoproliferative cancers (Bauer et al., 1977; Nagao et al., 1994; Gordon et al., 1997; Flanagan et al., 2012; Kleinschmidt-DeMasters et al., 2021), thymoma (Stoll et al., 1984), and renal cell carcinoma (Evans et al., 1990) have been described. Early and accurate diagnosis of MND provides the best chance of a successful outcome and enables the patient and caregivers to plan the future and participate in therapeutic decisions. This is even more imperative in possible paraneoplastic MND wherein extensive testing and referrals can delay diagnosis and the initiation of early

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management. Patients with atypical features of MND such as predominant LMN signs, persistent sensory symptoms, and systemic complaints are probably the most appropriate candidates for further study of a possible PND incorporating selective onconeural antibody screening with the neurological testing battery. In that regard, detecting high either serum titers of antiganglioside or myelin-associated glycoprotein antibodies in the presence of demyelinating polyneuropathy and motor CB, an elevated total protein, pleocytosis, abnormal cytology or oligoclonal bands in the CSF; or inflammation in a cutaneous nerve or muscle tissue biopsy specimen would appear to justify the search for occult systemic cancer since treatment might benefit both the tumor and a possible PND.

Paraneoplastic sensory neuronopathy Paraneoplastic sensory neuronopathy most commonly occurs in association with PEM in patients with SCLC and anti-Hu antibodies, but may be an isolated syndrome in some cases. Patients present with subacute and often asymmetric onset of numbness or pain that initially may mimic radiculopathy or multifocal neuropathy that progresses to involve all extremities and all modalities of sensation. As a result, patients develop severe sensory ataxia and dystonic or pseudoathetoid postures of the extremities. The disorder is often refractory to treatment; however, patients whose tumors are treated with or without concomitant immunotherapy are more likely to have symptom stabilization or improvement than those whose tumors are not treated (Graus et al., 2001). In the absence of a tumor or if tumor therapy is not feasible, immunotherapy is warranted as some patients may have transient responses.

Guillain–Barre syndrome Some patients with NHL and solid tumors can develop GBS, but the small number of cases precludes distinguishing paraneoplastic pathogenesis (Vigliani et al., 2004). Neurologic symptoms have been reported during active disease, in remission, and in some patients before cancer relapse. Such patients have the same response to PE and IVIg as those with idiopathic GBS. Patients with hematopoietic disorders treated with bone marrow transplants are at increased risk of GBS. Several pathogenic factors have been considered, including iatrogenically suppressed T cell function, humoral factors, graft-vs-host disease, and cytomegalovirus infection.

Subacute and chronic sensorimotor neuropathy In patients with cancer, peripheral neuropathy is common, but a paraneoplastic origin is rare. When it does

occur, it is most commonly associated with lung cancer. The onset of neuropathy usually follows the diagnosis of cancer but may precede it for several years (Vigliani et al., 2004). Most patients present with a distal symmetric polyneuropathy characterized by weakness, wasting, sensory loss, and decreased deep tendon reflexes that slowly worsen over the course of the disease with rare cranial nerve involvement. Neurologic symptoms may rarely stabilize, but more often slowly worsen or progress in a remitting or relapsing course. Some patients harbor anti-CRMP5 antibodies alone or combined with anti-Hu antibodies. In patients with sensorimotor neuropathy, the presence of anti-Hu antibodies indicates that the sensory deficits derive from DRG involvement. Treatment with corticosteroids or IVIg may lead to neurological improvement, particularly when demyelinating features predominate. Up to 10% of patients with peripheral sensorimotor neuropathy of unknown etiology have a monoclonal gammopathy. Plasma cell dyscrasias associated with peripheral neuropathy include monoclonal gammopathy of uncertain significance, multiple myeloma, Waldenstrom macroglobulinemia, cryoglobulinemia, monoclonal gammopathy with solid tumors, monoclonal gammopathy with angiofollicular lymph node hyperplasia (Castleman disease), and the combination of peripheral neuropathy, organomegaly, endocrinopathy, M protein, and skin changes of so-called POEMS syndrome.

Neuromyotonia and Morvan syndrome PNH is characterized by muscle cramps, stiffness, myokymia, fasciculation, and delayed muscle relaxation or neuromyotonia. It is often found in association with sensorimotor polyneuropathy and in patients with thymoma and SCLC. A subgroup of patients with neuromyotonia have antibodies to contactin-associated protein-like 2 (Caspr2) and in some instances, additional involvement of the CNS with cognitive impairment, memory loss, hallucinations, seizures, and autonomic dysfunction (Irani et al., 2010; Lancaster et al., 2011). The combination of neuromyotonia and CNS dysfunction is termed Morvan syndrome. Anti-Caspr2-associated syndromes occur with or without an associated tumor, usually thymoma. Patients with Caspr2-associated symptoms may have other immune-mediated disorders such as MG with acetylcholine receptor (AChR) or muscle-specific tyrosine-kinase receptor antibodies. The combination of symptoms related to neuromyotonia and those due to other autoimmunities such as fasciculation and muscle atrophy has resulted in some patients with Caspr2 antibodies being diagnosed with atypical MND. The detection of Caspr2 antibodies is therefore important as the associated symptoms often respond to immunotherapy.

PARANEOPLASTIC MOTOR DISORDERS

Lambert–Eaton myasthenic syndrome About 60% of patients with LEMS have an associated SCLC that is usually detected within 2 years of the onset of neurologic symptoms (Titulaer et al., 2008). Tumors other than SCLC are rare, but lymphomas have been reported in some patients. In the majority of patients, the first symptom is proximal lower extremity weakness. Less frequently, presenting symptoms include generalized weakness, autonomic dysfunction, aching, and stiffness of muscles. Autonomic dysfunction eventually affects 80% of patients and includes dry mouth, erectile dysfunction, constipation, and blurred vision. Cranial nerve involvement as manifested by diplopia, ptosis, slurred speech, and dysphagia is commonly mild or transient. Antibodies to VGCC are found in almost all patients with paraneoplastic and nonparaneoplastic LEMS while 10% of nonparaneoplastic LEMS patients have no detectable antibodies. The presence of antibodies to SOX1 is strongly associated with SCLC and therefore these antibodies are markers for paraneoplastic LEMS (Sabater et al., 2008; Titulaer et al., 2009). A simple clinical scoring system based on age, weight loss, smoking, Karnofsky performance status, presence of bulbar symptoms, and erectile dysfunction calculated within 3 months of LEMS onset helps distinguish cancer- and noncancerassociated LEMS patients (Titulaer et al., 2011). Scores directly correlate with increased risk of SCLC such that patients with the lowest scores have little to no risk of SCLC, while those with higher scores have close to 100% certainty of SCLC. In patients with paraneoplastic LEMS, treatment of the tumor usually results in improvement of the neurologic disorder. Plasma exchange and IVIg can lead to short-term benefits in those with acute deterioration, whereas long-term improvement can occur with maintenance 3,4-diaminopyridine, a drug that enhances the release of ACh, or immune suppression with corticosteroids, azathioprine, and cyclosporine. Acute worsening of neurologic symptoms usually heralds tumor recurrence.

LABORATORY EVALUATION Once the clinical suspicion for a PND is present, the next most important step in the diagnosis is to screen the blood and CSF for the presence of appropriate antineuronal specific autoantibodies. Clinicians and research scientists unfamiliar with PNDs should not be daunted by the lack of uniform nomenclature for some of these antibodies as many were originally named for the first two letters of the surname of the index case (Hu, Ri, Yo). One prevailing nomenclature is based on immunostaining criteria (Lennon, 1994); another employs the antibody and

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antigen characteristics using both immunohistochemistry and Western blot techniques (Dalmau and Posner, 1994). Notwithstanding, each terminology is specific to the associated neurologic disability and PND. The identification of one or more of these antibodies and their target neural antigens leads to the early diagnosis of occult cancer and in turn, supports the concept of the immunopathogenic basis of the PND. While there may be some overlap, each of the neural-specific autoantibodies is associated with a narrow spectrum of clinical syndromes and a relatively restricted subgroup of cancers. Failing to detect the antigen in the cancer of a patient with paraneoplastic antibodies should prompt a search for second cancer (Graus et al., 2001). The CSF of patients with an active and progressing PND show mild pleocytosis and elevation in the total protein and IgG level that may be a clue to the underlying etiopathogenesis. [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) combining structural and functional imaging is the preferred imaging study to detect occult cancer. In a cohort of 40 patients with clinically suspected PND, FDG-PET was associated with an overall sensitivity and specificity of 100% 97.3% for PND, with 80% positive predictive and 100% negative predictive values respectively (Antoine et al., 2000). This compares with a sensitivity and specificity of 50% and 100%, respectively for conventional body CT imaging, and 50% and 89% in the same cohort respectively, for a standard serum panel of screening onconeural antibodies (anti-Hu, anti-Ma2, anti-Yo, anti-Ri, anti-CV2, and antiamphiphysin) in the diagnosis of PND.

IMMUNOPATHOGENESIS PND is virtually always immune-mediated according to a mechanism that begins with the ectopic expression of an antigen by the occult tumor that is normally expressed exclusively in the nervous system. Some such onconeural antigens are also expressed in the normal testis, which like the brain is an immunologically privileged site. The tumor antigen is identical to the neural antigen (Carpentier et al., 1998), however, for unknown reasons, the immune system identifies it as foreign and mounts an immune attack against it that may inhibit the growth of the tumor and in a few instances obliterate it. As secreted antibodies and cytotoxic T-cells specific for the onconeural antigen are insufficient to cause the neurologic disease unless it crosses the BBB and reacts with neuronal targets, it is unsurprising to detect higher titers of the specific antibody in the CSF compared to circulating total serum IgG indicating local synthesis in the CNS presumably by intrathecal B-cells (Furneaux et al., 1990a).

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Dalmau et al. (1991) who investigated the causal role of anti-Hu IgG performed immunohistochemical studies of the brain and SCLC tumors of affected patients demonstrating IgG bound to the nuclei of neurons and the cytoplasm of glial cells, and neuropil deposits of IgG; control brains failed to show anti-Hu IgG, and brains without a known PND showed IgG in immediate perivascular areas and in very limited neuropil deposits. Human and experimental animal models suggest that the PND cannot be attributed to the infrequency of expression of the relevant encoded tumor antigens or to mutations in the genes encoding these antigens. For example, molecular analysis of the HuD gene encoding the PEM antigen in human lung cancer cell lines (Carpentier et al., 1998) shows that it is not mutated and that its expression highly correlates with tumor cell types displaying neuroendocrine features. This suggests that HuD is not involved in the etiology of lung cancer but may be involved in determining neuroendocrine cell development and differentiation in the tumor cell lines that express it. Yet it is still not known why a small number of SCLC patients mount a profound immune response to the HuD product, while almost all SCLCs express HuD. In Hu-D-associated PND, it is believed that sequestration of the onconeural antigen from immune surveillance in the CNS results in a lack of immune tolerance to these proteins when they are ectopically expressed in tumor cells. Yet even if antigens are indeed recognized as foreign by the immune system, it is not clear why all patients in whom the antigen is present in the tumor mount an immune attack. Moreover, while the anti-Hu antibody is found in about 15% of patients with SCLC, and usually at low titer, paraneoplastic syndromes associated with high titer antibodies occur in far fewer than 1% of patients with SCLC. There are two possible explanations (Posner and Dalmau, 1995). The first is that the target antigen is recognized as foreign only by individuals with specific haplotypes or that the presenting antigen is mutated in affected PND cases; however, these assertions lack substantiation. A second explanation is that the antigen is recognized as foreign by all haplotypes but appropriately expressed on the surface of tumor cells in only a small minority of patients. Many cancer cells do not express MHC class I antigens on their surface and, thus, would not be able to present the antigen to the immune system. In patients with paraneoplastic syndromes tumor cells may express MHC class I on their surface whereas in patients without paraneoplastic syndromes the tumors do not (Dalmau et al., 1995). These findings are convincing in SCLC-associated PEM, but more evidence to confirm these findings of differential tumor expression of MHC in other PNDs is needed.

In other investigations (Corradi et al., 1997) the ectopic expression of the antigen product of the cdr2 gene by ovarian tumors in PCD was associated with a robust immune response; while cdr2 mRNA is expressed in almost all tissues, the protein is expressed only in the brain and testis. The tissue-specific expression of cdr2 appears to be regulated at a posttranscriptional level, and as the brain and testes are considered to be immuneprivileged sites, its pattern of expression is compatible with the immunopathogenesis of PCD. In most PNDs with associated neural-specific antibodies, the antigen has been identified and the gene coding for the antigen has been cloned and sequenced (Table 11.2). Some of the antigens are expressed by all tumors of a given histologic type, whether or not the patient mounts an immune response against them while other tumors rarely express such antigens unless cancer causes a PND.

TREATMENT AND PROGNOSIS The simple treatment approach to PNDs which commences with the removal of the source of the tumor antigen by surgical resection cancer, radiation therapy and/or chemotherapy (Croteau et al., 2001; Vigliani et al., 2001) is generally coupled with immunomodulatory therapy employing PE and IVIg or immunosuppressive medication (Bain et al., 1996; Keime-Guibert et al., 2000). A relentless progression despite treatment suggests the contribution of additional factors in determining the ultimate prognosis including the participation of activated cytotoxic T-cells that recognize onconeural antigens, and the inextricable role of these antigens, in neuronal survival. Cytotoxic T-cells specific for the onconeural antigen cdr2 in the blood are the puted effectors of tumor-mediated Purkinje cell degeneration that occur in association with CD3+ ab T-cells in the CSF, especially in cases of active/progressive PCD (Albert et al., 2000). These cytotoxic T-cells, which are capable of killing targets expressing cdr2 on major MHC class I molecules (Albert et al., 1998) including intracellular proteins presented via small peptide fragments, provide a ready mechanism for immunity to PND-expressing tumor cells and neuronal target cells. The wide expression of Hu and cdr2 antigens respectively in the general population of SCLC and gynecologic cancers (Darnell, 1999; Darnell et al., 2000) underscores the importance of understanding the immune mechanism for tumor recognition in PND. The histopathologic features of tumors in association with PND differ from those without a PND by the presence of inflammatory cells (Peterson et al., 1992; Rosenblum, 1993; Cooper et al., 2001) and a more favorable prognosis (Altman and Baehner, 1976; Maddison et al., 1999; Rojas et al., 2000) that

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Table 11.2 Neural-specific autoantibody paraneoplastic neurological disorders Neuronal reactivity

Ag site

Cloned gene

Anti-Hu (ANNA-1) (Posner, 1994; Voltz et al., 1997) Anti-Ri (ANNA-2) (Buckanovich et al., 1996) Anti-Yo (PCA-1) (Furneaux et al., 1990b; Furneaux et al., 1989) Anti-Tr (Graus et al., 1997b) Anti-CRMP5 (Anti-Cv2) (Honnorat et al., 1996; Sabater et al., 2016) Anti-Ma1 (Dalmau et al., 1999)

Nucleus, cytoplasm Nucleus, cytoplasm PC cytoplasm

IAg

ELAVL4

IAg

NOVA1

IAg

PC cytoplasm Oligo, cytoplasm PC, nucleoi, cytoplasm

Anti-Ma2 (Voltz et al., 1999) Anti-GAD65 (Arino et al., 2015) VGCC-complex (Graus et al., 2002)

Autoantibody

Locus

Tumor

PND

1p33p32.3 14q12

SCLC

PEM/SN

B, G, L, Bl

POMA

Xq27.1

Ov, B, L,

PCD

IAg IAg

CDR34, CDR62 DNER CRMP5

2q36.3 2p23.3

HL SCLC, Thy

PCD PEM, PCD

IAg

Ma1

14q24.3

BSE, PCD

Subnucleus Cytoplasm Surface proteins

IAg IAg SAg

Ma2

8p21.2

CASPR2

Anti-NMDAR (Dalmau et al., 2007, 2008) Anti-mGluR1 (Nicoletti et al., 2011; Sillevis Smitt et al., 2000) Anti-mGluR5 (Nicoletti et al., 2011; Spatola et al., 2018) Anti-GABABR (Hoftberger et al., 2013) Anti-AMPAR (Graus et al., 2010b)

NR1 subunit NMDAR PC, Olf, Hippocampus Hippocampus, Str Hippocampus Hippocampus

SAg

GRIN1

9q34.3

SAg

GRM1

6q24.3

Sag

GRM5

SAg SAg

GABBR1 GRIA1

11q14.2q14.3 6p22.1 5q33.2

T, L, B, Colon, Par T L, Thy SCLC, Thy, B, P OvT, T, B, Thy, L HL, B, Thy, P HL, SCLC

Anti-Amphiphysin (Saiz et al., 1999)

Presynaptic nerve Presynaptic NMJ

AMPH

7p14.1

Anti-VGKC (Lennon and Lambert, 1989)

SCLC SCLC, Thy, L, B B, SCLS

CACNA1A 19p13.13 SCLC

LE, BSE LE, E, CA, POMA BSE, FBS LE SubCerebellarAtax BSE, LE LE LE SPS, PEM LEMS

AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AMPH, amphiphysin; B, breast; BSE, brainstem encephalitis; CA, cerebellar ataxia; CASPR, contactin-associated protein 1, Paranodin; CDR2, cerebellar degeneration-related autoantigen 2; CRMP5, collapsin response mediator protein 5; DNER, delta/notch-like epidermal growth factor-related receptor; E, epilepsy; ELAVL4, ELAV-like RNA-binding protein 4; FBS, faciobrachial seizure; GABABR, g-aminobutyric acid receptor; GAD, glutamic acid decarboxylase; GRIN1, glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 1; Hipp, hippocampal; HL, Hodgkin lymphoma; IAg, intracellular antigen; L, lung; LE, limbic encephalitis; LEMS, Lambert–Eaton myasthenic syndrome; LGI1, leucine-rich gene, glioma-inactivated, 1; Ma1, paraneoplastic ma antigen 1; NMDA, N-methyl-D-aspartate receptor; NMJ, neuromuscular junction; NOVA1, Nova alternate splicing regulator 1; Olf, olfactory; Oligo, oligodendrocytes; Ov, ovarian; OvT, ovarian teratoma; P, prostate; Par, parotid; PC, Purkinje cell; PCD, paraneoplastic cerebellar degeneration; PEM/SN, paraneoplastic encephalomyelitis/sensory neuronopathy; POMA, paraneoplastic opsoclonus-myoclonus ataxia; SAg, surface antigen; SCLC, small cell lung cancer; SPS, stiff-person syndrome; Str, striatum; SubCerebellarAtax, subacute cerebellar ataxia; T, testicular; Thy, thymus. 162 kDa major species antigen (34 kDa minor species antigen).

may not simply represent the detection of occult cancer at an earlier stage. Patients with low titers of anti-Hu antibodies without a PND often have a more limited SCLC than those without antibodies, and a more favorable response to chemotherapy (Dalmau et al., 1990; Graus et al., 1997a). In fact, a dominance of CD8-positive T-cells in the brain infiltrates patients with antibodies (to Yo, Hu, and Ma) (Fig. 11.1) (Jean et al., 1994; Verschuuren et al., 1996; Giometto et al., 1997; Dalmau et al., 1999; Blumenthal et al., 2006; Dauvilliers et al., 2013). The

probable roles of cytotoxic T-cells in neuronal death in these paraneoplastic cases are also documented in studies that showed that the infiltrating T-cells possess cytotoxic granules and are in close apposition to neurons (Fig. 11.1) (Bernal et al., 2002; Blumenthal et al., 2006). In paraneoplastic Hu and Ma2 antibody autopsy cases, cytotoxic T-cells release granzyme B (GrB) on the surface of neurons and CD107a on the surface of T-cells suggesting that neuronal damage is induced by the cytotoxic T-cellmediated response (Bien et al., 2012), mirroring the stages

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Fig. 11.1. Pathology of Hu (A–C), Ma2 (D–F), and glutamic acid decarboxylase (GAD) encephalitis (G–I). (A) CD3 staining in the basal ganglia of a patient with Hu antibodies; large numbers of T-cells are present in the perivascular space and in the parenchyma. Bar: 100 mm. (B) The same area as in (A), now stained for CD8, shows that most of the T-cells are cytotoxic T-cells. Bar: 100 mm. (C) Staining for granzyme B (GrB) reveals the presence of neurons (indicated by the red circle) with one or two GrB + T-cells in close apposition. The inset shows an enlargement of the neuron in the lower red circle. Bar: 20 mm. (D) Hematoxylin and eosin stain of the hippocampus of a patient with Ma2 antibodies. The left side shows an area with normal neurons. The right side (arrowheads) shows an inflammatory infiltrate in between the neurons. Bar: 50 mm. (E) Staining for CD8 shows that most of the inflammatory cells are cytotoxic lymphocytes. The inset shows an enlargement with appositions of T-cells to neurons. Bar: 50 mm. (F) Staining for CD68 reveals the activation of microglial cells in this area. Bar: 50 mm. (G) Nissl staining shows the hippocampus of a patient with GAD65 antibodies. In the upper right side, inflammation around a blood vessel is seen. Bar: 50 mm. (H) Staining for CD8 here also shows that most of the T-cells in the parenchyma are cytotoxic T-cells. Bar: 50 mm. The inset depicts multiple GrB + cytotoxic T-cells (arrowheads) in close apposition to a neuron (N). Bar: 50 mm. (I) CD68 shows moderate activation of microglial cells in this area. Bar: 50 mm.

of GrB-mediated cytotoxic T-cell attack in vitro (Hahn et al., 1994; Betts et al., 2003). Tan (1991) and Musunuru and Darnell (2001) note that target epitopes of several PND antigens in critical functional domains tied directly to neuronal survival promote apoptosis making them crucial elements in ultimate prognosis. Two such neuron-specific RNA-binding proteins, the Nova and Hu antigens, respectively, recognized by Ri and Hu antisera (Buckanovich et al., 1996; Okano and Darnell, 1997) target neuron-specific Nova1 and Nova2 of molecular weight 50–55 and 70–80 kDa, and Hu family of onconeural antigens of molecular 35–38 kDa (HuD, C, B, and A, officially known as ELAV a neuron-specific RNA-binding protein 4, 3, 2, and 1). The incubation of rat hippocampal and cerebellar slice cultures with anti-Hu or anti-Ri sera from multiple patients (Greenlee et al., 2014) showed significant differences in the irreversible binding of anti-Hu sera in the absence of T-cells or Fc receptor-positive immune cells, leading to cell death compared to the reversible uptake of anti-Ri sera that initially induced neuronal dysfunction.

By comparison, autoantibody binding of PCD disease sera containing the Yo antibody that targets a 52 kDa cdr2 leucine zipper epitope (Sakai et al., 1993), contributes to inappropriate cell cycle signals in Purkinje cells closely tied to c-Myc, mediating neuronal apoptosis. All PCD disease antisera target the cdr2 leucine zipper epitope (Sakai et al., 1993) and disrupt its ability to bind c-Myc in vitro. This is predicted to antagonize the actions of cdr2 to bind c-Myc in the cytoplasm and downregulate c-Myc-dependent transcription culminating in increased c-Myc activity. The phenotype of Purkinje promoter SV40 T antigen transgenic mice, which also activates a signaling pathway closely tied to the c-Myc signaling pathway (Feddersen et al., 1992) demonstrates that Purkinje neurons respond to aberrant activation of such pathways by inducing apoptotic cell death. Antibody-mediated neuronal apoptosis may be necessary but not sufficient to trigger the neurological degeneration clinically evident in patients with PND. A corollary of this is the infrequency with which PNDs are clinically

PARANEOPLASTIC MOTOR DISORDERS seen may result from the confluence of rare pathogenic events, including the expression of a tissue-restricted neuronal antigen in tumors whose function can be disrupted by an internalized onconeural autoantibody that triggers apoptotic neuronal degeneration.

FUTURE DIRECTION The field of cancer-related neurological disorders has dramatically advanced in the past several decades from cataloguing the clinical and neuropathological features to identifying causative and candidate onconeural antibodies that recognize target antigens and postulating likely cell-mediated mechanisms of tumor-directed injury leading to decreased neuronal survival and apoptosis. In the absence of other neurological biomarkers, applicable antibody profiles predictive of a specific cancer type than a specific neurological presentation are fostering unimaginable strides in cataloguing PND. Further achievements in this field include establishing models to study the pathogenicity of known onconeural antibodies and clarification of the relevance of other candidate antibodies and antigens. Parallel clinical investigations are needed to assess treatment responsiveness to available therapeutic options and their long-term outcomes for affected patients. As many human diseases including the PNDs arise from genetic and environmental factors and thus their interplay, even more insightful genetic studies incorporating genome-wide and epigenome-wide associations, in well-characterized cohorts, may foster the discovery of novel genes and pathways by which genetic and environmental factors influence PND development.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00015-6 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 12

The tauopathies GAYATRI DEVI* Department of Neurology and Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States

Abstract Tauopathies are a clinically and neuropathologically heterogeneous group of neurodegenerative disorders, characterized by abnormal tau aggregates. Tau, a microtubule-associated protein, is important for cytoskeletal structure and intracellular transport. Aberrant posttranslational modification of tau results in abnormal tau aggregates causing neurodegeneration. Tauopathies may be primary, or secondary, where a second protein, such as Aß, is necessary for pathology, for example, in Alzheimer’s disease, the most common tauopathy. Primary tauopathies are classified based on tau isoform and cell types where pathology predominates. Primary tauopathies include Pick disease, corticobasal degeneration, progressive supranuclear palsy, and argyrophilic grain disease. Environmental tauopathies include chronic traumatic encephalopathy and geographically isolated tauopathies such as the Guam-Parkinsonian-dementia complex. The clinical presentation of tauopathies varies based on the brain areas affected, generally presenting with a combination of cognitive and motor symptoms either earlier or later in the disease course. As symptoms overlap and tauopathies such as Alzheimer’s disease and argyrophilic grain disease often coexist, accurate clinical diagnosis is challenging when biomarkers are unavailable. Available treatments target cognitive, motor, and behavioral symptoms. Disease-modifying therapies have been the focus of drug development, particularly agents targeting Aß and tau pathology in Alzheimer’s disease, although most of these trials have failed.

INTRODUCTION Tauopathies are neurodegenerative diseases that are pathologically characterized by abnormal tau aggregates in neurons and glial cells. They are responsible for the majority of dementias worldwide, including Alzheimer’s disease (AD). Despite sharing pathological tau aggregation, tauopathies exhibit tremendous clinical and phenotypic heterogeneity, associated with variability in the predominant tau isoforms that aggregate, morphology of aggregates, cell types, and brain regions affected (Chung et al., 2021). Additionally, morphologies of tau inclusions can be different even within the same cell type, suggesting distinct mechanisms in each tauopathy. Pure tauopathies are a rarity, as most coexist with each other, and with other neurodegenerative pathology. For

instance, argyrophilic grain disease, an underrecognized tauopathy, is present in 18%–100% of cases of progressive supranuclear palsy and corticobasal degeneration, and in up to a quarter of patients with AD (Yokota et al., 2018). In an autopsy series of cases meeting neuropathological criteria for AD, less than a third had AD-only pathology, and even within this group, nearly a half had at least one infarct (Karanth et al., 2020). Because of the overlap of clinical syndromes between tauopathies, the positive predictive value of even an expert clinical diagnosis of AD, prior to the advent of biomarkers, ranged from 62% to 83% (Beach et al., 2012). Primary tauopathies arise from abnormal tau aggregates within neuronal or glial cells or in both cell types. Alzheimer’s is the prototypical secondary tauopathy,

*Correspondence to: Dr. Gayatri Devi, MD, 65 East 76th Street, New York, NY 10021, United States. Tel: +1-212-517-6881, Fax: +1-212-517-6921, E-mail: [email protected]

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where a second protein, Aß, is needed to drive neurodegeneration. In AD, tau aggregates are seen only in neurons and not in glial cells. Environmental tauopathies are primary tauopathies and include geographically isolated tauopathies and chronic traumatic encephalopathy. This review covers the structure and function of normal tau, the types of pathological tau, and describes salient clinical and pathologic characteristics of the major primary, secondary, and environmental tauopathies. We will discuss the challenges of both clinical and pathological diagnosis of tauopathies. Finally, we will address available, generally symptomatic treatments for these disorders, as well as disease-modifying drugs in development, primarily for Alzheimer’s disease.

STRUCTURE AND FUNCTION Normal tau Microtubules are tubulin polymers that are necessary for cell structure and function. Tau—for tubulin associated unit—is one of the most abundant of several microtubule-associated proteins (MAP) found in the nervous system. Tau catalyzes microtubule polymerization, promoting cytoskeleton structure and axonal transport (Weingarten et al., 1975). Other tau physiological functions include signal transduction, DNA/RNA protection, and regulation of synaptic function (Catarina Silva and Haggarty, 2020). Tau probably has many other undiscovered functions. For instance, tau exists in forms that do not associate with microtubules and interacts with many other proteins besides microtubules in tissue compartments outside the central nervous system (Lee and Leugers, 2012). Interestingly, tau is present in muscle, liver, and kidney tissue, and in human breast, prostate, gastric, and pancreatic cancer cell lines. The tau sequence is conserved across species, including mammals, amphibians, and nematodes (Lee and Leugers, 2012). In the brain, tau is present in neurons, primarily in axons and dendritic processes, and also in astrocytes and oligodendrocytes. In its native state, tau is unfolded and disordered, lacking a well-defined structure, and poised for rapid conformational change, with the majority of tau proteins interacting with neuronal microtubules. However, this very property of structural plasticity also makes tau much more likely to misfold (Kolarova et al., 2012; Catarina Silva and Haggarty, 2020). Native tau is highly soluble, contains several charged and hydrophilic residues, and shows little tendency for aggregation. Fast singlemolecule tracking of tau in living neurons shows tau binding to a microtubule for
40 ms, before moving to the next microtubule in a “kiss-and-hop” fashion, a technique that allows tau to modulate tubulin-microtubule balance and promote microtubule assembly, without interfering with axonal transport (Janning et al., 2014).

Six isoforms of tau are derived from differential splicing of exons of the microtubule-associated protein tau (MAPT) gene on chromosome 17q21 (Neve et al., 1986). Tau has an amino (N) and carboxyl (C) terminal end, a central proteinrich domain, and a repeat domain, with either three or four repeats (3R or 4R) and differing number of N-terminal inserts (0 N, 1 N, or 2 N) from differential splicing of exons of the MAPT gene yielding the six tau isoforms. The repeat domains are crucial for regulating microtubule stability and axonal transport. Therefore, during the fetal stage, 3R tau predominates, with dynamic properties promoting synaptogenesis and neural network formation, while in the adult brain 4R tau binds more tightly to microtubules (Goedert et al., 1989; Goedert, 2011). Full-length tau has 2 N-terminal inserts and 4R repeats and it is referred to as “2N4R” tau. The dominant forms found in human brain are 2N4R and 2N3R. Under physiological conditions, there are equal amounts of 3R and 4R. Under pathological conditions, there is a shift to the 2N4R configuration for most tauopathies.

Pathological tau The psychiatrist Alois Alzheimer first described aggregated tau in terms of neurofibrillary tangles (NFT) in 1906 in the eponymous dementia named for him by his department chairman, Emil Kraepelin (Devi and Quitschke, 1999). Nearly 60 years later, paired helical filaments (PHFs) were described as a major component of NFTs (Kidd, 1963). In 1975, the tau protein was isolated (Weingarten et al., 1975), and in the following decade tau was found to be the component of NFTs in 1985 (Brion et al., 1985; Grundke-Iqbal et al., 1986; Kosik et al., 1986). In its inherently disordered state, the tau protein is the most common misfolded protein. Site-specific hyperphosphorylation of tau is a hallmark of neurodegenerative tauopathies and common to all diseases with tau filaments, in which neuronal and glial cells exhibit various intracellular tau inclusions. Tau also undergoes other posttranslational modifications, such as acetylation, ubiquitination, and cleavage (Chung et al., 2021). These modifications affect tau solubility and tau-microtubule interactions, likely disrupting axonal transport, causing synaptic dysfunction and loss, and leading to neurotoxicity. The abnormal hyperphosphorylation of tau, an early event that appears to precede filament assembly, prevents usual tau interaction with microtubules, and detaches tau from microtubules, causing microtubule breakdown. The hyperphosphorylated tau then misfolds, oligomerizes, and begins to abnormally aggregate with other aberrantly modified tau proteins, forming insoluble, highly ordered, sheet-rich paired helical filaments (PHF) and NFTs (Kosik et al., 1986) (Fig. 12.1). 4R-tau is more aggregation prone than 3R-tau.

THE TAUOPATHIES

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Phosphatase

Monomeric P-Tau

Monomeric Tau

Kinase Microtubule loss Microtubule

Disrupted axon Tauopathy neuron

Healthy neuron

MAPT mutations, stress, disease

Misfolding

Hyperphosphorylated Tau

Aggregation

Soluble Tau oligomers

Insoluble Tau aggregates

Tau fibrills

Fig. 12.1. Schematic representation of tau function as a regulator of microtubule stability and dynamics in human neurons. Tau binding is regulated by phosphorylation via the concerted action of kinases and phosphatases. In disease, tau becomes hyperphosphorylated and no longer binds microtubules, contributing to axonal dysfunction. Together with posttranslational modification, tau misfolding drives oligomerization and aggregation into larger order insoluble fibrils such as NFTs and PHFs found in the somatodendritic space and processes of CNS neurons. Adapted from Catarina Silva, M., Haggarty, S.J., 2020. Tauopathies: deciphering disease mechanisms to develop effective therapies. Int J Mol Sci doi: 10.3390/ijms21238948 in open access.

Fast axonal transport is significantly impaired in tauopathies, likely due to alterations in the normal function of tau (Morfini et al., 2009). Effects of tau on axonal transport may be more complex than simply blocking motor access to the microtubules (Lee and Leugers, 2012). Pathologic tau may also act as a seed to promote aggregation of free, soluble tau (Gibbons et al., 2019). Tau seeds can transmit pathologic tau through intracerebral injection into wild-type or tau transgenic mice of recombinant tau protein, cell lysates of pathological tau strains, or brain tissue-derived tau seeds. Human brain-derived tau seeds injected into mouse brains replicate the neuropathologic lesions of the donor brain tauopathies, with identical affected cell types, lesion morphology, and brain regions affected (Chung et al., 2021). Intriguingly, neurons with NFTs may survive decades, suggesting tau aggregates may be protective (Morsch et al., 1999).

PRIMARY TAUOPATHIES Tau misfolding and aggregation from posttranslational modification of tau, primarily hyperphosphorylation, are implicated in all tauopathies, including AD. Tauopathies are mostly sporadic although genetic forms of tauopathy subtypes, indistinguishable from the sporadic, are not uncommon. An example is FTLD-17 dementia resulting from MAPT mutations on chromosome 17. Tauopathies may be divided into primary and secondary tauopathies, with an added group of environmental tauopathies. Primary tauopathies are neurodegenerative

diseases that result from aberrant tau aggregates. Environmental tauopathies similarly harbor tau aggregates but the aggregates arise from environmental triggers and are found in geographically isolated or at-risk populations. Secondary tauopathies implicate a second protein in the pathogenesis, with AD being the prototype secondary tauopathy with Aß protein as the additional pathological driver. Tauopathies vary based on tau lesion morphology and cell types affected (Fig. 12.2). Motor symptoms exist with all tauopathies. However, depending on the region of brain affected, the nature and type of motor disorder as well as time of onset during the disease course, is widely variable (Table 12.1).

Frontotemporal dementia Frontotemporal lobar degeneration (FTLD) is the term defining the pathology of the many clinical syndromes subsumed under the term “frontotemporal dementia.” Despite varied neuropathology, prominent frontal and temporal degeneration drive the clinical phenotypes. Three main proteins account for nearly all FTLDs. They are tau protein, the TAR DNA-binding protein of 43 kDa (TDP-43), and the “fused in sarcoma” protein (FUS). The majority of FTLDs are therefore FTLD-tau, FTLD-TDP, or FTLD-FUS with any remaining FTLD pathology being relatively rare. Over 40% of FTLD cases have a family history of either or both dementia and movement disorder (Rohrer et al., 2009).

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Fig. 12.2. Schematic depiction of the range of pathological tau lesions in different cell types in tauopathies. In the healthy brain (left), microtubule-binding protein tau interacts with neuronal microtubules to promote stability and facilitate axonal transport. While neurons have the highest expression level of tau, oligodendrocytes and astrocytes also express endogenous tau, albeit at lower levels. Microglia do not express endogenous tau. In a pathological condition (right), tau becomes aberrantly aggregated in the form of various inclusions, impaired in its physiological functions, such as supporting microtubule stability. In neurons, tau can accumulate in the forms of neurofibrillary tangles, neuropil threads, or Pick bodies. Tau also accumulates in astrocytes, mostly in the primary tauopathies as shown, and in the form of tufted astrocytes, astrocytic plaques, and GAIs. Moreover, tau aggregates in oligodendrocytes in the form of coiled bodies or GOIs. Microglia do not form tau inclusions, while accumulating studies have suggested that they may contribute to tau propagation. Abbreviations: CBD, corticobasal degeneration; GAIs, globular astroglial inclusions; GGT, global glial tauopathy; GOIs, globular oligodendroglial inclusions; NFTs, neurofibrillary tangles; PSP, progressive supranuclear palsy. Adapted from Chung, Deun C., Roemer, S., Petrucelli, L., Dickson, D.W., 2021. Cellular and pathological heterogeneity of primary tauopathies. Mol Neurodegener doi: 10.1186/s13024-021-00476-x in open access. Table 12.1 Tauopathies and motor symptoms Tauopathy type Primary tauopathy: FTLD-tau: Pick’s disease FTLD-tau: FTDP-17 FTLD-tau: corticobasal degeneration FTLD-tau: progressive supranuclear palsy FTLD-tau: globular glial tauopathy Anti-IgLON5 antibodies tauopathy Argyrophilic grain disease Primary age-related tauopathy Aging-related tau astrogliopathy Environmental tauopathies: Chronic traumatic encephalopathy Parkinsonian dementia complex of Guam Guadeloupean Parkinsonism Toxic Tauopathy, Northern France Secondary Tauopathy: Alzheimer’s disease

Motor symptoms

Time of onset

Parkinsonism Parkinsonism Asymmetric Parkinsonism, limb dystonia, atypical tremor Ocular apraxia, falls, axial dystonia Dysarthria, dysphagia, corticospinal tract findings Hyperreflexia, spasticity, limb weakness – – Parkinsonism

Late Early Early Early Early Early – – Early/late

Tremors, Parkinsonism, motor neuron features Parkinsonism Parkinsonism Parkinsonism Extrapyramidal syndrome, gait apraxia, myoclonus

Early/late Early Early Early Late

FTLD, frontotemporal lobe dementia; FTDP-17, frontotemporal dementia with Parkinsonism-17; IgLON5, immunoglobulin LON Family Member 5.

THE TAUOPATHIES FTLD-tau is the most common of the group, with aggregation of p-tau in neurons and glia. The major subtypes of FTLD-tau are Pick’s disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), globular glial tauopathy (GGT), and rare unclassifiable tauopathies. A frontotemporal dementia such as the clinically defined primary progressive aphasia, with its language-defined variants, may result from multiple pathologies, including FTLD-tau (29%)—primarily Pick’s and FTLD-TDP (25%), AD (44%), or some combination of these or other pathologies (Mesulam et al., 2021).

Pick disease Pick’s disease (PiD) is a tauopathy, with a rare 3R tau aggregation, as opposed to the majority of tauopathies, which are 4R. It usually presents clinically with deterioration of language, personality and judgment, including social disinhibition, and memory. While most cases are sporadic, a few familial cases have been linked to missense mutations in MAPT, also called frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Given the significant frontal and temporal lobe involvement, Pick’s disease most often presents with behavioral and executive impairments, also known as behavioral variant FTD, but can present as primary progressive aphasia (Irwin et al., 2016). In one series, the mean age of onset was 57 12 years, with mean disease duration of 9 years (Irwin et al., 2016). Loss of empathy was a common early feature and a large number of patients developed extrapyramidal features as the disease progressed. Axial rigidity, frequent falls, and disturbed eye movements all suggest supranuclear palsy, while asymmetric motor disturbance, alien limb syndrome, and ocular apraxia are associated with corticobasal syndrome. FTDP-17 was used to describe cases of FTLD and Parkinsonism associated with mutations in MAPT (Hutton et al., 1998). Within the FTLD field, sporadic and genetic FTLD were initially considered separate entities, although cases are pathologically indistinguishable. However, another mutation on chromosome 17, on the progranulin gene, was also found to be associated with FTLD and cases of FTLD with MAPT mutations but without Parkinsonism were identified (Boeve and Hutton, 2008). There is phenotypic variability between different FTDP-17 mutations and within the same mutation. For these reasons, it is recommended that FTDP-17 be considered a familial form of sporadic FTLD-taufamilial PiD (Forrest et al., 2018). As in PiD, changes in personality and behavior are often early signs of FTDP-17, along with aphasia. Many

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affected individuals develop features of Parkinsonism, including tremors, rigidity, and bradykinesia, that is not generally responsive to levodopa. With disease progression, inability to walk, as well as difficulty with eye movements, become prominent. Disease progression varies considerably from months to years. Pick bodies, prominent neuronal inclusions in the form of ballooned neurons, are well delineated, round, neuronal cytoplasmic inclusions reactive to p-tau and 3R tau but negative for 4R tau (Kovacs et al., 2013). Such ballooned neurons are also seen in other tauopathies such as CBD and argyrophilic grain disease (AGD). Pick body-like inclusions in hippocampal dentate gyrus neurons in AD are different from Pick bodies of PiD, histologically, and are both 3R and 4R positive (Kovacs et al., 2013). Glial lesions are less frequent than neuronal lesions in PiD, but Pick-body-like inclusions can be detected in oligodendrocytes in affected white matter. The neuroanatomical distribution of Pick bodies parallels brain atrophy. The circumscribed focal cortical atrophy (“lobar atrophy”) is a striking neuropathological feature, particularly in the anterior frontal and temporal lobes, as well as in the medial and inferior temporal cortices, the so-called “knife-edge” atrophy. There is severe neuronal loss and gliosis and secondary axonal loss in the subjacent white matter. The striatum, subthalamic nucleus, and the substantia nigra are variably affected.

Corticobasal degeneration Corticobasal degeneration is a sporadic 4R tauopathy with only a few MAPT mutations reported in rare familial cases. CBD symptoms typically begin in people from 50 to 70 years of age, and the average disease duration is 6 years. Patients present with cortical sensory deficits, alien limb phenomenon, highly asymmetrical Parkinsonism, which progresses to dystonia and myoclonus. Additional features include apraxia and cognitive deficits. Tremor, when present, is a positional or action tremor and irregular. Dystonia is most often of the upper limb and is less likely axial (Armstrong et al., 2013; Constantinides et al., 2019). Some patients present with PSP-like features such as postural instability and gaze palsy. PSP without CBD is estimated to be about ten times more common than PSP with CBD. CBD represents roughly 4%–6% of patients with Parkinsonism. Neuroimaging in CBD typically shows asymmetrical posterior parietal and frontal cortical atrophy, along with atrophy of the corpus callosum. A key histopathological feature of CBD is the ballooned neurons, which are swollen neocortical neurons containing p-tau. Importantly, CBD shares similarities with PSP in its prominent accumulation of 4R tau in both neurons and glial cells. Unlike the tufted astrocytes seen

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in PSP, tau-positive astrocytes in CBD appear as annular clusters of astrocytic cell processes, which have been named “astrocytic plaques,” given their resemblance to neuritic plaques centered on Aß in AD (Chung et al., 2021). Oligodendroglial coiled bodies may also be found in CBD but are less prominent than those seen in PSP. Another prominent pathological feature of CBD is tau accumulation in neuronal processes as neuropil threads in affected gray and white matter of cortical and subcortical regions. Neuropil threads are also frequent in AD, where the term was originally used. The cerebral cortex and basal ganglia are preferentially affected in CBD, unlike in PSP where the basal ganglia, subthalamic nucleus, and midbrain are disproportionately impacted.

Progressive supranuclear palsy PSP may be difficult to distinguish from Parkinson’s disease (PD), especially in the early stages, because of overlapping clinical features. The diagnostic criteria for PSP include postural instability, akinesia, oculomotor dysfunction, and cognitive and lingual disorders. As a common PSP variant, Parkinsonism predominant PSP is found in up to 35% of cases (Dale et al., 2020). PSP-P requires either akinetic-rigid predominantly axial and levodopa-resistant Parkinsonism or Parkinsonism with tremor and/or asymmetric and/or levodopa responsive. Parkinson’s disease with gait difficulty may be especially difficult to differentiate from PSP. The initial symptoms in two-thirds of cases are loss of balance, lunging forward when mobilizing, and falls, beginning between ages 60 and 70 years. Other common early symptoms are changes in personality common to FTD, general slowing of movement, and visual symptoms. Very rarely, cerebellar ataxia may be a presenting feature. The most common behavioral symptoms in patients with PSP include apathy, disinhibition, anxiety, and dysphoria. Other signs include facial muscle contracture, cervical dystonia, and vertical gaze paresis, with patients complaining of difficulty reading. However, this voluntary gaze paresis corrects with the oculocephalic reflex. Awide stare accompanied by a furrowed forehead with a frown, termed the “procerus sign,” is characteristic of PSP. Less than 1% of PSP patients have an affected family member. Frequently misdiagnosed as Parkinson’s, PSP is poorly responsive to levodopa and rarely presents with a rest tremor. Eye-movement abnormalities, pathognomonic in PSP are uncommon in PD. In addition to frequent falls early in the course of the disease, PSP patients also present with an arched or a straight back rather than the stooped posture of PD. Supportive care is the only management currently available for PSP.

PSP is characterized by neuronal and glial tau pathology, neuronal loss, and fibrillary astrogliosis, with the most severe neuronal loss found in the globus pallidus, subthalamic nucleus, and substantia nigra. Globose NFT or pretangles are frequent in these affected brain regions (Chung et al., 2021). As with other tauopathies, PSP pathology may coexist with that of CBD, AD, and Lewy bodies.

Globular glial tauopathy Globular glial tauopathy (GGT) is a rare nonfamilial 4R tauopathy, with a few cases linked to MAPT mutations. The clinical spectrum of GGT spans FTLD, motor neuron disease (MND) and both, leading to three GGT subtypes. In each GGT subtype (Ahmed et al., 2011, 2013), FTD-like symptoms reflect tau pathology affecting frontal and temporal cortices, while MND-like symptoms correspond to the involvement of motor cortex and corticospinal tract degeneration. Type I, with pathology in the frontal lobe, can present as FTD or PiD, with predominantly FTD clinical features. Type II GGT with pathology in the motor cortex and the corticospinal tract, presents with pyramidal and extrapyramidal features, and is often misdiagnosed as PSP, CBS, motor neuron disease, or primary lateral sclerosis. Type III, with involvement of the frontotemporal lobe as well as motor cortex and corticospinal tract, presents with dementia and frontal lobe features and motor neuron disease and is often misdiagnosed as PSP, CBS, or motor neuron disease. The major histopathological hallmarks of GGT are 4R tau-enriched, globular, tau-positive globular astroglial inclusions (GAIs) and oligodendrocytes and globular oligodendroglial inclusions (GOIs). There are significant differences in the seeding potency of GGT brain lysates in cell-based reporter assays compared to brain lysates of other tauopathies such as PSP, CBD, and AD, supporting the concept that GGT is a distinct tauopathy (Chung et al., 2019).

Anti-IGLON5-related tauopathy This recently described tauopathy is characterized by a unique rapid eye movement (REM) parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5 (Werner et al., 2021). Patients present at a median age of 70 with recurrent respiratory distress and progressive neurogenic dysphagia. They may be misdiagnosed as a motor neuron disease, with time of 2 years from symptom onset to diagnosis. In one series, all patients had dysarthria, muscle spasticity, hyperreflexia, atrophy and limb weakness, and occasional tongue and extremity fasciculations. Treatment with systemic corticosteroids may be of benefit.

THE TAUOPATHIES The pathology is restricted to neurons and predominantly involves the hypothalamus and tegmentum of the brainstem with the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms (Gelpi et al., 2016; Ganguly and Jog, 2020).

Argyrophilic grain disease Argyrophilic grain disease (AGD) is widely prevalent and just as widely unrecognized (Ferrer et al., 2008). The term argyrophilic grain was coined by Braak and Braak to describe numerous spindle-shaped 4R taupositive profiles scattered in the neuropils of demented patients without AD tau pathology (Braak and Braak, 1998). AGD is virtually unknown in clinical neurology because most cases are asymptomatic although some cases present with a dementia that is indistinguishable from AD. It is the second most common tauopathy after AD, with an incidence ranging from 9% in 65-year-olds to 31% in centenarians. In clinical cases, personality changes and psychiatric symptoms may be the presenting features and cognitive impairment may or may not be present. AGD may be an etiology of late-life psychosis. Interestingly, semantic memory impairment is not seen in AGD. To make matters complicated, AGD pathology frequently is seen with AD and other tauopathies, as well as in nontau neurodegenerative disorders such as Lewy body disease. In 545 serial autopsy cases from a general geriatric hospital, 18% of patients with both mild cognitive impairment and dementia had neuropathology consistent with AGD. AGD was found in a third of the brains of a series of cognitively normal subjects (Knopman et al., 2003). In PSP, the frequency of AGD ranges from 19% to 80% (Rodriguez and Grinberg, 2015). In CBD, AGD pathology is found in 41%–100% of cases (Ferrer et al., 2008; Yokota et al., 2018). It is not always easy to distinguish argyrophilic grains from cross sections of dystrophic neurites of AD pathology, and when appropriate stains are used, AGD copathology increases to over a quarter of all AD cases (Yokota et al., 2018). AGD progresses from the anterior entorhinal cortex, amygdala, and lateral hypothalamus to the entire entorhinal cortex, anterior CA1, eventually involving the neocortex and brain stem, as is characteristic of tau propagation (Saito et al., 2004).

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in those over 80 years of age with a family history of cognitive disorders. Even patients with severe PART typically exhibit mild cognitive loss and on occasion dementia but most patients with PART are asymptomatic. There are AD-like NFTs composed of PHFs, and positive for 3R and 4R tau, which is neuronal, as in AD, and unlike other tauopathies (Ferrer et al., 2020). However, unlike AD, PART is not associated with amyloid copathology or the APOE4 allele (Crary et al., 2014). PART can overlap with some types of FTLD-tau. “Definite PART” reveals frequent NFTs in the limbic system, including the CA2 region of the hippocampus, amygdala, and medial temporal lobe. “Possible PART” refers to patients with similar NFT pathology, with concomitant mild amyloid copathology.

Aging-related tau astrogliopathy Aging-related tau astrogliopathy (ARTAG) may present clinically with focal symptoms like aphasia when circumscribed to a small region. ARTAG is generally seen in persons 60 years and older and is rarely an isolated finding. A common copathology, ARTAG is detected in more than 65% of primary tauopathies. In cases with widespread pathology, dementia with or without Parkinsonism might be the clinical presentation. While the etiology and clinical significance of ARTAG are poorly understood, studies have shown that ARTAG is associated with significantly elevated levels of another astrocytic protein, aquaporin-4, and the major water channel in the brain. This suggests a role for blood-brain barrier dysfunction in the pathogenesis of ARTAG (Kovacs et al., 2018). ARTAG is defined by the presence of 4R tau-positive, thorn-shaped astrocytes in subpial, perivascular, and subependymal regions mostly in aged individuals, without neuronal involvement (Kovacs et al., 2016). A subtype of ARTAG presents with tau-positive granular/fuzzy astrocytes in the gray matter, especially in the amygdala. While astrocytic tau lesions are characteristic of other primary tauopathies such as PSP, CBD, and GGT, they are also observed in brains of neurologically normal elders (Kovacs, 2020).

TAUOPATHIES DUE TO ENVIRONMENTAL EXPOSURES Chronic traumatic encephalopathy

Primary age-related tauopathy Primary age-related tauopathy (PART) was previously considered normal aging or neurofibrillary tanglepredominant senile dementia (Crary et al., 2014). Cognitively normal persons may exhibit pathologically definite PART. Cognitive impairment in PART is more often seen

Chronic traumatic encephalopathy (CTE) is a sporadic tauopathy associated with repetitive traumatic brain injuries and related subconcussions and concussions. Contact sport players, particularly American football players, and military personnel are most at risk. In a population-based autopsy cohort of those with a history

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of playing contact sports, both athletes and nonathletes, 6% had CTE. In autopsies of gridiron football players, 99% of NFL players, 88% of college football players, and 64% of semiprofessional players had evidence of CTE (Bieniek et al., 2020). Symptoms generally appear at least 8–10 years after exposure to repeated brain injury although a single moderate injury can lead to CTE (Smith et al., 2019). Patients present with significant headaches, progressive behavioral and mood problems, and attentional and memory deficits progressing to a frank dementia. Some patients develop dysarthria and muscle atrophy, with motor neuron-type features. Parkinsonism and tremors may present in some patients along with gait imbalance. Some patients with CTE have chronic traumatic encephalomyelopathy with symptoms of motor neuron disease, muscle weakness, and ataxia (McKee et al., 2010). Prevention with helmets and avoidance of repeated concussions is key. The pathology of CTE needs to be distinguished from that of ARTAG, as both are found in the depths of the cortical sulci. CTE pathology is characterized by perivascular neuronal and glial tau lesions, while ARTAG spares neurons. CTE pathology is in an unpredictable distribution, while there is a characteristic distribution and progression in ARTAG (Chung et al., 2021). At the advanced disease stage, tau pathology in CTE is found in most cortical regions, including the medial temporal lobes. Progressive involvement of basal ganglia and brainstem is accompanied by pronounced brain atrophy. Additionally, diffuse Aß plaques can be detected in a subset of CTE, especially in older individuals. The conformation of tau filaments in CTE is distinct from that of AD, despite the shared 3R and 4R tau pathology. A unique hydrophobic cavity in the CTE tau core suggests that as-yet-unidentified factors contribute to CTE-specific tau aggregation.

Geographically isolated PSP-like tauopathies GUAM PARKINSONISM-DEMENTIA COMPLEX Guam Parkinsonism-dementia complex (PDC) is a geographically isolated tauopathy found in the Mariana Islands, the Ki peninsula of Japan, and the coastal plain of West New Guinea (Steele, 2005). The Chamorro population of Guam call it Lytico-bodig. Patients manifest Parkinsonism, with tremor, rigidity and bradykinesia as well as muscle atrophy, spasticity, maxillofacial paralysis, dysarthria, and dysphagia. A progressive dementia with restlessness, agitation, and pseudobulbar symptoms occur at the end stages with eventual paralysis of the respiratory musculature. Hirano

dubbed it ALS-PDC because of the motor neuron and Parkinson’s disease features (Hirano, 1992). Consumption by the Chamorro of bats feeding on Federico nuts (Cycas micronesica) with B-methylaminoL-alanine, a neurotoxin, or consumption of cycad seeds is thought to trigger the condition (Steele, 2005). Declining consumption of bats has led to reduction in incidence of the disease. The age at onset is also increasing as a result. Neuropathological features of Guam PDC include cortical atrophy and depigmentation in the substantia nigra and locus ceruleus. As with AD, Guam PDC exhibits 3R- and 4R-positive NFT pathology extensively distributed in the neocortex, hippocampus, and brainstem, but mostly in the absence of senile plaques. Neuropil threads are seen. Both gray and white matter are affected by tau pathology, and unlike AD, glial tau inclusions are often detected in Guam PDC in astrocytes and oligodendrocytes (Winton et al., 2006).

GUADELOUPEAN PARKINSONISM This tauopathy was seen among residents of the Guadeloupe islands in the French West Indies in the late 1990s. Clinically, these individuals displayed an atypical Parkinson syndrome with PSP-like features such as postural instability and vertical gaze impairment. Consumption of herbal teas and fruits containing alkaloid toxins that are potent inhibitors of mitochondria was associated with the condition (Caparros-Lefebvre et al., 2002). Histopathological analysis revealed pretangles, NFTs, and threads composed of hyperphosphylated tau in multiple brain regions including the midbrain, the striatum, and the cortex.

NORTHERN FRANCE TAUOPATHY Exposure to soil highly contaminated with arsenic and chromate from chemical plants may have contributed to an approximately 12-fold more than expected spike of PSP-like tauopathy in France from 2007 to 2014 (Caparros-Lefebvre et al., 2015). Patients often showed gait and gaze abnormalities.

Other conditions with tau aggregates Tau has also been described in Gerstmann-Str€ausslerScheinker disease, myotonic dystrophy, post-encephalitic Parkinsonism, prion protein cerebral amyloid angiopathy, SLC9A6-related mental retardation, subacute sclerosing panencephalitis, and Down’s syndrome (Goedert, 2011).

THE TAUOPATHIES

SECONDARY TAUOPATHIES Alzheimer disease Alzheimer’s disease (AD), the most common form of dementia, is a secondary tauopathy requiring both Aß amyloid deposition and tau aggregation for diagnosis. Most cases are sporadic and present in their 60s, 70s, and 80s, although in very rare familial cases, which constitute less than 5%, patients become symptomatic in their twenties (Devi et al., 2000). While memory impairment is the most common complaint, impairment of many other cognitive domains, including language and praxis may be an early feature. The prodromal phase of mild cognitive impairment may last many years. Illness trajectory and treatment response are influenced by coexisting brain pathology, systemic comorbidities, and sociodemographic variables including activity and educational level. The condition may best be considered a syndromic disorder rather than a monolithic disease, with varying presentations and prognosis based on the brain regions affected, and the individual’s brain and cognitive reserve (Devi, 2018). Neuropathological subtypes include limbic predominant, hippocampal sparing, and diffuse Alzheimer’s, based on the pattern of NFT deposition (Ferreira et al., 2020; Murray et al., 2011). The hippocampal sparing subtype of AD is most often associated with younger age, earlier motor symptoms, and a more aggressive progression (Ferreira et al., 2020). Based on neurocognitive profiles, up to eight cognitive clusters may be discerned, with distinct demographics, symptoms, and progression (Scheltens et al., 2016). Because of the existence of tau and other neurodegenerative copathology, and the tremendous symptom overlap between these diseases and normal aging, clinical diagnosis without biomarker confirmation is challenging. Sensitivity for a clinical diagnosis of AD in memory disorder centers ranged from 71% to 87% and specificity ranged from 44% to 81% (Beach et al., 2012). In an autopsy series of 184 persons with neuropathological AD, about a third had AD-only pathology, 50% had additional TDP-43 pathology, 22% had additional a-synuclein pathology, and 18% had additional combined a-synuclein and TDP-43 pathology. To further complicate matters, within each of these pathologically defined groups, between 30% and 50% of individuals had at least one infarct (Karanth et al., 2020). The greatest risk factors for sporadic Alzheimer’s disease are older age, female gender, and the APOE E4 allele. The E4 allele increases the risk for dementia by 3–4 times when compared with E3 carriers. Cardiovascular risk factors and an unhealthy lifestyle are associated with an increased risk. Rare protein-damaging

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variants in the SORL1, 46 ABCA7, 47, and TREM2 genes also increased risk, as intact protein products of these genes are essential for brain health (Scheltens et al., 2021). Mutations in the presenilin (PSEN) 1 gene on chromosome 14 and the PSEN2 gene on chromosome 1 are the most common cause of familial AD.

CLINICAL AND BIOMARKER DIAGNOSIS Formalizing a diagnostic approach to Alzheimer’s disease began with criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s and Related Disorders Association in 1984, which excluded other possible causes of dementia (McKhann et al., 1984). The International Working Group advocated, in 2010, for a diagnosis that incorporated biomarkers into the diagnostic framework (Dubois et al., 2010). In 2018, a purely biomarker amyloid, tau, and neurodegeneration (ATN) method of diagnosis was recommended (Jack et al., 2018). A combined clinical biomarker approach seems to be the most valid, as a solely biomarker-based approach has significant issues (Dubois et al., 2021). Low cerebrospinal fluid (CSF) levels of Ab in conjunction with high phosphorylated tau and total tau levels are consistent with a diagnosis of AD. Even in cognitively normal persons, 80% of those with abnormal CSF biomarkers progress to MCI in 6 years, while 90% of those with cognitive impairment develop dementia within a decade (Buchhave, 2012). Positron emission tomography (PET) to detect amyloid plaque and tau biomarkers are noninvasive, albeit expensive, imaging approaches. Cognitively normal individuals as well as others with MCI and abnormal Ab PET imaging are at increased risk for dementia (Jack et al., 2019). New biomarkers being investigated include neurogranin that increases early in the disease and is specific for Alzheimer’s disease. Levels of neurofilament light are increased in blood proportionate to CSF levels, making this an easy access biomarker. CSF biomarkers in AD differ from the FTLDs, helping with diagnostic clarification (Sch€oll et al., 2019; Mattsson-Carlgren et al., 2022). Pathology AD can be conceived of as a synaptic dysfunction disorder leading to failure of cortical circuitry (Knopman et al., 2021). Synaptic pathophysiology unifies genetic, neuropathologic, and clinical manifestations of AD and synaptic loss strongly correlates with cognition loss. Ab peptides, the additional protein found in aggregates in AD, are formed in the extracellular space by cleavage of the transmembrane amyloid precursor protein. Amyloidogenic, aggregation-prone, longer chain Ab oligomers formed by the action of b- and g-secretases

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are components of amyloid plaques, while shorter, soluble Ab peptides formed by a-secretase are excreted. Ab amyloid plaques are surrounded by decreased synaptic content for
50 mm, with presynaptic and postsynaptic marker loss (Spires-Jones and Hyman, 2014). Given the quantity of amyloid plaques in patients with AD, this translates to immense synaptic dysfunction and loss. Ab plaques may serve a protective function, helping to sequester and neutralize amyloidogenic Ab oligomer neurotoxicity. The theory that longer chain Ab oligomers, rather than insoluble Ab plaques, cause synaptic dysfunction is supported by the ‘Osaka’ mutation, found in a familial form of AD. This mutation accelerates Ab oligomerization but does not form amyloid fibrils or plaques, with rapid onset of dementia with characteristic Ab and tau levels in CSF without the presence of plaques (Tomiyama and Shimada, 2020). Additionally, this is the only known early onset AD mutation with a recessive inheritance. Although Ab begins to accumulate10–20 years prior to cognitive symptoms, tau accumulates in the temporal and parietal isocortex at a time much more proximate to cognitive impairment and continues to accumulate parallel with disease progression (Knopman et al., 2021). Tau is therefore more helpful with plotting disease progression. Additional alterations in microglia and astroglia drive disease progression before cognitive impairment is observed. Neuro-inflammation, alterations in vasculature, and dysfunction of the glymphatic system act in tandem or upstream to accumulating amyloid b. As first proposed by Braak and Braak, NFT pathology first develops in the trans-entorhinal cortex and subsequently appears in the limbic system, including the hippocampus and amygdala, then in isocortical regions, finally involving the primary cortices at the advanced and end stages (Braak and Braak, 1995). Tau lesions in AD include NFTs and neuropil threads composed of PHFs and straight filaments (SFs) that are immunoreactive for both 3R and 4R tau. Tau-positive glial lesions are not a feature of AD unless there is a comorbidity with other tauopathies such as ARTAG or AGD, which occurs often. On the other hand, reactive astrocytes and activated microglia are frequently detected in affected brain regions in AD.

TREATMENT This section details treatment of tauopathies and cognitive impairment in general and of Alzheimer’s disease specifically. Prevention is important both for environmentally associated tauopathies and for AD. The SPRINT-MIND trial found intensive blood pressure control with a systolic blood pressure T p.(Cys104Phe) and presented with clinical features similar to those of EA2, including episode phenomenology and duration (few hours), presence of interictal nystagmus, and response to acetazolamide (Escayg et al., 2000). The onset of symptoms was, however, later than in EA2, that is, in the third-fourth decade (Escayg et al., 2000). In a second family with EA5 due to the same CACNB4 variant originally reported, the father and child

PAROXYSMAL MOVEMENT DISORDERS

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exhibited episodes of ataxia with various combinations of unilateral numbness, weakness, headache, and loss of consciousness triggered by psychological stress, fatigue, sleep deprivation, or alcohol intake (Gonzalez Sanchez et al., 2019). Mild permanent cerebellar ataxia occurred in one case during the disease course (Gonzalez Sanchez et al., 2019).

onset was before the age of 20 years, and frequency of attacks varied from monthly events to only a few episodes per year. Attacks decreased in frequency with age (Kerber et al., 2007). Linkage analysis revealed a maximum locus with an LOD score of 2.95 (chromosome 19q13), but no candidate gene was identified within this region (Kerber et al., 2007).

Episodic ataxia type 6

Episodic ataxia type 8

EA6 is an AD disorder which has been reported in three kindreds so far (Jen et al., 2005; de Vries et al., 2009; Pyle et al., 2015; Iwama et al., 2018). The first EA6 case was a female child with recurrent attacks of ataxia with dysarthria, seizures, migraine, and prolonged alternating hemiplegia which lasted for days and were triggered by mild head trauma or febrile illness (Jen et al., 2005; Iwama et al., 2018). Her brain MRI revealed mild cerebellar atrophy and unilateral cortical hyperintensity most prominent in fluid-attenuated inversion recovery (FLAIR) and consistent with the hemibody affected by hemiplegia (Jen et al., 2005; Iwama et al., 2018). An EEG showed subclinical seizure activity in the left frontal temporal cortex and diffuse slowing on the right (Jen et al., 2005; Iwama et al., 2018). Subsequently, De Vries et al. reported a Dutch family with three affected individuals manifesting with typical EA2-like symptoms, including episodes of cerebellar dysfunction with a duration of several hours, interictal nystagmus, and response to acetazolamide (de Vries et al., 2009). Finally, a third family with two individuals affected with EA6 manifesting with episodes of cerebellar ataxia, dysarthria, and jerky pursuit was described (Pyle et al., 2015). EA6 is associated with monoallelic variants in SLC1A3, which maps on chromosome 5p13.2 and encodes the high-affinity excitatory amino acid transporter EAAT1 (Jen et al., 2005). EAAT1 is a trimeric complex which regulates neuronal excitability by coupling sodium-potassium-hydrogen-glutamate to rapidly remove glutamate from synaptic clefts (Malik and Willnow, 2019). Functional studies showed that variants in SLC1A3 lead to a reduced capacity of the glial EATT1 and reduced glutamate uptake, which may result in neural hyperexcitability and cause seizures and alternating hemiplegia (Jen et al., 2005; Malik and Willnow, 2019).

The locus EA8 was designated based on one single Irish kindred with 13 affected individuals over three generations (Conroy et al., 2014). The affected people presented with early childhood-onset episodes of unsteadiness, generalized weakness, and dysarthria. Additional clinical features include myokymia, nystagmus, and migraine without aura (Conroy et al., 2014). Attacks lasted from minutes to hours and were triggered by fatigue and stress (Conroy et al., 2014). In this kindred, the disease locus was mapped to an 18.5-Mb region at 1p36.13–p34.3, in which the Authors identified UBR4 as the possible causative gene since its protein product (i.e., ubiquitin protein ligase E3 component N-recognition 4) is predicted to interact with calmodulin and inositol 1,4,5-triphosphate receptor type 1 (ITPR1) (Conroy et al., 2014). The ITPR1 gene has been linked to AD SCA15 as well as AD and autosomal recessive SCA29 (Storey, 1993; Dudding et al., 2004; Klar et al., 2017). Although further evidence on this gene is needed to establish the phenotype, the association between rare heterozygous variants in UBR4 and EA has been replicated in a few cases (Choi and Choi, 2016).

Episodic ataxia type 7 EA7 was designated on the identification of a four-generation pedigree with seven members experiencing episodes of ataxia, muscle weakness, and dysarthria lasting between a few hours and 3 days (Kerber et al., 2007). Neurologic assessment was unremarkable in between attacks (Kerber et al., 2007). Episodes were triggered by excitement or exercise. In all, the affected age of

Episodic ataxia type 9 EA9 is characterized by episodes of cerebellar dysfunction manifesting with gait ataxia, dizziness, dysarthria, headache, vomiting, pain, or a combination thereof (Schwarz et al., 2019). The onset of symptoms was between the age of 6 months and 6 years in 21 subjects reported so far, with attacks occurring every few weeks or months and the episode duration ranging between minutes and hours (Schwarz et al., 2019). During the disease course, the onset of spells of cerebellar dysfunction was often preceded by neonatal- or infantile-onset tonic or generalized tonic–clonic seizures (benign familial infantile-neonatal seizure, BFNIS) which could be pharmacoresistant but usually remitted during infancy or early childhood. Some EA9 cases present with mild motor and/or speech and language developmental delay and/or autistic features or mildly impaired intellectual disability. However, others show normal psychomotor development. Interestingly, ataxic spells do not respond to sodium channel blockers, suggesting a distinct pathophysiologic mechanism, which, however, has not been

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identified so far. Cases of EA9 responding to acetazolamide have been reported. Treatment of ataxic episodes with acetazolamide is effective in about 50% of patients (Schwarz et al., 2019). EA9 is caused by heterozygous disease-causing variants in SCN2A, which maps on chromosome 2q24.3 and encodes the alpha-subunit of the voltage-gated neuronal sodium channel Nav1.2. Gain-of-function SCN2A variants were first linked to BFNIS manifesting in the first 3 months of life and remitting with age, whereas loss-offunction SCN2A variants are associated with a complex neurodevelopmental disorder featuring epilepsy, intellectual disability, and autistic traits (Sanders et al., 2018).

Other episodic ataxia Spells of cerebellar dysfunction resembling those of primary EA occur as a minor clinical feature in the context of complex genetic disorders or in isolation, thus representing less common manifestations linked to genes originally described with other phenotypes (e.g., PxDassociated genes). As discussed above, PRRT2-related disorders encompass three major phenotypes, that is BFIS, PKD with or without infantile seizures, and the ICCA syndrome. However, approximately 5% of cases harboring PRRT2 variants exhibit clinical manifestations such as EA, HM, developmental delay, and intellectual disability. The phenotypic heterogeneity of PRRT2associated disorders remains unexplained since most variants are loss-of-function, and no phenotype–genotype correlation has hitherto been identified (Gardiner et al., 2012). A further confirmation of the weak boundaries between EA and PxD is represented by the Glut1 deficiency syndrome (see above), which can manifest with a prominent EA phenotype, either isolated or combined, with ataxic spells responding to acetazolamide (Tchapyjnikov and Mikati, 2018). Episodes of vertigo, dizziness, and unsteadiness which are often triggered by febrile illness and show variable age at onset, duration, and frequency have been associated with monoallelic variants in the FGF14 gene. Nystagmus and tremor are described as interictal manifestations (Piarroux et al., 2020). FGF14 (chromosome 13q33.1) codes for fibroblast growth factor 14 and is highly expressed in granule and Purkinje cells, where it modulates the gating and axonal targeting of sodium and calcium channels (Piarroux et al., 2020). Intriguingly, the same gene is linked to SCA27, an adult-onset slowly progressive complex cerebellar ataxia, which again confirms the existence of overlapping pathomechanisms underpinning paroxysmal and permanent cerebellar dysfunction (Brusse et al., 2006). Finally, genes associated with mitochondrial disorders, such as PDHA1, DARS2, and TPK1, have been

described with episodic cerebellar dysfunction as a minor clinical feature in single cases. In these patients, laboratory findings, such as the detection of CSF and plasma lactic acidosis never found in primary EA, clearly pointed toward a mitochondrial etiology (Giunti et al., 2020).

CONCLUSIONS The clinical and genetic similarities among paroxysmal disorders are herein covered; in addition, neurologic episodic disorders including epilepsy and migraine are emerging and represent the premises for the conception of a shared pathophysiologic framework, which might prove as a great occasion to develop specific therapies. In fact, increased understanding of the genetic underpinnings of these conditions has provided insights into the shared mechanisms, revealing the role of ion channels and of proteins associated with the vesical synaptic cycle or involved in energy metabolism. There, however, remain unsolved questions to be answered. Whereas the expression patterns of some of the proteins responsible for PxD (i.e., PRRT2 and TMEM151A) seem to explain the age-dependent development of clinical features in humans and might further implicate some of these genes (i.e., PRRT2) in neurodevelopment, it is still difficult to explain how the same mutation in a certain gene can cause different phenotypes either in a given patient or family, or in separate families. Future studies should address this issue by exploring the putative role of modifier genes or environmental factors on phenotypic variability. In fact, the brain localization of the specific mutated protein does not seem to entirely explain the clinical phenotype. For instance, PNKD is also expressed at the cortical level, yet without causing any “cortical” paroxysms except for migraine in a few subjects (Gardiner et al., 2012). It is therefore likely that modifier genes and interacting proteins play a role in modulating the clinical phenotype. Therefore, one of the main objectives for future research should be shifting from the identification of the underlying single molecular cause of these conditions to the development of pharmacogenomics and related tailored therapeutic strategies (Tan et al., 2016).

ABBREVIATIONS Ach, acetylcholine; AD, autosomal dominant; ADCY5, adenylate cyclase 5; ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; AHC, alternating hemiplegia of childhood; ATP, adenosine triphosphate; ATP1A2, ATPase Na+/K+ transporting subunit alpha 2; ATP1A3, ATPase Na+/K+ transporting subunit alpha 3; BFIS, benign familial infantile seizures; BFNIS, benign

PAROXYSMAL MOVEMENT DISORDERS familial infantile-neonatal seizure; CACNA1A, calcium voltage-gated channel subunit alpha 1A; CACNB4, calcium voltage-gated channel auxiliary subunit beta 4; cAMP, cyclic adenosine-30 ,50 -monophosphate; CAPOS cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss; CBZ, carbamazepine; CHRNA4, cholinergic receptor nicotinic subunit alpha 4; CHRNB2, cholinergic receptor nicotinic subunit beta 2; COS, CV-1 in origin, carrying SV40; CSF, cerebrospinal fluid; DARS2, mitochondrial aspartyl-tRNA synthetase 2; D-DEMØ, dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø); DEPDC5, dishevelled, Egl-10, and Pleckstrin domain containing 5; DLAT, dihydrolipoamide S-acetyltransferase; EA, episodic ataxia; EA1, episodic ataxia type 1; EA2, episodic ataxia type 2; EA3, episodic ataxia type 3; EA4, episodic ataxia type 4; EA5, episodic ataxia type 5; EA6, episodic ataxia type 6; EA7, episodic ataxia type 7; EA8, episodic ataxia type 8; EA9, episodic ataxia type 9; EAAT1, excitatory amino acid transporter 1; ECHS1, enoyl-CoA hydratase, short chain 1; EEG, electroencephalogram; EKG, electrocardiogram; ER, endoplasmic reticulum; FGF14, fibroblast growth factor 14; FLAIR, fluid-attenuated inversion recovery; FOXG1, forkhead box G1; fT3, free triiodothyronine; GABA, gammaaminobutyric acid; GABBR2, gamma-aminobutyric acid type B receptor subunit 2; GABRA1, gammaaminobutyric acid type A receptor subunit alpha 1; GAP, GTPase-activating-protein; GATOR1, GTPaseactivating-protein activity toward rags; GCH1, GTP cyclohydrolase 1; Glut1, glucose transporter type 1; GNAO1, G protein subunit alpha O1; HEK, human embryonic kidney; HM, hemiplegic migraine; ICCA, infantile convulsions with choreoathetosis; ITPR1, inositol 1,4,5-triphosphate receptor type 1; KCNA1, potassium voltage-gated channel subfamily A member 1; KCNA2, potassium voltage-gated channel subfamily A member 2; KCNMA1, potassium calcium-activated channel subfamily M alpha 1; LOD, logarithm of the odds; MCT8, monocarboxylate transporter type 8; MR-1, myofibrillogenesis regulator 1; MRI, magnetic resonance imaging; mTORC1, mechanistic target of rapamycin complex 1; nAChR, nicotinic acetylcholine receptor; OCZ, oxcarbazepine; OMIM®, Online Mendelian Inheritance of Man; PDC, pyruvate dehydrogenase complex; PDHA1, pyruvate dehydrogenase E1 subunit alpha 1; PDHX, pyruvate dehydrogenase complex component X; PED, paroxysmal exercise-induced dyskinesia; pH, potential of hydrogen; PHD, paroxysmal hypogenic dyskinesia; PKD, paroxysmal kinesigenic dyskinesia; PNKD, paroxysmal nonkinesigenic dyskinesia; PRRT2, proline-rich transmembrane protein 2; PxD,

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paroxysmal dyskinesia; RIM(s), synaptic regulation Rab3-interacting molecule(s); RNA, ribonucleic acid; SCA15, spinocerebellar ataxia type 15; SCA27, spinocerebellar ataxia type 27; SCA6, spinocerebellar ataxia type 6; SCN2A, sodium voltage-gated channel subunit alpha 2; SCN8A, sodium voltage-gated channel subunit alpha 8; SLC16A2, solute carrier family 16 member 2; SLC1A3, solute carrier family 1 member 3; SLC2A1, solute carrier family 2 member 1; SNAP25, synaptosome-associated protein 25; TMEM151A, transmembrane protein 151A; TPK1, thiamine pyrophosphokinase-1; t-SNARE, target-localized soluble N-ethylmaleimide-sensitive-factor attachment protein receptor; UBR4, ubiquitin ligase E3 component n-recognition 4; VAMP2, vesicle-associated membrane protein 2.

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Tomlinson SE, Rajakulendran S, Tan SV et al. (2013). Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1. J Neurol Neurosurg Psychiatry 84: 1107–1112. Unterberger I, Trinka E (2008). Diagnosis and treatment of paroxysmal dyskinesias revisited. Ther Adv Neurol Disord 1: 4–11. Valente P, Castroflorio E, Rossi P et al. (2016). PRRT2 is a key component of the ca(2+)-dependent neurotransmitter release machinery. Cell Rep 15: 117–131. VanDyke DH, Griggs RC, Murphy MJ et al. (1975). Hereditary myokymia and periodic ataxia. J Neurol Sci 25: 109–118. Wang D, Pascual JM, De Vivo D (1993). Glucose transporter Type 1 deficiency syndrome. In: MP Adam, HH Ardinger, RA Pagon et al. (Eds.), GeneReviews((R)). University of Washington, Seattle, WA. Wang JL, Cao L, Li XH et al. (2011). Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain 134: 3493–3501. Weber YG, Storch A, Wuttke TV et al. (2008). GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest 118: 2157–2168. Weber YG, Kamm C, Suls A et al. (2011). Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect. Neurology 77: 959–964. Weber A, Kohler A, Hahn A et al. (2013). Benign infantile convulsions (IC) and subsequent paroxysmal kinesigenic dyskinesia (PKD) in a patient with 16p11.2 microdeletion syndrome. Neurogenetics 14: 251–253. Westenberger A, Max C, Bruggemann N et al. (2017). Alternating hemiplegia of childhood as a new presentation of adenylate cyclase 5-mutation-associated disease: a report of two cases. J Pediatr 181: 306–308.e301. Wu L, Tang HD, Huang XJ et al. (2014). PRRT2 truncated mutations lead to nonsense-mediated mRNA decay in paroxysmal Kinesigenic dyskinesia. Parkinsonism Relat Disord 20: 1399–1404. Yang L, You C, Qiu S et al. (2020). Novel and de novo point and large microdeletion mutation in PRRT2-related epilepsy. Brain Behav 10: e01597. Zhang X, Huang Z, Liu J et al. (2021). Phenotypic and genotypic characterization of DEPDC5-related familial focal epilepsy: case series and literature review. Front Neurol 12: 641019. Zhao SY, Li LX, Chen YL et al. (2020). Functional study and pathogenicity classification of PRRT2 missense variants in PRRT2-related disorders. CNS Neurosci Ther 26: 39–46.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00028-4 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 18

Pediatric neuropsychiatric disorders with motor and nonmotor phenomena DAVID S. YOUNGER1,2* 1

Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States

2

Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States

Abstract The concept of pediatric autoimmune neuropsychiatric disorders associated with group A beta-hemolytic streptococcus (PANDAS) has become seminal since first introduced more than two decades ago. At the time of this writing, most neurologists, pediatricians, psychiatrists, and general pediatricians will probably have heard of this association or treated an affected child with PANDAS. The concept of an acute-onset, and typically self-limited, postinfectious autoimmune neuropsychiatric disorder resembling PANDAS manifesting vocal and motor tics and obsessive-compulsive disorder has broadened to other putative microbes and related endogenous and exogenous disease triggers. These disorders with common features of hypometabolism in the medial temporal lobe and hippocampus in brain 18fluorodeoxyglucose positron emission tomography fused to magnetic resonance imaging (FDG PET-MRI), form a spectrum: with the neuropsychiatric disorder Tourette syndrome and PANDAS with its well-defined etiopathogenesis at one end, and pediatric abrupt-onset neuropsychiatric syndrome (PANS), alone or associated with specific bacterial and viral pathogens, at the other end. The designation of PANS in the absence of a specific trigger, as an exclusionary diagnosis, reflects the current problem in nosology.

INTRODUCTION There are new scientific terms to describe the factors associated with postinfectious immunity (Rappaport and Smith, 2010). The exposome relates all microbes in the environment with which we come in contact. With the human microbiome being the sum of the microbiota, the infectome comprises pathogenic microbes alone. Every infectious event evokes an inflammatory immune response directed against an intruding microbe. However, the response is generally self-limited and associated with full recovery. Imaging the host immune response and its effects on major brain networks has been challenging in neuropsychiatric disorders expressing motor and nonmotor manifestations. 18Fluorodeoxyglucose positron emission

tomography (PET) reveals the metabolic landscape of abnormal brain networks that give rise to motor and vocal tics (Pourfar et al., 2011) in Tourette syndrome (TS), distinguishing patients from controls. A similar strategy has been applied to the understanding of immune-related limbic encephalitis (LE) (Deuschl et al., 2020), pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal (GAS, PANDAS) (Nave et al., 2018) and autoimmune synaptic encephalitides (Graus et al., 2016). This chapter addresses the historical background, epidemiology, nosology, clinical presentation, laboratory investigation, and differential diagnosis and appropriate management of pediatric neuropsychiatric disorders, notably in the context of offending microbial pathogens, and their propensity to result in wide-ranging neuromotor

*Correspondence to: David S. Younger, MD, DrPH, MPH, MS, 333 East 34th Street, Suite 1J, New York, NY, 10016, United States. Tel: +1-212-213-3778, Fax: +1-212-213-3779, E-mail: [email protected]

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and neuropsychiatric sequelae in the context of hostrelated genetics and immunity.

as antigen-presenting cells (APCs) (Hamilos, 1989) through the expression of phagocytic receptors, Toll-like receptors (TLRs), and presentation of foreign antigens to B-cells and T-helper (TH or TH) cells (Zhu, 2018).

BACKGROUND Microbiome milieu The microbiome (Lederberg and McCray, 2001) refers to the ecological community of commensal, symbiotic, and pathogenic microorganisms sharing the host’s body space. Relman (1999) introduced modern molecular, cultivation-independent methods revealing the far greater distribution and diversity of microorganisms than originally thought. The human microbiome may be studied in different biological states using gene sequencing techniques employing 16S ribosomal ribonucleic acid (RNA) (Watts et al., 2017) to examine short nucleotide base sequences, which can be compared to stored libraries from numerous known pathogens. With more than 90% of cells in the human microbiome understood to be bacterial, viral, parasitic, fungal, or otherwise nonhuman in nature, and human metabolism and immunity attributed to the molecular genetic contribution of microbial and human interaction, human beings can be regarded as superorganisms.

Infection activates immunity The immune system is composed of innate (nonspecific) (Hejrati et al., 2020) and adaptive (specific) (Bonilla and Oettgen, 2010) arms that function interdependently. The innate system recruits antigen-specific responses by attracting cells to the site of infection and by transporting antigen to lymphoid tissues, with activation of adaptive effector cells, guided by the recognition of microbial antigens as either nonself or missing self. The former concept involves immune recognition of pathogenassociated molecular patterns (Kim et al., 2016) by pattern recognition receptors. The recognition of missing self is based on the recognition of molecules expressed only on normal, uninfected cells of the host. A primary immune response to a microbial pathogen that is identified and phagocytosed engenders an acute-phase response that attracts circulating neutrophils (Liew and Kubes, 2019), macrophages (Davies et al., 2013), natural killer (NK) (Liu et al., 2021) and dendritic cells (DCs) (Waisman et al., 2017), with secretion of complement proteins and cytokines, notably interleukins (IL) that resolve the infection. This first antigenic encounter initiates immunologic memory that affords protection against secondary challenges through the adaptive immune response begins with the actions of DCs acting

ADAPTIVE IMMUNITY B-cells (Mauri and Bosma, 2012) mature from pluripotent hematopoietic stems cells in the bone marrow and further differentiate into plasma cells and memory cells capable of producing antibodies, latching onto their targets in a lock-and-key specific fashion by surface B-cell-receptors (Treanor, 2012) that recognize cells displaying foreign antigens. They play key roles in immunity beyond antibody production, also serving as APCs, to produce cytokines that alter adaptive and innate cell effector functions (Dang et al., 2014). Through their initial contact between antigen-primed DC bearing peptide major histocompatibility (MHC) class II molecules (Rocha and Neefjes, 2008) and a naïve Th cells expressing a T-cell receptor (TCR) competent to recognize the soluble peptide (pMHC) class II displayed on the DC in the trimolecular complex (Hohlfeld, 1989), there ensues a Th cognate control of antigen-primed B-cells that direct a cell switch response (Huang, 2020) that activates peripheral blood development and entry in the germinal center for further differentiation and memory specificity. The lineage of T-cells is also derived from pluripotent hematopoietic stem cells in the bone marrow that pass though the thymus gland, where they achieve their final maturation, and become the most protective in recognizing virus-infected cells. Cytokines produced by antigenprimed B-cells control T-cell polarization, including CD4+ T-effector(eff ) cells (Th2, Th1, and Th17) (Mueller et al., 2013), regulatory T-cells (Treg) (Yin et al., 2021), and NK cells, each category of which provides specialized functions in the adaptive immune response. Th1 cells secrete interferon (INF)-g and activate macrophages, NK cells, and CD8+ T cells and play a key role in defense against intracellular pathogens. Th2 cells secrete IL-4, IL-13, and IL-25, providing an important barrier defense at mucosal and epithelial surfaces, and mobilizing and activating eosinophils, basophils, mast cells, and alternatively activated macrophages. Th17 cells secrete IL-17, IL-6, and tumor necrosis factor (TNF)-a, regulating acute inflammation, and work in concert with neutrophils in defense against extracellular bacteria. Pathogenic Th17 (Bot and Rossi, 2015) cells play a crucial role in the induction of autoimmune tissue injury while FoxP3+ regulatory T-cells (Sakaguchi et al., 2010) inhibit autoimmune tissue injury (Bettelli et al., 2006).

PEDIATRIC NEUROPSYCHIATRIC DISORDERS WITH MOTOR AND NONMOTOR PHENOMENA 369

Autoimmunity Autoimmune disease occurs when tissue damage is mediated by self-reactive (autoreactive) B-cell secreting antibodies and Teff-cells. Numerous tolerance mechanisms exist to limit potentially dangerous autoreactive cells, the disruption of immunoregulatory pathways that limit B-cell self-reactivity including receptor editing, clonal deletion, and anergy (Luning Prak et al., 2011). Idiopathic autoantibodies can arise as a result of breaches in central or peripheral tolerance selection checkpoints (Meffre and Wardemann, 2008). The binding of autoantibodies to self-antigens leads to the formation of immune complexes that activate innate effector functions via Fc-receptor activation of the complement cascade. However, other considerations need to be considered for the development of postinfectious autoimmunity. I-cubed (I3) (Younger, 2020) is shorthand for the multiplier effect of infection, immunity, and inflammation underlying postinfectious autoimmunity which postulates the evolution of autoimmune neurological and neuropsychiatric illnesses that evolve beyond a standard course of antibiotic treatment, when protective hostimmunity becomes the source of brain autoimmunity, conditioned by applicable environmental and predisposing genetic factors (Ermann and Fathman, 2001). The next section addresses the brain milieu and diseasespecific reactions that occur as a result of blood-brain barrier (BBB) disruption and activation of brain microglia in the course of postinfectious immunity.

BRAIN MILIEU Blood-brain barrier The BBB is comprised of a neurovascular unit of capillary vascular and neural cells, extracellular matrix components, and immune cells. Additional interactive cells include perivascular macrophages that reside between astrocyte end feet, resident microglia, and transmigrating leukocytes that penetrate the intact BBB via interactions with cellular adhesion molecules and mediate bidirectional cross talk for normal surveillance (Neuwelt et al., 2011; Benarroch, 2012; Daneman, 2012). BBB disruption accompanies a variety of inflammatory, autoimmune, and infectious conditions, with abnormal entry of plasma components, immune molecules, and cellular elements. There are mechanisms of BBB invasion that include the secretion of pore-forming toxins into brain microvascular endothelial cells (Nizet et al., 1997; Zysk et al., 2001; Lembo et al., 2010) with the production of higher toxin levels through a process involving IL-8 and intracellular adhesion molecule (ICAM) 1 enhancement (Doran et al., 2016). The complexity of the BBB

and the array of diseases, in which several components are affected, necessitates a multimodal approach to imaging these changes in vivo. Magnetic resonance imaging (MRI)-based assessment of BBB integrity is typically performed via T1-weighted dynamic contrast-enhanced (DCE) images (Wilhelm et al., 2016). [18F]fluorodeoxyglucose positron emission tomography (FDG PET) has less spatial resolution than MRI, but greater sensitivity for in vivo imaging of transport mechanisms, such as glucose transporter protein type 1 (GLUT1)-mediated glucose uptake in the brain (Zimmer et al., 2017), the dysfunction of which leads to images of parenchymal hypometabolism.

Brain microglia The immune system plays key roles in CNS development and refinement of neural networks through the interaction of resident brain microglia and local cytokines (Wolf et al., 2017). Microglia invade the brain early in development and transform into highly ramified phenotypes that act in surveilling the environment. At the synaptic level, microglia play a major role in synaptic pruning during postnatal development (Paolicelli et al., 2011). Activation of microglia strongly influences the pathologic outcome and response to stressors with release of cytokines, chemokines, and growth factors, and the orchestration of interacting infiltrating T-cells (Fig. 18.1). When microglia polarize into distinct proinflammatory phenotypes, they indirectly contribute to BBB dysfunction and vascular leak, while antiinflammatory microglia that serve a protective role can act in a stabilizing fashion (Ronaldson and Davis, 2020). Cerebral glucose uptake in humans is strongly influenced by microglial activity, and their activation in turn contributes to FDG PET signal alterations in patients with neurodegenerative diseases (Xiang et al., 2021). When microglia are activated from their resting state, they express high levels of the 18-kDa translocator protein receptors present on the outer mitochondrial membrane of microglia, which can be measured in vivo in the brain with the PET radiotracer [11C]PBR28 (Sandiego et al., 2015) and PK (Cagnin et al., 2002). This coupling between brain glucose hypometabolism and local immune responses due to significant and extended microglial activation seen on brain 18FDG-PET (Tondo et al., 2020) makes brain PET a useful biological marker for microglial-related pathological processes.

Cytokines Cytokines play critical roles in synaptic plasticity, especially in the temporal lobe hippocampus (HPC)

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Fig. 18.1. Activation of brain microglia. Microglia can develop a broad range of functional phenotypes. Their plasticity and their sensitivity to external signals enable fine control of their function, but also predispose them to develop maladaptive functions in response to dysregulated environmental signals. In response to compounds that cause degeneration (A), such as LPS and aggregated b-amyloid (Ab), naı¨ve microglia become activated via innate immunity (red arrows and far left). Microglia differentiate into phagocytes (B) that exhibit a cytotoxic phenotype and secrete tumor necrosis factor (TNF)-a and nitric oxide (NO) (C) and inhibit microglia to express major histocompatibility class II (MHC)-2 and to differentiate into antigen-presenting cells (APCs) (E). T-cells that infiltrate the brain and participate in a dialog with resident microglia (yellow arrows, and far right) include helper T-1 (Th1) cells that produce interferon (IFN)-g) and Th2 cells that produce interleukin (IL)-4), both inducing microglia to express MHC-II and B7-2 to function as APCs (D). Th2 cells releasing IL-4 downregulate TNF-a (a prominent player in the destructive phenotype of microglia) and upregulate IGF-1 (F). Once microglia are committed to a destructive phenotype under the influence of TNF-a, they lose their beneficial features and show impaired ability to cooperate with adaptive immunity and no longer function as APCs (G). Reproduced from Schwartz, M., Butovsky, O., Br€uck, W., et al., 2006. Microglial phenotype: is the commitment reversible? Trends Neurosci 29, 68–74 with permission.

and striatum, which may be relevant to pediatric neuropsychiatric illness. In vitro assays of organotypic HPC slices cocultured with microglia and aggregated lipopolysaccharide (LPS) serve as a model of brain adaptive immunity accompanied by the expression of major cytokine characteristics. In this model, investigators (Butovsky et al., 2006). showed that INF-g and IL-4, characteristic of proinflammatory and antiinflammatory T-cells, stimulated microglia to become neuroprotective. This was attributed to downregulation of TNF-a and upregulation of insulin-like growth factor (IGF) 1. However, the microglial phenotype of cytotoxicity correlated with expression of INF-g and enhanced activity of a signal transduction pathway with downregulating expression of class-II MHC proteins. In this model of protective autoimmunity, investigators (Butovsky et al., 2006) suggested that the beneficial or harmful expression of brain microglia depended on how they interpreted the threat, and that a well-regulated T-cell mediated response enabled them to alleviate, rather than exacerbate, stressful CNS situations. IL-1ß is a key proinflammatory cytokine that impairs long-term potentiation (LTP) in HPC (Prieto et al., 2019),

and in the striatum, its expression reduces the amplitude of excitatory postsynaptic currents within medium spiny neurons (Di Filippo et al., 2016), mediated by a Ca2+, calcium/calmodulin-dependent protein kinase II, and glutamate receptor (GluN2A) N-methyl-D-aspartate (NMDA) family-dependent mechanisms. TNFa, which is recognized for its role in regulating trafficking of neurotransmitter receptors, is upregulated in the striatum after a period of prolonged D2 dopamine (DA) blockade, and may be an adaptive regulator of synaptic strength (Lewitus et al., 2014). All of these processes have direct implication for pediatric neuropsychiatric disorders, with abnormal nonmotor and motor phenomena as discussed further below.

NEUROPSYCHIATRIC DISORDERS Tourette syndrome BACKGROUND Tourette syndrome (TS), named in honor of
Georges Albert Edouard Brutus Gilles de la Tourette (1857–1904), a pupil of Jean-Martin Charcot, both

PEDIATRIC NEUROPSYCHIATRIC DISORDERS WITH MOTOR AND NONMOTOR PHENOMENA 371 neurologists at the Salp^etrière hospital in Paris (Gilles de la Tourette, 1885), is a prototypical neuropsychiatric tic disorder that affects 4–6 of 1000 children (Bloch and Leckman, 2009; Serajee and Mahbubul Huq, 2015). It overlaps with obsessive-compulsive disorder (OCD) (Scharf et al., 2012) with a prevalence, in the latter, of 17% (Kurlan et al., 2001, 2002) to 41.7% (Apter et al., 1993) in community affected cases, with a lifetime prevalence of 66% (Hirschtritt et al., 2015). Although OCD typically emerges within a year of TS, one longitudinal analysis (Openneer et al., 2022) found that OC behaviors were a consistent predictor of tic onset, as did another study (Coles et al., 2011) that identified subthreshold OC behaviors present up to 5 years before meeting criteria for the diagnosis of OCD. TS is defined by the presence of two or more motor tics and at least one vocal tic, although not necessarily concurrently with onset 50% improvement in OC symptoms for 8 weeks after infusing 1 g/kg of IVIg every 3 weeks for 6 treatments. However, there were several limitations in this study: (1) the sample size (n ¼ 21) was small; (2) there was no control group; (3) the patient population was heterogeneous with differing ages (mean age 10.8 years, range 4–16 years) and duration of illness (mean 4.3 years, range 3–9 years), and antecedent treatments (all of whom received antibiotics, while some received CS and ADHD medications, and one subject received prior IVIg); (4) moreover, disease triggers were also diverse including GAS (PANDAS) cases; and (5) biomarkers were uninterpretable due to interference of IVIg. More recently, an Octapharma USA Inc. sponsored phase III RCT of the superiority of Panzyga 10% IVIg to placebo at 18 weeks with a crossover design (RCT NCT04508530) has been enrolling children with both PANS and PANDAS at six US study sites belonging to

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a network of nationwide pediatric clinics under the umbrella term, children’s postinfectious autoimmune encephalopathy (CPAE or PAE), adding yet another confusing clinical label to the existing nosology. Eligible subjects, similar to the designation of CPAE cases, have a myriad of pediatric disorders in association with OCD (including tic and restrictive eating disorders, severe anxiety, migraines, irritability and aggression, depression, age regression, sensory sensitivity, bedwetting, and hallucinations). One obvious study limitation is the lack of a standardized terminology and distinctive etiopathogenesis for PANS (consistent with the exclusionary nature of the diagnosis) (Chang et al., 2015), which with absent disease biomarkers, makes it difficult to test for, and understand the salutary effects of IVIg.

PANS with known postinfectious immune mechanisms In addition to GAS, two microbial pathogens, the novel coronavirus-2 (SARS-CoV-2) etiologic agent of the COVID-19 pandemic, and Borrelia burgdorferi spirochete (Burgdorfer et al., 1982), the vector of Lyme disease, each with well-described postinfectious autoimmune mechanisms, may manifest abrupt onset of OCD as described in the vignettes below. Brain FDG PET-MRI in both patients showed a similar pattern of hypometabolism centering on the MTL and HPC.

COVID-19 NEUROLOGICAL ILLNESS Background PANS associated with COVID-19 is illustrated below in the previously reported child (Younger, 2021a). Patient vignette A previously described 12-year-old child (Younger, 2021a) was initially well until the beginning of the COVID-19 pandemic when she contracted an upper respiratory infection (URI) with loss of taste and excessive fatigue after exposure to other infected family members, testing positive for COVID-19 infection by a positive reverse-transcriptase polymerase-chainreaction (RT-PCR) on a nasopharyngeal swab. Soon afterward, she showed elevated serum SARS-CoV-2 IgG-specific antibodies, at the same time manifesting OCD behaviors. Neurological examination showed no focal deficits. The Mayo Clinic ENS2 panel showed an insignificant rise in the serum GAD65 antibody level (0.03 nmol/L, reference value 40 years) Body distribution Focal Segmental Multifocal Generalized (leg involvement) Hemidystonia Temporal pattern Disease course (static, progressive) Variability (persistent, action-specific, diurnal, paroxysmal) Associated features Isolated dystonia Combined dystonia Complex dystonia Axis II. Etiology Nervous system pathology Evidence of degeneration Evidence of structural lesion No evidence of degeneration or structural lesion Inherited (AD, AR, XLR, XLD, Mito) Acquired Perinatal brain injury Infection Toxic Vascular Neoplastic Brain injury Psychogenic Idiopathic (sporadic, familial) AD, autosomal dominant; AR, autosomal recessive; XLR, x-linked recessive; XLD: x-linked dominant, mito: mitochondrial.

ISOLATED AND COMBINED DYSTONIAS: UPDATE

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adolescent (12–20 years), and adult-onset (>20 years), for consistency, the committee proposed a similar scheme distinguishing infancy (birth to 2 years), childhood (3–12 years), early adulthood (21–40 years), and late adulthood (>40 years). The terms focal, segmental, multifocal, generalized, and hemidystonia were not substantially revised, except that trunk involvement in generalized dystonia is now considered a key feature and leg involvement an additional one. Two important added terms in associated features are the designation of isolated dystonia (excluding tremor) and combined dystonias (with other movement disorders such as myoclonus, parkinsonism, and others). Isolated dystonia encompasses many cases previously described as “pure” or “primary,” while patients previously classified under “dystonia plus” or heredodegenerative would now be classified as having combined dystonia. The term isolated or combined now refers to the phenomenology and does not carry implications about the underlying etiology. Thus, combined forms of dystonia no longer require dystonia to be the predominant movement disorder or the prominent motor phenomenology as observed in foot dystonia in Parkinson disease and the mild dystonic features of myoclonus dystonia. Finally, the presence or absence of other neurologic or systemic features includes nonmotor features and the expected cognitive decline typically observed in neurodegenerative or progressive dystonia syndromes (Evatt et al., 2011; Stamelou et al., 2012). An example of a combined dystonia syndrome is Wilson disease, in which dystonia is combined with other neurological or psychiatric symptoms and liver disease (Rosencrantz and Schilsky, 2011). Axis II of etiology designates the presence of neuropathology, supporting degeneration, structural lesions, or the absence thereof. The designations under inherited, which retains the DYT classification as a helpful list for designating subtypes, is not a classification system or hierarchy. The acquired etiologies for dystonia are broad and inclusive and are countered with idiopathic (of unknown cause) dystonia. Idiopathic dystonia can be either sporadic or familial cases of yet-undefined etiology, as the case is for focal or segmental isolated dystonia with onset in adulthood (Charlesworth et al., 2012; Fuchs et al., 2013). Once the dystonia syndrome is identified, classified, and a preliminary evaluation has taken place, the next step is to establish the likeliest etiology, which may entail a focused neurogenetic evaluation and pharmacotherapeutic trial.

(Gonzalez-Latapi et al., 2021). A new Table 21.2 shows common dystonia syndromes that subcategorize patients with different clinical syndromes but are united by similar mechanisms. The authors find this an asset in clinical diagnosis and possible future research trials and approaches to rational drug design.

PATHOGENESIS

Isolated dystonia

Notwithstanding all the progress, there’s a definite need for further classification of isolated and combined dystonia syndromes based on similar disease mechanisms

The isolated syndromes vary with the age of onset, degree of focal or segmental presentation, and association with a genetic predisposition.

Genetic and biochemical Etiology investigations are mainly focused on genetic studies. Depending on the dystonia syndrome diagnosis and index of suspicion, the testing can be as focused as a single gene or biochemical test to identify the etiology. More commonly, however, the dystonia syndrome identifies a group of genes that may be abnormal for which commercial target gene panels can be performed at low cost. Lastly, if the dystonia syndrome suggests a broad gene panel or initial investigations do not narrow down the differential, but a genetic cause is highly suspected, whole exome sequencing can be considered. Whole exome sequencing (WES) may also reveal new mutations in genes known to play a role in dystonia diseases. It can also reveal novel genes with a pathogenic role in dystonia. WES may identify variants of unknown significance (VUS); however, its relevance should be carefully interpreted in discussion with a medical geneticist. In select cases when dopa-responsive dystonia Parkinsonism (DRD) is in the differential, a diagnostic trial of carbidopa-levodopa medication may be sufficient as a second-line investigation. A robust improvement in symptoms may support the diagnosis and provide treatment direction. Similarly, patients with dystonia of the vocal folds show a robust response to sodium oxybate in research studies and this can be used as a diagnostic tool (Shanker and Bressman, 2016; Simonyan et al., 2018).

DYSTONIA SYNDROMES Dystonia syndromes may be regarded as isolated, combined, or complex. Combined dystonia refers to dystonia combined with other movement disorders (Albanese et al., 2013). Complex dystonia refers to dystonia in association with other neurological or systemic features. Complex dystonia is beyond the scope of this chapter, but more details can be found in the review by Herzog et al. (2021).

Table 21.2 Clinical neurogenetic classification of dystonia Temporal pattern Dystonia syndrome (gene/DYTn)

Gene chromosomal locus

OMIM phenotype#

Onset age

Body distribution

Disease course

Variability

Isolated dystonia: Disruption integrated stress response pathway TOR1A/DYT1a AD THAP1/DYT6b AD, AR PRKRA/DYT16c AR KMT2B/DYT28d AD, de novo

9q34 8p21-22 2q31.2 19q13.12

128100 602629 612067 617284

Childhood Adolescence Childhood Childhood

Generalized Generalized Generalized Focal-Arms

Progressive Progressive Progressive Progressive

Persistent Persistent Persistent Persistent

Neurodevelopmental diseases YY1e AD TUBB4A/DYT4f AD TSPOAP1g AR

14q32.2 19p13.3 17q22

617557 128101 –

Childhood Adolescence Childhood

Generalized Generalized Generalized

Progressive Progressive Progressive

Persistent Persistent Persistent

Signal abnormality of striatal medium spiny neurons HPCAh AR 1p35.1 ANO3/DYT24i AD 11p14.3-p14.2 GNAL/DYT25j AD 18p11.21

224500 615034 615073

Childhood Childhood Childhood

Generalized Focal-cervical Focal-cervical

Progressive Progressive Progressive

Persistent Persistent Persistent

Combined dystonia Dystonia Parkinsonism: Disease of dopaminergic signaling Dopa-responsive dystonia GCH1/DYT5Ak AD 14q13 TH/DYT5Bl AR 11p15.5 SPRm AR 2p13.2

128230 605407 612716

Childhood Infancy Infancy

Generalized Generalized Focal-Legs

Progressive Progressive Progressive

Diurnal Diurnal Diurnal

Dopa-unresponsive dystonia TAF1/DYT3n XL ATP1A3/DYT12o AD SLC6A3p AR

314250 128235 613135

Adulthood Childhood Childhood

Generalized Generalized Generalized

Progressive Progressive Progressive

Persistent Persistent Persistent

Dystonia myoclonus: alterations in the cerebello-thalamic pathway Alcohol-responsive dystonia SGCE/DYT11q AD 7q21.3 CACNA1B/DYT23r AD 9q34.3

159900 618497

Childhood Childhood

Generalized Generalized

Progressive Progressive

Persistent Persistent

Alcohol-unresponsive dystonia KCTD17/DYT26s AD

616398

Childhood/ adulthood

Segmental

Progressive

Persistent

Inheritance pattern

Xq13 19q13.2 5p15.33

22q12.3

Paroxysmal dyskinesias: Disease of protein mislocalization and stability PRRT2/DYT10t AD 16p11.2 MR1/DYT8u AD 2q35 SLC2A1/DYT9v AD 1p34.2 ECHS1w AR 10q26.3 a

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Paroxysmal Paroxysmal Paroxysmal Paroxysmal

30% gene penetrance with non-manifest carriers. 60% gene penetrance with non-manifest carriers. c Jaw or laryngeal dystonia, sardonic smile, and parkinsonism. d Developmental delay (microcephaly, short-stature, intellectual decline, dysmorphisms). e Neurodevelopmental syndrome (intellectual disability, behavioral problems, eye abnormalities and dystonic features). f Whispering dysphonia, hobbling gait, ptosis, edentulous, facial atrophy. g Mild learning disability, cranio-caudal spread of generalized dystonia, dysarthria, dysphagia. h Dystonic tremor, psychiatric features, cognitive impairment and learning difficulties. i Tremulousness, isolated arm tremor. j Hyposmia. k Dystonia beginning in legs in childhood and evolves into Parkinson’s disease in adulthood. l Milder form: abnormal gait; Severe form: seizures, cognitive impairment, hypotonia, dysphagia, developmental delay. m Axial hypotonia, developmental delay, oculogyric crisis, muscle weakness, Parkinsonism, generalized dystonia. n Jaw dystonia evolves to generalized dystonia parkinsonism. o Rapid onset dystonia parkinsonism, CAPOS syndrome, AHC syndrome. p Orolingual and limb dyskinesia, dystonia, chorea or parkinsonian features. q Appendicular myoclonus, focal dystonia, psychiatric abnormalities, genetic imprinting determines symptom manifestation. r Action myoclonus of legs, psychiatric abnormalities, painful cramps of limbs, cardiac arrhythmias. s Upper limb myoclonus, cranio-cervical spread of generalized dystonia. t Paroxosymal kinesigenic dyskinesia (PKD), hemiplegia migraine, episodic ataxia, responsive to carbamazepine. u Paroxsymal non-kinesigenic dyskinesia (PNKD I), response to benzodiazepine. v Paroxsymal exercise-induced dyskinesia (PED), migraine, clumsiness, oculogyric crises, response to thiamine and ketogenic diet. w PED, developmental delay, infantile encephalopathy, choreoathetosis, optic atrophy, cardiomyopathy, sensorineural hearing loss, Leigh syndrome. Abbreviations: AD, autosomal dominant; AR, autosomal recessive; XL, X-linked; DYTn, dystonia number; OMIM, online Mendelian genetics in man (OMIM®, n.d.); TOR1A, torsin-1A, THAP1, thanato-associated protein domain containing apoptosis-associated protein 1 (THAP1); KMT2B, histone-lysine N-methyltransferase 2B; YY1, Yin and Yang 1 transcription factor; TUBB4A, tubulin beta class IVA; TSPOAP1, RIMS-binding protein 1 (RIMBP1); HPCA, hippocalcin; ANO3, anoctamin 3; GNAL, guanine nucleotide-binding protein, alpha-activating activity polypeptide olfactory type; GCH1, GTP cyclohydrolase I; TH, tyrosine hydroxylase, SPR, sepiapterin reductase; TAF1, TATA box-binding protein-associated factor 1; ATP1A3, ATPase; Na+/K+, transporting alpha-3 polypeptide; PRKRA, protein kinase interferon-inducible double-stranded; RNA-Dependent Activator; SLC6A3, solute carrier family 6 (neurotransmitter transporter, dopamine) Member 3, SGCE, sarcoglycan epsilon; CACNA1B, calcium channel voltage-dependent N-type alpha-1B Subunit, KCTD17, potassium channel tetramerization domain-containing protein 17; PRRT2, proline-rich transmembrane protein 2; MR1, myofibrillogenesis regulator 1; SLC2A1, solute carrier family 2 (facilitated glucose transporter) member 1, ECHS1, enoyl-CoA hydratase short-chain I mitochondrial. b

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EARLY-ONSET GENERALIZED DYSTONIA Dystonias that begin in childhood and rapidly progress to generalized forms are often due to a single gene mutation exemplified by four early-onset generalized dystonias. The most common monogenetic dystonia is DYT1TOR1A due to a mutation at chromosome locus 9q34 (Ozelius et al., 1997; Weisheit et al., 2018). The gene

TOR1A encodes the protein Torsin-1A, which facilitates protein transport through the endoplasmic reticulum/ nuclear envelope endomembrane system (Goodchild and Dauer, 2004). Mutations in Torsin-1A result in defects in endoplasmic reticulum/nuclear envelope function and disrupt protein trafficking targeted to the secretory pathway (Fig. 21.1) (Gonzalez-Latapi et al., 2021). Biochemically, mutations in Torsin-1A impair

Fig. 21.1. Biological role of dystonia-genes implicated in specific cellular functions. Expression of critical genes for neuronal development and function (exemplified here by dopamine receptor) is controlled by the DYT-genes YY1, THAP1, KMT2B, and TAF1. PRKRA, EIF2AK1, and EIF2AK2 and TOR1A are involved in the integrated stress response through modulation of eIF2 activity, which in turn regulates protein synthesis. Several other genes implicated in dystonias regulate autophagy, mitophagy, and lysosome function, including SQSTM1, VPS16, VPS41, or encode lysosomal proteins, including lysosomal hydrolases (e.g., GLB1, FUCA1) or lysosomal membrane proteins (e.g., NPC1 and NPC2). Several dystonia genes also express mitochondrial enzyme (ECHSS1) and mitochondrial membrane proteins (MR1S, MR1L) that play a role in fatty acid degradation and oxidative stress. Lastly, dystonia genes also disrupt microtubule accumulation (TUBB4A) particularly in the basal ganglia and cerebellum. Adapted and modified from Gonzalez-Latapi P, Marotta N, Mencacci N (2021). Emerging and converging molecular mechanisms in dystonia. J Neural Transm 128: 483–498. https://doi.org/10.1007/s00702-020-02290-z.

ISOLATED AND COMBINED DYSTONIAS: UPDATE activation of the eukaryotic initiation factor 2 alpha (eIF2a) signaling pathway, also known as the integrated stress response (ISR), which bidirectionally regulates the switch from short- to long-term plasticity and memory (Costa-Mattioli et al., 2007; Rittiner et al., 2016). Symptoms begin in early childhood or adolescence with one leg and spread to the other leg, arms, trunk, or head over 5 years, with 50% of patients developing generalized dystonia. Those who do not manifest symptoms by age 27 are called nonmanifesting carriers (Weisheit et al., 2018). DYT1-TOR1A generalized dystonia is highly prevalent in Ashkenazi Jews, with an estimated frequency of 1/2000 (Risch et al., 1995; Fr
ed
eric et al., 2007) and gene penetrance of 30% (Weisheit et al., 2018). DYT6 causes an early-onset dystonia due to mutations in the thanato-associated protein domain containing apoptosis-associated protein 1 (THAP1), a zinc-finger transcription factor (Fig. 21.1). Loss-of-function truncating and missense mutations of the THAP1 gene at chromosome 8p21-22 impair the ability of THAP1 to localize to the nucleus, thus preventing it from interacting with DNA and leading to transcriptional dysregulation (Sengel et al., 2011). Transcriptional analyses in a THAP1 genetic mouse model further implicated eIF2a pathway dysregulation and disruption of the integrated stress response pathway in this dystonia (Zakirova et al., 2018). DYT6-THAP1 gene mutations manifest as an autosomal dominant (AD) early-onset generalized dystonia that ultimately dysregulates the transcription pathway with 60% gene penetrance (Roussigne et al., 2003; Fuchs et al., 2009; Blanchard et al., 2011). Symptom onset begins in late adolescence with upper limb or cranial involvement and then becomes generalized. Unlike DYT1-TOR1A, DYT-THAP1 manifests with speech impairment and less commonly shows lower limb involvement. A clinical evaluation of these patients may be sufficient to identify the dystonia syndrome. Confirmatory testing with a single gene or a targeted gene panel may also be sufficient to diagnose the dystonia etiology. DYT16-PRKRA was first described in unrelated Brazilian families with autosomal recessive (AR) progressive, generalized, early-onset axial dystonia. Affected subjects manifested with oromandibular dystonia, a “sardonic smile,” laryngeal dystonia, and parkinsonian features (Camargos et al., 2008). Since patients can also present with parkinsonian features, it is often classified under both the integrated stress response pathway and dystonia parkinsonism. The disorder is due to a mutation in the protein activator of the interferoninduced protein kinase (PRKRA) gene at the chromosomal locus 2q31.2. DYT16 is another dystonia involving the eIF2alpha/ integrated stress response pathway.

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A major role of the Prkra protein is to activate the PKR kinase and eIF2alpha signal (Fig. 21.1). But, DYT16 mutations alter the kinase pathway activation and compromise the integrated stress response pathway (Burnett et al., 2020). Although patients with DY16 mutations present with parkinsonian features, they are generally unresponsive to levodopa (Santos et al., 2018). DYT-KMT2B is a generalized form of dystonia with symptom onset in infancy or childhood (Zech et al., 2016; Meyer et al., 2017). Dystonic symptoms begin in the lower limbs with rare reports of onset in the larynx, neck, or trunk. Patients exhibit features of complex dystonia with laryngeal, axial, cervical, and craniofacial involvement, mild dysmorphic features, and signs of cognitive impairment, developmental delay, short stature, and microcephaly correlative with abnormalities on brain MRI (Balint et al., 2018; Jain et al., 2021). The KMT2B gene encodes a histone lysine methyltransferase, a protein involved in epigenetic transcriptional regulation (Fig. 21.1). KMT2B is required for the early steps of development and contributes to epigenetic patterns during the differentiation of embryonic stem cells. Therefore, dysregulation of these developmental and epigenetic processes may play a role in the DYT-KMT2B syndrome (Shao et al., 2014; Meyer et al., 2017). Furthermore, cells from patients with KMT2B gene mutations showed decreased TOR1A and THAP1 protein expression suggesting that KMT2B gene mutations may be an upstream regulator of these DYT genes (Meyer et al., 2017). The YY1 gene encodes yin and yang 1, a zinc-finger transcription factor that participates in different cellular processes, including the activation of genes encoding ribosomal proteins and repression of genes involved in neurodevelopmental disorders (Huang et al., 2012). Genomic analysis of THAP1 and YY1 demonstrates that the two transcription factors act as coregulators of genes essential for oligodendrocyte lineage progression and implicate abnormal timing of oligodendrocyte myelination and maturation in the pathogenesis of dystonia (Fig. 21.1) (Yellajoshyula et al., 2017). Mutations of the YY1 gene were recently described as a neurodevelopmental syndrome with intellectual disability, behavioral problems, eye abnormalities, and prominent dystonic features (Gabriele et al., 2017; Carminho-Rodrigues et al., 2020). Brain hypomyelination has also been implicated in dystonia caused by mutations in the TUBB4A gene. TUBB4A mutations are associated with defects in microtubule accumulation (Fig. 21.1) (Duncan et al., 2017). Patients manifest with a range of neurological conditions ranging from severe hypomyelination of the basal ganglia and cerebellum, where the gene is highly expressed, to a milder form of generalized dystonia (Kancheva et al., 2015). Dystonia symptoms begin with laryngeal

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involvement and closure of the vocal folds (Wilcox et al., 2011; Balint and Bhatia, 2015; Lange et al., 2021; Bally et al., 2022), which then progresses to involve the jaw, arm, or neck muscles, frequently becoming generalized. Patients present with whispering dysphonia, hobbling gait, ptosis, lack of teeth, and facial atrophy (Kancheva et al., 2015). Homozygous mutations of the TSPOAP1 gene encoding the active zone RIM-binding protein 1 were recently identified in three unrelated families with AR forms of

dystonia, ranging from severe and progressive generalized dystonia to more focal forms (Mencacci et al., 2020a). RIMBPs are components of the presynaptic active zone. They control the precise localization of presynaptic voltage-gated calcium channels (VGCCs) and ensure tight coupling between presynaptic action potentials and synaptic vesicle exocytosis (Fig. 21.2, inset). Both loss and gain of gene mutations led to the disruption of spike-evoked VGCC and contributed to the pathogenesis of dystonia (Mencacci et al., 2020a). Symptoms

Fig. 21.2. Role of dystonia-associated genes in pre-and post-synaptic dopaminergic signaling and in presynaptic neurotransmitter vesicle release. The red asterisk indicates that the gene has been implicated in monogenic dystonias or other related hyperkinetic movement disorders. Several genes associated with DOPA-responsive dystonias are directly (i.e., TH, AADC) or indirectly (GCH1, SPR, PTS, DNAJC12) involved in dopamine synthesis, dopamine vesicular packaging (SLC18A2; encoding the vesicular transporter VMAT2), dopamine reuptake (SLC6A3; encoding the dopamine transporter DAT) and synaptic transmission (SGCE and ATPase 1A3). Multiple DYT-genes are involved in the signaling cascade downstream of dopamine and adenosine receptor activation in striatal medium spiny neurons, including genes encoding components of the G-protein coupled receptor machinery (i.e., GNAO1, GNB1, GNAL) or proteins controlling cAMP signaling (ADCY5, PDE10A, PDE2A). Other DYT-genes with less defined roles but that are likely to modulate dopamine signaling in striatal neurons are HPCA (a calcium sensor that influences the activity of potassium and calcium channels), KCTD17 (an adaptor for E3 ubiquitination in involved in controlling levels of synaptic proteins), and ANO3 (encoding a calcium-activated chloride channel). Several DYT-genes (TSPOAP1, KCNMA1, KCNA1, CACNA1A, CACNA1B, SYT1, PRRT2, UNC13A, PNKD) encode proteins involved in neurotransmitter vesicle release at presynaptic machinery. Finally, mutation in the glucose transporter (SLC2A1) gene can lead to decreased CNS glucose concentration. Adapted and modified from Gonzalez-Latapi P, Marotta N, Mencacci N (2021). Emerging and converging molecular mechanisms in dystonia. J Neural Transm 128: 483–498. https://doi.org/10.1007/s00702-020-02290-z.

ISOLATED AND COMBINED DYSTONIAS: UPDATE manifested in childhood with mild learning disability followed in adolescence with progressive generalized dystonia that displayed a craniocaudal gradient resulting in loss of ambulation, prominent dystonia, dysarthria, and dysphagia (Mencacci et al., 2020a). DYT-HPCA is another generalized dystonia inherited in an AR pattern (Charlesworth et al., 2015). The HPCA gene encodes hippocalcin, a neuron-specific calciumbinding protein that plays a role in synaptically evoked long-term depression (Takamatsu et al., 1994), dopaminergic postsynaptic pathways, and is highly enriched in striatal medium spiny neurons (Fig. 21.2) (Mencacci et al., 2020b). Mutation of the HPCA gene manifests in childhood with leg and rare neck involvement, leading to generalized dystonia with cervical, craniofacial, laryngeal, and prominent psychiatric features, including anxiety, depression, cognitive impairment, and learning difficulties. Affected family members may show a similar range of symptoms ranging from mild isolated dystonia to complex dystonia with neurocognitive difficulties, jerking of the trunk and limbs, episodic muscle cramps, involuntary movements, and speech difficulty (Tisch, 2018; Magrinelli et al., 2022).

ADULT-ONSET FOCAL OR SEGMENTAL DYSTONIA Dystonia involving a single body part most often affects the neck. Symptoms manifest with abnormal head tilt, neck rotation, shoulder position, and head tremor without directionality but with a null point (Warner et al., 2000; Ortiz et al., 2018). The initial clinical evaluation may reveal a sensory trick that transiently alleviates dystonia (Albanese and Lalli, 2009). Blepharospasm (Warner et al., 2000; Ortiz et al., 2018), which results from contractions of the orbicularis oculi muscles and causes excessive blinking and eye closure often associated with bright lights (Grandas et al., 1988). Oromandibular dystonia affects jaw muscles leading to opening, closure, and deviations, with frequent involvement of the tongue, pharyngeal muscles, and lower face. Involvement of the jaw muscles with face and eyes is classified as a segmental dystonia, Meige syndrome (Raoofi et al., 2017). Isolated contraction of laryngeal muscles, termed laryngeal dystonia or spasmodic dysphonia, presents with difficulty speaking and frequent speech interruption affecting the voice quality and is named for the abnormality of the vocal cords in adduction or abduction. The adductor type has increased closure of vocal folds, making it challenging to vibrate and produce sounds and leading to a harsh strained voice with frequent speech cut-offs. The abductor type, which results from open vocal folds, precludes adequate vibration leading to a whispering and breathy voice. Rarely, mixed cases result from a combination of the two (Ludlow, 2011).

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Upper limb task-specific dystonias include writer’s cramp and musician’s dystonia. Those with writer’s cramp report involuntary flexion or extension of the fingers, wrist, and elbow during writing, resulting in decreased speed, fluency, and legibility of writing (Hallett, 2006). Some patients exhibit a mirror phenomenon. However, using the nonaffected hand can lead to spread of dystonia and involve the unaffected hand in up to 25% of patients (Marsden and Sheehy, 1990; Goldman, 2015). Musician’s dystonia develops in the third to the sixth decade among individuals who play piano, violin, guitar, brass, or woodwind instruments, with selective involvement of the hand, lips, or facial muscles (Frucht et al., 2001; Frucht, 2004). Isolated lower limb dystonia, which is far less common in adults (Warner et al., 2000; Ortiz et al., 2018), can begin during a specific task such as walking or running. Importantly, isolated lower limb dystonia typically abates when patients walk or run backward. Over time, task-specific lower limb dystonia may involve additional motor tasks (Fung et al., 2013). Two AD forms of isolated dystonia are DYT24ANO3 and DYT25-GNAL (Charlesworth et al., 2012; Kumar et al., 2014; Balint and Bhatia, 2015). DYT24-ANO3 begins in the neck and larynx, and DYT25-GNAL begins in the neck alone and can extend to the upper arms, orofacial regions, and larynx or even generalize. The ANO3 gene encodes anoctamin-3, a transmembrane protein that belongs to a family of calcium-activated chloride channels. The GNAL gene encodes the guanine nucleotide-binding protein G subunit alpha protein, which plays a role in the signal transduction of the olfactory neuroepithelium and the basal ganglia. Notably, a gene network analysis showed that both genes were associated with postsynaptic signaling pathways and striatal medium spiny neurons (Fig. 21.2) (Mencacci et al., 2020b).

RED FLAGS Five dystonia presentations should be considered red flags (Fung et al., 2013). Isolated oromandibular dystonia in young adults and children may be associated with Lesch-Nyhan disease, glutaric aciduria, neuroacanthocytosis, and NBIA (Jinnah et al., 2006; Schneider et al., 2006a; Bader et al., 2010; Schneider and Bhatia, 2010). Adult-onset limb dystonia lacking task specificity should be suspicious for the synucleinopathy of Parkinson’s disease, atypical Parkinsonism, or corticobasal degeneration (Schneider et al., 2006b; McKeon et al., 2008). Prominent truncal dystonia, especially opisthotonos (backward bending of the trunk) combined with retrocollis (extension of the neck), can be a manifestation of tardive dystonia in association with dopamine receptor

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antagonists (Fung et al., 2013); while opisthotonos with retrocollis in children should lead to suspicion of encephalitis, Lesch-Nyhan disease, and Gaucher disease (Kalita and Misra, 2000; Jinnah et al., 2006). While an adult generalized dystonia may raise red flags for a neurodegenerative process, hemidystonia at any age should raise concerns for stroke, tumor, or another contralateral structural lesion of the cerebral hemisphere (Bhatia and David Marsden, 1994).

Combined dystonia When considering combined dystonia syndromes, two factors should be considered: (1) When dystonia is associated with another movement disorder determine which movement is more dominant. If the nondystonic movement is dominant, then the differential diagnosis should rest with the latter (Fung et al., 2013). (2) Whether the condition is inherited or sporadic.

DYSTONIA PARKINSONISM Dystonia parkinsonism is among the more wellrecognized forms of combined dystonias (TrenderGerhard et al., 2009; Kurian et al., 2011).

Dopamine-responsive dystonia AD DRD also referred to as DYT5A-GCH1 dystonia or Segawa disease (Segawa et al., 2003), is due to a heterozygous mutation in GCH1 on chromosome 1n 4q13. GCH1 encodes the enzyme that converts GTP to tetrahydrobiopterin (BH4), the cofactor for tyrosine hydroxylase, which is also the rate-limiting enzyme for dopamine synthesis (Fig. 21.2). Affected adults present with Parkinson’s disease (Trender-Gerhard et al., 2009; Kurian et al., 2011). Conversely, onset in childhood presents with dystonia, typically affecting the legs more than the arms. Leg involvement may result in an abnormal gait and show diurnal variation of symptoms worsening in the evening (Trender-Gerhard et al., 2009; Kurian et al., 2011). DRD may also be caused by a rare AR mutation in the tyrosine hydroxylase (TH) gene (L€ udecke et al., 1996) at the 11p15.5 chromosome locus encoding the enzyme that converts L-tyrosine to L-3,4dihydroxyphenylalanine (L-DOPA) associated with leg dystonia and an abnormal gait in the milder form (Fig. 21.2). Such patients show diurnal variation and improvement with levodopa. A moderate form of DYT5B-TH manifests with infantile Parkinsonism and shows a moderate response to levodopa while a severe form does not show symptoms of dystonia or diurnal variation and instead manifests with seizures, cognitive

impairment, hypotonia, swallowing difficulties, and developmental delay with a poor response to levodopa (L€udecke et al., 1996). A third DRD subtype is caused by a homozygous or compound heterozygous mutation in the gene encoding sepiapterin reductase (SPR) at chromosome 2p13.2 (Steinberger et al., 2004). Sepiapterin reductase is an enzyme that catalyzes the final two-step reaction in the biosynthesis of BH4. Mutation of the SPR enzyme results in dopamine deficiency (Fig. 21.2) (Blau et al., 1998, 1999). Symptoms vary from mild DRD affecting children’s legs to a severe form in infants with generalized dystonia, parkinsonism, and oculogyric crisis. Diagnosis can be particularly challenging in infants due to the initial nonspecific clinical presentation with axial hypotonia, developmental delay, and generalized weakness. However, all affected individuals show diurnal variation in symptoms, which can be a clinical clue to DRD. Diagnosis can be confirmed by cerebrospinal fluid (CSF) analysis showing decreased 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) and increased 7,8-dihydropterin consistent with SPR deficiency or genetic testing showing biallelic pathogenic variants of the SPR gene. Levodopa therapy is the mainstay of treatment (Shanker and Bressman, 2016). Other heritable forms of dystonia-parkinsonism have been described often in small cohorts, with limited or no response to levodopa therapy. DYT3-TAF presents as an X-linked (XL) dystonia-parkinsonism introduced by a founder effect in the Filipino population. Referred to as “lubag,” meaning “twisted” (Evidente, 1993), affected males in their 30s first manifest spasmodic blinking, and then over 7 years, develop generalization, with parkinsonism accompanying or preceding segmental or generalized dystonia (Kawarai et al., 2017). The disorder is due to a mutation in the TAF1 gene at chromosome Xq13 that encodes for the TATA-binding protein-associated factor-1 (Fig. 21.1). Women with skewed X-chromosome inactivation or atypical Turner syndrome may be susceptible. There is limited data on treatment efficacy. DYT12-ATP1A3 is an AD form of dystoniaparkinsonism that shows a rapid-onset, usually triggered by an event such as infection. DYT12-ATP1A3 is caused by different mutations in ATPase, Na+/K+ transporting, alpha-3 polypeptide (ATP1A3) gene at the 19q13.2 chromosome locus (de Carvalho Aguiar et al., 2004) encoding the alpha-3 catalytic subunit of the Na+/K (+)-ATPase transmembrane ion pump expressed in basal ganglia, hippocampus, and cerebellar neurons (Fig. 21.2). Affected children manifest asymmetric dystonia and parkinsonism; however, distinct heterozygous mutations in the ATP1A3 gene lead to another disease known as alternating hemiplegia of childhood (AHC2)

ISOLATED AND COMBINED DYSTONIAS: UPDATE (Brashear et al., 1993; Sasaki et al., 2014). Ten patients from three unrelated families with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) had the same heterozygous missense mutation in the ATP1A3 gene (Demos et al., 2014). Patients with DYT12-ATP1A3 are generally unresponsive to levodopa therapy (Brashear et al., 1993; Sasaki et al., 2014). The complex dystonia syndrome infantile-onset dopamine transporter deficiency syndrome (DTDS) is an AR disorder due to homozygous or compound heterozygous mutations in the solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 (SLC6A3) gene encoding the dopamine transporter (DAT1), on chromosome 5p15.33 (Fig. 21.2). Affected infants manifest orolingual and limb dyskinesia, dystonia, chorea, or hypokinesia with parkinsonian features (Kurian, 2017). Many patients are misdiagnosed as having cerebral palsy. Laboratory studies show an increased ratio of HVA to 5-HIAA in CSF in a ratio suggesting an increased ratio of dopamine to serotonin metabolites of HVA:5HIAA >4.0 (Bhatia, 2014). Such cases respond poorly to levodopa therapy (Bhatia, 2014; Kurian, 2017).

MYOCLONUS DYSTONIA The myoclonus-dystonia syndrome refers to patients with AD inheritable, myoclonic jerks involving mainly the upper limbs such as arms and neck muscles, and dystonia, usually torticollis or writer’s cramp, in most but not all affected patients. Patients also manifest psychiatric abnormalities, including panic attacks and obsessive-compulsive disorder. Up to 50% of myoclonus dystonia patients show mutations in a locus on chromosome 7q21 (Zimprich et al., 2001). In these patients, myoclonus dystonia is caused by a heterozygous mutation at 7q21.3 in the epsilon-sarcoglycan gene (SGCE) that encodes the epsilon member of the sarcoglycan family, single-pass transmembrane proteins in the dystrophin-glycoprotein complex (Fig. 21.2). Affected patients develop symptoms in the first decade of life determined by the parental origin of the pathogenic SGCE allele. If the pathogenic allele is paternally derived, then patients develop the disease. In contrast, only 5% of patients who inherit a maternally derived SGCE pathogenic allele develop symptoms (Roze et al., 2018). In DYT11-SCGE mutation-negative cases, myoclonus dystonia has also been reported due to mutations in the CACNA1B gene (Groen et al., 2015). Patients manifest with cervical and axial dystonia and psychiatric comorbidities. Unlike DYT11-SCGE, the myoclonus in CACNA1B increases with action. The CACNA1B gene

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encodes for presynaptic VGCC (Fig. 21.2) and is associated with cardiac arrhythmia and painful cramps in upper and lower limbs (Grimes et al., 2002; Groen et al., 2011, 2015). Since myoclonus dystonia due to mutations of both SGCE and CACNA1B genes are alcohol responsive, these patients are at high risk of developing alcohol dependency (Zimprich et al., 2001; Carecchio et al., 2013; Peall et al., 2014). In contrast, myoclonus dystonia in patients with DYT26-KCTD17 is not alcohol-responsive (Mencacci et al., 2015). Patients with DYT26-KCTD17 mutation initially develop myoclonus involving the upper limbs, followed by dystonia beginning in the craniocervical region with spread and progressive disease course (Mencacci et al., 2015). The KCTD17 gene is expressed in the brain with the highest expression in the putamen and thalamus. The KCTD17 gene encodes for the potassium channel tetramerization domain-containing protein 17 involved in postsynaptic dopaminergic transmission and is also highly expressed in striatal medium spiny neurons (Fig. 21.2) (Mencacci et al., 2015).

PAROXYSMAL DYSKINESIAS Three paroxysmal dyskinesias: (1) paroxysmal kinesigenic dyskinesias (PKD), (2) paroxysmal nonkinesigenic dyskinesias I (PNKD1), and (3) paroxysmal exercise-induced dyskinesias (PED) reveal AD inheritance with varied but typically childhood onset (Landolfi et al., 2021). PKD is the most common paroxysmal movement disorder clinically recognized by recurrent, brief dystonic postures (10 days) postconcussive symptoms? Br J Sports Med 47: 308–313. Martland HS (1928). Punch drunk. JAMA 91: 1103–1107. Mason J, Frazer AK, Avela J et al. (2020). Tracking the corticospinal responses to strength training. Eur J Appl Physiol 120: 783–798. Matveev R, Sergio L, Fraser-Thomas J et al. (2018). Trends in concussions at Ontario schools prior to and subsequent to the introduction of a concussion policy—an analysis of the Canadian hospitals injury reporting and prevention program from 2009 to 2016. BMC Public Health 18: 1324. McCrea M, Hammeke T, Olsen G et al. (2004). Unreported concussion in high school football players: implications for prevention. Clin J Sport Med 14: 13–17. McCrory P, Meeuwisse W, Johnston K et al. (2009). Consensus statement on concussion in sport—the Third International Conference on Concussion in Sport held in Zurich, November 2008. Phys Sportsmed 37: 141–159. McCrory P, Meeuwisse WH, Aubry M et al. (2013). Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012. Br J Sports Med 47: 250–258. McKee AC, Cantu RC, Nowinski CJ et al. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68: 709–735. Meehan 3rd WP, d’Hemecourt P, Comstock RD (2010). High school concussions in the 2008-2009 academic year: mechanism, symptoms, and management. Am J Sports Med 38: 2405–2409. Mild Traumatic Brain Injury Committee, American Congress of Rehabilitation Medicine (1993). Definition of mild traumatic brain injury. J Head Trauma Rehabil 8: 86–87.

MILD TRAUMATIC BRAIN INJURY AND SPORTS-RELATED CONCUSSION Mitsis EM, Riggio S, Kostakoglu L et al. (2014). Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: studies of a retired NFL player and of a man with FTD and a severe head injury. Transl Psychiatry 4: e441. Morgan CD, Zuckerman SL, Lee YM et al. (2015). Predictors of postconcussion syndrome after sports-related concussion in young athletes: a matched case-control study. J Neurosurg Pediatr 15: 589–598. Neurobehavioral Guidelines Working Group, Warden DL, Gordon B et al. (2006). Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury. J Neurotrauma 23: 1468–1501. Nortje J, Menon DK (2004). Traumatic brain injury: physiology, mechanisms, and outcome. Curr Opin Neurol 17: 711–718. O’Connor KL, Baker MM, Dalton SL et al. (2017). Epidemiology of sport-related concussions in high school athletes: national athletic treatment, injury and outcomes network (NATION), 2011–2012 through 2013–2014. J Athl Train 52: 175–185. Olsson KA, Lloyd OT, Lebrocque RM et al. (2013). Predictors of child post-concussion symptoms at 6 and 18 months following mild traumatic brain injury. Brain Inj 27: 145–157. Omalu BI, DeKosky ST, Minster RL et al. (2005). Chronic traumatic encephalopathy in a National Football League player. Neurosurgery 57: 128–134. discussion 128-134. Omalu BI, DeKosky ST, Hamilton RL et al. (2006). Chronic traumatic encephalopathy in a national football league player: part II. Neurosurgery 59: 1086–1092. discussion 1092-1083. Omalu B, Small GW, Bailes J et al. (2018). Postmortem autopsy-confirmation of antemortem [F-18]FDDNP-PET scans in a football player with chronic traumatic encephalopathy. Neurosurgery 82: 237–246. Oppenheimer DR (1968). Microscopic lesions in the brain following head injury. J Neurol Neurosurg Psychiatry 31: 299–306. O’Suilleabhain P, Dewey Jr RB (2004). Movement disorders after head injury: diagnosis and management. J Head Trauma Rehabil 19: 305–313. Paquin H, Taylor A, Meehan 3rd WP (2018). Office-based concussion evaluation, diagnosis, and management: pediatric. Handb Clin Neurol 158: 107–117. Peterson CL, Ferrara MS, Mrazik M et al. (2003). Evaluation of neuropsychological domain scores and postural stability following cerebral concussion in sports. Clin J Sport Med 13: 230–237. Ponsford J, Willmott C, Rothwell A et al. (1999). Cognitive and behavioral outcome following mild traumatic head injury in children. J Head Trauma Rehabil 14: 360–372. Powell JW, Barber-Foss KD (1999). Traumatic brain injury in high school athletes. JAMA 282: 958–963. Powers KC, Cinelli ME, Kalmar JM (2014). Cortical hypoexcitability persists beyond the symptomatic phase of a concussion. Brain Inj 28: 465–471.

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Pryor RR, Casa DJ, Vandermark LW et al. (2015). Athletic training services in public secondary schools: a benchmark study. J Athl Train 50: 156–162. Quatman-Yates CC, Hunter-Giordano A, Shimamura KK et al. (2020). Physical therapy evaluation and treatment after concussion/mild traumatic brain injury. J Orthop Sports Phys Ther 50: CPG1–CPG73. Randolph C, Millis S, Barr WB et al. (2009). Concussion symptom inventory: an empirically derived scale for monitoring resolution of symptoms following sport-related concussion. Arch Clin Neuropsychol 24: 219–229. Ranjan N, Nair KP, Romanoski C et al. (2011). Tics after traumatic brain injury. Brain Inj 25: 629–633. Rimel RW, Giordani B, Barth JT et al. (1981). Disability caused by minor head injury. Neurosurgery 9: 221–228. Ruff R (2005). Two decades of advances in understanding of mild traumatic brain injury. J Head Trauma Rehabil 20: 5–18. Ruff RM (2011). Mild traumatic brain injury and neural recovery: rethinking the debate. NeuroRehabilitation 28: 167–180. Ryan GM, Cope S (1955). Cervical vertigo. Lancet 269: 1355–1358. Sarmiento K, Mitchko J, Klein C et al. (2010). Evaluation of the Centers for Disease Control and Prevention’s concussion initiative for high school coaches: “Heads Up: Concussion in High School Sports”. J Sch Health 80: 112–118. Schepart Z, Putukian M (2018). Sideline assessment of concussion. Handb Clin Neurol 158: 75–80. Sharma R, Laskowitz DT (2012). Biomarkers in traumatic brain injury. Curr Neurol Neurosci Rep 12: 560–569. Siddique U, Rahman S, Frazer AK et al. (2020). Determining the sites of neural adaptations to resistance training: a systematic review and meta-analysis. Sports Med 50: 1107–1128. Sosnoff JJ, Broglio SP, Shin S et al. (2011). Previous mild traumatic brain injury and postural-control dynamics. J Athl Train 46: 85–91. Strathmann FG, Schulte S, Goerl K et al. (2014). Blood-based biomarkers for traumatic brain injury: evaluation of research approaches, available methods and potential utility from the clinician and clinical laboratory perspectives. Clin Biochem 47: 876–888. Sufrinko A, McAllister-Deitrick J, Elbin RJ et al. (2018). Family history of migraine associated with posttraumatic migraine symptoms following sport-related concussion. J Head Trauma Rehabil 33: 7–14. Tanaka K, Mizushima T, Saeki Y (2012). The proteasome: molecular machinery and pathophysiological roles. Biol Chem 393: 217–234. Teasdale G, Jennett B (1974). Assessment of coma and impaired consciousness. A practical scale. Lancet 2: 81–84. Tellier A, Della Malva LC, Cwinn A et al. (1999). Mild head injury: a misnomer. Brain Inj 13: 463–475. Vagnozzi R, Signoretti S, Tavazzi B et al. (2008). Temporal window of metabolic brain vulnerability to concussion: a pilot 1H-magnetic resonance spectroscopic study in

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concussed athletes—part III. Neurosurgery 62: 1286–1295. discussion 1295-1286. Vagnozzi R, Signoretti S, Cristofori L et al. (2010). Assessment of metabolic brain damage and recovery following mild traumatic brain injury: a multicentre, proton magnetic resonance spectroscopic study in concussed patients. Brain 133: 3232–3242. Vagnozzi R, Signoretti S, Floris R et al. (2013). Decrease in N-acetylaspartate following concussion may be coupled to decrease in creatine. J Head Trauma Rehabil 28: 284–292. Van Pelt KL, Lapointe AP, Galdys MC et al. (2019). Evaluating performance of national hockey league players after a concussion versus lower body injury. J Athl Train 54: 534–540. Weiner WJ (2001). Can peripheral trauma induce dystonia? No!. Mov Disord 16: 13–22. Wilde EA, McCauley SR, Hunter JV et al. (2008). Diffusion tensor imaging of acute mild traumatic brain injury in adolescents. Neurology 70: 948–955. Williams DH, Levin HS, Eisenberg HM (1990). Mild head injury classification. Neurosurgery 27: 422–428. Williams G, Galna B, Morris ME et al. (2010). Spatiotemporal deficits and kinematic classification of gait following a traumatic brain injury: a systematic review. J Head Trauma Rehabil 25: 366–374. Yard EE, Scanlin MM, Erceg LE et al. (2006). Illness and injury among children attending summer camp in the United States, 2005. Pediatrics 118: e1342–e1349. Yeates KO, Taylor HG, Rusin J et al. (2012). Premorbid child and family functioning as predictors of post-concussive symptoms in children with mild traumatic brain injuries. Int J Dev Neurosci 30: 231–237.

Zhang L, Yang KH, King AI (2004). A proposed injury threshold for mild traumatic brain injury. J Biomech Eng 126: 226–236. Zhou G, Brodsky JR (2015). Objective vestibular testing of children with dizziness and balance complaints following sports-related concussions. Otolaryngol Head Neck Surg 152: 1133–1139.

FURTHER READING American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders, Am Psychiatric Assoc, Arlington, VA. Brain Injury Association of New York State (2022). BIANYS Website [Online]. Available: https://bianys.org. Center for Disease Control (2022). Heads Up Concussion in Youth Sports Program [Online]. Available: https://www. cdc.gov/headsup/youthsports/index.html. Centers for Disease Control and Prevention (1997). Traumatic brain injury-Colorado, Missouri, Oklahoma, and Utah, 1990–1993, Morbidity and Mortality Weekly Report, Atlanta, GA. National Center for Injury Prevention and Control (US) (2003). In: (Us) NCFIPaC (Ed.), Report to Congress on mild traumatic brain injury in the United States: steps to prevent a serious public health problem. Centers for Disease Control and Prevention. National Research Council and Committee on Sports-related Concussions in Youth (2015). Sports-related concussions in youth: improving the science, changing the culture. Mil Med 180: 123–125. World Health Organization (2019). International Statistical Classification of Diseases and Related Health Problems, 11th edition.

Section 4 Therapeutics

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00010-7 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 25

Treatment of spasticity JONATHAN MARSDEN1*, VALERIE STEVENSON2, AND LOUISE JARRETT3 1

School of Health Professions, Faculty of Health, University of Plymouth, Plymouth, United Kingdom

2

Department of Therapies and Rehabilitation, National Hospital for Neurology and Neurosurgery UCLH, London, United Kingdom 3

Department of Neurology, Royal Devon and Exeter Hospital, Exeter, United Kingdom

Abstract Spasticity is characterized by an enhanced size and reduced threshold for activation of stretch reflexes and is associated with “positive signs” such as clonus and spasms, as well as “negative features” such as paresis and a loss of automatic postural responses. Spasticity develops over time after a lesion and can be associated with reduced speed of movement, cocontraction, abnormal synergies, and pain. Spasticity is caused by a combination of damage to descending tracts, reductions in inhibitory activity within spinal cord circuits, and adaptive changes within motoneurons. Increased tone, hypertonia, can also be caused by changes in passive stiffness due to, for example, increase in connective tissue and reduction in muscle fascicle length. Understanding the cause of hypertonia is important for determining the management strategy as nonneural, passive causes of stiffness will be more amenable to physical rather than pharmacological interventions. The management of spasticity is determined by the views and goals of the patient, family, and carers, which should be integral to the multidisciplinary assessment. An assessment, and treatment, of trigger factors such as infection and skin breakdown should be made especially in people with a recent change in tone. The choice of management strategies for an individual will vary depending on the severity of spasticity, the distribution of spasticity (i.e., whether it affects multiple muscle groups or is more prominent in one or two groups), the type of lesion, and the potential for recovery. Management options include physical therapy, oral agents; focal therapies such as botulinum injections; and peripheral nerve blocks. Intrathecal baclofen can lead to a reduction in required oral antispasticity medications. When spasticity is severe intrathecal phenol may be an option. Surgical interventions, largely used in the pediatric population, include muscle transfers and lengthening and selective dorsal root rhizotomy.

SPASTICITY: INTRODUCTION, DEFINITION, AND PRESENTATION Although clinically, “spasticity” is a commonly used term, it is important to review the definition and pathophysiology of spasticity as this has implications into understanding the impact of spasticity, its assessment, and the evidence base for its management.

⁎

Spasticity is one component of the upper motor neuron (UMN) syndrome and, as highlighted later, other associated features can significantly impact on function and should be considered when developing a management plan. Spasticity leads to an increased resistance to passive movement (hypertonia). Spasticity is usually defined as being due to hyperexcitable stretch reflexes (Lance, 1980). The stretch reflex can have a lower

Correspondence to: Prof. Jonathan Marsden, Chair in Rehabilitation, School of Health Professions (Faculty of Health), FF20, Peninsula Allied Health Centre, College of St Mark & St John, Plymouth, PL6 8BH, United Kingdom. Tel: +44-1752-587590, E-mail: [email protected]

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threshold, that is, they are triggered at lower velocities of stretch (as low as 10°/s compared to 200–300°/s in healthy participants). Further, the increase in the size of the muscle response for a unit change in the velocity of stretch can be larger; this is termed a change in gain of the reflex (Thilmann, 2003). More recently, broader definitions have been used that include all excessive muscle activity seen in an UMN syndrome (Pandyan et al., 2005). This therefore includes examples of spasms and spastic dystonia where there is ongoing muscle activity even when at rest. For the current chapter, the original definition will be used (i.e., hyperexcitable stretch reflexes) in discussing the management of associated excessive muscle activity such as spasms. People with spasticity have an increased resistance to passive movement of the relaxed limb. In the arm, the shoulder adductors and internal rotators, elbow flexors and pronators, wrist and finger flexors, and thumb adductors are usually more affected. In the leg, both extensors (e.g., ankle plantar flexors, knee extensors), flexors (e.g., hip and knee flexors), and hip adductors can be affected (Persson et al., 2020). With fast passive movements the resistance increases and a catch-and-give sensation may be felt when initial high resistance to movement suddenly reduces. This “clasp-knife phenomenon” is mainly seen at the knee (Pierrot-Deseilligny and Burke, 2012a). With repeated passive movements, the limb can become looser due to the phenomena of thixotropy. Muscles can be held in shortened positions (e.g., flexion at the elbow) and spasticity is frequently associated with pain. Volitional movements are slow and of reduced amplitude. Movements are frequently performed in stereotyped patterns (see Section “Movement and function”).

could also result in spasticity (Li et al., 2019). The effects of lesions at different levels are summarized in Fig. 25.1 (Brown, 1991; Sheean, 2008). As there is an excitatory input from the cortex to the dorsal RST, a cortical/ subcortical lesion can also result in spasticity (Fig. 25.1). Lesions affecting descending monoaminergic neuromodulatory pathways, which have serotonin or noradrenaline as their neurotransmitters, are also implicated in the cause of spasticity (Perrier et al., 2013; El Oussini et al., 2017; Li et al., 2019). The binding of a monoaminergic neurotransmitter to its receptor can trigger an intracellular cascade that ultimately affects the voltage-gated ion channel properties that determine the input–output properties of the nerve (Heckman et al., 2008). Through this mechanism, the effects of other descending or ascending pathway inputs (e.g., from RST and muscle spindle afferents) can be modulated. The effect of a neurotransmitter depends on the receptors; for example, there are seven serotonergic receptors in the spinal cord. As a generalization, serotonin leads to inhibition in dorsal horn regions (related to suppression of pain pathways) but excitation in more ventral (motor) regions of the spinal cord (Heckman et al., 2008, 2009). There is also inhibitory noradrenergic input from the locus coeruleus to interneurons processing muscle spindle group II afferents (Pierrot-Deseilligny and Burke, 2012c). Thus, damage to these neuromodulatory pathways may affect the balance of inhibition–excitation in spinal cord circuits but, as highlighted below, it may also lead to long-term plastic changes that ultimately cause spasticity and spasms.

PATHOPHYSIOLOGY OF SPASTICITY

The UMN lesion results in a reduction in inhibition in spinal cord circuits. For example, people with spasticity can show reductions in reciprocal inhibition, autogenic inhibition, and presynaptic inhibition when at rest or while moving. In fact reversals of inhibition to facilitation can be seen (e.g., Delwaide and Oliver, 1988; Crone et al., 1994, 2003, 2004; Nielsen et al., 1995; Morita et al., 2001; Knikou, 2005; see also Pierrot-Deseilligny and Burke, 2012a for a comprehensive review). The abnormalities in spinal cord inhibition do not always correlate with clinical measures of spasticity (Aymard et al., 2000). This may reflect difficulties in the clinical assessment of spasticity but may also reflect the fact that reductions in spinal cord inhibition may be necessary but not sufficient to cause spasticity.

Descending pathway damage Spasticity is seen following an UMN lesion. The UMN lesion is associated with damage to descending motor tracts. Animal studies, supported by human cases, highlight that an isolated corticospinal tract (CST) lesion does not cause spasticity (Nielsen et al., 2018; Li et al., 2019). In contrast, damage to brainstem tracts such as the dorsal reticulospinal (RST) can result in hyperexcitable stretch reflexes (Taylor et al., 1999a). This reflects the fact that the dorsal RST arising from the medulla provides inhibitory inputs to many spinal reflex circuits (Li et al., 2019). Imaging and physiological studies in humans have further highlighted the association of RST damage with spasticity in stroke (Ko et al., 2021) and incomplete spinal cord injury (Sangari and Perez, 2019). In contrast, the medial RST arising from the pons and vestibulospinal tract provides excitatory inputs to spinal reflex circuits and there is evidence that hyperexcitability of these tracts

Spinal cord inhibition

Adaptive changes Although animal models result in hyperexcitable stretch reflexes, these are usually seen soon after a lesion to a descending tract (e.g., Taylor et al., 1999a). In humans,

TREATMENT OF SPASTICITY (a)

Cortex

- Pre-motor - Supplementary motor Internal capsule

+

Ventromedial reticular formation

Bulbopontine tegmentum

Vestibular nucleus

(Excitatory)

(Inhibitory)

(b)

Medial reticulospinal tract

Dorsal reticulospinal tract Lateral corticospinal tract

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(c) –

+

+

Vestibulospinal tract

Spinal interneuronal network

Fig. 25.1. Excitatory or inhibitory effects are indicated by a + or , respectively. A lesion to the reticular formation can reduce its inhibitory effects on spinal interneuron circuits resulting in increased excitability. A lesion to the corticofugal (+) input to reticular formation can also result in increased excitability From Sheean G (2008). Neurophysiology of spasticity. In: M Barnes, G Johnson (Eds.), Upper motor neurone syndrome and spasticity: clinical management and neurophysiology, second edn. Cambridge University Press, Cambridge.

spasticity is not a release phenomenon that occurs immediately after the lesion but develops over time (Hiersemenzel et al., 2000). Neuron sprouting and changes in motor neuron properties may underlie some of these long-term changes. In animal models such as the SOD1 model of amyotrophic lateral sclerosis (ALS) with damage to serotonergic tracts, there are changes in serotonergic and noradrenaline (norepinephrine) receptors in the motor neuron such that they can become constitutively active (i.e., active without any need for activation by a neurotransmitter) (Murray et al., 2010, 2011a,b; Dentel et al., 2013). There is also the development of prolonged plateau potentials when the motoneuron is activated resulting in prolonged firing (Bennett et al., 2001). There is indirect evidence of plateau-like behavior in humans with spinal cord injury and changes in receptor activity (Nickolls et al., 2004; D’Amico et al., 2013). It may be that such changes are more important in the genesis of spasms rather than spasticity. Other adaptive changes include a reduction in normal postactivation depression (Lamy et al., 2009). Postactivation depression (also termed homosynaptic depression) is the usual decrease in motor neuron response with repetitive stimulation. It is related to a decrement in neurotransmitter release (Hultborn et al., 1996). In people with spasticity, this reduction in excitability does not occur and this correlates with the degree

of spasticity as measured clinically (Lamy et al., 2009). The development of spasticity seen can be viewed as an adaptive change in response to the lesion-induced reduction in motoneuron excitation and the ensuing spinal shock (Nielsen et al., 2018).

Spasticity and hypertonia Spasticity is not the only cause of hypertonia in people with an UMN syndrome. Hypertonia may also be caused by an increase in the passive stiffness of the limb. This can be caused by shortening of muscle fascicles and fibers (Friden and Lieber, 2003). Higher passive stiffness can also be caused by an increase in the amount, and possibly structure, of connective tissue surrounding the muscle (i.e., perimysium (de Bruin et al., 2014)). In children with cerebral palsy (CP), increases in passive stiffness can be also associated with a reduced number of sarcomeres (Smith et al., 2011; Handsfield et al., 2022) and contracture. Contractures are common; at least one contracture is seen in over 50% of people 6 months poststroke (Kwah et al., 2012). The changes in passive stiffness can occur quickly. For example, following a stroke, changes in passive stiffness of the wrist flexors can be recorded after 4 weeks while enhanced stretch reflexes were recorded after 12 weeks (de Gooijer-van de Groep et al., 2018). In cerebral palsy, changes in

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passive stiffness of the ankles can be recorded in 2 year old children, the youngest age assessed (WillerslevOlsen et al., 2013). Alongside this, the Achilles tendon can show an increase in compliance and features of tendinopathy (Gagliano et al., 2013). The more compliant tendon will affect the ability to quickly transmit forces generated by muscle contractions. The relative proportion of passive stiffness and spasticity in causing hypertonia can vary between muscle groups, conditions, and individuals. After stroke, for example, hypertonia in the finger flexors is felt to be predominately neural in origin (Li et al., 2006). Understanding the cause of hypertonia is important as this guides treatment options. Spasticity may be more amenable to pharmacological intervention and some targeted therapies while passive stiffness may be more amenable to physical interventions (e.g., casting, positioning, and stretching) and surgery (e.g., muscle lengthening). The cause of spasticity and hypertonia may vary with the time of occurrence (e.g., during or after musculoskeletal development/growth) and the lesion location (e.g., cerebral or spinal). A spinal cord lesion, for example, can affect descending pathways but also directly affect segmental interneuronal pathways and the local processing of inputs (Aguiar et al., 2018). In cerebral palsy, reductions in satellite cells that normally fuse with muscle cells and underpin muscle growth and hypertrophy result in the reduction in sarcomere number (Handsfield et al., 2022). This results in overstretched sarcomeres resulting in weakness, increased passive stiffness, and contracture (Lieber and Theologis, 2021). These changes may not occur in acquired, adult conditions that occur after muscle growth is complete. Hypertonia in an UMN syndrome may also be caused by contraction of the antagonist muscle. This is an intrinsic cause of stiffness due to the formation of active actin–myosin cross bridges within the muscle (Sinkjaer et al., 1993; Sinkjaer and Magnussen, 1994). Cocontraction (activation of agonist and antagonist muscles) is reported in UMN lesions (Knutsson and Richards, 1979; Rosa et al., 2014) although it is not ubiquitous (e.g., Gowland et al., 1992; Newham and Hsiao, 2001). Cocontraction may have several causes such as stretch activation of antagonist muscle (Musampa et al., 2007); heterosynaptic stretch reflexes where stretch in one muscle group affects a distant group (Dyer et al., 2011); or abnormal synergies (Dewald et al., 1995). Cocontraction also normally occurs in the initial stages of learning a new skill as the person stiffens their limb to reduce the degrees of freedom they try to control (Babadi et al., 2021). Thus, cocontraction seen after an UMN lesion may, in part, reflect the fact that people are trying to relearn movements (Busse et al., 2005). The initial resistance to passive movement of a relaxed muscle, termed the short range resistance, is in

part due to the presence of passive actin–myosin cross bridges that attach–detach in a non-ATP-dependent manner (Proske and Morgan, 1999). With a prior contraction, especially in a shortened position, there are more passive cross bridges and the initial resistance to movement is higher. After a prior stretch of a relaxed muscle, this resistance is lower (Hagbarth et al., 1985, 1995). This dependence of the stiffness of the muscle on the history of the muscle is termed thixotropy. Thixotropic changes can also affect the intrafusal muscle fibers of the muscle spindle such that a prior contraction results in enhanced spindle discharge and thus a larger stretch reflex (Proske et al., 1993). It may underlie the reduction in stiffness felt with repeated stretches in people with spasticity. The degree of thixotropic changes after stroke are not greater than that seen in healthy participants (Vattanasilp et al., 2000), but needs to be considered when assessing tone using passive movements. It is recommended that 3–5 movements are performed prior to measurement to reduce these thixotropic effects (Stevenson et al., 2016). Spasticity and increased passive stiffness should be distinguished from other causes of hypertonia such as extrapyramidal rigidity, dystonia, or paratonia. Rigidity is a cardinal sign of Parkinson disease being present in both akinetic and tremor-dominant presentations. Unlike spasticity, rigidity does not depend on the velocity of movement and affects the flexors and extensors equally giving rise to a uniform resistance to passive stretching in all directions termed “lead pipe” rigidity. Cogwheel rigidity in Parkinson disease occurs when there is a superimposed 6–9 Hz frequency tremor. Dystonia is defined as “sustained or intermittent muscle contractions resulting in abnormal, often repetitive, movements, postures, or both.” Voluntary movements typically increase the degree of dystonia. Paratonia is the inability to relax muscles during an assessment of tone. People can either involuntarily resist passive motion (gegenhalten) or assist passive movement (mitgehen). The resistance is not velocity dependent and be elicited in any movement direction unlike spasticity. The pathophysiology of these other causes of hypertonia are reviewed elsewhere (Ganguly et al., 2021; Chen et al., 2022).

Associated impairments with spasticity Hughlings Jackson originally described features of the UMN syndrome as being either positive (resulting from excitation or the release of lower levels from inhibitory higher control) or negative (related to the dissolution of neural function). Commonly encountered positive and negative features will be described in the following sections as these can significantly impact on function and should be managed alongside spasticity.

TREATMENT OF SPASTICITY

Positive features Clonus is the repetitive (3–8 Hz) contraction of a muscle, usually the ankle plantar flexors. It reflects repetitive activation of stretch reflexes (Hidler and Rymer, 1999). There is also the potential contribution of spinal cord oscillator circuits in mediating clonus at least following spinal cord injury (Beres-Jones et al., 2003). Eliciting this sign is, in part, a reflection of the skill of the examiner in maintaining a stretch stimulus in the presence of spasticity (activated stretch reflexes). Spasms are sudden contractions of the whole limb that can be extensor, flexor, or adductor. Flexor spasms are felt to be caused by disinhibition of long latency, polysynaptic flexor reflex afferent pathways. Other causes include abnormal oscillatory activity in spinal cord centers leading to synchronization of multiple muscle groups (Norton et al., 2003). Spasms can be caused by trigger factors (see below) with the pattern of contraction being modulated by the limb position. For example, after spinal cord injury flexor reflexes are larger when the hip is in extension compared to flexion (Knikou and Rymer, 2002; Knikou, 2007). Spastic dystonia is the presence of tonic muscle activity even when the person is resting (Trompetto et al., 2019). It may reflect a reduction in voluntary control following a corticospinal lesion combined with increased involuntary control due to a basal ganglia lesion (Nielsen et al., 2018). Cutaneomuscular responses can also be enhanced such that cutaneous stimuli result in increased muscle activity. Cutaneous stimulation of the plantar aspect of the foot, for example, can result in enhanced extensor activity in the limb (Kugelberg et al., 1960; Schomburg, 1990) limiting the ability to transfer weight through the foot. In contrast, the clasp-knife phenomenon where there is a sudden reduction in resistance following a stretch is caused by the inhibitory action of flexor reflex afferents including cutaneous, joint, and nonspindle group II–IV afferents (Pierrot-Deseilligny and Burke, 2012a). Associated reactions are an involuntary increase in upper limb muscle tone associated with increased effort (e.g., walking) (Kahn et al., 2016). Associated reactions correlate with the degree of spasticity (Bhakta et al., 2001) although they are not associated with a higher incidence of contracture (Ada and Q’Dwyer, 2001). Associated reactions may be associated with the increased activity associated with (re)learning new tasks or with spastic dystonia (Kahn et al., 2020). Abnormal synergies can also be seen in an UMN syndrome. In the arm, for example, shoulder abduction is accompanied by flexion of the elbow and difficulty in extending the fingers and wrist (Levin et al., 2016;

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Kopke et al., 2019) and an inability to control for interaction torques at the elbow that naturally occur with elbow–shoulder movements (Kamper et al., 2002; Laczko et al., 2017; Raj et al., 2020; Suvada et al., 2020). This synergy is more marked when the shoulder abductors are loaded, for example, by lifting the arm against gravity and moving it away from the trunk (Beer et al., 2007; Ellis et al., 2008). This can limit the “workspace” that a person can reach into and decrease endpoint reaching accuracy (Kamper et al., 2002; Suvada et al., 2020). Abnormal flexor synergies can also affect the ability to open the hand when grasping (Lan et al., 2017). There is evidence that some of this pattern may reflect stretch reflex action (Musampa et al., 2007) and/or an abnormal centrally generated synergy. The latter may be caused by activity in descending reticulospinal pathways whose activity is upregulated following damage to the corticospinal tract and altered drive in the monoaminergic modulatory pathways (Sukal et al., 2007; McPherson et al., 2018; Li et al., 2019).

Negative features As highlighted below (see Section “Movement and function”), associated negative features may be the primary factors affecting function and understanding their impact and relationship with spasticity will help guide effective goal-orientated treatment. Weakness (paresis) will accompany an UMN lesion and reflects direct damage to descending pathways (e.g., CST) as well as secondary disuse atrophy and changes in muscle. Muscle fiber types can also change. A change from slow fatigue resistant to fast fatigable fibers is more commonly observed (Hafer-Macko et al., 2008) with a higher proportion of fast fibers being associated with a lower walking speed poststroke (De Deyne et al., 2004). Balance can be impaired due to damage to outputs from postural centers arising from the brainstem and spinal cord and their coordination with higher centers (Jacobs and Horak, 2007) and/or damage to ascending sensory pathways (Nonnekes et al., 2013). Anticipatory postural adjustments that precede and accompany volitional movements are reduced in size or abolished after a UMN lesion (Tasseel-Ponche et al., 2015). Longer latency responses including transcortical stretch reflexes can be absent/reduced due to ascending/descending tract damage (Lee et al., 1983; Sinkjaer et al., 1999). These longer latency “functional” responses to perturbations when maintaining a posture involve a volitional component (Rothwell et al., 1980). They vary in size according to task conditions/aims (“central set”) and so provide flexible control of movement.

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As highlighted below (see Section “Movement and function”), these associated features may be the primary factors affecting function and understanding their impact and relationship with spasticity will help guide effective goal-oriented treatment. The excitability of the CST, for example, is a strong predictor of recovery of the hand and arm poststroke (Stinear et al., 2012, 2017).

Impact of spasticity Spasticity is associated with reduced quality of life (Schinwelski et al., 2019) and pain. It can impact on posture in lying, sitting, and standing, movements and activities such as walking, basic activities of daily living (ADLs) such as bladder and bowel management as well as instrumental ADLs and work.

Movement and function The role of spasticity in limiting movement and function remains controversial. When a spastic muscle is stretched during an isometric contraction, the resistance to movement is similar to that seen in healthy controls. This is, in part, because with an isometric contraction the degree of spinal cord inhibition in healthy participants’ decreases to levels normally seen in people with spasticity at rest (Crone et al., 1987; Lorentzen et al., 2018). Stretch reflex size normally modulates with posture and movement. For example, the ankle plantar flexor stretch reflex and H Reflex is larger at rest compared to standing and while walking it is larger during the stance phase than during the swing phase (Capaday, 2002; Klarner and Zehr, 2018). In people with spasticity, this modulation is reduced. The main effect is an increase in stretch reflex size during the swing phase compared to normal controls (Sinkjaer et al., 1996). Thus, enhanced stretch reflex activation in the ankle plantar flexors may limit active dorsiflexion in the swing phase. This may, in turn, limit how quickly people can move their joints and thus limit walking speed. In the arm, increased stretch reflexes in the finger and wrist flexors limit the ability to open the hand to grasp and release objects (Kamper et al., 2003); this is moderately associated with function and is a predictor of poor recovery (e.g., after stroke) (Lin and Sabbahi, 1999; Vaz et al., 2006; Plantin et al., 2019). Movement dysfunction in someone with spasticity may, however, be predominately caused by the associated negative signs described above. Finger and elbow strength, for example, after stroke is the main predictor of the grasp type used (García Álvarez et al., 2017) and of hand function (Kamper et al., 2006). Walking patterns associated with a spastic gait can have spasticity as a potential causative component but, frequently,

patterns are multifactorial. A stiff knee gait, for example, where there is a reduction in knee flexion in the swing phase, can be associated with spasticity in the rectus femoris (Akbas et al., 2020). However, other factors such as weakness in the muscles that initiate swing phase (plantar flexors and hip flexors), cocontraction and passive stiffness in the knee extensors may also contribute in conditions such as hereditary spastic paraplegia (HSP) (Marsden et al., 2012). Spasticity may actually aid function in some. For example, a stiffer limb may allow the ability to stand against gravity and enable transfers. In keeping with this, postural sway is smaller in people with HSP and who have higher plantar flexor tone (Marsden and Stevenson, 2013). Further clinical support for this comes from the observation of reductions in function with antispasticity medication. This may reflect the “unmasking” of underlying weakness, an exacerbation of weakness as a side effect of medication or an effect of medication on reflex responses (e.g., from group II afferents) underlying postural control. Direct evidence in humans that spasticity per se aids function is limited (Lorentzen et al., 2018). Recent animal models assessing the effects of spasticity on locomotion do, however, support this clinical observation (Yoshizaki et al., 2020).

Pain Pain is frequently seen in people with spasticity. For example, it is reported in 77%–85% in children with CP, 42.5% of people with ALS, and 30% of people poststroke (Paolucci et al., 2016; McKinnon et al., 2020; Verschueren et al., 2021; Heinen et al., 2022). The association of pain and spasticity may reflect common mechanisms. The loss of serotonergic pathways that may mediate adaptive changes in the motor neuron resulting in spasticity may also lead to overexcitation and sensitization of pain pathways with nociceptive stimulation leading to chronic pain (Fauss et al., 2022). Spasms may result in muscle ischemia and pain may be due to associated musculoskeletal deficits (e.g., hip displacement in CP and shoulder pain poststroke and spinal cord injury) (Poirot et al., 2017; Bossuyt et al., 2018; Marcstr€om et al., 2019; Schmidt et al., 2020). Shoulder pain after stroke, for example, can be caused by multiple factors including adhesive capsulitis, acromion impingement syndrome, rotator cuff injury, and complex regional pain syndrome (Xie et al., 2021). Poststroke arm pain is correlated with the degree of contracture in the wrist flexors and pain is in turn a predictor of developing contractures in the future (Pizzi et al., 2005; Matozinho et al., 2021). Pain can also be neuropathic in origin; this is reported in 60% of people living with a spinal cord injury

TREATMENT OF SPASTICITY (Andresen et al., 2016). Pain frequently interferes with sleep, attention, and quality of life (Ostojic et al., 2020).

ASSESSMENT OF SPASTICITY Given the multiple factors that can affect movement and function in someone with spasticity, it is important that spasticity is considered as part of a global assessment including sensorimotor impairment with contributions from members of a multidisciplinary team (Stevenson et al., 2016). As well as clinical assessments there are physiological and biomechanical measures of spasticity that have been used to understand the mechanisms of spasticity and as secondary outcomes in some clinical trials; documenting such outcome measures is extremely important when it comes to assessing the efficacy of treatments and evaluating changes over time.

Clinical assessment Tone is assessed using passive movements with the participant resting lying or sitting; the effect on movement is then inferred. Scales such as the Ashworth (and its derivatives) scale and the Tardieu scale use an ordinal rating of tone. The Tardieu test rates tone and measures range at different speeds and thus can allow a clinical differentiation of passive stiffness and spasticity. This is in contrast to the Ashworth scale that only rates the overall resistance during passive movement and relies on a standardized speed of movement (Pandyan et al., 1999, 2005; Haugh et al., 2006). Range of motion measured using goniometry can be used to detail contracture. The cerebral palsy-integrated pathways developed in Northern Europe, for example, provides a protocolized method of measuring joint range and the differences in range with fast and slow stretches alongside hip surveillance monitoring (Bugler et al., 2019; H€agglund et al., 2021; Gaston et al., 2022). Extensibility in two joint muscles (iliopsoas, hamstring, rectus femoris, and gastrocnemius in the leg and wrist flexors and biceps brachii in the arm) should be assessed. Here, one joint is fixed in a standard position while the range in the adjacent joint is recorded. Pain associated with spasticity may be rated on visual analog or numerical rating scales. Spasm frequency may be rated using the Penn spasm scale (Stevenson et al., 2016). Assessments of caregiver burden (e.g., Caregiver Burden Scale and the Zarit Burden Interview) are also relevant and useful (Ertzgaard et al., 2020). In keeping with the World Health Organization International Classification of Functioning, Disability and Health, measures should also include activity and participation. For example, the arm activity and leg activity measures (Ashford et al., 2013, 2017, 2021) can assess passive and active function while the Spasticity-related

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Quality of Life 6-Dimensions instrument measures quality of life (Turner-Stokes et al., 2022). Patient-reported outcome measures (PROMs) include the Multiple Sclerosis Spasticity Scale-88. This consists of 88 questions asking about how perceived spasticity affects different activities/symptoms (Hobart et al., 2006). For spinal cord injury, the PRISM (patient-reported impact of spasticity measure) and the spinal cord injury evaluation tool have been developed and validated (Ertzgaard et al., 2020).

Physiological and biomechanical assessment Spasticity can also be assessed using physiological assessments such as the H reflex which measures the reflex response to electrical stimulation of 1a afferents. Biomechanical measures include the simultaneous assessment of limb movement (position/velocity) and applied torque as a limb is passively moved at different speeds. Either standardized movements or standardized torques are applied (Pandyan et al., 2005, 2018). The Wartenberg pendulum test provides an objective assessment of knee extensor tone. In sitting with the thigh supported, the extended lower leg is released to drop against gravity (a standardized applied force) and the ensuing motion measured (Nordmark and Anderson, 2002). Measures such as ratio of the amplitude of the first swing and the rebound angle, the maximal velocity, and swing time are correlated with clinical assessments for spasticity (Nordmark and Anderson, 2002). Although mechanical devices to measure spasticity and differentiate the relative contribution of the components of hypertonia have been developed, these have not been implemented in clinical practice, possibly due to time constraints, ease of use, and cost (Pandyan et al., 2018). An assessment of spasticity at rest needs to be combined with an assessment of walking and other functional tasks (e.g., climbing stairs and manipulation). These can be video recorded and functions such as walking can be rated using observational gait analysis allowing them to be documented as an outcome measure. 3D motion analysis can also provide a more detailed assessment of how spasticity may affect walking (Roche et al., 2019).

Goal setting, education, and self-management The person with spasticity, their family, and carers are core to assessing and managing spasticity effectively. Goals can be one way to guide this multiperson interaction. The goals of treatment should not be to reduce spasticity per se but to achieve a clear aim that will impact on the quality of life (Stevenson et al., 2006). Goals should be SMART (specific, measurable, achievable, relevant, and time-bound) (Turner-Stokes et al., 2018). The goal attainment scale (GAS) provides a useful

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Table 25.1 Common goals for upper limb (Turner-Stokes et al., 2022) and lower limb spasticity (Ashford et al., 2019) Upper limb spasticity

Lower limb spasticity

Reduction of pain/discomfort

Improve body structure impairment (pain/discomfort; involuntary movements, prevention of contracture) Improve transfers, e.g., by reducing clonus and improving foot placement Improve mobility by enabling heel strike

Control of spasms and other involuntary movements Maintenance of range through ability to wear a splint with increased ease and comfort Improve passive function (ease of caring for the affected limb, e.g., maintaining palm or axilla hygiene, skin integrity, ease of dressing) Improve active function such as grasp and release of a cup

framework to set goals for the management of arm and leg spasticity (Ashford et al., 2019; Turner-Stokes et al., 2021). Commonly selected goals are summarized in Table 25.1 (Ashford et al., 2019; Turner-Stokes et al., 2022). The upper limb spasticity index and focal spasticity index measure severity of presentation, goals (using the GAS), and perceived global benefit (Turner-Stokes et al., 2022). For children, a shorter “3-milestones” GAS has been developed (Krasny-Pacini et al., 2017). When setting goals and recording outcome measures, clinicians should be aware of the impact that the act of “being measured” may have on patients and on the power dynamic that can, in turn, affect the therapeutic relationship and outcome of management strategies (Fletcher et al., 2019). Education as to the hypothesized causes underlying patients’ reported difficulties (e.g., pain, reduced function) and the role of measurement in assessing the effectiveness of treatment strategies can help alleviate the feeling that the patient is being judged (Jarrett and Keenan, 2016; Stevenson et al., 2016). This can be further reduced through the patient actively participating in goal setting and undertaking PROMs. Most interventions require a behavioral change, such as the use of splinting or establishing a stretching or positioning program. People with severe disability and their family have often developed a matrix of highly refined unique strategies that allows them to function effectively as a unit. Understanding the “precarious harmony” that a patient–family unit normally operates in (Jarrett, 2015) provides valuable insight as to what may or may not work as an intervention and people’s desire and ability to change. This may be achieved through communication styles such as motivational interviewing (Hedegaard et al., 2014) and the provision of active support for patients helping them to choose from, and expand on, professionals’ advice and guidance to help them foster

Improve passive function, e.g., ease of self-catheterization or perineal hygiene

and coproduce a management program (Jarrett and Keenan, 2016; Jones et al., 2016, 2017).

MANAGING TRIGGER FACTORS Spasticity and spasms can be exacerbated by multiple stimuli and trigger factors. These include cutaneous and proprioceptive inputs (e.g., skin stimulation and muscle and joint afferent stimulation) (Hornby et al., 2004), infection, pain (Matre et al., 1998), and pressure areas. Urinary tract infection (UTI), bladder fullness and calculi, and constipation are common triggers. Neurogenic urinary dysfunction frequently accompanies leg spasticity due to similarities in the lesion location (Joussain et al., 2019) and are associated with a higher incidence of UTIs (McKibben et al., 2015). Although stretch reflexes are enhanced with greater bladder filling in healthy participants (Porter and Krell, 1976), this effect may be more marked in people with neurogenic bladders and accompanying spasticity/spasms as there are plastic changes within the bladder wall with C fibers becoming mechanically sensitive after spinal cord damage (de Groat and Yoshimura, 2012). When a person presents with the development or exacerbation of spasticity, it is therefore important to initially assess for and treat any trigger factors before initiating or escalating medication. This may require amendments to the way they manage their skin integrity, transfers, and postures in sitting and lying or bladder and bowel management. Often, this can require input from different members of the multildisciplinary team (MDT), e.g., referral to urology or wheelchair services.

MANAGEMENT OF SPASTICITY An example of an algorithm for the management of spasticity is shown in Fig. 25.2. Decision pathways for specific aspects of management (e.g., botulinum toxin

Identification Of Spasticity

Assess for trigger and Aggravating factors

Assess Spasticity and document outcome measures

•

Any infections, red or broken skin; urinary frequency, urgency or retention, constipation or diarrhoea; pain; tight clothing or orthoses; poor posture and positioning or infrequent changes in position? Identify and manage as appropriate

Devise physiotherapy and Nursing plan

• • • • •

Is soft tissue and joint range maintained Consider stretching, standing and rehabilitation Optimise positioning and seating Educate for self management Continue to monitor and manage trigger factors

Does the Spasticity need further treatment?

• • •

Would treatment aid function Is there a negative impact on range, care or function? Is spasticity causing pain?

Is spasticity focal? Yes Focal

•

Is the problematic spasiticity confined to a single limb or a few small muscles?

•

Consideer Botulinum Toxin in conjunction with physiotherapy or splinting program

Spasticity continues to be a problem

• • •

Assess trigger factors Ongoing therapy and nursing interventions Consider generalised therapies

Generalised

• •

Start first line oral therapy (usually baclofen or gabapentin) Ongoing therapy and nursing interventions with monitoring of effectiveness

•

Assess trigger factors If first line therapy has a partial effect add second agent: usually gabapenin, baclofen or tizanidne If first line agent has no effect, withdraw and start a second agent usually gabapentin, baclofen or tizanidine Ongoing therapy and nursing interventions with monitoring of effectiveness

•

No Assess spasticity and document outcome measures Continue with treatment plan and monitor for change

No

Is spasticity generalised? Yes

Generalised spasticity continues to be a problem

• •

Generalised spasticity continues to be a problem

• • •

Assess trigger factors If suboptimal effect on oral agents or intolerable side effects: consider THC-CBD if spasticity is multiple sclerosis related Ongoing therapy and nursing interventions with monitoring of effectiveness

Generalised spasticity continues to be a problem

• •

Assess trigger factors Consider intrathecal baclofen or phenol

Fig. 25.2. Algorithm for the management of spasticity. Adapted with permission from Stevenson V, Jarrett L (2016). Spasticity management: a practical multidisciplinary guide. CRC Press, Andover.

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(BoNT) and intrathecal baclofen) have also been developed (Biering-Soerensen et al., 2022). Recording schedules for the management of leg and arm spasticity and care pathways, MDT clinical protocols, and patient information leaflets are available (e.g., Stevenson and Jarrett, 2016; Ashford et al., 2021). Management may require a combination of physical therapies, pharmacology, and surgical interventions.

Physiotherapy interventions SPLINTING, CASTING, POSITIONING, AND STRETCHING Orthoses to stretch the wrist and finger flexors can help to maintain range with low-level evidence that they can reduce spasticity (Salazar et al., 2019). Ankle-foot orthoses (AFO) can also maintain range in the ankle plantar flexors. The degree of spasticity will influence the orthotic selected. For example, a rigid AFO with a hinge that allows dorsiflexion in the stance phase may be required for people, who are ambulant with moderate– severe spasticity (Edwards and Charlton, 1996). However, it is important to consider other aspects such as the strength in the knee extensors and thus ability to control the knee in the stance phase (Piccinini et al., 2010). Serial casting applied to the ankle plantar flexors improves ankle range of motion measured at rest and while walking (Milne et al., 2020). The effects are greater when combined with BoNT injections (Dursun et al., 2017). Manual stretching does not seem to influence spasticity when measured clinically or experimentally though it may reduce patient-reported impact of clonus at the ankle. It may affect the range of movement but improvements are small (3–5°) (Katalinic et al., 2011). Greater improvements in range/passive stiffness are seen when stretches are applied with a constant torque (i.e., the stretch stimulus is always there) compared to a constant position stretch (where there will be tissue creep initially and then a loss of the stretch stimulus) or rhythmic stretches (Bressel and McNair, 2002; Chung et al., 2005). For constant torque stretches, greater applied torques and longer duration (>30 min) give rise to greater immediate improvements in passive stiffness (Marsden et al., unpublished observations) but the longterm effects of this needs to be systematically assessed. One way of providing a long-term, high-torque stretch to the ankle plantar flexors is with weight-bearing stretches (Ofori et al., 2016). For those with more marked disability, this can be achieved using a standing frame (Ofori et al., 2016). In people with progressive multiple sclerosis (MS), for example, standing 3 times/week over 20 weeks for 30 min results in improvements in leg joint range of motion and a reduction in spasm frequency compared to usual care (Freeman et al., 2019).

It is possible to achieve a prolonged stretch and avoid spasms through appropriate positioning; this should be considered over the 24 h period. Extensor spasms associated with lying supine can be avoided by using pillows and towels and T or E rolls to position the trunk, hips, and knees in a degree of flexion or in side-lying. Specialized sleep systems and electric profiling beds may be required in people with more severe spasticity (Pope, 2007a; Buchanan and Hourihan, 2016). Often, optimizing the sitting posture in a chair or wheelchair requires a specialist’s assessment. Potential aims of treatment include optimization of arm function, improved comfort and skin integrity, reduction of fatigue and spasms, and prevention or accommodation of contractures and bony deformity. Here, appropriate alignment of the pelvis and provision of sufficient trunk stabilization that provides support while permitting functional arm movements is essential. Support via headrests, tilt-in-space seating systems, and custom-molded systems may be required (Pope, 2007b).

EXERCISE Exercise may improve other components of the UMN syndrome such as impaired static and dynamic balance, weakness, and poor selective motor control. Combined muscle-strength training and stretching of sufficient intensity may be warranted to prevent and manage the nonneural components of hypertonia (Faturi et al., 2019; Estrada-Bonilla et al., 2020). For example, improvements in passive stiffness were observed in a trial of children with CP, who undertook combined 30 min of passive and 30 min of active training 3 times/week over 6 weeks. The stretches involved applying a constant torque to “strenuously stretch the calf muscle toward extreme dorsiflexion.” Using ultrasound recordings, they found elongation of muscle fascicles and reduced fascicular stiffness with an increase (normalization) in tendon stiffness (Zhao et al., 2011). Eccentric muscle contractions may also improve hypertonia and function by combining strength training with a lengthening muscle stretch (Davis et al., 2020; Manca et al., 2020). The importance of combining strengthening and stretching to manage and prevent contracture is supported by studies in animal models of contracture (Williams et al., 1988).

Pharmacological management Any drug intervention should complement other management strategies such as optimization of trigger factors, exercise, and stretching programs rather than given in isolation. The doses and side effects of commonly used drugs are summarized in Table 25.2. Important factors to consider when planning management include the distribution of spasticity (i.e., whether it

TREATMENT OF SPASTICITY

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Table 25.2 Doses and side effects of common antispasticity drugs Drug

Starting dose

Maximum dose

Baclofen

5–10 mg/day

Tizanidine

2 mg/day

Dantrolene

25 mg/day

Diazepam

2 mg/day

Clonazepam

0.25–0.5 mg, usually at night-time 300 mg/day (can start at 100 mg/day)

100 mg/day, usually in 3 Drowsiness, weakness, paresthesia, nausea, divided doses vomiting 36 mg/day, usually in 3 or 4 Drowsiness, weakness, dry mouth, postural divided doses hypotension a Monitor liver function 400 mg/day, usually in 4 Anorexia, nausea, vomiting, drowsiness, divided doses weakness, dizziness, paresthesia a Monitor liver function 40–60 mg/day, usually in 3 Drowsiness, reduced attention, memory or 4 divided doses impairment a Dependency and withdrawal syndromes 3 mg, usually in 3 divided Same as diazepam doses 3600 mg/day, usually in 3 Drowsiness, somnolence, dizziness, weight divided doses gain, respiratory depression a Dependency and withdrawal syndromes 600 mg/day in 2 divided Drowsiness, somnolence, dizziness, weight doses gain, respiratory depression a Dependency and withdrawal syndromes 12 sprays/day Dizziness, drowsiness, disorientation

Gabapentin

Pregabalin

25–75 mg/day

THC:CBD (Nabiximols, Sativex®)

1 Oromucosal mouth spray usually at night-time

Side effects

Adapted from Greenwood R, Stevenson VL, Marsden J et al. (2022). Neurorehabilitation. In: C Clarke, R Howard, M Rossor, S Shorvon (Eds.), Neurology: a queen square textbook, second edn. Blackwell Publishing. a Significant side effect.

affects multiple muscle groups or is more prominent in one or two groups) and severity of spasticity alongside the codeveloped treatment goals. For pharmacological interventions the time to peak bioavailability and the half-life of action determines the optimal dosing regimen (Stevenson, 2016).

ORAL AGENTS All oral medications for spasticity are associated with side effects, commonly weakness and drowsiness. Therefore, it is important to slowly increase the dose to determine the lowest effective dose (“start low and go slow”) (Stevenson, 2016). If common first-line drugs (e.g., baclofen and tizanidine) are only partially effective than what they are at the highest level that the patient can tolerate, they can be combined with other medications. If spasticity is then managed, and to minimize polypharmacy, a slow withdrawal of one of the medications could be performed to see whether the patient maintains the antispasticity effect with only one drug (Stevenson, 2016). There are only a few drugs available to manage spasticity; so, the importance of using them judiciously is recommended.

Baclofen Baclofen is a GABAB agonist. It reduces spasticity through its action on spinal inhibitory circuits. Baclofen can cause a 20% decrease in total stiffness at the ankle and can increase the soleus stretch reflex threshold in the early swing phase in people with MS (Neilsen and Sinkjaer, 2000; Nielsen et al., 2000). The reduction in spasticity is supported by clinical trials (Montane et al., 2004), although there is limited evidence of this leading to improvements in function in MS and spinal cord injury (SCI) (Paisley et al., 2002; Taricco et al., 2006). Baclofen does have a peripheral action on muscle affecting excitation–contraction coupling (Neilsen and Sinkjaer, 2000) contributing to the side effect of weakness. Side effects with baclofen are common, being seen in up to 75% of patients (Ertzgaard et al., 2017). Baclofen is rapidly absorbed with peak plasma levels occurring within 1 h. Therefore, it should be taken at least 30 min before a clinical effect is required, e.g., before getting out of bed in the morning. Baclofen is excreted by the kidneys and so the dose may need to be reduced in people with renal disease. It has a half-life of 3–4 h and so, 3 doses/day are usually required (Stevenson, 2016). Due to the risk of seizures, baclofen should not be

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suddenly stopped (Stevenson, 2016) and management protocols for anticipated interruptions in baclofen should be clinically available (Schmitz et al., 2021). Tizanidine Tizanidine is an a-2 adrenergic receptor agonist. Noradrenergic descending pathways arising from the locus coeruleus normally inhibit the processing of group II muscle spindle afferents; tizanidine may thus mimic this action. Synaptic actions of group I afferents are not influenced or may be enhanced through this pathway (PierrotDeseilligny and Burke, 2012c). Group II excitation can be increased after stroke and SCI although this finding is variable with changes at rest not always reflecting changes seen with tasks such as balance and walking (Pierrot-Deseilligny and Burke, 2012c). A reduction in spasticity with tizanidine does not confirm that spasticity is mediated by group II afferent pathways in a particular patient. Reductions in stretch reflex size by blocking excitatory influences (or by facilitating inhibitory influences) will reduce spasticity even though it is caused by other mechanisms (Pierrot-Deseilligny and Burke, 2012a). Comparative trials suggest that tizanidine is as effective as baclofen but the side effect of weakness may be slightly less marked (Groves et al., 1998) though postural hypotension can occur, which may limit its use in those with impaired balance and mobility. Like baclofen, it is also rapidly absorbed with peak plasma levels occurring within 1 h and has a 2–4 h half-life meaning 4 times daily dosing may be required. Tizanidine is extensively broken down by the liver reducing its bioavailability. Checking liver function prior to initiating treatment and monitoring this when increasing the dose and for the first few months is required (Stevenson, 2016). Gabapentin and pregabalin Gabapentin and pregabalin bind to subunits of voltagegated calcium channels (a2-d subunits). This is associated with reduced monoamine neurotransmitter release but the mechanisms of action are obscure. They are not, as originally designed, GABA mimetic and mechanisms do not seem to be related to a modulation of calcium currents (Sills and Rogawski, 2020). As the drugs have the effect of reducing neuronal excitability, an abrupt cessation should be avoided due to the risks of inducing seizures (Stevenson, 2016). The rate of absorption of pregabalin is 3 times higher compared to gabapentin. Pregabalin achieves a peak blood concentration within 1 h compared to 3 h for gabapentin. Randomized controlled trials in MS and SCI have shown a reduction in spasticity with gabapentin (Gruenthal et al., 1997; Mueller et al., 1997; Cutter et al., 2000)

though a crossover trial of gabapentin had no significant effect in the most common form of HSP (SPASTIN or SP4-gene linkage) (Scheuer et al., 2007). The antispasticity effects of pregabalin have only been assessed retrospectively (Bradley and Kirker, 2008). Both agents are effective in neuropathic pain; so, they may be particularly useful in people experiencing pain and spasm (Mathieson et al., 2020; Canavan et al., 2022). Both gabapentin and pregabalin were reclassified in the United Kingdom in 2019 as Schedule 3 controlled drugs under the Misuse of Drugs Regulations 2001, and Class C of the Misuse of Drugs Act 1971 over concerns of drug misuse and addiction; so, care must be taken when prescribing and escalating doses. In addition, gabapentin and, more recently, pregabalin have also been associated with reports of severe respiratory depression, including some cases without the presence of concomitant opioid medicines. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment; those using concomitant CNS depressants; and people older than 65 years might be at higher risk of experiencing these events and adjustments in dose or dosing regimen may be necessary. Cannabinoids The cannabinoid receptor CB1 is present within the central and peripheral nervous system. D9Tetrahydrocannabinol (THC) is one of 61 cannabinoids found in cannabis and is a partial CB1 receptor agonist (Carod Artal et al., 2022). Animal models show that THC is associated with a reduction in spasticity (Pryce and Baker, 2007; Baker et al., 2012; Pryce et al., 2013) with an action on sensory afferent transmission as well as central pathways being suggested (Pryce et al., 2014). However, due to the extensive expression of CB1 receptors other effects such as impaired short-term memory, coordination as well as anxiogenic and psychoactive effects can be seen with THC. Cannabidiol (CBD), another cannabinoid, reduces the anxiogenic and psychoactive effects of THC. Systematic reviews highlight that there is moderate evidence that these cannabinoids decrease spasticity, pain, sleep disturbance, and bladder overactivity in humans (Longoria et al., 2022). They are associated with adverse events such as dizziness and nausea (da Rovare et al., 2017). Cognitive effects occur in a dose-dependent manner but with no differences from placebo being seen 4 h after administration (Eadie et al., 2021; Chan and Silván, 2022). THC:CBD (Nabiximols, Sativex®) is an oromucosal spray that delivers 2.7 mg THC and 2.5 mg CBD in each 100 mL spray. In 2010, THC:CBD was licensed for moderate-to-severe MS-related spasticity for use

TREATMENT OF SPASTICITY in patients, who demonstrate a clinically significant improvement (defined as >20% improvement of spasticity rated by the participant on a numerical rating scale—a patient-reported measure with anchors of 0, no spasticity, and 10 the worst possible spasticity). In the pivotal trial, the patient cohort was enriched, only randomizing responders to ongoing treatment or placebo (Novotna et al., 2011). Use of an enriched design is controversial as is using a spasticity numerical rating scale as the primary outcome; thus, many regulatory bodies do not accept this as high-quality evidence despite further trials and some additional evidence of positive effects on the Ashworth scale in small-scale studies (Ferrè et al., 2016; Markovà et al., 2019). Currently, THC:CBD remains unlicensed by the United States (US) Food and Drug Administration and is variably reimbursed throughout Europe. In the United Kingdom, it was approved by the National Institute for Health and Care Excellence (NICE) in 2019 for moderate-to-severe MS-related spasticity as an add-on agent and appears to be particularly useful in those experiencing troublesome and often painful spasms with sleep disturbance (NICE NG114, 2019). Patients frequently report benefits using nonregulatory approved cannabinoids for symptom control including spasticity and pain; however, these are not recommended in the UK NICE guideline, nor is THC:CBD recommended for neuropathic pain. Other medications Benzodiazepines act indirectly (via chloride ionosphere complexes) as GABAA agonists. They reduce mono- and polysynaptic spinal reflexes and are associated with reductions in spasticity (Stevenson, 2016). However, they are associated with side effects of drowsiness and sedation. Both tolerance (need to increase the dose over time) and dependence can occur meaning that the drug should be reduced slowly to avoid a withdrawal syndrome. Toxic effects (ataxia, vertigo, and headache) can occur. They are absorbed quickly with peak plasma levels within 1 h and have a long half-life of 20–80 h. Due to their sedative effects, benzodiazepines are more frequently used at night-time. Clonazepam is less sedating than diazepam, and can be useful for nocturnal spasms and stiffness (Stevenson, 2016). Dantrolene acts peripherally reducing calcium ion release from the sarcoplasmic reticulum and thus reduces the force of muscle contraction. It can be a potential addition to centrally acting drugs. There is, however, a risk of hepatotoxicity with side effects affecting the gastrointestinal system. Liver function must be checked before and during dantrolene treatment (Stevenson, 2016). Alterations in serotonergic receptor activity on motoneurons, subsequent to descending serotonergic

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denervation, lead to the development of plateau potentials and thus spasms and possibly spasticity (see above). This system could therefore be a target for future treatment. In rat complete spinal cord models, for example, treadmill training combined with cyproheptadine (a 5-HT2 receptor antagonist) decreases the development of spasticity (hyperreflexia) while treadmill training and fluoxetine (a selective serotonin reuptake inhibitor) was associated with greater spasticity (Ryu et al., 2018). In humans with incomplete SCI, however, these findings have not been reproduced (Leech et al., 2014). In HSP case reports highlight that commencement of serotonergic reuptake inhibitors can lead to signs of a serotonergic syndrome including an increase in spasticity and spasms (Goffin et al., 2020).

Injectable therapies BOTULINUM TOXIN BoNT is a form of focal spasticity management. When injected into a muscle, the BoNT heavy chain binds to glycoproteins specifically found on the surface of cholinergic nerve terminals. After internalization, the BoNT light chain binds to the SNARE (soluble N-ethylmaleimide factor attachment protein receptor) protein complex, which is involved in the transportation and membrane fusion of vesicles containing the acetylcholine (ACh) neurotransmitter (Sauvola and Littleton, 2021). This leads to an inhibition of Ach exocytosis leading to paresis by chemical denervation. Different BoNT serotypes (e.g., A and B) target different proteins in the SNARE complex (Dressler, 2004). Only type A and type B are currently licensed for spasticity management, with BoNT-A being the most widely used. BoNT-A injections have their maximal effect at 5 weeks (Ojardias et al., 2022) and then gradually wear off. The initial phase of recovery is through axonal sprouting and this can be seen from about 28 days. A second phase occurs later at about 3 months when renewed vesicle release occurs from the existing terminal. Use of BoNT is limited by the total dose one can administer of a toxin and also the burden of treatment for the patient having numerous injections on a regular basis. Thus, its use is ideally suited for focal areas of problematic spasticity, e.g., pes equinovarus, fingers in the palm, flexed wrist, and elbow or adductor spasms. For more widespread or generalized spasticity, systemic treatments are recommended. Recommended doses vary with the preparation. For example, for the ankle plantar flexors a medium dose (approximately 300 U Botox® or 1000 U Dysport®) is recommended. Dosing recommendations for specific preparations for spasticity are provided in consensus guidelines (e.g., onabotulinum toxin A (Dressler et al., 2021)). Guidance to the target muscle using ultrasound,

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electromyography, or electrostimulation is superior to manual needle placement and greater effects are seen with endplate injections (Chan et al., 2017). Electrical stimulation over the motor point for 30–60 min after the injection (in line with the timing of BoNT uptake) is hypothesized to increase BoNT uptake into the targeted muscle. Due to variabilities in protocols, it is unclear whether this approach is more effective at reducing spasticity than the injection in isolation (Picelli et al., 2021). Although trials highlight that BoNT can reduce spasticity, the evidence that this is associated with an improvement in function and movement quality is less robust. For example, in trials of walking poststroke, improvements in 10 m-timed walk are observed but whether there is an alteration of the motion of the targeted joints is unclear (Andringa et al., 2019; Andraweera et al., 2021; Varvarousis et al., 2021). In people with mild–moderate finger and wrist flexor spasticity poststroke, BoNT produced no additional improvements in grasp release time or function (as assessed via the action research arm test, nine hole peg test) compared to physiotherapy alone (Wallace et al., 2020). BoNT does play an important role in the management of severe arm spasticity where the goals of treatment are to improve passive function (e.g., to aid hand opening to maintain palm hygiene, or to reduce elbow flexion to aid dressing) and prevent/treat pain and skin breakdown (Allison et al., 2018; Gupta and Addison, 2020; Marciniak et al., 2020). This is also associated with improvements in the quality of life and carer burden (Andringa et al., 2019; Marciniak et al., 2020). BoNT further decreases spasticity, reduces pain, and increases range of motion for people with hemiplegic shoulder pain. Targeted muscles vary (pectoralis major, biceps, subscapularis, infraspinatus, teres major, and supraspinatus) and intraarticular and intrabursal injections have also been described (Xie et al., 2021). BoNT can be provided in combination with other oral and regional pharmacological therapies and physical therapies such as positioning, splinting or casting, electrical stimulation, extracorporeal shock wave therapy (ECSWT), and exercise (Allart et al., 2022). For such adjuncts to be effective, it is crucial that appropriate services are coordinated so they occur soon after the injection.

PERIPHERAL NERVE BLOCK Phenol or alcohol necrolyses is another form of focal spasticity management. It is faster acting (within minutes), longer lasting (up to 6 months, with waning of effect due to partial nerve regeneration and sprouting), and cheaper than BoNT. However, it requires skilled

administration and can be associated with dysesthesia when given to mixed nerves compared to pure motor nerves (Karri et al., 2017). As with BoNT, it is more accurately administered with ultrasound and electrical stimulation guidance (Karri et al., 2017). The most commonly injected nerves include the obturator nerve (35.8%) and sciatic branches to the hamstrings and adductor magnus (27.0%) (Karri et al., 2017). Obturator nerve blocks can improve perineal hygiene and pain associated with severe adductor spasticity and spasms (Akkaya et al., 2010; Lam et al., 2015). They can also aid with positioning in sitting, reducing buttock–seat interface pressure in SCI and thus the potential for pressure ulcer development (Yas¸ ar et al., 2010). Obturator nerve blocks may be useful in managing scissoring gait and are associated with an increased base of support (Ofluoglu et al., 2003). However, temporospatial parameters of walking do not improve (Ofluoglu et al., 2003) and subjective reports suggest that some tasks such as stair climbing get more difficult. This may be because the hip adductors were acting as a secondary hip flexor. As with any other intervention, nerve blocks must be done in the context of a goal-orientated management plan and in conjunction with physical measures to optimize the effect.

INTRATHECAL BACLOFEN Intrathecal baclofen (ITB) is administered by a programmable, subcutaneously implanted pump containing a reservoir that is placed in the abdomen with a catheter tunneled into the intrathecal space. ITB can deliver low doses of baclofen (80% predicted, and score 2 on all ALS-FRS-r items) (Takei et al., 2017). The high energy demand required to maintain neurotransmission and ionic gradients makes mitochondria vulnerable to oxidative damage in all neurodegenerative disorders. Indeed, MNs from ALS patients display multiple mitochondrial alterations that have been suggested by ultrastructural studies. Furthermore, recent data indicate that oxidative stress is one of the major mechanisms implicated in mitochondrial dysfunction, contributing ultimately to neurodegeneration (Cunha-Oliveira et al., 2020). The majority of mitochondrial alterations have been characterized and described in patients carrying mutant forms of SOD1. Albeit exact mechanisms explaining how mutant forms of SOD1 can affect mitochondria homeostasis are still lacking, it has been suggested that the mutant enzyme can affect these organelles because of a toxic gain of function rather than of loss of activity (Menzies et al., 2002). Besides the toxic gain of function effect of mutant SOD1 enzymes, other mechanisms that have been detected in SOD1 models include impairment of mitochondrial biogenesis and removal of damaged organelles through mitophagy (Liu et al., 2013; Russell et al., 2013). Mitochondrial dysfunction has been demonstrated in the spinal cord of sporadic ALS patients (Palomo and Manfredi, 2015). Oxidative stress was also found to be increased in C9orf72 neurons. In these cells, interactome analysis revealed that polyglycine-arginine repeats arising from G4C2 gene expansion interact with mitochondrial proteins leading to an increase of mitochondrial membrane potential and ROS production that eventually lead to MN degeneration (Lopez-Gonzalez et al., 2016). These and other experimental evidence suggest that minimizing the effects of oxidative stress in mitochondria may be a reasonable strategy to increase MNs’ survival. Coenzyme Q10, an antioxidant and a mitochondrial cofactor, has been studied to serve this purpose. A placebo-controlled, double-blind, phase II clinical trial showed a good safety and tolerability profile for Q10, although no significant

NOVEL THERAPEUTIC APPROACHES FOR MOTOR NEURON DISEASE differences in ALSFRS-r scores were detected between coenzyme Q10 at 2700 mg/day and placebo (Kaufmann et al., 2009). Creatine is an organic compound that physiologically facilitates recycling of adenosine triphosphate in cells. It is known that creatine exerts several neuroprotective effects such as inhibiting activation of the mitochondrial permeability transition pore (O’Gorman et al., 1996). It has been demonstrated that creatine supplementation in SOD1 transgenic mice attenuated glutamate excitotoxicity and increasing longevity and motor performances (Andreassen et al., 2001). However, in humans, creatine did not exert obvious benefit on multiple markers of disease progression (muscle strength, ALSFRS-r, vital capacity, and fatigue) assayed in two placebo-controlled phase II clinical trials (Shefner et al., 2004; Rosenfeld et al., 2008). Urate is the end product of purine metabolism and it is a well-known endogenous antioxidant (Ames et al., 1981). The administration of its precursor, inosine, was shown to elevate urate concentrations in both serum and cerebrospinal fluid in two clinical trials on patients affected by PD (Parkinson Study Group SURE-PD Investigators et al., 2014; Bhattacharyya et al., 2016). The same compound was administered to a small cohort of ALS patients in a pilot, open-label trial. The trial demonstrated a positive biological effect of inosine on urate metabolism, as serum urate levels resulted elevated in patients treated with inosine, and biomarkers of oxidative stress and damage ameliorated during the treatment. However, no difference in term of ALSFRS-r scores were detected between the two groups (Nicholson et al., 2018). Dexpramipexole is the R(+) enantiomer of pramipexole, a well-known drug adopted in the treatment of PD and restless legs syndrome. Pramipexole is a dopamine agonist that is also known for its neuroprotective and antioxidant effects. While pramipexole has a high intrinsic dopaminergic receptor activity that causes several side effects, the enantiomer dexpramipexole displays a low affinity for dopaminergic receptors and it has been well tolerated by patients (Cheah and Kiernan, 2010). A clinical trial with dexpramipexole in ALS patients demonstrated that the drug not only was well tolerated but it also caused an attenuation in the slope of the decline of ALSFRS-r scores (KNS-760704, 300 mg/day) compared to the placebo arm (Cudkowicz et al., 2011). However, in a placebocontrolled, phase III study on a larger population, these promising results were not confirmed and no modification in the ALSFRS-r rate of decline was observed between the placebo and the treatment arms (Cudkowicz et al., 2013). Rasagiline (N-propargyl-1 (R) aminoindan; TPV1012) is a monoamine oxidase B inhibitor that is also used for the treatment of PD (Parkinson Study Group, 2002). Rasagiline, in combination with riluzole, increased the survival of SOD1 transgenic mice, ameliorating locomotion performances. However, this combined treatment did not

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downgraded the loss of MNs in the spinal cord of mice (Waibel et al., 2004). In humans, rasagiline was well tolerated but showed no effect in modifying the rate of decline in the ALSFRS-R in two different clinical trials (Macchi et al., 2015; Statland et al., 2019). A third trial in which patients were treated with rasagiline and riluzole showed that rasagiline might modify disease progression in a subset of patients with an initial slope of ALSFRS-r greater than 0.5 points per mount at baseline (Ludolph et al., 2018).

FUTURE DIRECTIONS Among the newest therapies under investigation for ALS, in the period from 2020 to 2022, 53 different drugs have entered clinical trials. Of those, 13 drugs have entered phase III studies. The most promising drugs undergoing evaluation include high-dose methylcobalamin, masitinib, AMX0035, CNM-Au8, and tofersen, all targeting different mechanisms of neurodegeneration. Tofersen (BIIB067) is a SOD1 mRNA ASO (NCT04856982) that has demonstrated to reduce SOD1 levels in the CSF of patients of 36% (compared to 3% in placebo-treated patients) (Miller et al., 2022). Methylcobalamine is a coenzyme of methionine synthase that was found to reduce clinical deterioration measured by ALSFRS-r by 43% at 16 months in a Japanese ALS cohort (Oki et al., 2022). Masitinib is a tyrosine kinase inhibitor that prevents microglial activation and if administered early could prolong survival by 2 years (Mora et al., 2021). AMX0035 was approved by the FDA in September 2022. It is a combination of sodium phenylbutyrate and taurursodiol that targets mitochondria and ER ameliorating cellular stress response and preventing apoptosis and it demonstrated to reduce clinical deterioration by 2.9 points at ALS-FRS-r at 2 years (Paganoni et al., 2020). Lastly, CNM-Au8 is a gold nanocrystal suspension that restores energy in brain cells and reduces TDP-43 aggregated in the cytoplasm (Ho et al., 2022). Poster number 154, in the Muscular Dystrophy Association clinical & scientific conference 2022) in the open-label, extension trial showed a reduction in the risk of death of 70% compared to patients who were initially treated with placebo (Meglio, 2022). Notwithstanding the large number of drugs tested in the last 2 years, in order to find effective strategies to address ALS, clinicians must possess all the elements that allow enrolment of the optimal population in clinical trials, with the ultimate goal of anticipating the administration of treatment in the preclinical phase, to prevent the spread of neurodegeneration, or at least starting it as close as possible to symptom onset. The current diagnostic delay is of about 9–12 months from the first symptom, which is far from being acceptable considering the very short window for treatment and the rapid course of the

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disease (Hardiman et al., 2017). With that knowledge, the joint effort of the scientific community has not only focused on experimenting novel therapies or repurposing drugs used for other diseases, but also on finding nonclinical biomarkers that could anticipate diagnosis to shorten time to therapy. Nonclinical biomarkers of disease of use in clinical practice are still lacking, although some have been proposed and show promising results (e.g., neurofilament light chains, magnetic resonance imaging, positron emission tomography, or electrophysiological measures). Development of biomarkers goes hand in hand with the finding of novel therapies. Future directions cannot ignore the role of biomarkers in drug development, particularly given the heterogeneity of the clinical features of the disease.

CONCLUSIONS The knowledge extracted from preclinical models of ALS has allowed testing a relative high number of therapies that were then experimented on patients in clinical trials. Unfortunately, most of them showed none or only a modest efficacy in modulating disease progression. Knowing that only three drugs are FDA-approved for the treatment of ALS (riluzole, edaravone, and AMC0035), the scientific community is lagging behind treatment of this disease. Further efforts are certainly warranted to find novel strategies to target the several molecular aspects of this neurodegenerative disease and to eventually bend its natural history. However, the rate of release of new drugs is constantly increasing and international networks are joining efforts in an unprecedented fashion, leaving space to hope that effective therapeutic strategies are soon to be released.

ABBREVIATIONS AAV, adeno-associated virus; ALSFRS-r, ALS Functional Rating Scale-revised; AD, Alzheimer disease; ALS, Amyotrophic lateral sclerosis; ASO, antisense oligonucleotides; BBB, blood–brain barrier; CSF, cerebrospinal fluid; CHI3L1, chitinase 3-like protein 1; C9Orf72, chromosome 9 open reading frame 72; CRISPR, clustered regular interspaced short palindromic repeats-associated; COX2, cyclooxygenase type 2; ER, endoplasmic reticulum; EMA, European medicines agency; FTY720, Fingolimod; FDA, Food and Drug Administration; FTD, frontotemporal dementia; FUS, fused in sarcoma; GA, glatiramer acetate; iPSC, induced pluripotent stem cells; mRNA, messenger RNA; MN, motor neuron; MND, motor neuron diseases; MS, multiple sclerosis; OS, oxidative stress; PD, Parkinson disease; PET, positron emission tomography;

ROS, reactive oxygen species; Tregs, regulatory T cells; RA, rheumatoid arthritis; S1P, sphingosine 1-phosphate; SOD1, superoxidase dismutase 1; TARDBP, transactive response (TAR) DNA-binding protein 43; TSPO, translocator protein; TREM2, triggering receptor expressed on myeloid cells 2; UPR, unfolded protein response.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00003-X Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 27

Botulinum toxin for motor disorders DELARAM SAFARPOUR1 AND BAHMAN JABBARI2* 1

Department of Neurology, Oregon Health & Science University, Portland, OR, United States

2

Department of Neurology, Yale University School of Medicine, New Haven, CT, United States

Abstract Botulinum neurotoxins are a group of biological toxins produced by the gram-negative bacteria Clostridium botulinum. After intramuscular injection, they produce dose-related muscle relaxation, which has proven useful in the treatment of a large number of motor and movement disorders. In this chapter, we discuss the utility of botulinum toxin treatment in three major and common medical conditions related to the dysfunction of the motor system, namely dystonia, tremor, and spasticity. A summary of the existing literature is provided along with different techniques of injection including those recommended by the authors.

Botulinum toxins (BoNTs) are a group of biologic toxins produced by the bacterial genus clostridia. Eight different serotypes of these toxins are now recognized (A,B, C,D,E,F,G,X) based on their immunological properties (Pirazzini et al., 2022). Currently, only types A and B are used in clinical practice. In the early 19th century, the German physician and poet, Justinus Kerner suspected that outbreaks of paralytic sickness caused by the consumption of rotten sausage in Europe were caused by a biologic toxin. He was also first to suggest the potential utility of such a toxin for the treatment of hyperactive movement disorders (citing chorea as an example) (Erbguth, 2004). In 1895, the bacteria responsible for botulism was isolated from the spoiled tissue by Professor Ermengem in Ghent, Belgium and called Bacillus botulinum. Several decades later, the name was changed to Clostridium botulinum in 1924 at the suggestion of Ida Bengtson, a Swedish-American bacteriologist. The major mode of action accounting for the paralytic effect of botulinum neurotoxin takes place in the neuromuscular junction (NMJ). Following intramuscular injection, the toxin molecule reaches NMJ through blood or lymphatics. Subsequently, via a series of elaborate enzymatic processes, it deactivates the synaptic protein

responsible for acetylcholine release from synaptic vesicles. The BoNT molecule consists of a light chain (LC) weighing 50kDa and a heavy chain (HC) weighing 100 kDa, connected by a disulfate bond (Fig. 27.1). The toxin complex is surrounded by a large nontoxic protein complex that, in case of botulinum toxin Aweighs approximately 700 kDa. After reaching the synaptic membrane, the binding site of the heavy chain (HC) attaches the toxin molecule to specific membrane receptors (SV2 and sialogangliosides for BoNT-A). The SV2 receptor then opens like a channel and lets the toxin enter the cytosol. Once inside, the disulfide bond of the toxin breaks due to the action of intracellular enzymes and the free light chain of the toxin reaches the targeted synaptic protein (SNAP25 for BoNT-A) (Rossetto et al., 2021). Deactivation of SNAP25 after exposure to the protease activity of the light chain results in inhibition of acetylcholine release and, hence, reduction or cessation of muscle contraction. Recent animal research has shown that after peripheral (intramuscular) injection of BoNT, the toxin molecule reaches the central nervous system through retrograde transfer suggesting that part of the paralytic effect of the toxin may be conducted centrally. In one study, injection of BoNT into the nasolabial musculature

*Correspondence to: Bahman Jabbari, MD, Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, United States. Tel: +1-914-482-8542, E-mail: [email protected]

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BoNT

L-PTC/A1

NTNH

A

B

Fig. 27.1. The molecular structure of botulinum toxin. From Rossetto O, Pirazzini M (2020). Molecular structure and mechanisms of action of botulinum neurotoxins. In: Jabbari B. (ed.) Botulinum Toxin Treatment in Surgery, Dentistry and Veterinary Medicine. Springer.

Table 27.1 Formulations of four botulinum toxins, commonly used for treatment of motor and movement disorder

Toxin name

Toxin serotype

Packaging (units/vial) Preparation

OnabotulinumtoxinA (Botox)

Serotype A 100, 200

IncobotulinumtoxinA (Xeomin)

Serotype A 50, 100, 200

AbobotulinumtoxinA Serotype A 300, 500 (Dysport) RimabotulinumtoxinB Serotype B 2500, (Myobloc) 5000, 1000

Vacuum dried powder Lyophilized powder

Lyophilized powder Sterile solution

Excipients Storage

Storage after reconstruction

HSA NaCl

Refrigerate (2–8°C)

Refrigerate at 2–8°C—use within 24 h

HSA Sucrose

Refrigerate at 2–8°C—use Frozen within 24 h refrigerated, or stored at room temperature Refrigerate 2–8°C Refrigerate 2–8°C—use within 4h Refrigerate No reconstruction is necessary. (2–8°C) If solution is further diluted, use within 4 h

HAS Lactose HAS NaCl Sodium Succinate

From Dashtipour K, Spanel P (2020). Types of toxins in commercial use, similarities and differences. In: B Jabbari (Ed.), Botulinum toxin treatment in surgery, dentistry and veterinary medicine. Springer Nature. Reprinted with permission from Springer Nature.

the rat mediated cleaved SNAP25 into the facial nucleus in the brain stem (Caleo et al., 2018). This was prevented by the delivery of antitoxin antibodies into the cerebral ventricles. In another study (Matak, 2020), injection of BoNT into the sciatic nerve of the rats affected by tetanus toxin relieved muscle spasms and the cleaved SNAP-25 appeared in the ventral horn of the spinal cord indicating retrograde neuronal transfer to central nervous system. Currently, four BoNTs are commonly used in clinical practice (Table 27.1).

BoNT has been widely used for the treatment of several motor disorders including dystonia, bruxism, tremors, tics, myoclonus, restless leg syndrome, tardive dyskinesia, and a variety of symptoms associated with Parkinson’s disease (Anandan and Jankovic, 2021). While BoNT is considered as the most potent biologic toxin (1–2 ng/kg by intravenous or intramuscular route can be lethal in human) (Kumar et al., 2016), if administrated by a knowledgeable clinician it is a safe therapeutic option with wide clinical uses (Jankovic, 2017). Effects

BOTULINUM TOXIN FOR MOTOR DISORDERS of BoNT in motor disorders are through temporary weakness of the targeted muscles. After intramuscular injection, the effect of the toxin typically occurs after 2–5 days from, reaches its peak at 5–6 weeks and lasts for 2–3 months (Schiavo et al., 2000). A recent study analyzed predictors of time to onset and duration of BoNT efficacy in 186 patients with oromandibular, limb and cervical dystonia, blepharospasm, and hemifacial spasm, as well as sialorrhea and parkinsonism (Ledda et al., 2022). Results of this study showed that age, type of toxin, clinical condition, and especially the dose of toxin used for the injections were important predictors of variability in BoNT efficacy. Although muscle weakness seems to be the primary mechanism of action of BoNT in management of motor disorders (Caleo and Restani, 2018), more recently evidence suggests that pharmacologic properties of BoNT also result in changes in electrophysiologic and morphologic properties of central nervous system through modulation of several neurotransmitters including glutamate, noradrenaline, dopamine, and glycine (Bozzi et al., 2006; Currà and Berardelli, 2009; Hok et al., 2021). This chapter covers three major indications for BoNT treatment in the area of motor disorders. These include dystonia, tremor, and spasticity. Except for tremor, the other two indications are currently approved by the FDA. It is important to note that the advent of newer toxin serotypes paves the way for further improvements in clinical practice and use of these toxins in different motor disorders in near future.

DYSTONIA Dystonia is characterized by sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures (Comella, 2018). Cervical dystonia and blepharospasm are the most common forms of focal dystonia (with prevalence of 4.98 per 100,000 and 4.2 per 100,000, respectively) (Steeves et al., 2012). Commonly used medications for the treatment of dystonia include anticholinergic agents, baclofen, benzodiazepines, dopamine agonists and antagonists as well as vesicular monoamine transporter 2 antagonists (tetrabenazine). Up to 74% of patients with dystonia receive these medications, either alone or in combination with BoNT injections (Pirio Richardson et al., 2017). The use of BoNT in treatment of cervical dystonia was first reported in 1985 (Tsui et al., 1985). Shortly thereafter, several other studies investigated the efficacy of BoNT in both subjective and objective symptoms related to cervical dystonia and reported significant improvement of neck posture, pain, and quality of life (Tsui et al., 1986; Gelb et al., 1989; Greene et al., 1990; Charles et al., 2012). The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) has been used as the primary efficacy

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measure in all trials of currently approved BoNTs (Espay et al., 2018). Three commercially available botulinum neurotoxinAs and one type B are the FDA approved for clinical use in cervical dystonia. These are onabotulinumtoxinA (Botox), incobotulinumtoxinA (Xeomin) and abobotulinumtoxinA (Dysport), and the rimabotulinumtoxinB (Myobloc) (Table 27.1). Chemodenervation with BoNT type A (BoNT-A) is recommended as the first line treatment for cervical dystonia (Albanese et al., 2011; Simpson et al., 2016). Cochrane review of double-blind, randomized, and placebo-controlled trials comparing single-session treatment with onabotulinumtoxinA (Botox) using doses from 100 to 250 U with rimabotulinumtoxinB (Myobloc/Neurobloc) doses of 5000–10,000 U in the treatment of cervical dystonia indicate no significant difference between the two groups in terms of efficacy (mean difference of
1.44 (95% CI
3.58 to 0.70)). The TWSTRS was lower for patients treated with BoNT type B after 2–4 weeks of injection. However, patients treated with BoNT-B were at increased risk of treatment-related sore throat/dry mouth (BoNT-B vs BoNT-A RR of 4.39; 95% CI 2.43–7.91) (Duarte et al., 2016). A recent study examined the efficacy of BoNT-B in 150 patients with cervical dystonia previously treated with BoNT-A. Final observation data from 122 patients who continued to receive BoNT-B for 1 year showed improvement in TWSTRS total score (from 39.9 at baseline to 34.3 at 4 weeks) and pain score (from 8.9 to 7.9); these improvements were sustained through six further injections both in the subgroup with resistance to type A and those who did not have resistance. Improvement of pain related to cervical dystonia was noted even with low doses (less than 5000 U). These finding support consideration of different formulations of BoNT for different clinical settings including pain (Kaji et al., 2021). A comparison of BoNT-B and -A in patients who had previously had good response to BoNT-A showed equivalent benefits for both types at 4 weeks after the treatment of cervical dystonia (with fewer adverse events and marginally longer duration of benefits in patients treated with BoNT-A) (Comella et al., 2005). In toxin-naïve patients with cervical dystonia, this efficacy was also reported to be similar between the two toxin types (improvement in TWSTRS total scores 4 weeks after BoNT-B was noninferior to BoNT-A) (adjusted means 11.0 (SE 1.2) and 8.8 (SE 1.2)). In addition, the median duration of effect of BoNT-A and BoNT-B was not different (13.1 vs 13.7 weeks, respectively; P ¼ 0.833) (Pappert and Germanson, 2008). Table 27.2 demonstrates the year of FDA approval for different botulinum toxins in cervical dystonia and the recommended total dose by FDA. Table 27.3 shows class I studies of botulinum toxins A and botulinum toxin B in cervical dystonia.

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Table 27.2 Federal Drug Administration (FDA)-approved botulinum toxins for use in cervical dystonia

Year of FDA approval Pivotal trial Maximum FDA recommended total dose

OnaBoNT-A

RimaBoNT-B

AboBoNT-A

IncoBoNT A

1999 Charles et al. (2012) 400 U

2000 Lew et al. (1997), Brashear et al. (1999) 10,000 U

2009 Truong et al. (2005, 2010) 1000 U

2010 Comella et al. (2011) 400 U

Adopted from Spiegel LL, Ostrem JL, Bledsoe IO (2020). FDA approvals and consensus guidelines for botulinum toxins in the treatment of dystonia. Toxins (Basel) 12.

Table 27.3 Class I studies of botulinum toxins in cervical dystonia Intervention

Class of evidence in CD

Class I trials (comparison used)

Botulinum toxin type A

A

OnabotulinumtoxinA AbobotulinumtoxinA

Botulinum toxin type B

A

Charles et al. (2012) (placebo) Brans et al. (1996) (trihexyphenidyl) Poewe et al. (1998) (placebo) Truong et al. (2005) (placebo) Truong et al. (2010) (placebo) Odergren et al. (1998) (onabotulinumtoxinA) IncobotulinumtoxinA Comella et al. (2011) (placebo) Benecke et al. (2005) (onabotulinumtoxinA) Brashear et al. (1999) (placebo) Lew et al. (1997) (placebo) Brin et al. (1999) (placebo) Comella et al. (2005) (onabotulinumtoxinA) Pappert and Germanson (2008) (onabotulinumtoxinA)

Adopted from Bledsoe IO, Comella CL (2016). Botulinum toxin treatment of cervical dystonia. Semin Neurol 36: 47–53.

The common window of injection, based on most BoNT type A product labels is at least 12 weeks (Greene et al., 1990). However, survey studies have reported that some patients with shorter therapeutic response prefer shorter injection intervals (Sethi et al., 2012). A recent observational study reported that patients who received the injections in longer intervals were more likely to report satisfaction in symptom control at peak effect and end of cycle compared to those who received these injections in shorter intervals (Colosimo et al., 2019). Results of a recent survey of 209 patients with cervical dystonia from four countries (France, Germany, the United Kingdom, and the United States) showed that symptom reemergence between injections was common (88%) and the time from injection to symptom reemergence was 10.5 weeks. Severity of symptoms was lowest at the peak treatment effects and increased as the effects of the treatment started to wane. Symptoms severity was reported at their highest, 1 day before the next session. As anticipated, the impact of symptoms of cervical dystonia

on quality of life followed the pattern of symptoms control after the injections (Comella et al., 2021). The specific 12 weeks injection interval recommendation was based on the findings from a retrospective study of individuals who had received an older formulation of onabotulinumtoxinA during the 1980s and the early 1990s (Greene et al., 1994). This study had suggested that intervals shorter than 3 months and use of higher doses of BoNT were associated with the development of resistance to the toxins, which could be due to antigenicity of associated proteins in older formulation. However, the newer formulations of BoNT are less antigenic. In case of onabotulinumtoxinA, new formulation (introduced in 1997) has considerably less protein and in incobotulinumtoxinA accessory proteins are removed which makes the previous concern for the development of resistance a much less possibility (Benecke et al., 2005). While many patients with cervical dystonia benefit from previously described 12 weeks intervals for injections, other have reported a decline in the therapeutic

BOTULINUM TOXIN FOR MOTOR DISORDERS benefits of injections at a mean of 9.5 weeks with several different formulations. These patients may benefit from shorter intervals of 10 for injections to alleviate symptoms (Sethi et al., 2012). It is important to note that the early waning of response is representative of variations in response to BoNT treatment between patients (Comella et al., 2022). A recent phase 4, open-label randomized study, compared two injection intervals for incobotulinumtoxinA in patients with cervical dystonia. Comparison between shorter intervals of 8  2 weeks with longer intervals of 14  2 weeks after eight injection cycles showed that the shorter intervals were effective (and noninferior to longer intervals) for patients with benefits lasting less than 10 weeks. Adverse effects were comparable between groups and there was no secondary loss of treatment effect (Comella et al., 2022). Table 27.4 demonstrates commonly injected muscles and the recommended dose of different toxins in cervical dystonia. An investigational type of BoNT, injectable daxibotulinumtoxinA (RT002), that has been shown in preclinical studies to exhibit less diffusion that onabotulinumtoxinA and offer greater duration of effect, was subject of an open-label, dose escalation study. DaxibotulinumtoxinA resulted in mean reduction in TWSTRS total score of

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38% at week 4 postinjection, 50% at week 6, and 30% at week 24 and the mean duration of response was 25.3 weeks (95% CI, 20.14–26.14). There was no apparent dose-related increase in the incidence of adverse events reported with the use of this toxin (Jankovic et al., 2018). Beside the commonly described motor symptoms of cervical dystonia, including abnormal posture, movements, and contractions in neck muscles (Dauer et al., 1998; Singer and Velickovic, 2008), majority of patients have neck pain (Charles et al., 2014). Many others suffer from other nonmotor symptoms including anxiety, social anxiety, and depression (Zurowski et al., 2013; Berman et al., 2017). These nonmotor symptoms can be major contributors to disability, and social isolation, could influence assessment of dystonia treatment effects and have profound effects on patients’ quality of life. Since pain is a major complaint of many patients with cervical dystonia, clinicians should consider pain management as one of the core symptoms for optimization of the injection parameters (Jabbari and Machado, 2011; Rosales et al., 2021). Despite safety and efficacy of BoNT therapy in cervical dystonia, approximately one-third of these patients discontinue therapy due to lack of benefits, side effects, and cost (Jinnah et al., 2018). It has been suggested that

Table 27.4 Commonly injected muscles for treatment of cervical dystonia and recommended dose of botulinum toxin

Muscle

Action of the muscle

Sternocleidomastoid

Semispinalis capitis

Unilateral: Ipsilateral flexion and contralateral rotation Bilaterally: head and neck flexion Unilateral: flexes and rotates he head slightly to the same side Bilaterally: extends neck and head Extension, lateral flexion, and rotation of neck

Semispinalis cervicis

Bilaterally, extends the head and neck

Obliquus capitis Trapezius

Bilaterally: extends the head Unilateral: ipsilateral head rotation Elevates, retracts, and rotates scapula

Levator scapulae

Elevates the superior angle of the scapula

Scalene anterior

Bilateral: elevates ribs during inhalation

Scalene medius

Unilateral: ipsilateral neck flexion, contralateral rotation

Scalene posterior

Anterior neck flexion

Splenius capitis

Recommended starting dose of botulinum toxin (units, range) ona/incoBoNT A: 20–50 U aboBoNT/A: 40–120 U ona/incoBoNT A: 40–100 U aboBoNT/A: 100–350 U ona/incoBoNT A: 20–100 U aboBoNT/A: 60–300 U ona/incoBoNT A: 20–60 U aboBoNT/A: 60–140 U ona/incoBoNT A: 10–20 U aboBoNT/A: 60–200 U ona/incoBoNT A: 25–100 U aboBoNT/A: 60–300 U ona/incoBoNT A: 20–100 U aboBoNT/A: 60–200 U ona/incoBoNT A: 15–50 U aboBoNT/A: 30–100 U ona/incoBoNT A: 15–50 U aboBoNT/A: 30–100 U ona/incoBoNT A: 15–50 U aboBoNT/A: 30–100 U

Adopted with modifications from Dashtipour K, Lew M (2007). Cervical dystonia. In: MA Stacy (Ed.), Handbook of dystonia. Informa Healthcare; Jost WH, Druzdz A, Pandey S et al. (2021). Dose per muscle in cervical dystonia: pooled data from seven movement disorder centres. Neurol Neurochir Pol 55: 174–178. 



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treatment failure in complex cervical dystonia may be due to inadequate injection of the deep muscles of the neck that are not easily accessible such as longus colli (Bhidayasiri, 2011). Also, there are not adequate data available for the treatment of patients with more complex forms of cervical dystonia including anterocollis or retrocollis; patients with these forms of cervical dystonia are often excluded from clinical trials (Papapetropoulos et al., 2008). Ongoing research into alternative BoNT subtypes and formulations with potentially less immunogenicity are critical for the development of guidelines for the treatment of complex cervical dystonia and patients with less favorable response to BoNTs (Kane et al., 2015).

Cranial dystonia Common cranial dystonias include blepharospasm (with or without levator inhibition), orofacial dystonia, lingual dystonia and oromandibular dystonia (OMD) (jaw opening, jaw closing, or deviation type), Meige syndrome (blepharospasm plus involvement of pharyngeal, lingual, or jaw muscles), and apraxia of eye opening (due to levator inhibition). These syndromes can occur alone or more commonly in combination (Hallett et al., 2009).

Blepharospasm Blepharospasm is caused by phasic or tonic, often bilateral contractures of the orbicularis oculi muscles that result in increased rate of bilateral eye closure. In most advanced blepharospasm, severe tonic contractions can lead to functional blindness (Hallett et al., 2008). Blepharospasm responds well to BoNT injections (Hallett et al., 2009). Depending on the technique used for injection ptosis can occur in 3.2%–18% of patients and is due to spread of BoNT to levator palpebrae muscle (Cakmur et al., 2002). Although spread of the BoNT is more common following upper eyelid injections, it can also occur following injection of the corrugators (Yi et al., 2022). Less common side effects of injections in the upper or lower eyelid include eye dryness, eye weakness, ocular itching, diplopia blurred vision, or hematoma in the injection site (Park et al., 1993; Price et al., 1997; Cillino et al., 2010). It is important to consider starting with lower doses of BoNT and gradually increase the dose based on treatment response as side effects, especially severe Ptosis can influence patients’ compliance to injections. The dose per eye is divided into four portions and injected in four sites into the orbital portion of the orbicularis oculi (the average recommended starting dose per eye: onaBoNT-A: 20U, incoBoNT-A: 20 U, aboBoNT-A: 60 U). Preseptal (PST) and pretarsal (PTS) injections are the two most common injection approaches for the treatment of blepharospasm. A recent randomized clinical trial compared ocular complications and efficacy of these two

approaches in the treatment of blepharospasm and reported higher rate of lagophthalmos (incomplete eye closure) in PST BoNT injection group (Sanguandikul et al., 2021).

Oromandibular dystonia OMD can present as a focal or segmental dystonia affecting the lower face, jaw, tongue, pharynx, and mouth in a varying combination (Reich and Factor, 2019). OMD may be present at rest or be task specific, triggered by speech or eating. These symptoms may cause chewing difficulties, dysarthria, dysphagia, breathing difficulties or involuntary humming, and grunting sounds (Jankovic, 1988; Tolosa and Martí, 1988). In a recent study, clinical examination of 2020 patients with OMD reported that perioral musculature was most commonly involved in patients with OMD (85%), followed by jaw (61%) and tongue (17%). Several studies have reported that OMD is more commonly present in women with an average age of 50 years (Sinclair et al., 2013; Scorr et al., 2021). Oral medications may benefit only one-third of the patients and efficacy is significantly limited by compliance and side effects (Balash and Giladi, 2004; Vazquez-Delgado and Okeson, 2004). Treatment of OMD with BoNT was first reported by Blitzer et al. (1989). A retrospective study by Sinclair and Blitzer et al. analyzed pattern of BoNT injection for the treatment of OMD (Sinclair et al., 2013). They reported that among the 59 patients treated with BoNT between 1995 and 2011, 47.5% had jaw closing dystonia which was associated with lateral deviation in 53%. These patients were initially treated with BoNT injection into masseter  temporalis muscles; those with lateral jaw deviation were injected into external pterygoid. The internal pterygoid approach was used only in 3.4% of cases. Patients with jaw opening dystonia, initially received external pterygoid injections and if symptoms were ongoing, anterior digastric injections were added later. Long-term treatment with BoNT improves the quality of life and has minimal side effects when administered by an experienced clinician (Saraf et al., 2022; Yoshida, 2022). Table 27.5 demonstrates different types of jaw dystonia and suggested doses for different muscles. The doses are for onabotulinumtoxinA (Botox).

Task-specific dystonia Task-specific dystonia (TSD) is a form of focal dystonia that occurs in the context of specific patterns of movements. In most cases, BoNT injection is the treatment of choice. Musician’s dystonia and sport-related dystonia (golf, tennis, running) are common examples of this category.

BOTULINUM TOXIN FOR MOTOR DISORDERS

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Table 27.5 BoNT-A (onabotulinumtoxin) treatment algorithm for different types of OMD OMD type

Initial muscles injected and recommended dosea Subsequent injections

Jaw closing dystonia

Masseter (25–50 U) If no response: (1) consider internal pterygoid May consider anterior/mid temporalis (15–25 U) (external injection) 10 U, (2) double initial dose to previously injected muscles Add 7.5 U external pterygoids (intraoral) and If partial response: (1) consider internal pterygoid consider anterior portion temporalis 15–25 U (external injection) 10 U, (2) increase masseter  temporalis dose by 5–10 U External pterygoid (7.5 U) Consider anterior digastric (5 U) if not previously May consider anterior digastric (5 U) injected Consider anterior portion temporalis (15–25 U) If partial response, increase external pterygoid dose by (5–10 U) Consider platysma (7.5 U) If no response, double initial dose to previously injected muscles External pterygoid (7.5 U) Consider anterior temporalis (15–25 U) if not previously injected Consider anterior temporalis (15–25 U) If partial response, increase initial external pterygoid dose by 2.5–10 U depending on level of desired weakness If no response, double external pterygoid dose Depending on predominant direction of jaw movement, consider higher dose to contralateral external pterygoid and ipsilateral anterior temporalis

Jaw closing dystonia with lateral deviation Jaw opening dystonia Jaw opening dystonia with lateral deviation If concurrent platysma contraction Lateral deviation jaw dystonia

Adopted with modifications from Sinclair CF, Gurey LE, Blitzer A (2013). Oromandibular dystonia: long-term management with botulinum toxin. Laryngoscope 123: 3078–3083. a The number of injection points per muscle is five for each masseter and temporalis, and three for each external and internal pterygoid/digastric/ platysma.

Musician’s dystonia often affects exclusively while playing a musical instrument and can present as musician’s focal hand dystonia (Conti et al., 2008; Bledsoe et al., 2021) in professional piano, violin, drum players, or as embouchure dystonia in wind instrument players (Ray and Pal, 2022). There are several studies in literature on use of BoNT injections in focal hand dystonia, including double-blind studies with incobotulinumtoxinA (Tsui et al., 1993; Cole et al., 1995; Kruisdijk et al., 2007; Frucht et al., 2021), retrospective case series (Poungvarin, 1991; Hsiung et al., 2002; Jabusch et al., 2005; Schuele et al., 2005; Lungu et al., 2011), prospective case series (Rivest et al., 1991; Karp et al., 1994; Priori et al., 1995; Pullman et al., 1996; Wissel et al., 1996; Behari, 1999; Djebbari et al., 2004; Lungu et al., 2011), review articles (Gupta and Pandey, 2021), and case reports. Pharmacological treatments (trihexyphenidyl, benztropine, chlorpheniramine, atropine, levodopa, and baclofen) offer minimal benefits and are mostly used as an adjunct to BoNTs (Schuele et al., 2005). Under careful EMG guidance and dose titration, the results with ona and incobotulinum toxin A injections have been favorable and side effects proved to be minor and not disabling. The dose of toxin varies over a wide range of 2.5–160 U. It is

recommended that the dose be slowly titrated until the desired effect is achieved. In most patients, a mean dose of 40–80 U of ona/incobotulinum toxin A can be effective (Cohen et al., 1989; Jankovic et al., 1990; Gupta and Pandey, 2021). Chemo denervation with BoNTs is now considered as the therapeutic intervention of choice in management musician’s dystonia (Zakin and Simpson, 2021). However, despite improvement and satisfaction reported by majority of the patients, return to the level of performance predating onset of dystonia is unlikely.

TREMOR Tremor is defined as an involuntary, rhythmic oscillation due to muscle contraction (Louis, 2016). Severe tremor, especially when involving the dominant hand, often causes disability. The task force on tremor of the International Parkinson and Movement Disorder Society classifies tremor syndromes into six categories (Bhatia et al., 2018). Due to their muscle relaxation effect, BoNT injections have been studied and found effective for the treatment of variety of tremors (Lotia and Jankovic, 2016; Liao et al., 2022).

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Essential tremor Essential tremor (ET) is most common form of human tremor (Lenka et al., 2017) and, the one that most frequently studied for BoNT treatment. The frequency of ET ranges from 4 to 12 Hz (usually 5–8) and it is best seen during posture (stretched hands or holding a glass of water). Elan and McCreary assessed the worldwide prevalence of ET through meta-analysis of 42 populationbased studies (Louis and McCreary, 2021). The median crude prevalence between ages 60 and 65 was 6.9% rising to 9.3% in the older population. Betablockers (e.g., propranolol) and primidone and topiramate are commonly used for the treatment of ET. In one review, the recommended daily dose was cited as 40–240, 62.5–750, and 100–333 mg for propranolol, primidone, and topiramate, respectively (Schneider and Deuschl, 2014). Although effective, both drugs are associated with several side effects. With primidone sedation, dizziness, nausea, and vertigo are common limiting factors. Approximately 30% of treated ET patients discontinue the anti-ET medications either due to side effects or due to gradual reduction in efficacy (Lenka and Louis, 2021). Deep brain stimulation is effective but it is a surgical procedure, and many patients are not willing to undergo surgery or deal with a lifelong chest embedded stimulator requiring tasking stimulator adjustments (elderly in particular). Furthermore, DBS carries a 3%– 4% risk of complications including intracerebral hemorrhage (Baizabal-Carvallo et al., 2014). MR-guided ultrasound thalamotomy is the most recent procedure for the treatment of disabling ET. The results are promising and still being evaluated in term of longevity (Elias et al., 2016).

Botulinum toxin treatment In 1991, Jankovic and Schwartz in an open-label study reported the results of onabotulinumtoxinA (Botox) injection into affected muscles of 51 patients with tremor, 12 of whom had ET. Tremor improved in 67% of the patients. About 60% of the patients with ET after injection into forearm muscles demonstrated transient hand weakness (Jankovic and Schwartz, 1991; Samotus et al., 2019). In a later double-blind placebo-controlled study (Table 27.6), Jankovic et al. again showed improvement of hand tremor after BoNT injection into forearm muscle. The authors suggested that a customized injection approach and avoiding injection of extensor muscles may reduce the frequency and severity of hand weakness following BoNT treatment of ET. Since then, Jabbari and Mittal at the Yale University and Jog and his coworkers at London-Ontario (Western University) studied the customized approach injections in ET and focused

on using a new technique (kinematic) in order to achieve better results. Jog and his coworkers in a series of openlabel publications, introduced the technique of tremor kinematic analytic method for the treatment of ET and PD tremor (Rahimi et al., 2015; Samotus et al., 2019, 2020). Jabbari and Mittal designed a focused EMG technique with customized injection approach for the treatment of these two kinds of tremors. Both the Yale and Western University investigators have shown in blinded studies that these techniques effectively reduce the severity of essential tremor, but do not cause severe hand weakness following upper limb injections (Table 27.6). The recently published Yale and London-Ontario (Western University) blinded studies (Mittal et al., 2018; Jog et al., 2020), in addition to effectiveness demonstrated far less side effects (finger and hand weakness) with BoNT therapy compared to the previous studies. The Yale protocol was based on the premise that the main determinant of culprit muscles responsible for ET is electromyography since the typical tremor sound coming from EMG needle can define the involved muscles more accurately than clinical observation. Customization should be based on the identification of all or nearly all muscles that are significantly involved. In this protocol, muscles that in the experience of investigators were often involved in tremor were screened by EMG and only the involved muscles were injected. These muscles were flexor carpi ulnaris (FCU), flexor carpi radialis (FCR), flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), extensor carpi radialis (ECR), extensor carpi ulnaris (ECU), pronator teres (PT), and supinator. In addition, larger doses (Table 27.7) were injected into biceps and triceps since many patients with ET demonstrate proximal tremor. Also, all patients had injection of lumbrical muscles. The EMG unit was a small and handheld unit (Dantec’s Clivus EMG) defining that defined sound of the tremoring muscle. The total dose of incobotulinumtoxinA used for one extremity ranged between 90 and 100 U. In experienced hands, all injections can be done within 40–45 min. Biceps, triceps, and lumbrical muscles were injected in every patient. In view of the designers of Yale protocol, lumbrical muscles often contribute to upper limb ET and PD tremor. They can be easily identified at mid-palm by flexing the metacarpophalangeal joints. Each of the lumbrical muscles is attached to a flexor tendon and can be injected at mid-palm slightly toward the thumb side of the tendon. The injections can be carried quickly by a thin, gauge 30 needle for all four in a couple of minutes; injecting lumbricals does require EMG. In July 2021, the FDA approved the injection of lumbricals along seven new muscles under Botox Expansion for the treatment of spasticity.

Table 27.6 Double-blind placebo-controlled studies of botulinum toxins in upper limbs, essential tremor Authors and year

Study design

Jankovic et al. (1996)

#Pts

Toxin

Dose units

Outcome measure(s)

Results

Adverse effects

DB-PC Parallel

25

onaA

Initial: 50 U, if no response, 100 U at 4 weeks

75% of patients who received onaA improved vs 25% of controls, but no significant difference in functional rating

Mild (52%) to moderate (42%) extensor weakness

Brin et al. (2001)

DB-PC Parallel

133

onaA

DB-PC Crossover

28

incoA

Postural tremor improved at 6, 12, and 16 weeks in low-dose and high-dose groups. Kinetic tremor improved at 6 weeks Significant improvement of tremor at weeks 4 and 6 (P < 0.05)

Mild hand weakness in low dose and pronounced weakness in high dose

Mittal et al. (2018)

Initial: 50 U, if no response, 100 U at 4 weeks 100 (mean dose), 120 (maximum)

0–4 Tremor severity ratine, accelerometry, sickness impact profile 0–4 Severity rating, grip strength, functional disability, QoL FTM, PGIC, writing, spiral drawing, accelerometer

Jog et al. (2020)

DB-PC Parallel

30

incoA

200 or less mean 116

FTM part B motor score, PGIC, kinematic-based efficacy

Decreased tremor severity, increased hand function significantly

Six patients developed slight hand weakness. One patient had moderate-to-severe weakness of extensors Two patients reported mild hand weakness

CGIC, clinician global impression of change; DB-PC, double-blind placebo-controlled; FTM, Fahn-Tolosa-Marin motor performance score; incoA, incobotulinumtoxinA (Xeomin); onaA, onabotulinumtoxinA (Botox); PGIC, patient global impression of change; Pts, patients; QoL, quality of life.

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Table 27.7 Yale protocol: screened muscles and applied doses Dose (units)

Muscle Flexor carpi ulnaris (FCU) Flexor carpi radialis (FCR) Flexor digitorum superficialis (FDS) Flexor digitorum profundus (FDP) Pronator teres Supinator

10 10

Extensor carpi radialis Extensor carpi ulnaris Biceps Triceps Lumbrical muscles of the hand

2.5–5 2.5–5 20 20 10

Comment

10 10 5 5

One patient only

2.5 U/muscle

Only active muscles were injected.

In the London-Ontario technique (Western University), investigators used a new device that provided kinematic assessment of tremor severity. Motion sensor devices that were placed on forearm, wrist, elbow, and shoulder captured the tremor severity; this information was used to select the most appropriate muscles for incobotulinumtoxinA injection. Using this technique, the authors have shown, in a multicenter study (Table 27.7) (Jog et al., 2020) significant improvement of upper limb tremor in ET along with very few side effects. This technique has the advantage over the Yale technique of not being painful. However, the unit is not yet in the market and probably is considerably more expensive than portable handheld EMG; Dantec-Clivus handheld EMG unit is currently priced at $3500. A blinded and multicenter study comparing Yale and London-Ontario techniques would be useful to discern comparable efficacy and side effect after BoNT therapy (Mittal et al., 2020). Such of a study can discern more precisely the time spent with each method, as well as comparing financial feasibility of the two methods.

Essential head tremor Essential head tremor is a common feature in patients with essential tremor occurring in 10.9%–18% of cases and as many as 60.6% of cases in more selected samples (Dogu et al., 2005; Louis et al., 2005, 2017). It is usually regular and not associated with head posture. In 30%– 40% of the patients, it does not respond to medications (Mittal et al., 2020). Pahwa et al. studied the effect of onabotulinumtoxinA injections into the neck muscles in 25 patients with essential head tremor (Pahwa et al., 1995). Sternocleidomastoid (SCM) and splenius capitis

(SC) muscles were injected bilaterally. The dose for each SCM was 40 and for each SC muscle was 60 U, respectively. Clinical observer rating showed 50% improvement in the toxin injected group but no significant difference with placebo regarding rating scales. Most patients developed neck weakness, which might be due to the early injection technique (1995). The lack of this study’s significance might have been influence by the small number of patients. Occurrence of head tremor on exam is suggested as a marker of transition to essential tremor in individuals at risk of ET (Louis et al., 2017). In most cases, head tremor is subtle and may be seen during sustained voice activation. Often patient is not aware of the presence of tremor and, therefore, may not necessarily seek treatment until it is more severe (Louis et al., 2008).

Dystonic head tremor In clinical practice, this tremor is more common than ET’s head tremor (Lotia and Jankovic, 2016). In a study of 311 patients collected from seven centers along the globe, 57.6% of the patients with cervical dystonia demonstrated dystonic head tremor (Pahwa et al., 1995). Dystonic tremor was seen in patients with longer duration of cervical dystonia and correlated best with the torticaput subtype of cervical dystonia. Data from large cohorts of cervical dystonia indicate that associated dystonic head tremor responds well to BoNT treatment regardless of the type A toxin used (Fasano et al., 2014; Pandey et al., 2020).

Essential voice tremor Between 10% and 25% of patients with ET demonstrate voice tremor (Lotia and Jankovic, 2016). It can be horizontal, vertical, or combined laryngeal tremor. A majority of patients with essential voice tremor (EVT) respond well to BoNT injection into laryngeal muscles. EMG-guided injections are performed through thyroarytenoid and posterior cricothyroid muscles. The dose is small and, in case of onaA (Botox), the recommended starting dose is 1 U for bilateral and 2–3 U for unilateral injections. In one open-label study of 15 patients with EVT (Hertegård et al., 2000), 67% of the patients found the injections beneficial. Acoustic analysis showed significant decrease in fundamental frequency during sustained vowel phonation (P < 0.01). Transient dysphagia is a common finding after BoNT treatment of EVT. With the small doses indicated above, dysphagia is usually mild. In the experience of one author of this chapter (B.J.), patients are often satisfied with improvement of their voice for 3–4 months and do not mind subtle dysphasia, which lasts usually 1–2 weeks.

BOTULINUM TOXIN FOR MOTOR DISORDERS

Parkinson rest tremor Earlier, small open-label, studies suggested that BoNT injections in the forearm muscles could benefit the Parkinson rest tremor, though the results may not be as robust as ET (Henderson et al., 1996; Pullman et al., 1996). Finger weakness was reported as a frequent side effect of this treatment. More recently, BoNT therapy of PD tremor was evaluated by the researchers using customized and innovative technology. Rahimi et al. (2015) in an open-label, 38 weeks study using kinematic technology (as described in Section “Essential tremor”) assessed the efficacy of incobotulinumA (Xeomin) in forearm and arm of patients with PD tremor. A total of 28 patients were studied. Injections were performed into flexors and extensors of the wrist, pronator, supinator, biceps, and triceps with a total dose varying from 100 to 370 U. Authors noted significant decrease in mean UPDRS item 20 (rest tremor) at weeks 16 (P ¼ 0.006) and 32 (P ¼ 0.014) postinjection. The FTM tremor severity scores also improved notably at week 6 (P ¼ 0.024). About 10 patients developed muscle weakness, which the investigators considered mild but resulted in several withdrawals. In a follow-up study of a larger group of patients (Samotus et al., 2020) with four cycles of injections, the same groups of authors again showed the efficacy of customized injections of BoNTs in PD. This study in addition to functional improvement (noted in previous study) showed significant improvement of quality of life in 23% of the patients. However, 50% of the patients developed mild hand tremor that forced 6 to withdraw from the study. The total dose of incobotulinumtoxin used in this study varied from 90 to 270 U. Mittal et al. (Samotus et al., 2020) reported the result of a double-blind placebo-controlled, crossover design study using incobotulinumtoxinA injections for relief of Parkinson tremor. About 30 patients completed the study (16 toxin, 14 placebo). The injection paradigm was same as described for Yale protocol above under ET tremor (customized approach with detailed EMG screening). The total applied dose varied from 100 to 120 U. The study showed significant improvement (P < 0.01) in several rating scales: UPDRS sections 16, 20, and 21, as well as NIH CGC tremor severity and PGIC. Quality of life improved in more patients receiving toxin but the difference with placebo did not reach statistical significance possibly due to small number of patients. Five patients developed hand weakness; it was mild in 3, but severe and disabling in 2 patients which cleared within 2 months.

SPASTICITY Spasticity is a velocity-dependent stretch reflex in the absence of volitional activity (Lance, 1980). Affected

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patients present with progressive increase in muscle tone that eventually leads to muscle contracture and disability. Spasticity is caused by damage to the central nervous system (CNS ¼ brain and spinal cord), most commonly by trauma, stroke, perinatal injury, or multiple sclerosis. Treatment starts with physiotherapy and pharmacotherapy; commonly used medications for the treatment of spasticity include benzodiazepines (diazepam or clonazepam), tizanidine, baclofen, and dantrolene. In severe cases of lower limb spasticity, baclofen pump is helpful. Both baclofen pump and high doses of medications (used in severe spasticity) can subject the patients to serious side effects. All three commonly used BoNT-As are now FDA approved for the treatment of spasticity. For ona and aboA, approval includes adults and children (2 years of age or older) and covers both upper and lower limbs. For incobotulinumtoxinA, current FDA approval is for upper limb spasticity. These approvals are based and supported by several high-quality (Class I) studies that have clearly shown significant reduction in muscle tone and improvement of quality of life in both adults (Simpson et al., 1996; Brashear et al., 2002; Pittock et al., 2003; Kaji et al., 2010a,b; Rosales et al., 2012; Gracies et al., 2015, 2017; Elovic et al., 2016; Do et al., 2017; Wein et al., 2018; Abo et al., 2020; Masakado et al., 2020) and children (Ubhi et al., 2000; Kaji et al., 2010b; Thorley et al., 2012; Carraro et al., 2016; Delgado et al., 2021; Heinen et al., 2021; Oleszek et al., 2021; Dimitrova et al., 2022) after BoNT injection. Limited studies have shown the efficacy of botulinumtoxinB (Myobloc) in the treatment of spasticity. The Assessment and Guidance Committee of American Academy of Neurology has given Myobloc a level B efficacy (probably effective) (Simpson et al., 2016) based on availability of one Class I study (Gracies et al., 2014). Spastic muscles are often painful. Two double-blind placebo-controlled studies have shown that intramuscular injection of onabotulinumtoxinA significantly reduces also the associated pain in poststroke spasticity (Marciniak et al., 2012; Wissel et al., 2016). The results of comparative studies between different type A toxins in spasticity are not available; currently, one ongoing clinical trial is comparing the efficacy and side effects of ona and incobotulinum toxins in this area (Esquenazi et al., 2021a). Long-term follow-ups after several cycles of injections (every 3–4 months) have shown sustained efficacy (reduced spasticity, improved quality of life, improved ambulation) in a sizeable number of treated adults and children with safe profile (Marciniak et al., 2020; Esquenazi et al., 2021b; Lin et al., 2021). In one study of children with cerebral palsy, long-term follow-up (several years) after repeated injections demonstrated reduced mortality (Lin et al., 2021).

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It has been shown that the effect of botuliumtoxinA on spasticity is dose dependent (O’Dell et al., 2018) hence, the search for the highest dose that can be injected safely per session, has triggered several investigations. In adults, for upper extremity spasticity, the FDA approved doses up to 500 U for onaA and incobotulinumtoxinAs (Botox and Xeomin) and 500–1000 U for abobotulinumtoxinA (Dysport), respectively. For the lower extremity, the recommended dose for onabotulinumtoxinA is between 300 and 400 U and for abobotulinumtoxinA is up to 1500 U. In clinical practice, when spasticity is severe and especially in muscular individuals, this dose limits appears insufficient. Hence, recent years have witnessed investigations in search of higher safe doses (Intiso et al., 2020; Santamato, 2022). As a result, moderate and high-quality studies have shown that in case of incobotulinumtoxinA doses as high as 800–1200 U/ session caused no significant side effects (Intiso et al., 2014; Dressler et al., 2015; Wissel et al., 2017). In case of onabotulinumtoxinA (Botox), one large retrospective study of 342 patients (889 injections) found no serious side effects for dose up to 600 U/session (Chiu et al., 2020; Kirshblum et al., 2020) and a smaller retrospective study concludes that doses of up to 800 U/session raised no safety issues (Chiu et al., 2020). For abobotulinumtoxinA (Dysport), doses up to 1500 U/session were found to be safe and devoid of serious side effects in a double-blind placebo-controlled study of patients with hip adductor spasticity (Hyman et al., 2000). In small children, a dose of 15–16 U/session was found to be safe for onabotulinumtoxinA (Oleszek et al., 2021), although most blinded studies that reported safety in children have used lower doses of 4–10 U/kg. In regard to abobotulinumtoxinA, no significant safety issues (not different from placebo) were reported in children with spasticity with 30 U/kg (Delgado et al., 2021). On the technical side, certain questions remain to be answered. In hereditary spastic mouse early injection of onabotulinumA into muscles prevents contractures compared to untreated mice (Cosgrove and Graham, 1994). In case of human, spasticity (regardless of cause) is early treatment helpful and if so, how early after the onset of spasticity the treatment with BoNT should begin (especially in case of children)? Is more dilution of the toxin with saline and larger injected volume more helpful due to better distribution inside the muscle? Does repeated injection of large doses of the toxin (high-dose treatment) lead to the development of neutralizing antibodies and subsequent unresponsiveness? This is especially a concern with ona and abobotulinumtoxinA both of which have antigenic proteins. It is recommended to do the BoNT injections (more than one/muscle) close to motor points, which are usually distributed along the longitudinal axis of the muscle.

However, in children during the growth motor points may be displaced. In adults, the recommended dose for large muscles is 50–100 U (even 150 in very severe spasticity) for ona and incoA toxins. For small muscles, the dose varies from 5 to 25 U. The comparable dose for abobotulinumtoxinA would be 2.5–3 times larger than other two type A toxins, though in reality, the toxin doses are not exactly comparable (Moeini-Naghani et al., 2016).

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00006-5 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 28

Lysosomal storage disorders: Clinical and therapeutic aspects GREGORY M. PASTORES1,2* 1

Department of Medicine (Clinical Genetics), National Center for Inherited Metabolic Disorders, Mater Misericordiae University Hospital, Dublin, Ireland 2

Department of Medicine (Genetics), University College of Dublin School of Medicine, Dublin, Ireland

Abstract The lysosomal storage disorders are hereditary metabolic disorders characterized by autosomal recessive inheritance, mainly caused by deficiency of an enzyme responsible for the intra-lysosomal breakdown of various substrates and products of cellular metabolism. This chapter examines the underlying defects, clinical manifestations, and provides context for the expected clinical outcome of various available therapy options employing enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction, and enzyme enhancement therapies.

INTRODUCTION The lysosomal storage disorders (LSDs) encompass a heterogeneous group of conditions, caused mostly by a deficiency of an enzyme responsible for the intra-lysosomal breakdown of various substrate(s); by-products of cellular metabolism (Platt et al., 2018). Historically, the LSDs were grouped according to the composition of the storage or tissue deposits, e.g., sphingolipidosis (GM2gangliosidosis, Fabry and Gaucher disease), mucopolysaccharidosis (or glycosaminoglycans build up: Hunter and Hurler syndrome). More recently, classification has been based on the nature of the protein defect. For example, defects of enzyme activity such as betahexosaminidase A and alpha-galactosidase A (AGAL) deficiency are associated with Tay-Sachs disease (TSD) and Fabry disease, respectively. In other cases, the defect may be due to a faulty transmembrane transport protein, which prevents the lysosomal egress of metabolized substrates (e.g., cystinosin defect as the cause of cystinosis) (Saftig et al., 2010). Incidentally, names attached to diseases are eponyms in recognition

of the physician/scientist who first provided a clinical description of the condition, often as a case report. These clinical accounts were of an earlier era, before the underlying biochemical or molecular defects were known. LSDs are inherited disorders, primarily transmitted in an autosomal recessive fashion. Diagnosis can often be missed, particularly in the absence of a positive family history. Additionally, the age of onset can range from infancy to adulthood; while most clinicians may be more familiar with severe “classic” variants presenting in childhood, they often rarely consider late-onset forms in their differential diagnosis. Furthermore, signs of tissue storage, such as hepatosplenomegaly, viewed as a suggestive clue may be absent, especially in subtypes associated predominantly with neurodegenerative features (e.g., TSD, neuronal ceroid lipofuscinosis). More recently, diagnosis has been facilitated by multiplex enzyme assays and/or molecular analysis relying on a gene panel or whole exome sequencing (Millington and Bali, 2018). In terms of genetic diagnosis, it should be noted that certain sequence alterations that are

*Correspondence to: Dr. Gregory M. Pastores, MD, National Center for Inherited Metabolic Disorders, Mater Misericordiae University Hospital, Dublin, Ireland. E-mail: [email protected]

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uncommon or not previously described may not be clinically significant (i.e., a variant of uncertain significance, VOUS). Ideally, testing should be undertaken by specialized laboratories; besides their technical expertise, consultants associated with these facilities are usually on hand to provide guidance on appropriate testing and the subsequent interpretation of test results. Three disorders are X-linked: Fabry disease, Danon disease, and Hunter syndrome (Mucopolysaccharidosis type II) (Platt et al., 2018). Classically affected males follow a characteristic pattern, but individual signs may be nonspecific and the diagnosis not appreciated until the full spectrum of clinical features has become manifest. Also, carrier females for the Fabry or Danon disease trait may develop clinical problems, but age at onset and severity tend to be more variable when compared to the course encountered in male patients (MacDermot et al., 2001; Brambatti et al., 2019). On the other hand, female carriers of the Hunter syndrome trait do not develop signs or symptoms of the condition; although there are exceptions, that is, carrier females with an X-autosome translocation (which would lead to skewed lyonization) (Lonardo et al., 2014). The focus of the current chapter is on currently available therapies and strategies under investigation. Table 28.1 provides a list of diseases mentioned, with their underlying defect(s) and clinical manifestations, as context for therapeutic indications and observed clinical outcomes.

THERAPEUTIC OPTIONS Therapeutic options have become available (Table 28.2) or are in clinical trials for several LSDs. Therapeutic responses will only be described briefly, as the primary objective of this section is to call attention to strategies, mechanism of drug action, and their current limitations. The principal option with the broadest application is enzyme replacement therapy (ERT), which entails the regular intravenous infusion of the cognate enzyme; as a recombinant formulation generated by genetic manipulation of mammalian cells (one exception is the production of a recombinant glucocerebrosidase where production is plant-based) (Concolino et al., 2018). ERT was initially suggested as a potential approach in the 1960s, when certain LSDs such as Pompe disease were attributed to an underlying enzyme deficiency (Fratantoni et al., 1968). Subsequently, it was discovered that a majority of lysosomal enzymes are soluble glycoproteins that are secreted and taken up by various cells types via mannose-6-phosphate (M6P) surface receptors. In experimental studies involving mixed tissue cultures, it was observed that normal fibroblasts when placed

together with those obtained from patients with Mucopolysaccharidosis (MPS) type I (Hurler syndrome) or MPS II (Hunter syndrome) resulted in clearance of the storage material (Fratantoni et al., 1968). These findings served as the rationale for hematopoietic stem cell transplantation (HSCT). The introduction of ERT came later, as two developments were necessary for its realization: First, modification of the cognate enzyme to expose or enrich for M6P carbohydrate residues required for its cellular uptake. Second, industrial-scale production of the recombinant enzyme so that sufficient doses could be made available for regular administration to affected individuals. HSCT was initially performed using bone marrow cells from a healthy donor, but currently undertaken in children using cord blood stem cells (Kose et al., 2021). Enzyme activity is generally measured in potential donor cells beforehand to ensure that normal levels are present, as cells from carrier donors tend to have lower enzyme concentrations and thus best avoided. With HSCT, stem cells from a healthy donor given to a recipient can migrate across the blood-brain barrier (BBB); ultimately, these donor cells (transformed into microglia) establish themselves within the central nervous system (CNS) of an affected patient and eventually replace the host (defective) cells. Restoration of enzyme activity facilitates the clearance of storage material, which halts disease progression for selected LSDs. Today, HSCT is the preferred option for treating patients with severe MPS type I (Hurler phenotype), ideally before the age of 2 years to achieve the best cognitive outcome (Braunlin et al., 2019). HSCT has also been undertaken in other MPSs, such as Hunter syndrome (type II) and Sanfilippo syndrome (type III), but it has not had an impact on neurologic prognosis as seen in children with Hurler syndrome who have undergone the procedure (Kubaski et al., 2017; Seker Yilmaz et al., 2021). The basis for these observations is not fully understood at this time. It is possible a greater amount of enzyme is required which cannot be derived from HSCT; in other words, insufficient enzyme activity to correct the underlying pathology in these MPS subtypes. It should be noted that although patients with Hurler syndrome benefit from HSCT, residual problems— mainly related to the associated skeletal dysplasia— persist, and the procedure is associated with significant morbidity and mortality risks. Thus, attenuated form of MPS type I (Hurler-Scheie phenotype) are mainly managed with ERT, which is also available for other MPS subtypes (II, IV, VI, and VII) for which the corresponding recombinant enzyme preparation has been produced (Parini and Deodato, 2020).

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Table 28.1 Selected LSDs, underlying defect(s), and associated clinical features Disease

Defect

Cystinosis

Danon syndrome Fabry disease

LAMP2 a-Galactosidase A

Gaucher disease

b-Glucosidase

Hunter syndrome (MPS-II) Hurler syndrome (MPS-I) Krabbe disease (globoid cell leukodystrophy) Metachromatic leukodystrophy (MLD) Neuronal ceroid lipofuscinosis (NCL)h Niemann-Pick disease type C (NPC) Pompe disease

Iduronate 2-sulphatase a-L-Iduronidase b-Galactocerebrosidase

Sanfilippo syndrome (MPSIII)

Type A: sulfamidase Type B: N-acetyl-aglucosaminidase b-Hexosaminidase A

Tay-Sachs disease

Wolman disease

a

Clinical manifestations Nephropathic form: renal Fanconi syndrome progressive to renal failure, poor growth, hypophosphatemic ricketsa Ocular form: photophobia resulting from corneal cystine crystal accumulationa Hypertrophic cardiomyopathy, skeletal myopathy, mental retardationb Progressive impairment of renal and cardiac functions, stroke, acroparesthesia, angiokeratomac Non-neuronopathic form: anemia, thrombocytopenia, hepatosplenomegaly, bone infarcts, aseptic bone necrosisd Non-Neuronopathic form: oculomotor apraxia, developmental delay, seizuresd Coarse facial features, skeletal dysplasia, joint contractures, hepatomegaly, respiratory and cardiac impairmente Progressive central and peripheral demyelinationf,g

Aryl-sulfatase deficiency Type 2: tripeptidyl peptidase 1, TPP1

a-Glucosidase

Lysosomal acid lipase deficiency

Blindness, rapid cognitive and motor decline, and seizuresi Neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease (ataxia, psychiatric disturbances)j Infantile and childhood/adult forms: progressive muscle weakness, respiratory failure, cardiomyopathy (infantile cases only)k Developmental delay, protracted disease course-dementia, MPS-related somatic features are more subtlel

Infantile onset: developmental arrest with regressionm,n Late-onset: progressive weakness with muscle atrophy, dysarthria, ataxia, psychiatric manifestationsk Severe form: liver dysfunction, altered lipid profile, calcified adrenal glands, splenomegalym Attenuated form: cholesterol ester storage disease (CESD): slower progression of above featuresm

Elmonem et al. (2016). Cenacchi et al. (2020). c El-Abassi et al. (2014). d Stirnemann et al. (2017). e Suarez-Guerrero et al. (2016). f Bradbury et al. (2021). g van Rappard et al. (2015). h There are at least 13 genetically distinct causes of NCL, some of which are lysosomal enzymes such as TPP1 (deficiency in CLN2) and palmitoyl protein thioesterase-1 (PPT1; deficient in CLN1). i Nita et al. (2016). j Kohler et al. (2018). k Leal et al. (2020). l Andrade et al. (2015). m Pericleous et al. (2017). n Vanier (2010). LAMP2, lysosome associated membrane protein; MPS, mucopolysaccharidosis. b

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Table 28.2 Therapeutic options for LSDs currently in clinics. Option

Disease for which treatment is available

● Hematopoietic stem cell transplantation ● Enzyme replacement therapy (biologic)

● MPS I (severe Hurler syndrome), Krabber disease and MLD ● Gaucher, Fabry, MPS I, II, IV, VI and VII, Pompe disease, LAL deficiency ● Neuronal ceroid lipofucinosis type 2

– Intravenous – Intraventricular ● Small molecule chemical agent – Pharmacologic chaperone – Substrate synthesis inhibition ● Gene therapy (ex vivo lentiviral-mediated)

● Fabry disease ● Gaucher disease ● Metachromatic leukodystrophy

LAL, lysosomal acid lipase.

HSCT has been and continuous to be undertaken for certain patients with Krabbe disease (globoid cell leukodystrophy) and metachromatic leukodystrophy (MLD). The corresponding enzyme substrates (i.e., galactocerebroside and sulfatide) are components of myelin and disruption of their metabolism leads to leukodystrophy and peripheral neuropathy. Promising results, including increased survival, were seen initially in infants with Krabbe disease subjected to HSCT—when performed during the first weeks of life and while asymptomatic. The observation prompted the introduction of newborn screening (NBS) first in New York State in 2006 (Kwon et al., 2018). However, long-term follow-up of transplanted infants has revealed residual gross motor function difficulties, thus further studies are required to ascertain full benefit in the long run. The presence of a noxious principle (psychosine) that is not fully cleared until full engraftment has been established may be partly responsible, and its impact on disease course only noted or unmasked over time and with the child’s further development. Psychosines are a by-product of intermediary metabolism, when there is incomplete degradation of glucosylceramide and related substrates such as galactocerebroside (D’Auria et al., 2017). Studies have shown that psychosines are toxic lysosphingolipid which disrupt lipid rafts and vesicular transport critical for the function of glia and neurons (Sural-Fehr et al., 2019). Another point to consider is that NBS based on the determination of enzyme activity alone does not distinguish clinical subtype, that is, early infantile vs late-onset (including adult onset) cases. Additional information may be derived from mutation analysis, but the wide heterogeneity in causal mutations makes accurate prognostication difficult. Indeed, genotype-phenotype correlations for most LSDs is often imperfect, and one should be cautious in counseling regarding prognosis,

based on knowledge regarding genotype alone. Currently, the appropriate time to intervene by HSCT in late-onset cases of Krabbe disease requires the serial monitoring of diagnosed cases for onset of symptoms, when procedural risks can be justified. In these cases, there is concern of potential over medicalization during a period an asymptomatic individual is leading an otherwise “normal” life (Kaczmarek, 2019). Mixed results have also been seen in some transplanted patients with MLD; although it impacts brain white matter disease, improvement of the peripheral neuropathy is limited; thus, morbidity may accrue from neuropathic pain, foot deformities, and neurogenic bladder disturbances (Beerepoot et al., 2019). This experience has prompted studies to examine the potential of genetically modifying cells ex vivo, obtained from affected individuals (autologous transplant) (Biffi et al., 2013), to enhance the amount of enzyme released over levels obtained with traditional HSCT using donor cells (allogeneic transplant). The use of autologous cells portends a more favorable immunogenic profile, although a chemotherapy conditioning regimen is still necessary, partly to help establish a niche in bone marrow for corrected cells to proliferate. The initial results were very promising (improved survival, delayed disease onset, and amelioration of symptoms) (Biffi et al., 2013); this has prompted screening of newborn infants in the Veneto region of Italy where the pivotal studies were undertaken. Long-term data is awaited to ascertain the extent of well-being among transplanted cases. Enzyme replacement therapy (ERT) was first demonstrated to be safe and efficacious in the management of patients with Gaucher disease (GD) type 1 (i.e., non-neuronopathic form). Interestingly, the first enzyme formulation given to these patients had been purified from human placenta. It had also been modified to expose alpha-mannosyl (rather than M6P) residues

LYSOSOMAL STORAGE DISORDERS (Barton et al., 1991). It had been discovered that alphamannosyl receptors was the appropriate target for cells of monocyte (macrophage) lineage (the principal cell type implicated in GD) (Pontow et al., 1992). Current enzyme formulations given to GD patients and others with selected LSDs are generated by genetic manipulation of mammalian cells to express the wild-type human enzyme (i.e., recombinant preparations) (Marchetti et al., 2022). In contrast to the GD drug, the formulation given to the other patients with LSDs for which ERT is available are designed to expose M6P residues. ERT is not a cure, and patients need to be treated for life to continue to derive benefit. The management of Fabry disease (FD) will serve to illustrate the outcome seen in patients on ERT. Affected individuals infused with recombinant alphagalactosidase A show stabilization of renal function, or experience a delay in the need for dialysis or kidney transplantation (Mehta et al., 2010). However, those with significant proteinuria prior to the initiation of treatment continue to show progression, albeit at a slower pace. Similarly, patients with cardiomyopathy and underlying fibrosis remain at risk for arrhythmias that has been associated with sudden cardiac death (Vardarli et al., 2021). In these cases, close monitoring is required, as the placement of an intra-cardiac device may be potentially lifesaving (Vardarli et al., 2021). It is possible the risk of stroke is reduced, but it has also become apparent that achieving an optimal outcome in patients with FD on ERT requires the use of adjunctive therapies; these may include angiotensin converting enzyme (ACE) inhibitors in those with proteinuria, antihypertensive agents, and lipid-lowering and antiplatelet-aggregating agents for primary and secondary stroke prevention (Mehta et al., 2010). Furthermore, treated patients may also continue to experience breakthrough neuropathic pains; but this can be managed with potent analgesics and opiates, if necessary. Thus, the benefit of ERT is best realized in patient diagnosed and initiated on therapy in a timely fashion; although what this constitutes for female FD patients continues to be debated. As evident from the above experience, even though ERT has been transformative it does not address all problems a patient may develop. Treated individuals with MPS continue to require physical therapy for joint contractures, as those with Pompe disease and significant myopathy who experience ambulatory difficulties. Indeed, some patients with MPS and Pompe disease may develop obstructive sleep apnea despite ERT and can benefit from CPAP (Gonuldas et al., 2014; Boentert et al., 2016), and given the diaphragmatic involvement in Pompe disease progression to respiratory insufficiency may necessitate mechanical ventilation (Boentert et al., 2016).

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Two further issues with ERT should be kept in mind: the development of antidrug antibodies and its limitations in patients with primary CNS involvement. Patients with mutations leading to nonsense-mediated RNA decay do not generate the enzyme; these patients tend to have a classical, severe and early onset disease course. Infusion of a recombinant formulation in these cases leads to the formation of antibodies that can inactivate the activity of the enzyme (Lenders and Brand, 2018). This is apparent among those monitored by serial biomarker measurements, as an increase in serum levels after an initial decline in concentration following the initiation of treatment. The impact of antibody formation on clinical outcome has been most evident in infantile patients with Pompe disease. Initially, there is resolution of cardiomyopathy following the introduction of ERT, but then patients either go on to display significant gross motor problems or eventually deteriorate and require assisted ventilation (Desai et al., 2019). In these instances, immune modulation has been demonstrated to induce tolerance (Desai et al., 2019). The impact of antibody formation in patients with other LSDs has been more challenging to determine, as the benefit from ERT to begin with is modest. For Fabry disease, the recombinant drug has been PEGylated, in the hope it would be less immunogenic (Schiffmann et al., 2019). Interestingly, the drug (pegunigalsidase) has also been found to have a prolonged half-life in circulation and the potential to improve biodistribution (Schiffmann et al., 2019). Its safety and effectiveness when compared to the currently commercially available enzyme (agalsidase beta) is under investigation (ClinicalTrials.gov Identifier: NCT02795676). Also, there can be infusion-related adverse events (IRAE; e.g., fever, chills, risk of anaphylaxis). Fortunately, these IRAEs can be managed adequately by the use of premedication (usually a combination of antihistamines, antipyretics, and occasionally steroid) and by slowing the rate of infusion. The majority of AEs tend to be transient, although there are occasions when severe recurrent problems may necessitate treatment interruption. In some cases with progression to an advanced stage, ERT may also be terminated, as further gains would not be anticipated. Unfortunately, intravenously administered enzyme therapy does not allow sufficient access across the blood-brain barrier (BBB). Various methods have been devised to potentially overcome this hurdle; but thus far, only intracerebroventricular (ICV) administration of the recombinant enzyme tripeptidyl peptidase 1 (TPP1) in children with neuronal ceroid lipofuscinosis type 2 (CLN2) has been established to modify disease course (Schulz et al., 2018). Cerliponase alfa is recombinant TPP1. Treatment with ICV cerliponase alfa has been shown to result in

562

G.M. PASTORES

a slower decline of motor and language functions among patients with CLN2, when compared to observations among natural history (untreated) controls (Schulz et al., 2018). Apart from common AEs, including convulsions, electrocardiography abnormalities, pyrexia, vomiting, and upper respiratory tract infections, there have been ICV device-related problems. Thus, the management of affected children remains challenging. Furthermore, long-term studies are required to ascertain the influence of treatment on ultimate quality of life and survival. Enzyme enhancement therapy (EET): An alternative to ERT is the use of a pharmacologic chaperone (PC), small molecules that can save certain mutated enzymes from premature destruction and lead to restoration of its activity within the lysosome (Chaudhuri and Paul, 2006). During the synthesis of lysosomal enzymes, a protein quality control system within the endoplasmic reticulum (ER) checks for the presence of sequence defects that can lead to misfolding; identified faulty proteins are channeled to a degradation process (ERAD) and cleared from cells by the ubiquitin-proteasome complex (Hwang and Qi, 2018). Small molecule drugs that can reversibly bind to the active site of mutated lysosomal enzymes have been discovered; paradoxically, rather than neutralizing the enzyme altogether, these drugs help to restore the mutant enzyme’s functional conformation, saving it from destruction and eventually enabling its delivery to the lysosome. The higher binding affinity of the enzyme’s substrate within the lysosome allows it to displace the drug, and aiding the metabolism of storage material. Migalastat is the first of this drug class to become available, after it had been shown to be a reversible active site-specific inhibitor of AGAL (Germain et al., 2016). Clinical trials revealed that its use has stabilized or slowed disease progression among treated individuals with Fabry disease who were either naïve to or previous recipients of ERT (Germain et al., 2016). An advantage of the use of small chemical drugs over ERT is the option of oral administration, and as a nonbiologic it does not trigger an immune response. However, the use of migalastat in patients with Fabry disease is only feasible in those with an “amenable” mutation (60% of cases), as structural mutations which result in missing sections of the enzyme (i.e., truncated proteins resulting from a frameshift mutation) cannot be “rescued.” Moreover, depending on the type of mutation, the degree of enzyme enhancement may be variable and thus responses seen in treated individuals may be uneven. Substrate reduction therapy (SRT): The characterization of disease-causing mutations revealed that certain defects can result in the production of an enzyme which exhibits residual activity. This finding partly explains the

late onset of disease in some patients, as the rate of substrate accumulation and its downstream detrimental effects would occur at a slower pace. Although LSDs are a consequence of the inability to degrade substrate (as opposed to over production), it was felt that reducing substrate synthesis to a level that would match the reduced capability of the mutant enzyme could potentially be disease-modifying, a strategy referred to as substrate synthesis inhibition or more frequently termed as SRT (Platt and Jeyakumar, 2008). Miglustat, an orally administered imino-sugar which partially inhibits ceramide-specific glucosyltransferase (involved in glycosphingolipid synthesis), was the first of this drug class to gain regulatory approval; after it was shown to be effective in stabilizing and/or reversing clinical manifestations among individuals with GD1 (Pastores et al., 2009). An even more potent agent, eliglustat, has been shown to be efficacious; also, it exhibits a more favorable safety and tolerability profile (Mistry et al., 2018). These observations have led to the use of eliglustat as either a first-line treatment option or an alternative following an initial period of improvement with ERT (Roldan-Sastre et al., 2021). Unfortunately, eliglustat is a P-glycoprotein analogue and effluxed from the CNS. Thus, eliglustat is not anticipated to alter the primary CNS manifestations of neuronopathic GD subtypes (GD2 and 3). Other drugs are being examined (e.g., venglustat) to evaluate their safety and efficacy for the neuronopathic forms of GD (ClinicalTrials.gov Identifier: NCT02843035), and also a late-onset form of Tay-Sachs disease (GM2-gangliodidosis) (ClinicalTrials. gov Identifier: NCT04221451). Meanwhile, miglustat that appears to gain some access across the BBB has been approved in Europe for the treatment of Niemann-Pick type C (NPC) based on its ability to reduce ganglioside synthesis (Pineda et al., 2018). Clinical trials revealed some benefit, including partial amelioration of swallowing problems and increased survival (Pineda et al., 2018). Unfortunately, it does not appear to halt the inexorable progression of disease; thus, clinical trials are underway with other medications (described in the next section). The lack of full benefit from the use of miglustat may be partly due to its inability to address other downstream mechanisms of disease, beyond ganglioside accumulation.

Investigational approaches Among the major challenges relating to the development of treatment for LSDs, particularly those subtypes associated with primary CNS involvement relate to the following: ●

Lack of a systematic assessment of natural history and disease burden (i.e., quantitative evaluation of disease severity and its rate of progression and

LYSOSOMAL STORAGE DISORDERS

●

sources of morbidity). This is important, as such data can be used as benchmarks to measure the influence of treatment on disease course. Limited CNS access of current orally or intravenously administered therapies; favored as these routes would not be as invasive, when compared to direct introduction into the ventricles or brain parenchyma.

Although there are several case reports and cohort studies, disease severity and the rate of its progression have not been quantitatively mapped out for most LSDs. In addition, the putative factors that influence outcome have not been fully delineated. Moreover, it is recognized that genotype phenotype correlations even within the same family can be imperfect. An attempt to address this hurdle include screening for potential biomarkers that can correlate with disease burden and can be monitored to assess treatment response. Several such biomarkers (e.g., chitotriosidase, PARC/CCL18, glucosylsphingosine) (Revel-Vilk et al., 2020) have been identified in Gaucher disease which do serve this role. Biomarkers identified for other LSDs, e.g., lyso-Gb3 (globotriaosylsphingosine) in Fabry disease (Simonetta et al., 2020), oxysteroids in NPC (Mengel et al., 2020), are less than ideal in terms of their application. In any case, regulatory agencies are increasingly insisting on clinical benefit rather than surrogate response measures. This section will highlight selected therapeutic options under active investigation (Table 28.3). While “proof of concept” has been examined using cells obtained from affected individuals or in animal models, clinical trials will be required to ascertain their safety and efficacy. Experience has shown that in most cases it has not been possible to replicate findings from cellular studies when carried over to the organismal level; similarly, animal model studies have not been uniformly translated into positive outcomes when conducted in human patients. In terms of biologic or protein-based therapies administered intravenously, it has been possible to create

Table 28.3 Investigational therapeutic options for LSDs. ● “Chimeric” proteins ● Histone deacetylase (HDAC) inhibitors ● Heat shock proteins congener ● Gene therapy, including CRISPR/Cas9-gene editing ● Enhanced stop-codon read-through Examples of relevant drugs and their potential indication are noted in the text.

563

“chimeric” or fusion proteins. This is achieved through conjugation of the candidate enzyme with another peptide or protein (e.g., insulin, transferrin, or an antibody) recognized by receptors on the surface of endothelial cells that would enable its uptake and transcytosis across the BBB (Sonoda et al., 2018). As an example, a BBB-penetrating fusion protein, JR-141, which consists of an antihuman transferrin receptor (hTfR) antibody and intact human iduronate2-sulfatase has been produced. Intravenous administration of JR-141 into knock-in Hunter syndrome mice model was shown to gain access to the brain, resulting in reduced accumulation of the glycosaminoglycan (GAG) substrate (Sonoda et al., 2018). A drug under investigation for patients with NPC1 is arimoclomol, a heat shock protein congener. Heat shock proteins (HSP) are endogenous molecular chaperones that prevent protein misfolding and promote lysosomal homeostasis (Bozaykut et al., 2014). which acts to augment the natural response to cellular stress by inducing the heat shock response (HSR). Arimoclomol behaves as an HSP, promoting the correct processing and folding of the NPC1 protein (Kirkegaard et al., 2010). Studies have revealed that it helps preserve cellular function and prevent cell death in cells experiencing lysosomal stress and may turn out to have a broad indication (Kirkegaard et al., 2010). When given orally, arimoclomol can cross the BBB. This drug is currently in clinical trials (ClinicalTrials.gov Identifier: NCT02612129). In terms of pharmacologic drug approaches, these may include the use of histone deacetylase (HDAC) inhibitors. HDACs are enzymes involved in regulating chromatin structure and transcription; their inhibition can lead to altered expression of certain genes that may be implicated with particular physiopathology (Ho et al., 2020). A recent study has shown that the HDAC inhibitor LBH589 (panobinostat) corrects cholesterol-storage defects in human NPC1 mutant fibroblasts, which is attributed to increased expression of the activity NPC1 protein (Ho et al., 2020). Apart from enhanced NPC1 protein expression, LBH589 also reduced proteolytic processing of SREBP2 and increased cholesterol esterification (Maceyka et al., 2013), mechanisms of action consistent with improved cholesterol delivery out of the lysosome and into the endoplasmic reticulum for further metabolism. Apart from gangliosides, cholesterol is a major storage material found in NPC1-defective cells. In these experiments, the effects of LBH589 were examined in cells with the NPC1 I1061T mutation; known to display residual transport function activity. As this mutation accounts for 15%–20% of all NPC1 disease alleles, it has the potential to benefit a significant number of patients, if proven effective. Moreover, when orally administered LBH589 can get across the BBB (Pipalia et al., 2011).

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G.M. PASTORES

A cholesterol chelating agent, 2-hydroxypropyl-bcyclodextrin (HPBCD), was identified to alter disease course in studies of an NPC animal model (Kondo et al., 2016). It is currently in clinical trials but with a quite complicated design and conduct because HPBCD is excreted rapidly and only poorly crosses the human BBB (ClinicalTrials.gov Identifier: NCT03879655). Thus, treatment requires a high-dose HPBCD infusion several times per week and/or its intrathecal injections. Another drug of interest is ambroxol, a substance that has been used as an expectorant as it promotes mucus clearance and ease productive cough. Drug screening had unexpectedly shown that it can also function as a pharmacologic chaperone for mutant glucocerebrosidase (Maegawa et al., 2009). In an open-label pilot study involving five patients with neuronopathic GD a highdose oral ambroxol in combination with ERT has been reported to lead to improvement, including relief from myoclonus, which led to recovery of gross motor function in two patients, allowing them to walk again (Narita et al., 2016). An item of possible interest: Epidemiologic and family studies revealed that individuals with GD and their carrier relatives have an increased risk for Parkinson disease (PD) (Do et al., 2019). This has incited investigations of the basis for this propensity, and also the consideration of strategies to increase deficient glucocerebrosidase (GBA1) enzyme activity as a therapeutic option. Currently, it is not certain whether lipid accumulation (which appears to promote the formation of synuclein aggregates in vulnerable neuronal populations) or reduced enzyme activity from protein misfolding and development of Lewy bodies is the predominant basis. At any rate, ambroxol is being evaluated for its potential as a treatment for PD, in patients with and without GBA1 mutations (Ishay et al., 2018). Gene therapy had been undertaken in several animal models of LSDs, and currently several clinical trials are proceeding to ascertain its application to human patients. Approaches have included both in vivo and ex vivo strategies, using a variety of vectors; mainly adenoassociated virus and lentivirus (Nagree et al., 2019). The choice of the later vector may be partly because it does not rely on host cell genome integration, and thus avoids the risk of insertional mutagenesis. LSDs for which gene therapy is in clinical trials include Gaucher (ClinicalTrials.gov Identifier: NCT04145037) and Fabry disease (ClinicalTrials.gov Identifier: NCT04999059). Both trials are sponsored by AvroBio, one of several biotechnology companies with an interest in the development of therapies for LSDs. A more recent development relates to the examination of the potential of mRNA-based therapy, wherein the RNA transcript rather than DNA sequence of the gene

of interest is introduced into cells. One formulation entails the RNA transcript for AGAL being packaged in lipid nanoparticles (to preserve mRNA integrity in circulation and allow targeted intracellular delivery). When given to a Fabry disease mouse model, it has been shown to lead to a reduction in the levels of relevant biomarkers known to be elevated in affected cases (Zhu et al., 2019). In this study, the drug was directed toward liver (hepatocyte) deposition, which enabled high-level production and secretion of the enzyme, this represents an “organoid” approach relying on endogenous production, rather than the infusion of exogenous enzyme. There are two other therapeutic strategies. The first is enhanced stop-codon read-through. In Hurler syndrome, two premature stop codons (Q70X and W402X) represent two of the most common alpha-L-iduronidase gene defects, accounting for up to 70% of MPS I (Hurler syndrome) disease alleles. Studies in CHO-K1 cells expressing these mutations revealed that gentamicin allowed the transcript to be read, with resultant increased enzyme activity (Keeling et al., 2001). The other is CRISPR/Cas9-gene editing that may be another option for the correction of deleterious mutations, through homology directed repair and by supplying a corrected template to the affected patient’s cells (Christensen and Choy, 2017).

CONCLUSIONS Although no curative therapy for LSDs exists, there are disease-specific treatments that are available and have been shown to modify outcome. Several approaches are also under investigation for LSDs as alternatives and perhaps more importantly for those conditions without extant therapies. Meanwhile, prognosis for those variants with primary CNS involvement remain guarded or poor. However, it is critical not to dismiss supportive management as these can foster improvement in quality of life for affected individuals and their families. Ideally, assessment and follow-up of affected individuals should be carried out at comprehensive care centers, and so-called, Centers of Excellence (COE), which are mainly academically-based, that can draw on specialists from multiple disciplines, as required, to deal with problems, such as alterations in sleep cycle, feeding difficulties, physical handicap and psychologic stress, among others. Even for those with an approved treatment, optimal outcomes may necessitate the use of adjunctive therapies, such as the provision of antiplatelets aggregating agents in patients with Fabry disease on ERT or PC for primary or secondary stroke prevention. At a COE, there is also active data collection for submission to registries to enhance knowledge about the disease and its treatment.

LYSOSOMAL STORAGE DISORDERS As LSDs are inherited disorders, families should be provided with genetic counseling so they may understand reproductive risks, prognosis, and therapeutic options. Preimplantation genetic diagnosis and/or prenatal diagnosis may be an option some families can choose. The development of treatment for LSDs—as “orphan” disorders—has been a profitable enterprise for several biotechnology companies that continue to work in collaboration with academic clinical investigators to seek breakthroughs in drug development that can lead to meaningful outcomes. More recently, patient advocacy groups have become critical partners in this endeavor, by facilitating data collection on the natural history of disease and supporting clinical trials recruitment, and even with financial assistance in some cases. Thus, one can be genuinely optimistic about what the future may bring.

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potential therapeutic agents for Niemann-Pick Type C disease. Mol Genet Metab 118: 214–219. Kose S, Aerts-Kaya F, Uckan Cetinkaya D et al. (2021). Stem cell applications in lysosomal storage disorders: progress and ongoing challenges. Adv Exp Med Biol 1347: 135–162. Kubaski F, Yabe H, Suzuki Y et al. (2017). Hematopoietic stem cell transplantation for patients with mucopolysaccharidosis II. Biol Blood Marrow Transplant 23: 1795–1803. Kwon JM, Matern D, Kurtzberg J et al. (2018). Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease. Orphanet J Rare Dis 13: 30. Leal AF, Benincore-Flo´rez E, Solano-Galarza D et al. (2020). GM2 gangliosidoses: clinical features, pathophysiological aspects, and current therapies. Int J Mol Sci 21 (17): 6213. Lenders M, Brand E (2018). Effects of enzyme replacement therapy and antidrug antibodies in patients with Fabry disease. J Am Soc Nephrol 29: 2265–2278. Lonardo F, Di Natale P, Lualdi S et al. (2014). Mucopolysaccharidosis type II in a female patient with a reciprocal X;9 translocation and skewed X chromosome inactivation. Am J Med Genet A 164A: 2627–2632. MacDermot KD, Holmes A, Miners AH (2001). AndersonFabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 38: 769–775. Maceyka M, Milstien S, Spiegel S (2013). The potential of histone deacetylase inhibitors in Niemann–Pick type C disease. FEBS J 280: 6367–6372. Maegawa GH, Tropak MB, Buttner JD et al. (2009). Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem 284: 23502–23516. Marchetti M, Faggiano S, Mozzarelli A (2022). Enzyme replacement therapy for genetic disorders associated with enzyme deficiency. Curr Med Chem 29: 489–525. Mehta A, Beck M, Eyskens F et al. (2010). Fabry disease: a review of current management strategies. QJM 103: 641–659. Mengel E, Bembi B, Del Toro M et al. (2020). Clinical disease progression and biomarkers in Niemann-Pick disease type C: a prospective cohort study. Orphanet J Rare Dis 15: 328. Millington DS, Bali DS (2018). Current state of the art of newborn screening for lysosomal storage disorders. Int J Neonatal Screen 4: 24. Mistry PK, Balwani M, Baris HN et al. (2018). Safety, efficacy, and authorization of eliglustat as a first-line therapy in Gaucher disease type 1. Blood Cells Mol Dis 71: 71–74. Nagree MS, Scalia S, McKillop WM et al. (2019). An update on gene therapy for lysosomal storage disorders. Expert Opin Biol Ther 19: 655–670. Narita A, Shirai K, Itamura S et al. (2016). Ambroxol chaperone therapy for neuronopathic Gaucher disease: a pilot study. Ann Clin Transl Neurol 3: 200–215. Nita DA, Mole SE, Minassian BA (2016). Neuronal ceroid lipofuscinoses. Epileptic Disord 18 (S2): 73–88.

Parini R, Deodato F (2020). Intravenous enzyme replacement therapy in mucopolysaccharidoses: clinical effectiveness and limitations. Int J Mol Sci 21. Pastores GM, Giraldo P, Cherin P et al. (2009). Goal-oriented therapy with miglustat in Gaucher disease. Curr Med Res Opin 25: 23–37. Pericleous M, Kelly C, Wang T et al. (2017). Wolman’s disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol Hepatol 2 (9): 670–679. Pineda M, Walterfang M, Patterson MC (2018). Miglustat in Niemann-Pick disease type C patients: a review. Orphanet J Rare Dis 13: 140. Pipalia NH, Cosner CC, Huang A et al. (2011). Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts. Proc Natl Acad Sci USA 108: 5620–5625. Platt FM, Jeyakumar M (2008). Substrate reduction therapy. Acta Paediatr 97: 88–93. Platt FM, d’Azzo A, Davidson BL et al. (2018). Lysosomal storage diseases. Nat Rev Dis Primers 4: 27. Pontow SE, Kery V, Stahl PD (1992). Mannose receptor. Int Rev Cytol 137B: 221–244. Revel-Vilk S, Fuller M, Zimran A (2020). Value of glucosylsphingosine (Lyso-Gb1) as a biomarker in gaucher disease: a systematic literature review. Int J Mol Sci 21. Roldan-Sastre A, Aguado C, Martin-Belmonte A et al. (2021). Cellular diversity and differential subcellular localization of the G-protein galphao subunit in the mouse cerebellum. Front Neuroanat 15: 686279. Saftig P, Schroder B, Blanz J (2010). Lysosomal membrane proteins: life between acid and neutral conditions. Biochem Soc Trans 38: 1420–1423. Schiffmann R, Goker-Alpan O, Holida M et al. (2019). Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: a 1-year phase 1/2 clinical trial. J Inherit Metab Dis 42: 534–544. Schulz A, Ajayi T, Specchio N et al. (2018). Study of intraventricular cerliponase alfa for CLN2 disease. N Engl J Med 378: 1898–1907. Seker Yilmaz B, Davison J, Jones SA et al. (2021). Novel therapies for mucopolysaccharidosis type III. J Inherit Metab Dis 44: 129–147. Simonetta I, Tuttolomondo A, Daidone M et al. (2020). Biomarkers in Anderson-Fabry disease. Int J Mol Sci 21. Sonoda H, Morimoto H, Yoden E et al. (2018). A BloodBrain-barrier-penetrating anti-human transferrin receptor antibody fusion protein for neuronopathic mucopolysaccharidosis II. Mol Ther 26: 1366–1374. Stirnemann J, Belmatoug N, Camou F et al. (2017). A review of gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 18 (2): 441. Suarez-Guerrero JL, Go´mez Higuera PJ, Arias Flo´rez JS et al. (2016). Mucopolysaccharidosis: clinical features, diagnosis and management. Rev Chil Pediatr 87 (4): 295–304.

LYSOSOMAL STORAGE DISORDERS Sural-Fehr T, Singh H, Cantuti-Catelvetri L et al. (2019). Inhibition of the IGF-1-PI3K-Akt-mTORC2 pathway in lipid rafts increases neuronal vulnerability in a genetic lysosomal glycosphingolipidosis. Dis Model Mech 12. van Rappard DF, Boelens JJ, Wolf NI (2015). Metachromatic leukodystrophy: disease spectrum and approaches for treatment. Best Pract Res Clin Endocrinol Metab 29 (2): 261–273.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00017-X Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 29

Growth factors and molecular-driven plasticity in neurological systems DOUGLAS W. ZOCHODNE* Division of Neurology, Department of Medicine and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada

Abstract It has been almost 70 years since the discovery of nerve growth factor (NGF), a period of a dramatic evolution in our understanding of dynamic growth, regeneration, and rewiring of the nervous system. In 1953, the extraordinary finding that a protein found in mouse submandibular glands generated a halo of outgrowing axons has now redefined our concept of the nervous system connectome. Central and peripheral neurons and their axons or dendrites are no longer considered fixed or static “wiring.” Exploiting this molecular-driven plasticity as a therapeutic approach has arrived in the clinic with a slate of new trials and ideas. Neural growth factors (GFs), soluble proteins that alter the behavior of neurons, have expanded in numbers and our understanding of the complexity of their signaling and interactions with other proteins has intensified. However, beyond these “extrinsic” determinants of neuron growth and function are the downstream pathways that impact neurons, ripe for translational development and potentially more important than individual growth factors that may trigger them. Persistent and ongoing nuances in clinical trial design in some of the most intractable and irreversible neurological conditions give hope for connecting new biological ideas with clinical benefits. This review is a targeted update on neural GFs, their signals, and new therapeutic ideas, selected from an expansive literature.

NEUROTROPHIN GROWTH FACTORS: GENERAL COMMENTS In 1953, Rita Levi-Montalcini, working in the laboratory of Viktor Hamburger in St. Louis, discovered a soluble extract from a mouse sarcoma tumor that caused remarkable outgrowth of axons from explanted sympathetic ganglia (Levi-Montalcini and Hamburger, 1953). An unforgettable “halo” of processes emerging from this collection of neurons was the first biological assay of NGF (nerve growth factor), a soluble protein that later, with Stanley Cohen, was isolated and purified. LeviMontalcini’s research trajectory, a remarkable story, included seminal work at her home despite her exclusion from her academic appointment by the fascist Italian government. Cohen and Levi-Montalcini were awarded

the Nobel prize in Medicine or Physiology in 1986 for their discovery of NGF. It was the first and prototype protein member of a family now known as neurotrophins. A neurotrophin is defined as an endogenous soluble protein regulating the survival, growth, or synthesis of proteins for the function of neurons (Hefti et al., 1993). However, as the neurotrophin family grew, other investigators began to identify a wider series of additional growth factors with structural and signaling differences from the NGF family. Within the specific neurotrophic (NGF-related) family, five members have been described, all signaling through related tropomyosin receptor kinase (Trk) receptors: NGF, BDNF (brain-derived neurotrophic factor) (Barde et al., 1982; Leibrock et al., 1989), NT-3

*Correspondence to: Dr. Douglas Zochodne, 7-132 Clinical Sciences Building, 11350-83 Ave, Edmonton, AB, Canada. Tel: +1-780-248-1928; Fax: +1-780-248-1807, E-mail: [email protected]

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[neurotrophin-3] (Maisonpierre et al., 1990; Hory-Lee et al., 1993), NT-4/5 [neurotrophin 4/5] (Berkemeier et al., 1991), and NT-6 [neurotrophin 6] (Gotz et al., 1994) (Table 29.1). The primary receptors for these proteins have been labeled Trk A for NGF, Trk B for BDNF and NT 4/5 and Trk C for NT-3 with some promiscuity in their specificity. Neurotrophin 6 (NT-6) is only found in teleost fish (Leggieri et al., 2019). A key feature of neurotrophins is their retrograde transport by axons from target tissues to support parent neurons during development and injury, the basis of the “neurotrophic hypothesis” of neuron survival. NGF, NT-3, and BDNF are all transported retrogradely into dorsal root ganglia (DRG) sensory neurons of adult rats (Hendry et al., 1974; Schmidt and Yip, 1985; DiStefano et al., 1992). BDNF is also retrogradely transported by motor neurons (DiStefano et al., 1992). The uptake of neurotrophins at nerve terminals or growth cones is packaged into endosomes with their phosphorylated Trk receptors allowing them to signal either locally, along their route or once they reach the perikarya. After arrival, they may impact the transcriptional activity of the neuron and cycle between the cytoplasm and cell membrane interacting with resident nontransported Trk receptors. Also once in the perikarya, some endosomes may also be transported and signal within dendrites that are found in motor, but not sensory peripheral neurons. Trk receptors, in turn, are transported by neurons anterogradely driving expression at the nerve terminal where they ligate neurotrophins (Scott-Solomon and Kuruvilla, 2018). Retrograde signaling by target-derived neurotrophic factors forms a key element of the concept that competition among developing neurons and their axons for limited supplies determines which neurons survive into adulthood. Axotomy, or section of the axon of neurons, interrupts retrograde signaling by growth factors. Overall, Trk receptors mediate differentiation, survival and loss of proliferative capacity of subpopulations of neuronal cells utilizing a series of interacting intracellular second messengers. In addition to their impacts on growth, neurotrophin signaling pathways have a major role in interrupting apoptotic neuron death but are not expected to interrupt necrotic neuron damage. In developing neurons, axotomy leads to severe and widespread retrograde apoptosis, an outcome that may be rescued by growth factors, provided they express the appropriate receptors. In adults, retrograde loss following axotomy is far less prominent and there is debate as to whether it occurs at all. However, there are substantial changes that do develop in adult neurons following axotomy, from morphological alterations to wide changes in gene expression, described as regeneration-associated genes (RAGs). Neurotrophin molecules pair up as dimers to

Table 29.1 Neurotrophins and other growth factors. Classical Neurotrophins and their peripheral nerve targets

Nerve growth factor (NGF)

Brain-derived neurotrophic factor (BDNF) Neurotrophin-3 (NT-3)

Neurotrophin-4/5 (NT-4/5)

Receptor

Target tissue (PNS)

TrkA (Tropomyosin receptor kinase A), p75 TrkB (Tropomyosin receptor kinase B), p75 TrkC (Tropomyosin receptor kinase C), p75 TrkB (Tropomyosin receptor kinase B), p75

Small fiber sensory neurons sympathetic neurons Motor neurons Sensory neurons

Large sensory neurons Sympathetic neurons Motor neurons Motor neurons Sensory neurons Sympathetic neurons

Other growth factors Factors that act on the gp 130 receptor complex Ciliary neurotrophic factor (CNTF) Leukemia inhibitory factor (LIF) Cardiotrophin-1 (CT-1) Growth factors discovered in other tissues with actions on the nervous system Fibroblast growth factors (FGFs) Epidermal growth factor (EGF) Platelet-derived growth factors (PDGF) Erythropoietin Transforming growth factor b (TGFb) Hepatocyte growth factor (HGF) Macrophage stimulating protein (MSP) Midkine (MK) and Pleiotrophin (PTN) Osteopontin and clusterin Insulin related growth factors Insulin Insulin-like growth factor I and II (IGFI and IGFII) Cytokines Interleukin-1 Interleukin-6 Interleukin-11 Bone morphogenetic proteins (BMPs) Other Glial-derived neurotrophic factor (GDNF) Vascular endothelial growth factor (VEGF) Angiopoietins

bind to Trk receptors, in turn causing Trk dimerization and tyrosine autophosphorylation of their intracellular moieties (Jing et al., 1992). Autophosphorylation, in turn, activates a series of intracellular pathways

GROWTH FACTORS AND MOLECULAR-DRIVEN PLASTICITY IN NEUROLOGICAL SYSTEMS 571 (Glass and Yancopoulos, 1993). While more than one pathway may promote survival in response to receptor tyrosine kinase (RTK) activation, two appear particularly important. PI3K activated by RTK is localized to plasma membranes, and activates PDK1/2 then Akt (pAkt is the phosphorylated, active form). pAkt, in turn, (also known as PKB) interrupts several components of the apoptosis cascade including BAD, caspase-9, p53, and the forkhead transcription factor FKHRL1. Roles of the PI3K-PDK1/2-pAkt pathway supporting axonal outgrowth have been extensively examined (Namikawa et al., 2000; Brunet et al., 2001) (for review see Franke et al., 2003; Hanada et al., 2004). Redundant support of neurons by RTKs, perhaps of lesser importance, occurs through the Ras-mitogen-activated protein kinase (MAPK) pathway molecules, interacting with a cascade of downstream molecules, as discussed below (Campenot and Eng, 2000; Kaplan and Miller, 2000; Nakagomi et al., 2003). All of these pathways may be amenable to newer downstream approaches toward enhancing or amplifying growth factor actions. Neurotrophins and other molecules associate with an additional membrane receptor, p75, originally described as the “low affinity” NGF receptor. However, p75 is activated by all of the members of the neurotrophin family as well as proneurotrophins, molecular precursors of mature neurotrophins (see below). Despite some debate, the consensus has been that p75 signals neuron and Schwann cell (SC) apoptosis when it is activated in the absence of Trk receptors (Rabizadeh et al., 1993), but together with Trk receptors, it may enhance neurotrophin action and transport (Chao and Hempstead, 1995). p75 also directly signals growth cones, particularly in collaboration with Rho GTPases, one of a family of GTPase switches that impact growth cone dynamics (Luo et al., 1997; Niederost et al., 2002; Yuan et al., 2003). RhoA, a Rho GTPase family member, acts through Rho kinase (ROCK or ROK) to enhance myosin II phosphorylation and actin-mediated growth cone retraction (Niederost et al., 2002). In one example, p75 interacts with NOGO, a myelin protein constituent, to activate RhoA/ROK and inhibit axon regeneration (Conrad et al., 2005; Schwab and Strittmatter, 2014). Rho GTPases also influence growth cone turning, an important property that impacts the success of correct axon navigation during regeneration (Giniger, 2002; Yuan et al., 2003). p75 receptors bind to proneurotrophins, including at growth cones, allowing interactions with a range of axon types (Lee et al., 2001; Ibanez, 2002). Moreover, their predilection to inhibit growth depends on whether they are collaborating with proneurotrophin, in which case it may inhibit, instead of facilitating growth cone retraction by RhoA/ROK (Kaplan and Miller, 2003; Yamashita

and Tohyama, 2003; Gehler et al., 2004). Other growth factors, such as insulin also inhibit RhoA/ROK signaling (Begum et al., 2002; Xu et al., 2004). Finally, p75 also participates in retrograde signaling in association with proneurotrophins, sortilin, and Rab5+,7+ vesicle proteins. These assemble into a retrograde signaling endosome and form a traveling “death complex” that includes other constituents including DLK (dual leucine zipper kinase)-JNK (c-Jun N-terminal kinase)-JIP3 (JNKinteracting protein 3) and others (Pathak and Carter, 2017). This cluster of proteins, as suggested by their designation, facilitates apoptosis. Neurons and glial cells support themselves and their neighboring cells in several ways (Fig. 29.1). Autocrine actions involve self-support by the release of proteins that then ligate their own receptors. For example, DRG neurons express both TrkC and NT-3 by the same population of cells (Tojo et al., 1996). BDNF also provides autocrine support in sensory neurons (Acheson et al., 1995). It is also plausible that autocrine-elaborated neurotrophins may offer protection in adult neurons that allow them to resist retrograde apoptosis following axotomy. Paracrine support involves local signaling among neighboring cells, such as neuron-glial communication. Some growth factors such as insulin and IGFs support neurons through the circulation, termed endocrine support. Finally, as will be explored in more detail below, there are complex and overlapping interactions and actions of the classical neurotrophins with other non-neurotrophin

Fig. 29.1. Simplified schematic showing examples of sites of neural growth factor delivery to the spinal cord including autocrine, paracrine, and endocrine actions.

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growth factors. For example, CNTF and LIF (see below) actions may antagonize those of NGF on DRG sensory neurons whereas FGF1 may facilitate (Mulderry, 1994; Forthmann et al., 2015). NGF may stimulate BDNF transcription (Apfel et al., 1996). Another example is the modulation of chick embryonic sensory neuron NT-3 and NT-4 mediated survival by TGF-b and LIF (Krieglstein and Unsicker, 1996). A relatively unexplored concept is how exosomes released extracellularly from neurons or glial cells might transport neurotrophins and other growth factors as an intercellular signaling mechanism (Huo et al., 2021).

SPECIFIC NEUROTROPHIN GROWTH FACTORS NGF NGF is a 118 amino acid protein, coupled as a homodimer that mainly supports small sensory and sympathetic neurons that express its high-affinity TrkA receptor. Its impact is especially prominent during development (Fagan et al., 1996). NGF-TrkA act at growth cones, and endosomes are retrogradely transported as a dimer complex to the cell body (Reichardt and Mobley, 2004). Participating proteins in this transport include dynein, dynactin, CLIP-170, and others are combined to allow signaling within growth cones, the perikarya (cell body) or even dendrites in some neurons. Perikaryal actions include activation of transcription factors and transcriptional targets within nuclei (Yamashita and Kuruvilla, 2016). Overall, endosome NGF-TrkA complexes allow differential sorting and spatiotemporal fine-tuning of its signaling (ThiedeStan and Schwab, 2015). However, neurotrophin receptor transport may be only one of several forms of overall retrograde axon signaling, some of which are more rapid and do not involve neurotrophins (MacInnis and Campenot, 2002). Concurrently, anterograde TrkA receptor transport and possible translocation of TrkA may occur from areas of lower NGF content to areas of higher content that allow neurons to adjust their sensitivity to NGF (Thiede-Stan and Schwab, 2015). Mice with TrkA knockout have severe neuronal loss in sensory and sympathetic ganglia, as well as loss of neurons in the cholinergic forebrain, all incompatible with prolonged survival (Smeyne et al., 1994). NGF and TrkA counteract axotomy-induced changes in adult DRG sensory neurons (Verge et al., 1996) for example, reversing both neuronal atrophy and declines in peptide and protein expression (SP, a and b CGRP, neurofilament M subunit, TrkA, p75, flouride-resistant acid phosphatase). NGF/TrkA also prevents contrary increases, for example, in galanin, NPY, VIP, and CCK after axotomy (Verge et al., 1996).

It is interesting that NGF administered in supraphysiological doses may cause local pain at the injection site. With chronic administration, it may induce hyperplastic actions such as subpial axon sprouting after intraventricular injection or hyperinnervation of perivascular catecholamine sympathetic fibers in the brain (Isaacson and Billieu, 1996).

BDNF BDNF was initially identified in glioma cell line conditioned media and then isolated as a small basic 119 amino acid protein from porcine central nervous system tissue that acts on TrkB receptors (Monard et al., 1973, 1975; Barde et al., 1982). In humans, the gene is thought to have at least nine promoters and 17 transcripts (Notaras and van den Buuse, 2019). Mature BDNF (mBDNF) arises from pre-proBDNF precursors cleaved to yield proBDNF which then is cleaved either to mBDNF (that acts as a dimer) or a “truncated” form of BDNF. mBDNF, proBDNF, and the prodomain of proBDNF are all thought to be biologically active (Notaras and van den Buuse, 2019). Both proBDNF and mBDNF directly ligate p75 receptors to promote apoptosis (Notaras and van den Buuse, 2019). TrkB receptors can be rapidly “mobilized” for action by signals from calcium, cAMP, PKA, and N-glycosylation, allowing movement from the endoplasmic reticulum to synaptic and other membrane sites (Andreska et al., 2020). Downstream targets from the ligation of TrkB include the MAPK, PI3K-pAkt, and PLCg pathways (Palasz et al., 2020). BDNF is retrogradely transported by motor axons from target muscle or from proliferating SCs but it is also anterogradely transported (DiStefano et al., 1992; Meyer et al., 1992; Piehl et al., 1994; Griesbeck et al., 1995; Kwon and Gurney, 1996; Notaras and van den Buuse, 2019). It acts as a survival factor for motor neurons, for example, rescuing axotomized neonatal, spinal, and cranial motor neurons from apoptosis (Oppenheim et al., 1992; Yan et al., 1993). BDNF also supports survival and outgrowth from neural placode-derived sensory but not sympathetic ganglia (Lindsay and Rohrer, 1985) (Fig. 29.2). Given these findings, BDNF knockout mice survive postnatally for only a few weeks with the loss of vestibular and DRG, but not facial motor neurons (Jones et al., 1994). In contrast, TrkB knockout mice have shorter life spans, and loss of both spinal and cranial (facial) motor neurons and DRG sensory neurons (Klein et al., 1993). The lesser impacts of BDNF knockout compared to those of its receptor may occur because of compensatory NT-4/5 that also binds to TrkB. Some of the survival actions of BDNF involve the facilitation of the antiapoptotic factor Bcl-2 (Allsopp et al., 1995). BDNF enhances hippocampal synaptic efficacy

GROWTH FACTORS AND MOLECULAR-DRIVEN PLASTICITY IN NEUROLOGICAL SYSTEMS 573

Fig. 29.2. Application of exogenous BDNF enhances the neurite outgrowth of adult rodent sensory neurons compared to phosphate-buffered saline controls (Bar ¼ 100 mm).

(Levine et al., 1996), enhances the maturation of cerebellar granular cell NMDA receptors (Muzet and Dupont, 1996) and promotes neuromuscular junction development and innervation (Wang et al., 1995; Braun et al., 1996; Kwon and Gurney, 1996). Both intraventricular BDNF and NT-4/5 prevent retrograde loss of cholinergic immunoreactivity in axotomized hypoglossal motor axons (Yan et al., 1994a; Tuszynski et al., 1996). Several mechanisms alter BDNF action. In the brain, ependymal cells express nonfunctional truncated TrkB receptors that lack a cytoplasmic tyrosine kinase signaling moiety. These aberrant receptors then sequestrate and attenuate BDNF actions (Yan et al., 1994b; Anderson et al., 1995; Eide et al., 1996). Complexities in BDNF regulation include the finding that NGF acting through TrkA regulates BDNF transcription in DRG cells (Apfel et al., 1996). There is also a separate gene called anti-BDNF that is thought to code for BDNF antisense transcripts, likely causing an endogenous type of gene transcript knockdown (Notaras and van den Buuse, 2019). Finally, a series of miRNAs have been linked to BDNF that up or downregulate it, with an impact on a range of neurological and neurodegenerative disorders but reviewed elsewhere (Eyileten et al., 2021).

but unlike NGF it supports large DRG sensory neurons that relay muscle spindle activity and proprioception (Chalazonitis, 1996). Thus, as might be expected, NT-3 is retrogradely transported by large sensory neurons (DiStefano et al., 1992; Yan et al., 1993). However, motor neurons and muscle spindles also express NT-3 (Hory-Lee et al., 1993; Copray and Brouwer, 1994; Tojo et al., 1996). NT-3 reverses axotomy-related changes in neurofilament subunit expression, p75 expression and TrkC in sensory neurons (Verge et al., 1996) but also supports the survival and differentiation of motor neurons, neuromuscular synapses, central noradrenergic cells and sprouting within the corticospinal tract (Henderson et al., 1993; Lohof et al., 1993; Wong et al., 1993; Arenas and Persson, 1994; Schnell et al., 1994; Wang et al., 1995). It has no influence on adult sympathetic neurons (Birren et al., 1993). While the actions of NT-3 are primarily mediated through Trk C, cooperative activation of Trk B and C also promote the survival of hippocampal and cerebellar granule neurons (Minichiello and Klein, 1996). NT-3 knockout mice have severe loss of proprioceptive sensory neurons and sensory organs (Farinas et al., 1994). TrkCdeficient mice have a loss of muscle sensory spindle sensory axons (Klein et al., 1994).

NT-4/5 NT-4/5 is constructed from 116 amino acids and ligates the TrkB receptor and consequently has actions that overlap with BDNF. It supports the survival of developing sensory and sympathetic neurons (Berkemeier et al., 1991) and signals through retrograde transport in collaboration with p75 receptors (Ibanez, 1996). Within muscles, NT4/5 serves as an activity-dependent trophic signal for adult rat motor neurons (Funakoshi et al., 1995). Like BDNF, NT4/5 also prevents retrograde facial motor neuron loss after axotomy in newborn rats and adults and prevents declines of choline acetyltransferase in axotomized adult motor neurons (Koliatsos et al., 1994; Friedman et al., 1995).

NON-NEUROTROPHIN GROWTH FACTORS CNTF and family

NT-3 NT-3 is a 119 amino acid basic protein, also acting as a dimer (Hohn et al., 1990; Maisonpierre et al., 1990; Radziejewski et al., 1992). NT-3 primarily binds to Trk C with limited binding to TrkB (Chao, 1992). As described above with TrkB, Trk C is also found in truncated nonfunctional forms that may sequester and diminish NT-3’s actions (Valenzuela et al., 1993). NT-3’s actions are largely confined to sensory neurons,

Ciliary neurotrophic factor (CNTF), is a 200 amino acid protein that was discovered to support sympathetic neuron survival in the embryonic chick ciliary ganglion (Skaper et al., 1984; Manthorpe et al., 1986; Lam et al., 1991). It belongs to, and shares signaling cascades with the alpha-helical cytokine superfamily that includes leukemia inhibitory factor (LIF), interleukin 6, granulocyte colony-stimulating factor and oncostatin M (Bazan, 1991; Hall and Rao, 1992). CNTF, LIF and a related

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growth factor, cardiotrophin-1 receptors share interactions with gp130, a signaling transducer. The CNTF receptor complex includes LIFRb (LIF receptor b), CNTFRa and gp130 that when ligated activates the JAK/STAT pathway, Ras/ERK, mTOR, and pAKt. Its impacts include neuroprotection, neurogenesis, and oligodendrocyte survival among other metabolic and nonneuronal actions (Arakawa et al., 1990; Sendtner et al., 1990; Pasquin et al., 2015). CNTF is expressed by astrocytes, Schwann cells, and skeletal muscle fibers (Stockli et al., 1991). SCs are the primary source of CNTF in the peripheral nervous system which is then taken up and retrogradely transported, particularly after injury, by motor and sensory axons (Curtis et al., 1993). Levels of CNTF mRNA decline in SCs if their contact with axons are lost, for example, distal to a nerve injury (Sendtner et al., 1992). In adults, CNTF prevents neuronal degeneration of axotomized medial septal neurons (Hagg et al., 1992) and substantia nigra dopaminergic neurons (Hagg and Varon, 1993). Systemic injections induce sprouting by adult motor neurons (Gurney et al., 1992; Kwon and Gurney, 1994).

Insulin and IGFs In addition to their metabolic actions, insulin and the related insulin-like growth factors (IGFs, somatomedins) act as neuron trophic molecules. Their construction is closely related. Mature insulin has A and B disulfidelinked chains with a C domain that is cleaved off from proinsulin. C-peptide can be measured in the blood as a surrogate marker for pancreatic islet function. Insulin-like growth factors I and II (IGF-I and IGF-II) are single-chain polypeptides with A and B domains, a connecting C domain like proinsulin, and a D domain (Le Roith and Roberts, 1993). Insulin and IGFs cross occupy each other’s receptors to activate common downstream pathways (Ullrich et al., 1986; Steele-Perkins et al., 1988). Receptors for insulin, IGF-1, and IGF-2 are all expressed in the adult brain and insulin and IGF-1 receptors are in the peripheral nervous system. Insulin, not synthesized in the brain, nonetheless accesses its brain receptors through CSF pathways whereas low levels of IGFs are synthesized in the adult brain. By definition then, insulin’s CNS actions are endocrine whereas IGFs are endocrine but also local paracrine and autocrine (Fernandez and TorresAleman, 2012). IGF-2 is expressed in the meninges and choroid plexus and its further transport into the brain is facilitated by low-density lipoprotein receptor-related proteins 1 and 2 (LRP1 and 2) (Fernandez and TorresAleman, 2012). The intracellular domains of insulin and IGF-1 receptors undergo autophosphorylation following binding, resulting in tyrosine kinase activity and activation through the IRS-1 and 2 (Insulin receptor substrate-1 or 2)

docking protein pathways (White, 1997). IRS-1 is frequently colocalized with insulin and IGF-1 receptors, and its serine/threonine and tyrosine phosphorylation sites activate PI3K-pAkt, along with Shc, Grb-2, S6 kinase, PKCE kinase, MAP2 kinase, Raf1 kinase, and cfos (Heidenreich, 1993; Folli et al., 1994; Fadool et al., 2000). IGF action is regulated by six IGF-binding proteins (IGFBPs) (Baxter and Martin, 1989). In the peripheral nervous system, IGF-1 receptors (IGF-1Rs) are expressed on neurons and SCs to support regeneration and myelination (Cheng et al., 1996, 1999; Gao et al., 1999). IGF-1 supports cerebellar and hippocampal neuron survival in the brain (Fernandez-Sanchez et al., 1996; Lindholm et al., 1996). Overall, there are widespread impacts of IGF-1 on a spectrum of neurological models and disorders through direct impacts on neurons, glia and immune regulation (Shandilya and Mehan, 2021). For example, microglial IGF-1 may participate in neuroinflammation (Fernandez and Torres-Aleman, 2012). IGF-2 acts on the IGF2/mannose 6-phophate receptor (M6P) that is involved in growth and development, proteolytic activation of growth factors and in the delivery of lysosomal enzymes. Altered trafficking of IGF-2/ M6P has been suggested to underlie neurodegenerative disorders (Wang et al., 2017). Insulin receptors (IRs) are expressed on the perikarya of sensory neurons in DRG, nodes of Ranvier, distal dermal and epidermal axons, and on regenerating axons (Sugimoto et al., 2000, 2002). Moreover, IR expression rises after injury and in models of experimental diabetic neuropathy (Brussee et al., 2004; Xu et al., 2004), allowing insulin to promote regeneration and promote skin reinnervation in diabetic neuropathy. Interestingly these actions develop independently and at much lower doses than those associated with glucose-lowering and they can be achieved by intrathecal delivery, local near nerve delivery, or skin injection (Singhal et al., 1997; Brussee et al., 2004; Xu et al., 2004; Toth et al., 2006a,b; Guo et al., 2011). Intranasal insulin acting through CSF access reverses experimental diabetic neuropathy (de la Hoz et al., 2017).

GDNF and its relatives GDNF (glial cell line-derived neurotrophic factor) is a member of the TGFb (transforming growth factor b) family. Originally isolated from rat glial cells, GDNF originates as a 211 amino acid precursor secreted as a 134 amino acid mature form. Within endosomes, GDNF undergoes glycosylation, is transported and thereby offers signaling not unlike NGF (Cintron-Colon et al., 2020). There are several related GDNF family members including neurturin, artemin, and persephin. Signaling

GROWTH FACTORS AND MOLECULAR-DRIVEN PLASTICITY IN NEUROLOGICAL SYSTEMS 575 receptors include two components: membrane-bound GFRa1-4 (for GDNF, neurturin, artemin, and persephin respectively) linked to the anchor GPI (glycosylphosphatidylinositol) and a receptor tyrosine kinase common to all known as RET (rearranged during transformation). When ligated, GFRa coreceptors activate RET dimers with cytoplasmic kinase domains that autophosphorylate tyrosine residues and downstream signals such as MAPK and PI3K, interactive with Src (Wang, 2013). Interestingly, RET mutation with loss-of-function is the basis for Hirschsprung disease, a genetic disorder of intestinal innervation. GDNF also triggers “transsignaling” utilizing released soluble GFRa1. The soluble receptor “captures” GDNF and presents it to RET receptors on nearby cells and their lipid rafts or it is attached to the extracellular matrix where it interacts with RET (Ibanez et al., 2020). In this way, GFRa1 may act as a guidance cue and potentiator of neurite outgrowth. RET MAPK activation impacts extracellular adhesion, synaptogenesis, and dendrite branching. GDNF-GFRa1 also independently interacts with NCAM (neural cell adhesion molecule) and its receptor, whereas GDNF alone may interact with immobile syndecan, a heparan sulfate proteoglycan (Sariola and Saarma, 2003; Cintron-Colon et al., 2020). TGFb, and Met receptor tyrosine kinase are additional collaborating molecules. GDNF supports several neuronal populations. These include midbrain dopaminergic neurons, cerebellar Purkinje cells, spinal motor neurons, newborn rat facial motor neurons, axotomized adult facial nucleus motor neurons, and GABAergic embryonic neurons (Lin et al., 1993; Henderson et al., 1994; Mount et al., 1995; Yan et al., 1995; Price et al., 1996). GDNF is considered a highly potent survival factor for motor neurons in the peripheral nervous system during development, and in the retrograde axotomy-induced cell death and degeneration as occurs in motor neuropathies (Cintron-Colon et al., 2020). In adults, GDNF is also expressed in skeletal muscle, where it helps to maintain the neuromuscular junction and from which it is retrogradely transported by motor axons (Henderson et al., 1994; Yan et al., 1995; Cintron-Colon et al., 2020). It is thus upregulated in denervated muscles (Cintron-Colon et al., 2020). Distal to an injury during axon degeneration, GDNF and GFRa-I expression initially rises in SCs whereas long-term denervated stumps experience substantial declines associated with impaired support of regrowth (Hoke et al., 2000, 2002). As part of its crosstalk between axons and SCs, GDNF may also influence the timing of axon myelination. For example, when exogenous GDNF was administered to rats, SCs not only proliferated, but initiated inappropriate hypermyelination of small caliber axons (Hoke et al., 2003).

Neurturin, the second member of the GDNF family, has 121 amino acids and binds to GFRa2 together with RET. It has a role in the development and maintenance of the parasympathetic nervous system (Fielder et al., 2018). Artemin, the third member of the GDNF family, has 113 amino acids and binds to GFRa3 together with RET. It has been identified in developing nerve roots, SCs, and embryonic vascular smooth muscle cells (Zhu et al., 2020). Its receptor GFRa3 is found in DRGs and SCs. Roles include modulation of sensory afferent pain signaling, sympathetic neuron development, nerve regeneration and protection of hippocampal and dopaminergic neurons. Persephin, the final member of the GDNF family, has a predicted 96 amino acids and binds to GFRa4, but is only detectable at low levels in the adrenal gland, cerebellum, spinal cord, and testis (Fielder et al., 2018). It supports dopaminergic neurons, motor neurons but not sensory or sympathetic neurons (Milbrandt et al., 1998). Downstream pathways for neurturin, artemin, and persephin are thought to be similar to GDNF and include MAPK and PI3K-pAkt with Src. As in the case of GDNF, it is suggested that they also interact with NCAM.

Growth factors of other tissues The fibroblast growth factor (FGF) family (Unsicker et al., 1993) was originally divided as acidic FGF (aFGF or FGF-1) and basic FGF (bFGF or FGF-2), each 155 amino acids, but now includes at least 23 members (Reuss and Halbach, 2003). FGFs are bound in the extracellular matrix by heparan sulfate proteoglycans and when released, they act on receptor tyrosine kinases (Lobb, 1988). FGFs ligate alternatively spliced receptors (FGFRs1-4) with subtypes FGFR1b,c,2b,2c,3b, and 3c (Klimaschewski and Claus, 2021). Regulation of FGFs, especially secreted members, occurs through FGFbinding proteins (FGFBPs, types 1–3) (Taetzsch et al., 2018). Moreover, each FGFBP has its own sequence for secretion, binding heparin, and FGF binding. Most FGFBPs enhance FGF action by coordinated agonist action at targets or perhaps by displacing FGFs from sequestered heparin binding sites. FGFR1 has a nuclear localization signal and is translocated to the nucleus facilitated by FGF-2 ligand and b importin (Forthmann et al., 2015). Within the nucleus, FGFR1 molecules are retained in the intramolecular space or bound to nuclear substructures, a localization that influences their dynamics and interactions. For example, this may allow interaction with transcription factors such as CREB-binding protein, retinoic acid receptors (RARs), retinoid X receptors (RXRs), Nurr77 and Nurr1 (nuclear receptor subfamily four group A members 1,2). Moreover, this localization allows collaboration with NGF and TrkA (Forthmann et al., 2015).

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FGFs have been shown to have multiple roles during early brain development but also during adulthood and following injury. For example, unilateral cortical infarction in rats treated with aFGF was associated with increased concentration of NGF and NGF transcripts ipsilateral to the lesion (Figueiredo et al., 1995). FGF-1 is a survival factor for injured rat spinal neurons (Lee et al., 2002) whereas FGF-2 mRNA is increased in embryonic, but not adult spinal cord injuries (Qi et al., 2003) perhaps reflecting the better success of embryonic recovery from injury. FGFs influence cholinergic differentiation (Unsicker et al., 1993). FGFs also support nerve regeneration. Thus, FGF receptors 2, 7, and 8, are expressed in DRG sensory neurons (Tanaka et al., 2001; Li et al., 2002; Salvarezza et al., 2003) and may be upregulated postinjury (Kato et al., 1992). FGF-2-potentiated motor neuron sprouting by CNTF (Gurney et al., 1992) and rescued adult DRG sensory neurons in rats after a sciatic nerve section (Otto et al., 1987). Both neuronal and glial actions may contribute to conflicting FGF actions in the peripheral nervous system (Unsicker et al., 1993). For example, FGF-2 null mice paradoxically had faster axonal degeneration and reinnervation that are thought to be secondary to impacts on SC differentiation (Jungnickel et al., 2004) and overexpression of FGF-2 in SCs did not improve facial nerve motor recovery (Haastert et al., 2009). However, others have suggested that FGF-2 induces SC proliferation (Ribeiro-Resende et al., 2012) and its lentiviral overexpression in silicone conduits across transected nerves improved regeneration (Allodi et al., 2014). Mice lacking both FGFR1 and 2 in SCs developed abnormalities of nociceptive unmyelinated axons normally supported by unmyelinated SCs (Furusho et al., 2009). FGFs also impact both developing and adult neuromuscular junctions (Taetzsch et al., 2018). Additional growth factors have actions on the nervous system. Epidermal growth factor (EGF) (Morrison, 1993) is a 53 amino acid protein, and its receptors (EGFR or ErbB1 or HER-1) are tyrosine kinase proteins that bind to several high (TGF-a, heparin-binding EGF, and b-cellulin) or low-affinity ligands (Romano and Bucci, 2020). Similar to neurotrophins, EGFR is incorporated into early endosomes to traffic within neurons. EGF is expressed in astrocytes, oligodendrocytes, DRG sensory and other neurons, SCs, satellite glial cells, and progenitor cells. It may also be expressed in skin nerves and sensory organs (Romano and Bucci, 2020). EGFR signaling is thought to support neuron survival, neurite outgrowth, and is thought to act as a signal to astrocytes to secrete other growth factors. EGF plays an important role in promoting stem cell development into neurons (Reynolds and Weiss, 1992).

Platelet-derived growth factor (PDGF) is a 172 amino acid protein with receptors found on neurons, astrocytes, oligodendrocytes, microglia, and SCs. There are five functional subunits (AA,AB,BB,CC, and DD) that signal through two receptors PDGFR-a and -b. Downstream pathways include ERK and pAkt. PDGF can mediate neuroprotection, neurogenesis, synaptic function, and development (Landreth, 2006; Sil et al., 2018). Transforming growth factor s (TGFbs) are a large family of 32 members divided among TGFbs 1–3 (390–412 amino acids), activin, growth and differentiation factors 1–3 (GDF), BMPs 2–11,15 (bone morphogenetic proteins, see below) and others (Galbiati et al., 2020). TGFb ligands bind to a type II receptor (TGFBRII) that phosphorylates a type I receptor (TGFBRI), which in turn signals SMAD transcription factors. Downstream pathways activated also include MAPK, PI3K-pAkt, and other non-SMAD pathways (Galbiati et al., 2020). TGFb supports neuron protection and outgrowth (Ho et al., 2000; Knoferle et al., 2010) and also exerts anti-inflammatory actions that may be of benefit in neurodegenerative disorders (Meyers and Kessler, 2017). TGFb types 1 and 2 are present in the peripheral nervous system (Puolakkainen and Twardzik, 1993; Jiang et al., 2000; Day et al., 2003). Bone morphogenetic proteins (BMPs) are members of the TGF-b family of proteins that are also classified as cytokines (see below) and were initially discovered to support the formation of bone and cartilage. There are currently 15 isoforms (Hart and Karimi-Abdolrezaee, 2020). BMPs act on heterotrimeric type I and II serine/threonine kinase surface receptors that operate through SMAD protein phosphorylation and its translocation to nuclei for transcriptional signaling (see review (Goulding et al., 2020). BMPs have widespread actions including an impact on nerve regrowth and striatal neurons (Sampath and Reddi, 1983; Sampath et al., 1987; Gratacos et al., 2002; Wang et al., 2007). In addition to extensive and multilevel impacts on neuron and glial development, BMPs in the CNS of adults, widely expressed, regulate neuron precursor cells (Hart and Karimi-Abdolrezaee, 2020). Concurrent expression of endogenous BMP inhibitors, such as noggin, chordin, and BMP-binding endothelial regulator (BMPER) modulate BMP actions. Erythropoietin (EPO) is a 165 amino acid circulating protein primarily secreted by the kidney that stimulates erythropoiesis. EPO receptors are mainly heterodimers (one component of the classical receptor and the other of CD131, or cytokine b-common subunit) in nonerythroid tissues, with a soluble form that inhibits EPO signaling by sequestering EPO. EPO receptors signal intracellularly largely through the JAK-STAT pathway and PI3K pathways (see Vittori et al., 2021). EPO is most

GROWTH FACTORS AND MOLECULAR-DRIVEN PLASTICITY IN NEUROLOGICAL SYSTEMS 577 often considered in its support of RBC production and thus in the context of anemia associated with renal failure. However, both EPO and its receptor are expressed on neurons and SCs where they act to improve nerve regeneration. EPO also rescues spinal motor neurons following nerve root injury and may promote the survival of dopaminergic neurons (Campana and Myers, 2001; Noguchi et al., 2015; Sundem et al., 2016; Geary et al., 2017; Zhang et al., 2017; Vittori et al., 2021). Interestingly, it has been suggested that loss of EPO during renal failure accounts for uremic neuropathy, a disorder that had previously only been reversed by renal transplantation (Bolton et al., 1971). While unproven, routine administration of exogenous EPO analogues to renal failure patients may reduce the prevalence of uremic neuropathy. Midkine (MK) and Pleiotrophin (PTN) are members of the midkine family of heparin-binding growth factors (Kadomatsu and Muramatsu, 2004). Sharing 50% amino acid homology, both are cysteine- and basic amino acid-rich proteins. MK was isolated from carcinoma cells whereas PTN was extracted from rodent brain (Xu et al., 2014). Both proteins interact with protein tyrosine phosphatase z (PTPz), integrins, neuroglycan, low-density lipoprotein receptor-related protein (LRP-1), anaplastic lymphoma kinase (ALK), Notch and N-syndecan, either separately or at the same time. Downstream, they activate b-catenin, PI3K, MAPKs, JAK/STAT, and other pathways with impacts on mitogenicity, survival, oncogenesis, angiogenesis, inflammation, differentiation, and stem cell renewal (Xu et al., 2014). Both PTN and MK promote neurite outgrowth (Li et al., 1990; Kaneda et al., 1996). PTN is upregulated in nerve stumps distal to injury and is localized to SCs, macrophages and endothelial cells (Blondet et al., 2005; Mi et al., 2007). Osteopontin and clusterin are secreted proteins, largely extracellular, that have come to attention in neuron systems because of their differential expression in motor and sensory axon pathways (Wright et al., 2014). Osteopontin, also listed as T-lymphocyte activation protein 1, Eta-1, or secreted phosphoprotein 1 (Spp1), is a glycoprotein that impacts cellular differentiation, adhesion, migration, and differentiation. Clusterin is a heterodimeric glycoprotein that is involved in protein folding and apoptosis. Wright et al. (2014) identified upregulation of osteopontin and clusterin within nerve roots, respectively, housing motor or sensory axons. In light of these findings, genetic deletion of osteopontin within grafted nerves reduced motor axon regrowth whereas deletion of clusterin impaired sensory reinnervation. Selective extracellular protein cues from SCs for axons in adults, not previously identified, may help promote more specific regeneration to proper targets. Hepatocyte growth factor (HGF), or “scatter factor” is a 728 amino acid pleiotropic molecule originally

identified as a mitogen for hepatic cells. HGF acts through c-Met tyrosine kinase receptors [also known as Met; see reviews (Maina and Klein, 1999; Kitamura et al., 2019)]. HGF is secreted as a single-chain precursor that is processed into a mature double-chained protein that binds as a dimer to two Met receptor molecules. Downstream pathways include PI3K, PLCg, and others (Sakai et al., 2015). HGF has influences on neurodevelopment, cell survival, regeneration, and proliferation. While Met inhibitors are under development as anticancer therapies, small molecule HGF mimetics are also in development for the treatment of neurological disorders (Sakai et al., 2015). HGF provides autocrine support for spinal motor neurons, acts as a SC mitogen and may have synergistic interactions with NGF through PI3K, PLC-g, and Ras/MAPK pathways (Krasnoselsky et al., 1994; Maina and Klein, 1999; Hoke et al., 2006; Landreth, 2006). Met is also expressed in small caliber sensory neurons and in dermal axons with local HGF and Rac1 where it may contribute toward local skin axon growth and plasticity (Cheng et al., 2010). Macrophage-stimulating protein (MSP) is a growth factor related to HGF (Landreth, 2006). Vascular endothelial growth factor (VEGF), originally termed “tumor angiogenesis factor,” was discovered as a secreted factor from tumors that caused angiogenesis and increased vascular permeability (Folkman et al., 1971; Carmeliet and Storkebaum, 2002; Storkebaum and Carmeliet, 2004). VEGF has several alternatively spliced variants with sizes that vary from 121 to 206 amino acids and its receptors VEGFRs 1–3 (also known as KDR, kinase insert domain, or FLK1, fetal liver kinase receptor) are found on endothelial cells. It impacts cell mitosis and migration. VEGF receptors are also expressed in sensory ganglia neurons, neuronal growth cones and SCs where they support adult sensory axon outgrowth, neuron survival, SC proliferation, and satellite cell survival (Sondell et al., 1999a,b; Hobson et al., 2000). VEGF may allow collaborative vascular and axon growth into new tissues or following injury. Angiopoietins 1–4 are a distinct group of vascular growth factors of 496–498 amino acids that combine as multimers to activate receptors named Tie 1 and 2 (tyrosine kinase with immunoglobulin-like and EGFlike domains 1,2) and to signal through the PI3K-pAkt pathway. Angiopoeitin1 and Tie 2 are also expressed in neurons and are neuroprotective, offering regenerative impacts that parallel those offered to the vascular system, not unlike VEGF (see reviews Fagiani and Christofori, 2013; Yin et al., 2019a).

Cytokines Cytokines are 8–15 kDa secreted proteins originally described in relation to immune cells such as

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macrophages and lymphocytes. Cytokines nominally include interleukins, lymphokines, monokines, interferons, tumor necrosis factors, colony-stimulating factors, and chemokines. Not all are relevant to neurons, and some overlap in function and signaling with CNTF, TGF-b, and BMPs described above. In relationship to CNTF for example, the leukemia inhibitory factor (LIF) is a cytokine that signals the LIF receptor (LIFR), which associates with a high-affinity-converting subunit glycoprotein 130 (gp130), similar to the receptors of IL-6 (Davis and Pennypacker, 2018). Three downstream signaling pathways are JAK/STAT, PI3KpAkt, and Ras/ERK. LIF is generated by endothelial cells and astrocytes in the brain where it confers neuroprotection, antioxidant activity and promotion of remyelination in oligodendrocytes (Cheema et al., 1994a,b). Most importantly LIFR offers modulation of immune cell signaling, particularly microglia as an anti-inflammatory molecule although it can be pro-inflammatory in some models (Davis and Pennypacker, 2018). Brain trauma activates the expression of NGF through interleukin-1 b (IL-1b) (DeKosky et al., 1996). In peripheral nerves, IL-1 synthesized by macrophages stimulates NGF production in peripheral nerves by nonneuronal cells (Lindholm et al., 1987). In contrast, IL-6 has actions that differ from most cytokines in that it may act directly as a growth factor (Richardson and Lu, 1994; Gadient and Otten, 1996). Chemokines (chemotactic cytokines) are a large (>50 members) subfamily of low molecular weight cytokines that are primarily considered in signaling among inflammatory cells. Chemokines operate through the activation and binding of G-protein-coupled receptors (Rostene et al., 2011). Their roles as neuronal signals have also been considered and they are synthesized by neurons, astrocytes, microglial cells, and invading inflammatory cells in the brain. They are classified as alpha (CXC), beta (CC), gamma (C), or delta (CX3C) and their receptors are transmembrane proteins that impact calcium signaling, potassium channels, and vesicle release. Receptors are respectively classified as CXCR, CCR, CR, and CX3CR. CXCR4 and CCR5 chemokine receptors are coreceptors for human immunodeficiency viral (HIV) entry into the brain (Feng et al., 1996). Their roles in direct neuronal signaling include modulating the electrical activity of dopaminergic neurons but their impact on PD pathology may also be related to impacts on associated inflammation (Liu et al., 2019). A newly encountered family of five proteins (types 1–5) related to CC chemokines is known as FAM19A (Family with sequence similarity 19 A) (Sarver et al., 2021). Also called neurokines, the proteins are found in the CNS and PNS neurons (types 1–4 during development into adulthood and type 5 in astrocytes). FAM19

members bind GPCRs (G-protein-coupled receptors) of the rhodopsin-like family. They have impacts on neural stem cell fate, adhesion and survival, and on immune cells overall thereby impacting learning, behavior, locomotion, and sensory perception.

Some additional growth-related factors A number of other molecules have been considered as potential growth factors in the nervous system but with varying penetration into the literature: extracellular nucleotides and nucleosides (Neary et al., 1996), arachidonic acid (Katsuki and Okuda, 1995), and CGRP (calcitonin gene-related peptide), the latter as an indirect promoter of nerve regeneration by acting as a mitogen for SCs cells (Cheng et al., 1995; Toth et al., 2009). CNRF (cysteinerich neurotrophic factor) is a non-neurotrophin growth factor isolated from the mollusk Lymnae stagnalis. CNRF promotes neurite outgrowth and influences motor neuron electrophysiological properties by acting on the p75 receptor (Fainzilber et al., 1996). CDNF (cerebral dopamine neurotrophic factor)/mesencephalic astrocyte-derived neurotrophic factor (MANF) protects dopamine midbrain neurons in models of PD (Lindholm et al., 2007; Lindahl et al., 2017; Sidorova and Saarma, 2020). Glucagon-like peptide (GLP-1) is a peptide synthesized by intestinal epithelial cells, classified as an incretin, that contributes to glucose distribution by enhancing insulin secretion. GLP-1 receptors are expressed in adult DRG sensory neurons and GLP-1 agonists increase neurite outgrowth of adult sensory neurons (Himeno et al., 2011; Kan et al., 2012). GLP-1 agonism also improved experimental diabetic neuropathy (Himeno et al., 2011; Jolivalt et al., 2011; Kan et al., 2012).

GROWTH FACTOR DELIVERY Despite the widespread and exciting impacts identified with a range of growth factors discussed, one of the most difficult aspects of translation is how to deliver them to a diseased or damaged brain, spinal cord, or nerve. Unimpressive clinical trials have highlighted this challenge, with negative results often attributed to a lack of delivery of the growth factor to the tissue at risk or problematic timing, particularly late in the development of a chronic disorder. For example, neurons may be irretrievably lost prior to the delivery of a growth factor meant to rescue them. Concentrations decline quickly after delivery by vein, peritoneal cavity or local injection delivery and only small amounts of these protein molecules may cross the blood-brain or blood-nerve barrier. Poduslo and Curran (1996) compared specific neurotrophin blood-brain and nerve barrier permeability: BDNF was approximately rated as BDNF¼NT-3>CNTF>>NGF for both barriers.

GROWTH FACTORS AND MOLECULAR-DRIVEN PLASTICITY IN NEUROLOGICAL SYSTEMS 579 As highlighted by Padmakumar et al. (2020) the limitations in growth factor delivery arise from properties such as their size, charge, hydrophilicity, and stability as well as pharmacokinetic features such as short half-life, low pK, rapid inactivation, rapid clearance, limited permeability, protein binding, and potential immunogenicity. Finally, there are the blood-brain, blood-spinal cord, and blood-nerve barriers mentioned above, but also subcompartments within each of these neural tissues that results in possible off-target actions. Additional challenges are the differential expression of receptors, the development of receptor resistance to their ligands, variations in the expression of receptors after injury and competition with receptors that lack intracellular signaling subunits. Delivery systems have included nanoparticles, liposomes, microparticles in hydrogels, and synthetic electrospun nanofibers with embedded growth factors (Padmakumar et al., 2020). For example, Reis et al. (2018) describe the use of coaxial electrospun microfibers as scaffolds with encapsulated FGF-2 to treat spinal cord injury. Growth factors have been delivered by viral vectors such as AAV (adeno-associated virus), HSV1 (herpes simplex virus-1), RV (retrovirus) or lentivirus (LV), or by engineered cell delivery, discussed below. Complications of viral therapy include nonspecific gene expression or insertional mutagenesis, gene silencing, and immune reactions (Parambi et al., 2022). Chemical modifications of viral capsids may aid in delivery. In the case of injured spinal cords or nerves, scaffolds to bridge the injury or transection site have been considered and may be engineered from synthetic or natural fibers (Muheremu et al., 2021). While inexpensive to produce, they may generate harmful inflammatory reactions associated with an acidic and toxic local microenvironment. “Natural” products include macromolecular proteins, collagen, fibrin, hyaluronic acid, and chitosan that, in turn, can be embedded with growth factors. An alternative is the use of mini-osmotic pumps, fibrin glue, polyglycolic acid/polylactic acid, polyethylene glycol, agarose, as well as acellular tissues (Muheremu et al., 2021) to deliver neurotrophic factors to the injury site. However, it is unclear for how long they should be administered and whether cocktails of growth factors are to be preferred, perhaps working separately on motor and different classes of sensory or autonomic axons in the spinal cord or nerve. Several cell types have also been administered to the injured nervous system, both to replace lost endogenous cell populations and to supply growth factors. These include, for example, MSCs (mesenchymal stem cells), neural stem cells (NSCs), embryonic stem cells (ESCs), fibroblasts, Schwann cells, olfactory ensheathing cells (OECs) (Jin et al., 2021), and perhaps iPSCs (induced

pluripotential stem cells). MSCs (mesenchymal stem cells) are also used to generate neurons requiring a stable source of GFs to make them transdifferentiate (see reviews (Gupta and Singh, 2022; Teli et al., 2021). This requires priming by growth factors. Their subsequent differentiation into neuron-like cells may provide both overall cellular replacement and a source of trophic factors. The MSC secretome is acellular and includes a fraction that contains peptides, cytokines, and growth factors and a fraction that includes extracellular vesicles (EVs), a transport vehicle for molecules. EVs have advantages including the ability to cross the blood-brain barrier by transcytosis and cargoes that include small regulatory RNAs. MSCs have been manipulated to secrete BDNF, NGF, VEGF, HGF, and likely others in the pipeline. Drawbacks of using MSCs include cellular heterogeneity, invasive injection requirements, and difficulties in dose estimation (Teli et al., 2021).

GROWTH FACTOR SIGNALING CASCADES Growth factor signals converge upon some critical common pathways within neurons or glial cells. These include MAPK-ERK, PLC-Y1-IP3-DAG, JAK-STAT, and PI3K-pAkt signaling pathways. Fig. 29.3 provides a simplified overview of several of these pathways. The PI3K-pAkt pathway has been of particular interest in regeneration. Its interruption impairs distal axon outgrowth in sensory neurons (Mearow et al., 2002; Jones et al., 2003). The p85 PI3K regulatory subunit interacts with phosphorylated epitopes of the cytoplasmic domain of activated receptor tyrosine kinases, utilized by many growth factors including insulin, IGF-1, and the neurotrophins. Subsequently, the p110 catalytic subunit (PIK3CA) of PI3K promotes the conversion of PI-4,5-P2 (phosphoinosityl 4,5 diphosphate; PI(2)P) to PI-3,4,5-P3 [PI(3)P] that in turn, phosphorylates to activate downstream Akt/PKB. PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a phosphatase that inhibits the conversion of PI(2)P to PI(3)P and its knockdown enhances pAkt activity. pAkt, in turn, has several targets including glycogen synthase kinase 3b (GSK-3b), a multifunctional serine/threonine kinase, localized to leading edges of growth cones where it acts to suppress growth cone extension and axon formation (Eickholt et al., 2002). When phosphorylated through the PI3K-pAkt signaling pathway, GSK-3b activity is shut down (Dodge et al., 2002; Chin et al., 2005). pAkt also inhibits FOXO3A nuclear signaling to suppress apoptosis. Inhibition of PTEN in this overall pathway thereby has impacts that include facilitation of growth cone extension, axon formation, and neuron survival.

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Fig. 29.3. Simplified schematic illustrating some major neural growth factor intracellular signaling pathways.

The impact of PTEN inhibition or knockdown has expanded to models of spinal cord injury, optic nerve injury, striatal dopamine neuron survival, rescue of cortical neurons from oxygen-glucose deprivation, stroke models, and aging in C. elegans (Ohtake et al., 2015). Pharmacological inhibition or siRNA knockdown of PTEN in the local microenvironment of regenerating peripheral nerves dramatically increases their outgrowth (Christie et al., 2010). In the peripheral nervous system, PTEN knockdown rescued the impairment of regeneration in diabetic sensory axons (Singh et al., 2014). NEDD4 is a ubiquitin E3 ligase that normally is expressed and degrades PTEN in sensory neurons. Its knockdown increases PTEN expression and reduces neurite outgrowth of sensory neurons (Christie et al., 2012). More recently, the intersection and synergy of transcription factor molecules and trophic factors that influence regenerative growth are being considered (Qian and Zhou, 2020). Examples include PI3K-pAkt activated by growth factors, that is enhanced by PTEN deletion, and transcriptome activation resulting in substantial impacts on overall cellular growth by this “double hit.” Further examples of interactions include, for example, BMP-Smad1 signaling, also a transcription pathway (Parikh et al., 2011; Sun et al., 2011; Saijilafu et al., 2013). mTOR (mammalian target of rapamycin) is a serine/ threonine kinase and nutrient and amino acid sensor that forms the core of multiprotein complexes, mTORC1, and mTORC2. TORC1 truncates lifespan, an action opposite that of caloric restriction by Querfurth and Lee, (2021).

mTORC1 supports protein translation and is a negative regulator of autophagy. It includes the subunits mTOR, a regulatory protein Raptor, GbL/mLST8, PRAS40 (proline-rich Akt substrate) and Deptor. It is inhibited by TSC1/2 (tuberous sclerosis protein complex1/2) which in turn is inhibited by pAkt. Thus PI3K-pAkt is an important promoter of mTOR activity. Rapamycin is the canonical inhibitor of mTOR. mTORC1 is thought to act downstream of many growth factors and downstream of it is p79S6K that promotes ribosome biogenesis and GLUT3 which impacts glucose transport in neurons. It also negatively regulates Akt and insulin signaling among other actions. For example, its negative regulation of autophagy is thought to impair neuroprotection, although this role might instead be helpful in the abnormal autophagy of degenerative disorders (Heras-Sandoval et al., 2014). mTORC2 has components Rictor (rapamycin-insenstive companion of mTOR) instead of Raptor in addition to GbL/mLST8, mSIN1, PRR5/Proctor, and Deptor and is instead activated by TSC1/2. TORC2 increases Akt activation, an opposing action to mTORC1. In axons, mTOR is locally translated following anterograde delivery of its mRNA involving the RNA-binding protein nucleolon. Transport and expression are dramatically heightened after injury, allowing for expression locally at the injury site. Within axons, mTOR is thought in turn to broadly regulate local translation, a localized action now thought to have an important role in axonal function, survival, and regrowth (Terenzio et al., 2018).

GROWTH FACTORS AND MOLECULAR-DRIVEN PLASTICITY IN NEUROLOGICAL SYSTEMS 581 The Ras/ERK pathway, or Ras (rat sarcoma)-Raf (rapidly accelerated fibrosarcoma)-MEK (mitogenactivated protein kinase), or MAP2K-ERK (extracellular signal-regulated kinase); and closely related ERK1 and ERK2, sometimes called ERK1/2 pathway, also known as the MAPK pathway (mitogen-activated protein kinase), has a major role in signal transduction following growth factor receptor autophosphorylation (Hausott and Klimaschewski, 2019). Growth factor receptors interact with Ras which activates the protein kinase Raf, that in turn phosphorylates MEK1 or MEK2 (MEK¼MAPK and ERK kinases), phosphorylating and activating ERK1 and ERK2. These second messenger pathways are of importance during peripheral nerve regeneration both within axons and in partnering SCs (Napoli et al., 2012). This is a highly complex pathway that has also been divided into differing cascades including the Raf/ERK pathway activated by mitogens and growth factors, the p38 pathway activated by neurotoxic stress (inflammatory cytokines, oxidative stress, radiation) and growth factors, and the JNK pathway. ERK, p38, and JNK all activate transcription factors (Sahana and Zhang, 2021). Through intermediate molecules that include GRB2 and SOS, Ras is GTP-bound, activated and recruits Raf to the plasma membrane, activating MEK and eventually ERK at threonine and tyrosine residues. Other activators involved in the ERK cascade include cAMP, PKA (protein kinase A), the transcription activator CREB, and DAG (phospholipid diacylglycerol), in addition to a large cascade (not listed here) (Miningou and Blackwell, 2020). Activated ERK is retrogradely transported up axons to the nucleus of injured neurons where it dimerizes and phosphorylates the transcription factors ELK1, c-Fox or c-Jun, thereby impacting regeneration (Perlson et al., 2005). ERK also has local actions in growth cones that include the polymerization of actin and microtubules (Goold and Gordon-Weeks, 2005; Hausott and Klimaschewski, 2019). Inhibition of ERK impairs nerve regeneration, however there is a complexity to its actions and its impact on dissociated neurons that may not be clear-cut (Agthong et al., 2009; Kimpinski and Mearow, 2001; Tucker and Mearow, 2008). cAMP is a key growth factor downstream of neurotrophin receptors. BDNF increases cAMP levels by inhibiting its degradation by phosphodiesterases (Batty et al., 2017). cAMP activates PKA (protein kinase A) which in turn activates the transcription factor cAMP-response element binding protein (CREB). While not thought to directly interact with GFs, the WNT (Wingless-related integration site)- Catenin pathway is associated with neuron survival and growth. Wnts are secretory glycoproteins that act in an autocrine or paracrine fashion on receptors from the Fzd (frizzled) family and possess canonical b-catenin signaling

pathways (as well as two further noncanonical pathways not discussed further here). b-catenin in the absence of Wnt is bound within a “destruction complex” that includes four other proteins (GSK 3b, APC, Axin, and CK1). Wnt ligation to its receptor complex or knockdown of APC (adenomatous polyposis coli), a tumor suppressor factor (mutated in colon carcinomas), frees b-catenin from the destruction complex. This in turn allows it to signal within the nucleus through the transcription factors, T-cell factor/lymphoid enhancer factor (TCF/LEF). There is substantial diversity in this signaling pathway that includes noncanonical pathways, multiple Wnt subtypes, Fzd diversity and interacting receptor proteins and further complexity within the destruction complex components. There are 19 Wnt members with 15 receptors and coreceptors that include Frizzled1–10, low-density lipoprotein, receptor-related protein 5/6 (LRP5/6), and others (Jiang et al., 2021). While proposed for dopaminergic signaling in Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS), this pathway has wide actions in the nervous system (Marchetti, 2018; Jiang et al., 2021), including a postulated role in astrocyte-neuron-microglial crosstalk. The JAK/STAT pathway (Janus kinase/signal transducer and activator of transcription) interacts with over 50 cytokines and growth factors (Hu et al., 2021). Several STAT proteins are tyrosine phosphorylated and dimerized, enter the nucleus and impact transcription. JAK has four members (JAK1,2,3 and TYK2) and STAT has seven members (STAT1,2,3,4,5a,5b,6). Once activated by receptor intracellular transphosphorylation, JAK forms a docking site for STATs which are then phosphorylated, dissociated, and form dimers that move to DNA promoters, including their participation as part of a transcription complex. This is the canonical pathway but other signal pathways are described involving mitochondria, endoplasmic reticulum, and chromatin remodeling (Hu et al., 2021). Most activators studied are immune interleukins and interferons but also growth factors such as CNTF, PDGF, HGF, and others.

NEUROTROPHINS, OTHER GROWTH FACTORS AND HUMAN DISEASE Experimental motor disorders Resilience of motor neurons can be evaluated by their retrograde response to axon transection or axotomy. As an example, BDNF and NT-3 rescue adult rat corticospinal neurons from axotomy-related cell death (Giehl and Tetzlaff, 1996). BDNF and CNTF synergistically prevent motor neuron degeneration and associated limb paralysis in the wobbler mouse, a model of human motor neuron disease (Mitsumoto et al., 1994; Ikeda et al., 1995). BDNF-TrkB and p75 are proposed to treat ALS

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by reversing motor terminal loss at the neuromuscular junction (Lanuza et al., 2019). CNTF improved progressive motor neuronopathy (pmn) in mice, an additional model of human ALS (Sagot et al., 1995, 1996). In transgenic ALS mice, retrograde delivery of IGF-1 in a recombinant adeno-associated virus (AAV) impacted disease progression when delivered into muscle, spinal cord or brain (parenchyma or ventricles) (Kaspar et al., 2003; Lepore et al., 2007; Dodge et al., 2008, 2010; Shandilya and Mehan, 2021). VEG given by intraventricular delivery or through intrathecal cloned human neural stem cells was also of benefit in experimental ALS (Hwang et al., 2009; Dodge et al., 2010). Protection in ALS models was also provided by LIF (Azari et al., 2001) and intrathecal HGF (Ishigaki et al., 2007), and cortical injection of neural progenitor cells expressing GDNF (Thomsen et al., 2018). In contrast, elevated TGFb in CSF, plasma and muscle of ALS patients suggests that it may instead contribute to the disease, especially TGFb1. To complicate matters, some neuroprotection is reported from TGFb2 (Galbiati et al., 2020). The overall roles of mTOR and autophagy in experimental ALS appear conflicting although a trial of rapamycin to suppress mTORC1 has been planned (Querfurth and Lee, 2021). Finally, manipulation of MAPK and Wnt signaling cascades, mainly using inhibitors, has been proposed for the therapy of motor neuron disease (Jiang et al., 2021; Sahana and Zhang, 2021).

Experimental parkinsonism The impact of several growth factors on neurons of the substantia nigra has prompted their application to models of human PD. They include IGF-1, NT-3, and bFGF (Nakao et al., 1996). It has been reported that NGF, BDNF, bFGF, and NT-5 but not NT-3 protected striatal

neurons from the MPP+ neurotoxin that targets dopaminergic nigral neurons (Kirschner et al., 1996). NGF generated from striatal neural stem cell transplantation reduced excitotoxic damage (Martinez-Serrano and Bjorklund, 1996). In the 6-hydroxydopamine (6-OHDA) rat model of PD, infusion of NT-4/5 but not NT-3 enhanced the function of nigral grafts (Haque et al., 1996) and fibroblast grafts producing BDNF prevented striatal dopaminergic neural loss (Katsuki and Okuda, 1995). BDNF also improved dopamine content and synaptic plasticity in several additional, albeit not all models [reviewed by Palasz et al., 2020]. GDNF is also of benefit in PD models, where it offers protective and regenerative impacts on midbrain dopaminergic neurons the crosstalk with pathological PD genes (Beck et al., 1995; Tomac et al., 1995; Sauer et al., 1995a,b; Conway et al., 2020). The case for FGFs in PD may be preliminary (Liu et al., 2021), however BMP transcripts and receptors were attenuated in human PD nigral neurons. Moreover, BMP2 treatment improved experimental PD (Goulding et al., 2020). Intraventricular PDGF-BB improved preclinical mouse PD models (Sil et al., 2018). Overall, four trophic factors, PDGF, GDNF, Neurturin, and CDNF were recommended for clinical trials based on preclinical evidence (Sidorova and Saarma, 2020). Downstream of growth factors, mTOR’s role in autophagy may yield additional therapeutic targets for PD although, like ALS above, whether the mTOR protein complex is protective or contributory is unclear (Querfurth and Lee, 2021).

Nerve regeneration The impact of growth factors and their downstream pathways on regenerating axons is shown schematically in Fig. 29.4 and their actions in axons and growth cones are reviewed elsewhere in the monograph

Fig. 29.4. An schematic overview of the actions of growth factors on sensory axons and growth cones. MFs, myelinated axons; UMFs, unmyelinated axons.

GROWTH FACTORS AND MOLECULAR-DRIVEN PLASTICITY IN NEUROLOGICAL SYSTEMS 583 “Neurobiology of Peripheral Nerve Regeneration” (Zochodne, 2008) and in newer reviews (Duraikannu et al., 2019; Idrisova et al., 2022). Since neurotrophins “turn off” features of the cell body regeneration program, their potential impact on fiber regeneration is uncertain. An important feature of local growth factor expression by SCs during regrowth is that the time course of their selective expression that determines whether new motor or sensory axons will partner with them to send their axons to the appropriate target. For example, motor neuron-supporting neurotrophic factors GDNF and PTN have peak expression at 15d following injury, an inflection point that supports motor axons growing to partner with these SCs into the correct branch of the denervated nerve (Brushart et al., 2013; Gordon, 2014, 2020). Overall, ventral motor roots express PTN, VEGF-1, and IGF-1 whereas sensory nerves express BDNF, NT-3, HGF, and GDNF. Denervation upregulates PTN and GDNF in motor SCs, and NGF, BDNF, VEGF-1, and IGF-1 in sensory SCs (Bolivar et al., 2020). Sensory branch SCs synthesizing NGF, BDNF, and IGF-1 also peaked around 15d following injury allowing SCs to support regrowing sensory axons. Thus, there is delayed specificity of reinnervation as determined by the time course of trophic factor expression of SCs. The added roles of osteopontin and clusterin in helping with this selectivity were discussed earlier. Complicating these ideas of specificity has been other work suggesting wider benefits from NGF than might be expected, for example, on both motor and sensory axon regrowth (He and Chen, 1992; Kemp et al., 2011). Locally delivered CNTF by a mini-osmotic pump as well as insulin and IGF-1 improved regeneration following sciatic nerve transection (Glazner et al., 1993; Newman et al., 1996; Xu et al., 2004). FGFs 1 or 2 applied to transected nerves or placed within collagen-filled conduits have been associated with improvement in regeneration, whereas FGF2 lessened retrograde sensory neuron apoptosis and supported SCs (Klimaschewski and Claus, 2021). An alternative to harvested sural nerve grafts to span sites of nerve transection has been bioartificial grafts with embedded growth factors. This approach has demonstrated benefits using NGF within a conduit (Lee et al., 2003) or within laminin constructs or allografts (Yin et al., 2019b; Idrisova et al., 2022). As important as the delivery of the growth factor, is the gradient required to encourage growth in the proper direction toward a distal stump without stalling where growth factors are plentiful (Kemp et al., 2007). Gradients are also important in spinal cord injury where trauma is often accompanied by a cavitary vacuole that requires axon crossing. Determinants of success depend on the administered concentration and its decline over distance. Other complications are noise from thermal fluctuations that influence ligand-receptor association, receptor saturation, and

other problems (Dravid et al., 2020). Direct injection into silicone tubes has been an approach used by several investigators, for example, FGF-2 lentivirus (Allodi et al., 2014) and VEGF in matrigel-filled silicone tubes (Hobson et al., 2000). Agents applied with hydrogel and other biomaterials or plasmids have included FGF21 or bFGF (Aebischer et al., 1989; Lu et al., 2019), VEGF with NGF (Fang et al., 2020; Li et al., 2021), plasmid VEGF (Haninec et al., 2012), an adenoviral construct coding for VEGF (Hillenbrand et al., 2015), NGF, and VEGF on magnetic nanoparticles (Giannaccini et al., 2017), VEGF-b in hydron pellets (Guaiquil et al., 2014), and peptides mimicking VEGF and BDNF (Rao et al., 2020). The evidence for NGF, BDNF, NT-3, HGF, and VEGF within regeneration conduits has recently been reviewed (Carvalho et al., 2019).

Peripheral neuropathies Peripheral neuropathies, including those with a predominant demyelinating phenotype such as CMT1A or CIDP, all share the common feature of primary or secondary axonal injury, an important determinant of long-term disability. Theoretically, the regrowth of damaged motor or sensory axons, after the inciting damage is over, could be supported by neuronal growth factors. Some insight into the properties of injured peripheral neurons is available through the analysis of the retrograde changes that occur following axotomy. Some, but not all of these changes may be identified in experimental models of neuropathy. For example, NGF and NT-3 may benefit experimental diabetic neuropathy, including changes in axonal conduction, by reversing diabetesrelated alterations in sensory neuron peptide expression (Tomlinson et al., 1996) [see review (Zochodne, 1996)]. However, Trk neurotrophin receptors may decline and contribute to neurodegeneration in long-term models of diabetic neuropathy (Zochodne et al., 2001). In diabetes, the availability of neuron trophic support from insulin and IGFs may be impaired in diabetes (Ishii, 1995). In keeping with this, low subhypoglycemic doses of insulin (that do not alter elevated diabetic glucose levels) from the near nerve, intrathecal, intranasal (to access nerve root sleeves and DRGs) or intraepidermal injection improve experimental diabetic neuropathy (Singhal et al., 1997; Brussee et al., 2004; Guo et al., 2011; de la Hoz et al., 2017). Sensory neurons, including their distal dermal branches, express IRs and human skin expresses IR mRNA (Guo et al., 2011; Bautista et al., 2020). Collateral sprouting is a process of potential recovery from severe neuropathic deficits. It involves the generation of axon branches from adjacent intact neurons that invade and reinnervate nearby denervated target organs. It differs from regenerative sprouting in that regrowing

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axons from this process do not arise from damaged neurons or axons. Collateral sprouting may allow a route for functional recovery of proximal nerve lesions unlikely to regrow toward targets, or disorders with dropout of neuron perikarya (neuronopathies). Diamond et al. (1992) brought unique attention to collateral sprouting by demonstrating that NGF supported collateral, but not regenerative skin sensory reinnervation. Further work identifying the differing growth factor requirements of collateral sprouts will be of interest. Given the difficulty of reproducibly generating a variety of long-term models of human neuropathy, other trials have been limited. NT-3 benefits large fiber toxic sensory neuropathy caused by high doses of pyridoxine (Helgren et al., 1997) whereas NGF offered support for DRGs in experimental taxol neuropathy (Schmidt et al., 1995). NGF may also improve cisplatin neuropathy (Apfel et al., 1991). Growth factor support has been considered in inherited neuropathies, such as Charcot-Marie-Tooth (CMT) disease. Depending on the specific mutation, SC deficits in maturation and function are likely to be contributory and autocrine NT-3, IGF1, PDGF-BB all play roles in maturation (Sahenk and Ozes, 2020). In particular, NT-3 is thought to be essential for SC survival during regeneration-related remyelination. Injection of AAV1. CMV.NT3 intramuscularly into trembler mice, a model of demyelinating inherited polyneuropathy, resulted in sustained NT-3 levels and improvements in the model. Abnormalities of EGFR trafficking and degradation within endosomes have been identified in CMT2B caused by a mutation of the RAB7 gene (Saveri et al., 2020).

Other A wide range of additional preclinical alterations have been described for neuronal growth factors, however not all reviewed here in depth. In aging rats, for instance, there are declines in TrkB and TrkC mRNA transcripts in spinal motor neurons (Johnson et al., 1996). In contrast, experimental cerebral infarcts of rats had transient rises in BDNF, NGF, and TrkB expression, perhaps suggesting a role in early recovery (Kokaia et al., 1995). VEGF administration has also been proposed as a repair mechanism following ischemic cerebral infarction through its actions on neurons, neuron stem cells, and blood vessels (Moon et al., 2021). FGFs have also been proposed for stroke treatment (Ay et al., 1999). Polymer-encapsulated hamster kidney fibroblasts implanted into the striatum and secreting human CNTF offered neuroprotection in a primate quinolinic acid-induced model of human Huntington chorea (Emerich et al., 1997). NGF infused around fetal neuronal grafts improved outcomes in adult rats with fluid percussion brain injuries (Sinson et al., 1996).

Growth factors may help to repair spinal cord injury (SCI) (Muheremu et al., 2021). For example, specific tracts within the spinal cord may have differential responsiveness to neurotrophin family members. Thus, for NGF the ventral spinothalamic tract; for BDNF the rubrospinal, vestibulospinal, and reticulospinal (medial and lateral) tracts; for NT-3 the lateral corticospinal tract, ventral corticospinal tract, fasciculus gracilis and cuneatus (Dravid et al., 2020). Fibroblasts secreting BDNF enhanced regeneration of rubrospinal axons and recovery of forelimb function after implantation in hemisectioned rat cervical spinal cords (Liu et al., 1999), but BDNF grafts had no influence on growth in other work (Lu et al., 2001). Implanted fibroblast grafts secreting NGF, NT-3, or bFGF into the central canal of adult rat spinal cords attracted sensory and noradrenergic dorsal root fibers into the graft (Nakahara et al., 1996). Overall, the potential impacts of FGF ligands (FGF 1 and 2) in SCI are summarized (Haenzi and Moon, 2017). For example, bFGF encapsulated into core-shell microfiber and implanted into hemisectioned rat spinal cords improved recovery and reduced gliosis (Reis et al., 2018) whereas NT-3 improved corticospinal tract regrowth with some functional recovery (Grill et al., 1997). Added cAMP to NT-3 offered further benefits (Lu et al., 2004). NT-3 and BDNF supported axonal regeneration through semipermeable guidance channels across transected rat thoracic spinal cords (Xu et al., 1995). Preclinical data summarizing the impacts of GDNF in experimental SCI are summarized by Rosich et al. (2017). Overall, GDNF approaches with varying success have included its use in direct infusates, microspheres, guidance channels, olfactory ensheathing cells, fibroblasts or neural stem cells, or gelatin foam sponges with adenoviral transduction. Benefits included reduction of lesion size, neuroprotection, axon regeneration, modulation of inflammation, and improved functional recovery. More recently, GDNF overexpressed in bone marrow mesenchymal stem cells improved recovery from a rat contusion thoracic SCI when injected locally (Shahrezaie et al., 2017). Improvements in remyelination and functional recovery in contused adult thoracic spinal cords were noted after oligodendrocyte precursor cells transfected with CNTF-expressing retroviruses were transplanted (Cao et al., 2010). Some BMPs appear to improve SCI by modulating reactive astrocytosis, glial scarring, and extracellular matrix remodeling whereas other BMPs either promote or inhibit neuron survival, axon regeneration, and regulate myelination (Hart and Karimi-Abdolrezaee, 2020). Exogenous HGF was administered to rat SCIs using a Herpes simplex virus-1 vector and was associated with attenuated tissue damage and improved motor function (Kitamura et al., 2007). Other preclinical studies in SCI using HGF are reviewed (Kitamura et al., 2019).

GROWTH FACTORS AND MOLECULAR-DRIVEN PLASTICITY IN NEUROLOGICAL SYSTEMS 585 There has been advocacy for the protective effects of growth factors in the development and developmental disorders, stroke (beyond the brief references above), multiple sclerosis, Alzheimer’s disease, epilepsy, neurotrauma, Huntington disease, psychiatric disorders, and others, although not reviewed here.

SPECIFIC CLINICAL TRIALS Motor neuron disease Unfortunately, human trials of specific growth factors have not identified robust and unequivocal benefits in ALS). For example, despite early promise, recombinant methionyl human BDNF in a Phase III trial had no overall benefit beyond a post hoc subgroup survivor analysis (Anonymous, 1999; Ochs et al., 2000). The current consensus is that there exists insufficient clinical evidence for the impact of BDNF on ALS (Miranda-Lourenco et al., 2020). Recombinant human insulin-like growth factor-1 (rhIGF-1) given subcutaneously for 9 months had either no benefit (Borasio et al., 1998; Sorenson et al., 2008) or mild slowing of functional impairment (Lai et al., 1997). In trials, IGF-1 was associated with tachycardia, dyspnea, hypoglycemia, hypotension, and microvascular proliferation (Le Roith, 1997; Shandilya and Mehan, 2021). Two Phase II–III trials of subcutaneous recombinant human CNTF (rhCNTF) were of no benefit but instead had increased mortality in one of the trials (Anonymous, 1996; Miller et al., 1996). Side effects included injection site reactions, cough, asthenia, nausea, anorexia, weight loss, and unexpected increased salivation. A compound thought to have growth factor activity, Xaliproden, provided modest slowing of respiratory function in a subset of patients but did not significantly slow the rate of limb function deterioration (Lacomblez et al., 2004). An open labeled multicenter safety trial of granulocyte colony-stimulating factor in patients with ALS, to recruit reparative bone marrow cells into the CNS, had a reduction in CSF inflammatory markers but no impact on the disease course (Chio et al., 2011). A recent summary of attempts to treat ALS with growth factors is provided in two concurrent reviews (Bartus and Johnson, 2017a,b).

Polyneuropathy Neither have growth factors found clear clinical indications from clinical trials in polyneuropathies. A multicenter Phase III trial of subcutaneous recombinant human NGF (rhNGF) in diabetic neuropathy did not identify benefits (Apfel et al., 2000) despite encouraging Phase II data. The latter may have been compromised by inadequate blinding from NGF-related injection site pain (Apfel et al., 1998). In HIV-related peripheral

neuropathy, rhNGF improved pain but not loss of epidermal innervation (McArthur et al., 2000). A smaller trial of subcutaneous recombinant human BDNF (rhBDNF) did not identify significant improvement in insulintreated diabetic patients with neuropathy (Wellmer et al., 2001). A limited randomized pilot trial of subcutaneous BDNF in Guillain-Barre syndrome did not identify benefits (Bensa et al., 2000). NT-3 improved sural nerve pathology, sensory loss and clinical scores in CMT1A patients but there have been no additional trials because of the agent’s short half-life, costs, and loss of availability (Sahenk et al., 2005; Sahenk and Ozes, 2020).

Other Benefits in manual muscle strength from recombinant human IGF-1 were reported in a small Phase II trial in myotonic muscular dystrophy (Vlachopapadopoulou et al., 1995). In early mild Alzheimer disease and mild cognitive impairment (MCI), intranasal insulin, a route that accesses the cerebrospinal fluid (CSF), improves attention, verbal memory, and functional status along with the Ab40/42 serum ratio (Reger et al., 2008). A recent Phase I/II trial of recombinant intrathecal human HGF in SCI has demonstrated safety and a suggestion of efficacy, with Phase III trials awaited (Nagoshi et al., 2020). A substantial number of growth factors, including BDNF, NT-3, and GDNF have been studied in PD (Ebendal et al., 1994). Intracerebroventricular GDNF did not improve PD and its access to the substantial nigra was questioned. Side effects were nausea, vomiting, anorexia, weight loss, electrical sensations, and asymptomatic hyponatremia (Nutt et al., 2003). Open labeled intraputaminal recombinant human GDNF in PD did not improve clinical scores despite improved 18F Dopa uptake and were hampered by infusion-related complications and neutralizing antibodies (Lang et al., 2006). In contrast, a small Phase I trial only involving 10 patients, with intraputaminal GDNF infusion suggested benefit (Slevin et al., 2007). Overall, despite the initial promise, intraputaminal GDNF has not achieved its trial primary endpoints (Barker et al., 2020). A multicenter doubleblinded randomized trial of AAV2-delivered intraputaminal neurturin compared to sham surgery in 58 patients with advanced PD did not demonstrate improvements over 1 year. Moreover, there were serious adverse effects in both groups that included myocardial infarction, pulmonary embolism, postoperative confusion, hemorrhage, seizures, mental changes, and urinary retention (Marks et al., 2010). Subcutaneous erythropoietin and PDGF-BB by intraventricular catheter have also been trialed in limited numbers of PD patients indicating safety, but not robust improvement (Sil et al., 2018;

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Vittori et al., 2021). Recent PD trials, none with clear benefits, are summarized in recent reviews (Chmielarz and Saarma, 2020; Sidorova and Saarma, 2020).

Summary and overall limitations in the clinical use of growth factors Despite considerable and appropriate enthusiasm for their use, trials of neural growth factors have waned. Critical problems, some highlighted above, have contributed to this limited record of success. For example, trophic factor dosing may have been too low, perhaps by several orders of magnitude. However, trophic factors in high concentrations may inhibit signaling, indicating a biphasic response, or may generate negative feedback signals (Sidorova and Saarma, 2020). In the case of insulin, resistance develops to its trophic actions with higher or prolonged dosing (Singh et al., 2012). It is thought that if some growth factors signal in a short-term pulsatile fashion, then prolonged infusion may be counterproductive. Delivery destinations and systems have been flawed but refinements may have better success. While viral drug delivery poses risks of a serious inflammatory reaction, there is a possibility that alternative nanoparticle or embedded use may be superior. The use of the intranasal delivery route, which directly accesses the CSF, may be a fruitful avenue for future work. Targeted neurological disorders may not involve a growth factor-sensitive pathway. For example, in ALS, it is questionable whether extrinsic support can rescue diseased motor neurons under siege from as yet unidentified mechanisms (Peviani et al., 2007; Kirby et al., 2011). Substantial motor neuron loss may precede clinical recognition and diagnosis. It is also unclear whether the role of growth factors would be mainly rescue, prevention, or regeneration. Growth factors are selective and require robust knowledge of where their receptors are expressed. In diabetes, only some neurons targeted by the disorder may be sensitive to rhNGF, such as small TrkA-expressing nociceptive neurons. Trial endpoints, such as those in diabetic polyneuropathy may not have been designed to address specific neuron subpopulations. In the case of non-TrkA neurons, NGF might ligate p75 receptors in either neurons or SCs with unpredictable results. A related concern is that the disease or the treatment may downregulate receptor expression, rendering the trophic factor less efficacious. Finally, for disorders such as PD, or ALS, targeting the trophic factor to the key site of disease for the appropriate period of time may be very challenging given that these proteins do not cross the blood-brain barrier. There are clinical conditions thought to relate to overexpression of neurotrophic factors, for example, the actions of NGF in chronic pain of arthritis and bladder overactivity (Kashyap et al., 2018). For these,

targeted therapy has been developed employing the antiNGF monoclonal antibody tanezumab. The role of growth factor mimetics, developed by modeling the relevant receptor binding site and its interaction with a ligand, is a newer development that may offer a way to bypass difficulties with growth factor administration. In addition to agents thought to have indirect actions on growth factor receptors, several selective TrkA agonists have been developed (Josephy-Hernandez et al., 2017). Positive-allosteric modulators (PAMs) are small molecules that avoid direct activation and nonspecific pleiotropic actions, but that synergize with the signaling of endogenous growth factors. Compound D3 is an example of a partial TrkA agonist. Several TrkB agonists identified by screening are also described (Josephy-Hernandez et al., 2017). Thus, despite all of the serious limitations that have inhibited the exploitation of neural growth factors, they continue to offer promise. Their numbers are widening and mechanisms are becoming better understood. Finally, strategies exploiting their downstream signaling pathways selectively with targeted molecules may allow eventual approaches to reverse “permanent” neurological impairment.

ACKNOWLEDGMENT DZ has been supported by the Alberta Heritage Foundation for Medical Research (AHFMR) and has received grant support from the Canadian Institutes of Health Research, the Canadian Diabetes Association, and the Juvenile Diabetes Research Foundation.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00011-9 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 30

Applied strategies of neuroplasticity BRIAN P. JOHNSON AND LEONARDO G. COHEN* Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States

Abstract Various levels of somatotopic organization are present throughout the human nervous system. However, this organization can change when needed based on environmental demands, a phenomenon known as neuroplasticity. Neuroplasticity can occur when learning a new motor skill, adjusting to life after blindness, or following a stroke. Following an injury, these neuroplastic changes can be adaptive or maladaptive, and often occur regardless of whether rehabilitation occurs or not. But not all movements produce neuroplasticity, nor do all rehabilitation interventions. Here, we focus on research regarding how to maximize adaptive neuroplasticity while also minimizing maladaptive plasticity, known as applied neuroplasticity. Emphasis is placed on research exploring how best to apply neuroplastic principles to training environments and rehabilitation protocols. By studying and applying these principles in research and clinical practice, it is hoped that learning of skills and regaining of function and independence can be optimized.

INTRODUCTION

SOMATOTOPIC ORGANIZATION

We live in an ever-changing world. From using new technologies and leisurely activities to using a prosthesis for the first time, one must often adapt to the constraints of the environment and new situations. Fortunately, the nervous system is also malleable to environmental constraints that require learning new skills. This chapter outlines neuroplastic processes and different applications of neuroplasticity related to motor skill learning and physical rehabilitation. Specifically, we discuss adaptive and maladaptive neuroplasticity following injury in the presence and absence of interventions, and how learning and neuroplasticity overlap. Of particular interest are the various methodologies used over time to quantify neuroplastic changes, as well as neuroplasticity related to stroke rehabilitation. An understanding of the principles of neuroplasticity, and how to apply these principles, is important to understanding how to best maximize function and independence for individuals with neurologic diagnoses who may experience adaptive and/or maladaptive neuroplasticity.

Human anatomy is represented in a somatotopic fashion in the cortical motor regions. This was demonstrated through direct microelectrode stimulation of the cortex in animals (Penfield and Boldrey, 1937), and indirectly through invasive and noninvasive stimulation (e.g., transcranial magnetic stimulation [TMS]) of the human cortex (Duque et al., 2005). It has since been found that somatotopic organization is widespread throughout the nervous system (van der Zwaag et al., 2013).

NEUROPLASTICITY The representations of body parts in the nervous system are not static, but rather dynamic. Changes in the environment or damage to the body or nervous system (Rijntjes et al., 1997; Werhahn et al., 2002) can result in experience-dependent changes to somatotopic organization and functioning. Neuroplasticity can be described simply as the modification of the nervous system’s structure and/or function in response to novel environmental

*Correspondence to: Leonardo G. Cohen, M.D., National Institutes of Health, Building 10, Room 7D54, 9000 Rockville Pike, Bethesda, MD 20892, United States. Tel: +1-301-4969782, Fax: +1-301-4027010, E-mail: [email protected]

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stimulations and situations (Stee and Peigneux, 2021). Synaptic plasticity is best thought of in terms of spiketime-dependent plasticity. Bliss and Lomo (1973) described spike-time-dependent plasticity in the rabbit hippocampus, when a presynaptic neuron stimulates a postsynaptic neuron. This stimulation then causes the creation of additional neurotransmitter receptors on the postsynaptic neuron and results in a lower threshold for stimulation by the presynaptic neuron, known as long-term potentiation (LTP). The idea of neuronal connections being strengthened by repeatedly firing together also works in the opposite way: the lack of action potentials from presynaptic to postsynaptic neurons can cause weaking of connections, known as long-term depression (LTD). LTP and LTD work via synaptic sprouting or pruning, respectively (Walker and Detloff, 2021). Neuroplasticity has also been thought to include neurogenesis, though the role and extent of human neurogenesis remains controversial (Stee and Peigneux, 2021). More recently, neuroplastic changes have also been found in the thickness of the myelin sheath and axon diameter (Fields, 2015; Xin and Chan, 2020; Tremblay et al., 2021). While the discussion thus far has been exclusive to the brain, neuroplasticity can occur throughout the nervous system. For example, Liu and Chambers (1958) described neuroplastic changes of intact dorsal root axons in cats following dorsal horn injury. Although neuroplasticity can occur throughout the nervous system, here we focus on brain plasticity rather than that of the spinal cord, which has been recently reviewed elsewhere (Walker and Detloff, 2021). Plasticity can occur in the healthy brain when learning or forgetting, for example, new skills. It has been also documented in the injured brain as a result of neuronal damage or death (Kleim and Jones, 2008; Dayan and Cohen, 2011). These modifications can develop within minutes, such as after 5–30 min of repetitive thumb movement to one direction (Classen et al., 1998). But it is the volitional act of moving the thumb, and not passive movement, that produces these neuroplastic changes (Kaelin-Lang et al., 2005). Longer bouts of motor skill practice may cause cortical motor map changes, which last up to several days (Molina-Luna et al., 2008). Large-scale changes in the nervous system are thought to require more than just movement, but rather afferent input dictating that neuronal connections must be refined in order to complete the desired function(s) (Nudo et al., 1996; Plautz et al., 2000). For example, squirrel monkeys trained on a well-retrieval task demonstrated behavioral improvements and greater neuroplastic changes if the diameter of the well was smaller, and thus more difficult (Nudo et al., 1996). Indeed, rodents trained to reach and grasp pellets from the well with the largest diameter

showed little behavioral improvements or neuroplastic changes (Plautz et al., 2000). On a more macroscopic level are the theories of equipotentiality and variation. Equipotentiality is the theory that the hemisphere contralateral to the damaged one can take over function for the damaged region(s) function. Interestingly, it has recently been shown that neuroplastic changes, as determined by magnetic resonance imaging (MRI), from 2 weeks to 3 months poststroke are different depending on whether the left (LHS) or right (RHS) hemisphere sustained the stroke (Chen et al., 2021). “Both LHS and RHS groups showed statistically common plasticity independent of the lesioned hemisphere, including 1) gray matter (GM) expansion in the ipsilesional and contralesional precuneus, and contralesional superior frontal gyrus; 2) GM shrinkage in the ipsilesional medial orbital frontal gyrus and middle cingulate cortex. On the other hand, only RHS patients had significant GM expansion in the ipsilesional medial superior and orbital frontal cortex” (Chen et al., 2021). Vicariation, on the other hand, involves reorganization of other brain regions, particularly ones adjacent to the damaged areas, to take over function for the damaged region(s) (Puderbaugh and Emmady, 2022). Aside from brain lesions, vicariation is also evidenced after amputation of a hand digit. In this case, the cortical tissue which represents the surrounding digits expand into the deafferented cortical representation, which previously represented the amputated digit (Merzenich et al., 1984). Measuring neuroplastic changes can be difficult and controversial. Invasive microelectrode and TMS have been used to measure cortical representations, allowing the measurement of neuroplastic changes. For example, TMS has been used to assess neuroplasticity within the motor cortex following motor training by systematically mapping anatomical representation in response to motor-evoked potentials (MEPs) (Wittenberg et al., 2003; Duque et al., 2005; Reis et al., 2008). For example, skilled racket ball players have been found to have larger hand representation in the motor cortex and enhanced MEP amplitude relative to less skilled racket ball players and people who have not played racket ball (Pearce et al., 2000), and braille readers who are blind have a larger cortical representation of the braille-reading digit relative to the contralateral digit or people who are not braille readers (Pascual-Leone et al., 1993, 1995). In addition to cortical representation of use-dependent anatomy, others have used TMS to demonstrate increased cortical excitability of the motor cortex following motor learning, but not simply motor performance (Lotze et al., 2003). Other methods that provide complementary information about neuroplasticity include MRI with diffusion weight

APPLIED STRATEGIES OF NEUROPLASTICITY imaging (DWI), magnetoencephalography (MEG), and electroencephalography (EEG) (Buch et al., 2021; Stee and Peigneux, 2021). However, these indirect measures allow for the elucidation of subcortical changes. Neuroimaging measures are also useful in the study of the mechanisms involved with motor control and motor learning (Catalan et al., 1998).

ADAPTIVE NEUROPLASTICITY By inducing a virtual focal lesion via use of TMS, the role of specific areas of the brain can be studied (Cohen et al., 1997; Amedi et al., 2004). An early example of this within a single sensory modality was the discovery that individuals who are blind and read braille have significantly larger cortical representations of the finger used for braille reading relative to all other fingers (Pascual-Leone et al., 1993). Across modality neuroplastic changes can occur as well. For example, blind individuals reading braille with their fingers activate the primary visual cortex (Sadato et al., 1996). This activation plays a functionally adaptive role because disruption of occipital activity with TMS affects reading (Cohen et al., 1997).

MALADAPTIVE NEUROPLASTICITY But neuroplastic changes can also be maladaptive and negatively affect human function. For example, immobilization of movement or amputation can cause motor map changes in which adjacent anatomical representations in the cortex can expand into the nonused area (Merzenich et al., 1984). These cortical modifications which occur following an amputation can be associated with phantom limb pain (Cohen et al., 1991; Karl et al., 2001). Initially following a stroke, diaschisis occurs at site(s) of injury and multiple neuroplastic processes occur in the regions adjacent to injury (B€ utefisch et al., 2003; Murase et al., 2004). Movement of a paretic hand results in increased activity in the contralesional hemisphere. Contralesional activation could play adaptive (Gerloff et al., 2006) or maladaptive (Murase et al., 2004) roles depending on various factors, one of them being via interhemispheric influences (Jones and Schallert, 1994; Adkins et al., 2004). From a clinical point of view, it is usually easier for patients to use the nonparetic arm for daily activities (Kwakkel et al., 2004), which then reinforces inhibitory effects onto the injured regions (Andrews and Steward, 1979; Taub et al., 2006). This pattern is often called “learned nonuse” and may require specific rehabilitation strategies (Mark and Taub, 2004; Allred et al., 2005; Sunderland and Tuke, 2005).

APPLIED NEUROPLASTICITY Neuroplastic changes occur in the cortex after an injury to the nervous system or other long-term anatomical

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changes, often regardless of treatment (Chen et al., 2002; Floel and Cohen, 2006). Conversely, behavioral and neuromodulatory interventions can also cause adaptive or maladaptive neuroplasticity following damage to the nervous system (Nudo, 1999). The crucial role of treatment teams to ensure that adaptive plasticity is optimized, while maladaptive plasticity is minimized has been referred to as applied neuroplasticity (Nudo, 1999). Both adaptive and maladaptive plasticity can, and do occur following neurologic injury. Following a stroke, neuroplastic cascades occur in three phases: (1) days, (2) weeks, and (3) months and beyond (Puderbaugh and Emmady, 2022). In the first 48h, cell deaths occur in lesioned areas, while surviving neural networks adapt to sustain functioning. Over the next few weeks, further anatomical and/or functional changes develop resulting in synaptic plasticity and formation of new pathways. In the long term, adaptive and maladaptive neuroplasticity reorganize the brain based on environmental input and the individual’s activity. It is important to note though that spontaneous recovery of the brain following stroke has been found to account for the majority of motor gains poststroke (Cramer, 2008; Zeiler and Krakauer, 2013). It is typically within the first 3 months following injury that individuals show the greatest gains in functioning and neural reorganization, with smaller effects between 3 and 6 months, and yet even smaller after 6 months (Zeiler and Krakauer, 2013). It is these first 3 months that are often called the “critical period” of recovery. Basic science investigations documented critical periods, for example, in newborn cats in which one eye was sewn shut after birth (Hubel and Wiesel, 1970). Kittens that had the sutures removed from the eye before 3–8 weeks showed the ability to gain eyesight in the eye, whereas those with the sutures removed afterward were not able to gain eyesight. However, in individuals with stroke, it has been found that providing physical rehabilitation too early (i.e., within the first 48 h) can be detrimental to recovery (Dromerick et al., 2009). Therefore, rehabilitation should be initiated several days after sustaining the injury. It is important to keep in mind though that individuals can continue to show functional improvements and neuroplastic changes years or decades following their injury (Whitall et al., 2011; Wilkins et al., 2017).

REHABILITATION AND NEUROPLASTICITY Rehabilitation interventions can be broadly categorized as restorative, compensatory, or adaptive. Restorative interventions aim to regain or maintain someone’s level of functioning in the same way as currently (or prior to injury). For example, strength and balance exercises

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could be done to regain the ability to ascend and descend stairs independently following a stroke. A compensatory approach, on the other hand, can involve adopting new strategies to regain or maintain a level of functioning. For example, adopting a new kinematic strategy to ascend and descend stairs safely given the consideration of impairments of the paretic leg. Finally, adaptive interventions often involve changing the environment to aid an individual in regaining or maintaining their level of functioning. In the example of ascending and descending the stairs following a stroke, an adaptive intervention might be to install handrails on both sides of the stairs or encourage the individual to wear an orthosis on the paretic leg. Many restorative and compensatory interventions that focus on improving performance of activities of daily living are known to induce neuroplasticity (Katz and Dwyer, 2021). Similar to the notion that not all movement activities induce neuroplasticity, neither do all forms of physical rehabilitation elicit neuroplasticity. Following a review of the literature, Adkins et al. (2006) concluded that cortical neuroplasticity is elicited by task-specific motor training, while aerobic exercise seems linked to angiogenesis, and anaerobic exercise to spinal neuroplasticity. Anaerobic exercises’ effect on neuroplasticity in the brain are not clear (Adkins et al., 2006; Hortobágyi et al., 2021). Consistently, aerobic exercise has been shown to decrease age-related hippocampal atrophy and is thought to indirectly influence neuroplastic effects through the release of brain-derived neurotrophic factor (BDNF) (Barrientos et al., 2011; Erickson et al., 2011). Exaggerated amounts of exercise increases cortisol levels and seems to impair neuroplasticity. Indeed, Smith et al. (2021) recently found that light physical activity among older adults may be enough to promote neuroplasticity. The therapist’s treatment plan can also influence neuroplastic events. Factors manipulated by the therapist include the specificity of the task to actual real-life activities (Bayona et al., 2005; Michaelsen et al., 2006; Hubbard et al., 2009; Narayan Arya et al., 2012), the instructions used, feedback, and reward, among others (Kleim and Jones, 2008; Maier et al., 2019; Johnson and Cohen, 2022). An enriched, motivating, and engaging rehabilitative environment has been shown to have a positive influence on neuroplasticity and rehabilitation (Zeiler and Krakauer, 2013; Hilal et al., 2017). This may be done through the release of neurotrophic factors. Indeed, rats in an enriched environment have been found to have increased numbers of oligodendrocytes and astrocytes (Bayne, 2018; Ajagbe͓ et al., 2021). The patient’s motivation, attention, and ability to memorize, among others are highly influential as well (Kleim and Jones, 2008; Maier et al., 2019).

Constraint-induced movement therapy is considered to be the gold standard intervention for people with a variety of neurologic movement disorders, including stroke (Wolf et al., 2006, 2008). The intervention involves constraining the nonaffected limb and being forced to use the affected limb in repetitive practice of tasks (often functional tasks). The intervention therefore has many repetitions of using the paretic hand in challenging, functional, and motivating activities. However, to participate in the intervention, the individual must have a certain amount of motor function to be able to perform the activities. Use of TMS has shown large neuroplastic changes following the use of constraint-induced movement therapy (Liepert et al., 1998; Sawaki et al., 2008). For the lower extremities, body weight-supported treadmill training is often used to promote highly repetitive, functionally relevant, task-related forced use of the affected leg (Clos et al., 2021). Numerous repetitions are required to induce neuroplastic changes. Neuroplasticity studies in animals typically involve hundreds or thousands of repetitions of the trained movements (Kleim et al., 1998; Plautz et al., 2000). However, human neurorehabilitation typically involves performance of only a fraction of movements performed in basic science studies to induce neuroplasticity (Birkenmeier et al., 2010; Kimberley et al., 2010). Studies have shown that increasing the number of repetitions performed by individuals with stroke and brain injuries (though still not to the amount as in animal studies) leads to better functional outcomes (Langhorne et al., 2011; Veerbeek et al., 2014; Lang et al., 2015), but a ceiling effect seems to occur (Lang et al., 2016; Basso and Lang, 2017). One possibility to allow for even further increased repetitions than could be performed with in-person therapists is through the use of robotic devices (Norouzi-Gheidari et al., 2012; Braun and Wittenberg, 2021), which can also cause neuroplastic effects (Kantak et al., 2013). However, such devices have generally not been superior to conventional therapy after stroke, given equal dosing (Kwakkel et al., 2008; Norouzi-Gheidari et al., 2012; Rodgers et al., 2019). Virtual reality approaches also exhibit limitations (Saposnik et al., 2016). This suggests that other variables are important to neuroplasticity and functional improvements as well. Therefore, it appears as though neuroplastic and functional improvements following human brain injury require more than just an increase in repetitions. Other strategies that can be added to traditional physical rehabilitation include other novel interventions (e.g., robotics, motor imagery, intermittent hypoxia, environmental enrichment, brain–computer interfaces, virtual reality, etc.) and perhaps combining the use of peripheral

APPLIED STRATEGIES OF NEUROPLASTICITY stimulation and brain stimulation (Gandiga et al., 2006; Nitsche et al., 2008; Rossini et al., 2015; Braun and Wittenberg, 2021). Peripheral nerve stimulation is often used during rehabilitation of individuals with neurologic diagnoses (Conforto et al., 2018). Depending on the frequency, duration, and amplitude of the applied stimulus, motor (e.g., neuromuscular electrical stimulation and functional electrical stimulation) or sensory (transcutaneous electric nerve stimulation) nerves can be stimulated (Braun and Wittenberg, 2021). If volitional movement is possible, patients are often asked to attempt to move along with the motor nerve stimulation to produce a closed-loop movement (i.e., volitional motor efferent and sensory afferent activity). Producing a closed-loop movement via an electromyographic-triggered motor nerve stimulator has previously been found to be the most effective type of neuromuscular electrical stimulation to promote motor recovery in individuals with stroke (de Kroon et al., 2005). A recent study in rodents found that paired peripheral stimulation with rehabilitative motor training led to cortical layer V activity and corticospinal axon sprouting, as well as improved motor function that was unmatched with either peripheral stimulation or rehabilitation along (Hu et al., 2022). In addition to being used to assess cortical neuroplastic changes, TMS, and other electrical stimulation types (e.g., transcranial direct current stimulation [tDCS]; transcranial alternating current stimulation, etc.), can be used to modulate cortical excitability and inhibition to influence increased activity among targeted damaged regions while also being able to inhibit other intact regions that might competitively inhibit the damaged areas (Gandiga et al., 2006; Nitsche et al., 2008; Buch et al., 2011; Tanaka et al., 2011). Multiple sessions of repetitive TMS (rTMS) of 1 Hz over the contralesional motor cortex have been used before physical therapy sessions to balance cortical excitability between the hemispheres and enhance use-dependent plasticity in individuals with stroke (Avenanti et al., 2012). Alternatively, multiple sessions of 5 and 10 Hz rTMS over the ipsilesional hemisphere of individuals with stroke have been used to enhance motor learning (Brodie et al., 2014) and functional recovery (Chang et al., 2010; Sasaki et al., 2013), respectively. Use of tDCS has also allowed for the enhancement of motor learning in healthy adults (Fan et al., 2017; Focke et al., 2017; Rumpf et al., 2017) and functional recovery in individuals with stroke (Khedr et al., 2013; Marquez et al., 2015). However, there has been more variability of effects of tDCS studies compared to TMS studies due in large part to the multitude of different settings and setup methods that can be done with tDCS (Buch et al., 2017).

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More recent types of stimulation also exist. Using intracranial electrodes in individuals with epilepsy, Herrero et al. (2021) showed that intermittent theta burst stimulation of the sensorimotor cortex increased sensorimotor network beta band synchronization for 3 min following stimulation, suggesting a short neuroplastic effect. Similarly, Awad et al. (2021) used deep brain stimulation to the subthalamus, thalamus, and pallidum to evoke short-term neuroplasticity.

LEARNING AND NEUROPLASTICITY Given the previous information of what has, and has not been shown to induce neuroplasticity, one common theme is related to learning. Motor skills are learned with two simultaneously developing timescales (Smith et al., 2006). The first learning timescale develops fast and accounts for early improvements in skill, but also is forgotten fast. The second learning timescale, on the other hand, develops slowly overtime and accounts for late learning. But this second timescale also decays slowly and is thus difficult to forget. The actual rate of time required for both of these timescales to develop and decay depends on the motor skill and its complexity (Dayan and Cohen, 2011). Motor skill learning not only occurs while actively training (i.e., online learning or acquisition) and passively while not training (i.e., offline learning or consolidation) (Dayan and Cohen, 2011). The learning process can occur more than once, when consolidated motor memories are reactivated and then reconsolidated (Censor et al., 2014; Johnson et al., 2021). Using MRI, structural changes of the brain have been shown over weeks, and even months, of healthy adults training on a novel motor task (Ungerleider et al., 2002; Doyon and Benali, 2005; Floyer-Lea and Matthews, 2005; Meister et al., 2005). Furthermore, within-session (Duque et al., 2005) and between-session (Stee and Peigneux, 2021) cortical changes have been observed. Between-session changes in motor skill, known as consolidation, can occur while awake, while asleep, or both depending on the task (Song and Cohen, 2014; Stee and Peigneux, 2021). For motor skill learning, explicit skills have been consistently shown to require sleep to consolidate, while implicit skills require the passage of time regardless of wakeful state (Robertson et al., 2004; Albouy et al., 2013). The timescale of consolidation has historically been thought to require multiple hours (Brashers-Krug et al., 1996; Shadmehr and Holcomb, 1997). But recent research has shown consolidation of motor skills over a period of seconds during wakeful rest between motor practice trials. Neural replay of the practiced task occurs during these rest periods

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(Buch et al., 2021). This between-trial consolidation accounts for nearly all motor learning within the practice session (B€ onstrup et al., 2019, 2020). For sleep-based consolidation, much work has focused on nonrapid eye movement sleep (NREM). It is during NREM that sleep spindles, slow waves, and sharp-wave ripples, all hypothesized indicators of memory replay (Euston et al., 2007; Ji and Wilson, 2007; Peyrache et al., 2009), repeatedly appear over brain regions previously utilized in learning tasks prior to sleep and are associated with offline learning (Nishida and Walker, 2007; Latchoumane et al., 2017). Furthermore, sleep spindles have been found to increase corticostriatal activity and are associated with subsequently increased corticostriatal functional connectivity and offline motor learning in rats (Lemke et al., 2021). Other animal studies have shown neuroplastic changes that occur over a period of sleep, including at the synapse, astrocytes, and myelin thickness (Bellesi et al., 2015, 2018; Raven et al., 2018; Stee and Peigneux, 2021). Related to this, many individuals with stroke (Johnson and Johnson, 2010), brain injury (Zuzuárregui et al., 2018), and other neurologic diagnoses (Dunietz et al., 2020) have sleep apnea. While it remains unknown how many of these individuals had sleep apnea before their injury or onset of diagnosis vs being caused by the injury or diagnosis itself, studies looking into pairing continuous positive airway pressure (CPAP) therapy with traditional physical rehabilitation showed a benefit for those with sleep apnea (Johnson et al., 2019). Indeed, individuals with sleep apnea have been found to demonstrate decreased sleep-dependent motor memory consolidation (Djonlagic et al., 2012), which can be reversed with the use of CPAP (Landry et al., 2014; Djonlagic et al., 2015).

CONCLUSIONS The human brain is capable of shifting representations of anatomy, movements, and computations when needed following learning, environmental constraints, or injury. Some of these neuroplastic changes are adaptive, while others are maladaptive. Especially following a neurologic injury, neuroplasticity will occur whether interventions are applied or not. It is thus important to apply neuroplasticity principles during rehabilitation to maximize one’s adaptive, and minimize maladaptive, neuroplasticity. Doing so will hopefully allow individuals with neurologic diagnoses to live independently.

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Handbook of Clinical Neurology, Vol. 196 (3rd series) Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment D.S. Younger, Editor https://doi.org/10.1016/B978-0-323-98817-9.00029-6 Copyright © 2023 Elsevier B.V. All rights reserved

Chapter 31

Passive tau-based immunotherapy for tauopathies FRANCESCO PANZA1*, VINCENZO SOLFRIZZI2, ANTONIO DANIELE3,4, AND MADIA LOZUPONE5 1

Unit of Research Methodology and Data Sciences for Population Health, National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, Bari, Italy

“Cesare Frugoni” Internal and Geriatric Medicine and Memory Unit, University of Bari “Aldo Moro”, Bari, Italy

2

3

Department of Neuroscience, Catholic University of Sacred Heart, Rome, Italy

4

Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy

5

Department of Translational Biomedicine and Neuroscience (DiBrain), University of Bari Aldo Moro, Bari, Italy

Abstract Tauopathies are heterogeneous clinicopathological entities characterized by abnormal neuronal and/or glial inclusions of the microtubule-binding protein tau. In secondary tauopathies, i.e., Alzheimer’s disease (AD), tau deposition can be observed, but tau may coexist with another protein, i.e., amyloid-b. In the last 20 years, little progress has been made in developing disease-modifying drugs for primary and secondary tauopathies and available symptomatic drugs have limited efficacy. Treatments are being developed to interfere with the aggregation process or to promote the clearance of tau protein. Several tau-targeted passive immunotherapy approaches are in development for treating tauopathies. At present, 12 anti-tau antibodies have entered clinical trials, and 7 of them are still in clinical testing for primary tauopathies and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, PNT00, and APNmAb005). However, none of these seven agents have reached Phase III. The most advanced anti-tau monoclonal antibody for treating AD is semorinemab, while bepranemab is the only anti-tau monoclonal antibody still in clinical testing for treating progressive supranuclear palsy syndrome. Two other anti-tau monoclonal antibodies have been discontinued for the treatment of primary tauopathies, i.e., gosuranemab and tilavonemab. Further evidence will come from ongoing Phase I/II trials on passive immunotherapeutics for treating primary and secondary tauopathies.

INTRODUCTION In the last decade, tauopathy was coined as an umbrella term depicting many heterogeneous clinicopathological, neurodegenerative disorders, all characterized by abnormal neuronal and/or glial inclusions of the microtubulebinding protein tau forming hyperphosphorylated insoluble aggregates (Spillantini et al., 1997; Josephs et al., 2011; Spillantini and Goedert, 2013; Arendt et al., 2016). In 1997, the term tauopathy was first used

to describe an entity coined “familial multiple system tauopathy with presenile dementia” (Spillantini et al., 1997). Hyperphosphorylated insoluble tau aggregates are the primary neuropathological feature of tauopathies, which can have varying and almost overlapping clinical presentations, resulting in a complex spectrum of clinical syndromes and tauopathy-associated diseases (Josephs, 2017). At present, more than 26 different tauopathies have been identified (Sexton et al., 2022), with a

*Correspondence to: Francesco Panza, MD, PhD, Unit of Research Methodology and Data Sciences for Population Health, National Institute of Gastroenterology “Saverio de Bellis” Research Hospital, Castellana Grotte, Bari, Italy. Tel: +39-80-7835692. E-mail: [email protected]

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subclassification into primary and secondary or nonprimary tauopathies (Kovacs, 2015; Panza et al., 2019). In primary tauopathies considered to be diseases, the abnormal tau accounts for the primary underlying neurodegenerative process, although some primary tauopathies do not have a clinically defined presentation and may be considered age-related processes. In secondary or nonprimary tauopathies, tau deposition can be observed, but tau may coexist with another protein. However, in secondary tauopathies, tau pathology is associated with another type of pathology, not necessarily presupposing a pathological role for tau pathology downstream to this other type of pathology (Arendt et al., 2016); therefore, in this context, the term mixed tauopathies should be preferred. Secondary or mixed tauopathies include Alzheimer’s disease (AD) in which amyloid-b (Ab) is also present, while pathological tau deposition primarily manifests as neurofibrillary tangles (NFT). Other secondary tauopathies are Lewy body disorders in which a-synuclein is also present, subacute sclerosing panencephalitis (Spillantini et al., 1999), chronic traumatic encephalopathy (CTE) (Mez et al., 2017), Down’s syndrome (Bussiere et al., 1999), Niemann-Pick disease-type C (Bussiere et al., 1999), and myotonic dystrophy (Spillantini et al., 1999). In the past two decades, little progress has been made in developing effective disease-modifying drugs for primary and secondary tauopathies and available symptomatic treatments have limited efficacy. This chapter summarizes recent advances in the development and challenges of tau-related biomarkers and treatments for tauopathies, with a major emphasis on passive tau-based immunotherapy.

PRIMARY TAUOPATHIES CONSIDERED TO BE DISEASES At present, there is no established clinical test that could reliably identify tauopathies antemortem (Coughlin and Irwin, 2017). Therefore, in the absence of a specific biomarker, the diagnosis of primary tauopathies considered to be diseases needs the mandatory recognition of syndromes that are specific and highly suggestive of a tauopathy, while the gold diagnostic standard remains neuropathological examination at autopsy. Therefore, tauopathies are best viewed as clinicopathological entities characterized by distinct underlying neuropathological substrates associated with various clinical syndromes (Irwin, 2016). Primary tauopathies are considered diseases that mainly correspond to the major class of frontotemporal lobar degeneration (FTLD) neuropathology (i.e., FTLD-Tau) (Hutton et al., 1998; Mackenzie et al., 2020; Josephs et al., 2011; Panza et al., 2020), presenting with several forms of frontotemporal dementia (FTD)

clinical syndromes, such as the behavioral variant of FTD (bvFTD) (Rascovsky et al., 2011) and primary progressive aphasia (PPA) (Gorno-Tempini et al., 2017). FTLD-Tau also includes atypical dopaminergic-resistant parkinsonian syndromes, i.e., progressive supranuclear palsy syndrome (PSPS) (H€oglinger et al., 2017) and corticobasal syndrome (CBS) (Armstrong et al., 2013). At present, the terms progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are reserved for neuropathological diagnosis since these pathological entities can show a wide range of clinical presentations, including those with a purely motor disorder (PSPfreezing of gait or PSP-parkinsonism).

Age-related primary tauopathies The presence of aggregated tau protein in the brain does not always represent a disease process. At present, three principal age-related tauopathies are under investigation: argyrophilic grain disease (AGD) (Braak and Braak, 1987), primary age-related tauopathy (PART) (Crary et al., 2014), and aging-related tau astrogliopathy (ARTAG) (Kovacs et al., 2016). AGD is characterized by the presence of silver-positive grain-like structures identified primarily in the medial temporal lobe (Braak and Braak, 1987), but at present there is no definitive clinical feature associated with the presence of this neuropathological condition (Josephs, 2017). Therefore, it remains to be determined whether AGD may be considered truly a neurodegenerative disease. PART is a recently coined term referring to the presence of tau deposition in neurons within limbic structures of the brain, in the absence, or minimal presence, of Ab deposition (Crary et al., 2014). Whether PART is a prodromal stage of AD or a distinct entity remains unclear (Duyckaerts et al., 2015). Moreover, PART is one of the putative causes of cognitive impairment of suspected non-Alzheimer’s disease pathophysiology (SNAP), with which patients fulfill clinical AD criteria with positive tau biomarkers and no significant Ab biomarkers (Jack et al., 2016). While PART is characterized by tau deposited in neurons, ARTAG is characterized by tau deposition in thorn-shaped astrocytes and granular or fuzzy astrocytes, which are distinct from the astroglial lesions of primary tauopathies (Kovacs et al., 2016). Lesions can predominate in subpial, subependymal, or perivascular spaces, or in gray and white matter, with a predilection for the amygdala and medial temporal lobe (Kovacs et al., 2017). Although ARTAG might be a prodromal stage of other tauopathies (Ling et al., 2016), there is no clinical correlate associated with the presence of this condition to date.

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TAU PROTEIN STRUCURE AND FUNCTION AND TAUOPATHIES

DISEASE-MODIFYING APPROACHES FOR TREATING TAUOPATHIES

The “microtubule-associated protein tau” or “tau,” encoded by the microtubule-associated protein tau (MAPT) gene located on chromosome 17q21 (Neve et al., 1986), regulates the stability of microtubules by promoting tubulin polymerization, with also a major role in axonal transport (Neve et al., 1986). Tau is located within neurons, predominantly within axons (Kempf et al., 1996), and also in oligodendrocytes and astrocytes with similar function (LoPresti et al., 1995). In physiological conditions, tau protein is unfolded and phosphorylated, while the abnormal form found in primary tauopathy brains is characterized by hyperphosphorylated and aggregated tau that has a b-pleated sheet conformation (Jeganathan et al., 2008). During disease pathogenesis, normal tau is also subject to various posttranslational modifications such as phosphorylation, decreased O-GlcNAcylation (by increasing phosphorylation), acetylation, nitration, glycation, polyamination, sumoylation, ubiquitination, conformational change, and C-terminal truncation, all of which may affect its function. The binding of tau to microtubules is regulated by its phosphorylation/dephosphorylation equilibrium (Lindwall and Cole, 1984). Intercellular spread of tau aggregates may promote further aggregation via conformational change in a prion-like manner (Holmes and Diamond, 2014). Tau can exist as monomers, oligomers, filaments, and aggregated inclusions. Under physiological conditions, tau activity is regulated in part by alternative mRNA splicing of the MAPT gene producing six different tau isoforms (Goedert et al., 1989), either with 3 or 4 repeat domains in the C-terminal part (Andreadis et al., 1992). The splicing-in of exon 10 results in isoforms with four repeated microtubulebinding domains (MTBDs) (4R tau), while the splicing out of exon 10 results in isoforms with three repeated MTBDs (3R tau). In the healthy human brain, there are equal amounts of tau with 3 and 4 repeated MTBDs, while some primary tauopathies are characterized by a predominance of isoforms with four repeated MTBDs (4R tauopathies), some by a predominance of isoforms with 3 repeated MTBDs (3R tauopathies), and some by an approximately equal mix of isoforms with 3 and 4 repeated MTBDs (3R + 4R tauopathies). Moreover, Big tau is another less discussed tau isoform which is also generated from alternative splicing of pre-mRNA from the MAPT gene and with an extra exon 4a, leading to its higher molecular weight
110 kDa. Due to its large size and few phosphorylated sites, Big tau was hypothesized to have a lower propensity to form pathological misfolding. In fact, in tauopathies, the peripheral nervous system, where Big tau is mainly expressed (Fischer and Baas, 2020), is spared.

AD is a secondary or nonprimary tauopathy, i.e., tau deposition can be observed, but tau may coexist with another protein, Ab. Drugs directed against Ab, the purported initial cause of the AD, have been pursued for at least 20 years without significant clinical success. However, in the last three decades, the great efforts spent in searching for disease-modifying therapeutics for AD led to aducanumab, a human recombinant anti-Ab IgG1 monoclonal antibody, the first new compound since 2003 to be approved by the US Food and Drug Administration (FDA) for the treatment of mild cognitive impairment (MCI) or mild dementia stage due to AD, due to its Ab-lowering effects considered “reasonably likely” to produce clinical benefits, and the first drug with the aim of modifying the disease course ever to be approved. Apolipoprotein E (APOE) genotype, an established risk factor for AD, may provide guidance in drug-related risk stratification, given that the presence of an APOE e4 allele in patients treated with aducanumab is strongly associated with amyloid-related imaging abnormalities and exhibits a gene dose effect (Lozupone et al., 2023). Moreover, in January 2023, the US FDA has approved lecanemab, another anti-Ab monoclonal antibody, the second-ever disease-modifying treatment for AD, with a recent Phase III randomized clinical trial (RCT) conducted on about 1800 people with early-stage AD, that found that the antibody slowed cognitive decline by 27% over 18 months of treatment (van Dyck et al., 2023). After a decade of obstacles with anti-Ab agents for AD, drug developers have turned their attention to tau protein. However, at present, treatment of primary tauopathies considered to be diseases is largely supportive and disease modification remains an unmet goal (Panza et al., 2019). Currently, no US FDA-approved disease-modifying therapy (DMT) available for clinical phenotypes of primary tauopathies, except riluzole for FTD-amyotrophic lateral sclerosis (ALS) (Tsai and Boxer, 2016), and treatment is focused on the management of neuropsychiatric symptoms (NPS). Drugs used in AD, such as cholinesterase inhibitors or NMDA receptor inhibitors (memantine), provide no benefits in PSPS (Litvan et al., 2001; Liepelt et al., 2010) or FTD (Mendez et al., 2007; Kishi et al., 2015) and may even have a negative impact on cognitive or motor symptoms, respectively. Symptomatic treatment may be an important part of the general treatment of FTD variants. However, the number of RCTs of symptomatic treatment of FTD and the mean sample size referenced in the few existing guidelines or systematic reviews (Li et al., 2015; O’Brien et al., 2017) could be considered small if compared with the usual number recruited in studies in AD patients.

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At present, used treatments are mostly off-label medications targeting symptomatic management, with minimal evidence from RCTs to support their use; these rely on modulation of neurotransmitter levels, without targeting the underlying FTLD pathophysiology. Furthermore, symptomatic treatment of challenging behaviors in FTD variants (e.g., disinhibition, agitation, aggression) with selective serotonin reuptake inhibitors or antipsychotics has yielded mixed results (Li et al., 2015; O’Brien et al., 2017; Panza et al., 2019). The development of potential DMT for FTLD-Tau (primary tauopathies) has been guided by recent advancements in the understanding of the neuropathology and pathophysiology of these diseases (Panza et al., 2019). In fact, genome-wide association studies (GWAS) that showed shared genetic risk between CBD, PSP, and FTLD (Yokoyama et al., 2017) reinforce the concept of tauopathies as a distinct clinicopathological entity. Possible DMT effects of novel drugs may be obtained targeting potential underlying mechanisms. The underlying pathology of FTLD-Tau consists of abnormal tau aggregates, and therefore treatments are being developed to interfere with the aggregation process of tau protein. The description of PART in AD, the leading secondary tauopathy, as a distinct entity may question the amyloid cascade hypothesis. On this basis, tau-based therapeutic approaches for treating FTLD-Tau/primary tauopathies considered to be diseases, as well as AD, fall under four general categories: inhibition of phosphorylation/acetylation, inhibition of aggregation, reduction of tau aggregates (immunotherapeutics), and increase of microtubule stabilization (recovering tau loss of function effects) (Panza et al., 2016, 2019). All these approaches have actually reached the clinic for primary tauopathies.

Active immunotherapeutics Active immunization may be an attractive therapeutic approach because it can induce a sustained autoantibody response in small doses. Furthermore, unlike passive immunity, the therapeutic effects should not be limited by the production of antidrug antibodies. Among taubased therapeutic approaches, full-length recombinant human tau to immunize C57BL/6 wild-type mice was the first tau-based active immunization approach but led to encephalomyelitis with neurological and behavioral deficits, axonal damage, and inflammation (Rosenmann et al., 2006). However, the feasibility of this approach was later demonstrated with a 30-amino acid tau phospho-peptide spanning amino acids 379–408, including phospho-Ser at positions 396 and 404, in two different transgenic mouse models of disease, the JNPL3 (P301L) and htau/presenilin 1 (PS1) lines. A specific antibody response was elicited, with reduced tau burden and

attenuation of the severity of behavioral and cognitive phenotypes (Panza et al., 2019). AADvac1 was the first anti-tau vaccine to enter RCTs and it was designed to target misfolded tau in AD, an approach inspired by research on tau cleavage generating an N-terminally truncated fragment (Paholikova et al., 2015). AADvac1 is a synthetic peptide derived from amino acids 294–305 of the tau sequence, i.e., KDNIKHVPGGGS, inside the repeat domain of 4R tau, coupled to keyhole limpet hemocyanin through an N-terminal cysteine, and is administered with an Alhydrogel alum adjuvant (Kontsekova et al., 2014). In preclinical studies in transgenic tau rats, the vaccine reduced tau pathology and associated behavioral deficits (Panza et al., 2019). Findings from the first Phase I trial (NCT01850238) extending to a follow-up open-label trial (NCT02031198) in 30 patients with mild-tomoderate AD were indicative of effective immunogenicity and acceptable safety, with stable cognitive assessment measures and no attributable brain atrophy (Novak et al., 2017; Panza and Logroscino, 2017). In June 2017, a 2-year, open-label Phase I pilot trial of two doses of AADvac1 (40 or 160 mg) was started in 30 people with nfvPPA (NCT03174886, AIDA). Primary outcomes included adverse events and measures of immunogenicity such as anti-AADvac1 antibody titer and subclass. Secondary outcomes include change in cerebrospinal fluid (CSF) biomarkers such as neurogranin, phosphorylated neurofilament heavy chain protein, tau, phospho-tau pT181, N-terminal tau, Ab1–40, Ab1–42, ubiquitin, a-, b-, and g-synuclein, chitinase3-like protein (YKL-40), monocyte chemoattractant protein-1 (MCP-1), change in serum biomarkers such as neurofilament light, MRI, and a range of clinical measures including the Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDRSB) and others. The trial was designed to run at three sites in Germany until July 2020. At present, the status of this RCT was active, not recruiting. Considering the shared NFT pathology among different tauopathies, positive results might open the way for using this tau vaccine for other tauopathies including PSPS (Shoeibi et al., 2018).

REDUCTION OF TAU AGGREGATES: PASSIVE IMMUNOTHERAPEUTICS FOR TAUOPATHIES Tau pathology can propagate from region to region in the brain via conformational change in a prion-like manner, while alterations in tau processing may impair tau physiological functions (Holmes and Diamond, 2014). Since the tau immunotherapy was first reported effective in the JNPL3 mice model in 2007, an active vaccine like AADvac1 and passive immunotherapeutic antibodies such as

PASSIVE TAU-BASED IMMUNOTHERAPY FOR TAUOPATHIES semorinemab, bepranemab, tilavonemab, zagotenemab, and BIIB076 have emerged for primary and secondary tauopathies (AD) (Panza and Lozupone, 2022). Passive antibodies are designed to recognize different sites of action (extracellular or intracellular) and tau epitopes, which offer a safer option than active vaccines in reducing the risk of immunological adverse effects. In addition, passive immunization also provides greater specificity for targeted epitopes. Passive antibodies can enter neurons to target intracellular tau proteins, which are mediated by receptor or bulk endocytosis. Besides, anti-tau antibodies are also able to reduce AD progression by preventing the spread of extracellular tau. To date, 12 anti-tau antibodies have entered clinical trials, and 7 of them are still in clinical testing (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, PNT00, and APNmAb005) for primary tauopathies and AD (Table 31.1). However, the development of anti-tau antibodies is not as advanced as those anti-Ab, and none of the seven agents have reached Phase III RCT (Song et al., 2022). The most advanced anti-tau monoclonal antibody for treating AD (secondary tauopathy) is semorinemab (RO7105705, MTAU9937A, RG6100), while bepranemab (UCB0107, UCB 0107, Antibody D) is the only anti-tau monoclonal antibody still in clinical testing for treating primary tauopathies (PSPS). Two other anti-tau monoclonal antibodies have been discontinued for the treatment of primary tauopathies, i.e., gosuranemab (BIIB092, BMS-986168, IPN007) and tilavonemab (ABBV-8E12, C2N 8E12, HJ8.5).

Semorinemab (RO7105705, MTAU9937A, RG6100) Semorinemab is a humanized IgG4 monoclonal antibody targeting the extracellular N-terminal domain of tau

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(amino acid residues 6–23). This was selected for development because it may bind all known isoforms of fulllength tau (including hyperphosphorylated and oligomerized species). A murine version of semorinemab reduced tau-related toxicity in cell culture and tau accumulation in a transgenic mouse model of tauopathy (Ayalon et al., 2021). In 2017, findings from a Phase I study of 74 volunteers comprising both healthy controls and people with mild-to-moderate AD showed dosedependent target engagement and a favorable safety profile. In fact, the trial had not generated serious adverse events (AEs), while minor AEs related to the drug were bruising and pain at the injection site. Semorinemab plasma half-life was 32 days, and plasma and CSF concentration increased with dose (Ayalon et al., 2021). Recently, the safety and efficacy of this anti-tau antibody was evaluated in 457 individuals with prodromal to mild AD in a Phase II RCT (Tauriel) (Teng et al., 2022). In this RCT, semorinemab treatment did not slow the rate of cerebral tau accumulation or clinical decline in prodromal to mild AD. Furthermore, semorinemab showed an acceptable and well-tolerated safety profile, but despite exploration of a wide dose range for this antitau monoclonal antibody (1500–8100 mg), there was no consistent evidence for dose-dependent effects across end points and/or time points (Teng et al., 2022). APOE status and sex also failed to demonstrate consistent treatment effects attributable to this anti-tau antibody (Teng et al., 2022). For biomarker analyses, Tauriel showed that treatment with semorinemab elicited maximal increases in plasma tau but did not slow NFT accumulation measured by Genentech Tau Probe 1 (GTP1) positron emission tomography (PET) in the brain of prodromal to mild AD patients relative to placebo (Teng et al., 2022). Furthermore, the drug did not reduce CSF markers of

Table 31.1 Ongoing double-blind, placebo-controlled trials of passive immunotherapeutics for the treatment of primary and secondary tauopathies Anti-tau antibody

Patient population

N

Phase

Completion1

ClinicalTrials.gov identifier

Semorinemab Bepranemab Bepranemab E2814 E2814 JNJ-63733657 Lu AF87908 PNT00 APNmAb005

AD AD PSPS AD AD AD AD Healthy adults Healthy adults

272 421 25 8 168 420 86 49 40

II II I I/II II/III II I I I

August 2023 July 2025 Completed September 2024 October 2027 November 2025 June 2023 Completed January 2023

NCT03828747 NCT04867616 NCT04185415 NCT04971733 NCT05269394 NCT04619420 NCT04149860 NCT04096287 NCT05344989

1

According to: ClinicalTrials.gov on January 18, 2023. AD, Alzheimer’s disease; PSPS, progressive supranuclear palsy syndrome.

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neuronal degeneration and inflammation, such as neurofilament light chain, neurogranin, S100B, interleukin-6, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) (Panza and Lozupone, 2022). Surprisingly, it increased CSF levels of the astrocytic inflammation marker chitinase 3-like 1 (CHI3L1, also known as YKL-40), which is known to rise as AD progresses, and it is linked to brain shrinkage (Lananna et al., 2020). Fundamentally, semorinemab is an antibody without effector function and as such is believed not to elicit microglial activation and consequent inflammatory responses (Lee et al., 2016). Notwithstanding these negative findings in subjects at an earlier stage of the disease, in November 2022, at the 14th Clinical Trials on Alzheimer’s Disease Conference, findings from another Phase II RCT (Lauriet, NCT03828747) in a prespecified modified intent-totreat population of 241 subjects with a diagnosis of probable mild-to-moderate AD confirmed by Ab positivity via PET or CSF testing have been announced (Lee et al., 2016). Data on this population showed a 42.2% reduction in the rate of cognitive decline with semorinemab compared to placebo on the 11-item Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADASCog11), coprimary outcome measure of the trial assessing the severity of cognitive symptoms in dementia, though no benefit of the other cognitive or functional outcomes were found (Panza and Lozupone, 2022). This treatment effect was observed consistently in prespecified subgroups based on disease severity, baseline tau load, and APOE status. ADAS-Cog11 domain analyses showed that the semorinemab treatment effect was driven predominantly by the memory domain (Lee et al., 2016), a core feature of AD. Biomarker analyses reported no identifiable treatment effect on global or regional tau distribution, as assessed by GTP1 PET, and a pronounced increase of plasma tau levels with semorinemab treatment, which is suggestive of peripheral tau binding (Panza and Lozupone, 2022). The CSF biomarker dataset was not available. Plans on a Phase III RCT will depend on additional data from Lauriet’s ongoing long-term extension study and completed biomarker measurements.

Gosuranemab (BIIB092, BMS-986168, IPN007) Gosuranemab was the first humanized monoclonal antitau antibody in clinical development for the treatment of PSPS. Gosuranemab antibodies were originally isolated from pluripotent stem cells from people with familial AD, targeting extracellular fragmented forms of tau (Panza et al., 2020) that are believed to cause neuronal hyperactivity and stimulate Ab production (Bright et al., 2015). A Phase Ia RCT has been conducted to

assess the safety and tolerability of single intravenous doses of gosuranemab in healthy individuals over a follow-up period of 8 months (NCT02294851). In a similar study on 48 patients with PSPS, the safety, pharmacokinetics, and immunogenicity of multiple doses of gosuranemab was also assessed (NCT02460094). At the end of the double-blind, placebo-controlled part of this study, patients could choose to enter an 18-month, open-label extension to assess the long-term safety and tolerability of gosuranemab. Results indicated that gosuranemab was safe and well-tolerated and that all doses reduced levels of free extracellular tau in the CSF by >90%. However, in the study that involved patients with PSPS, statistically significant brain atrophy was seen at day 85 in patients who received the treatment compared with those who received placebo (Boxer et al., 2019). A 52-week randomized controlled trial (PASSPORT) was conducted to test a 50 mg mL1 intravenous infusion of gosuranemab in 459 patients with PSPS; the trial was prematurely interrupted in December 2019 (NCT03068468). Another study (TauBasket) conducted to investigate the efficacy of BIIB092 in four primary tauopathies (CBS, FTLD-tau, PPA, and CTE) was also terminated in December 2019 (NCT03658135) on the basis that the Phase II PASSPORT study in PSPS missed its primary and secondary end points (Panza et al., 2020).

Tilavonemab (ABBV-8E12, C2N 8E12, HJ8.5) Tilavonemab is a recombinant humanized IgG4 antibody that recognizes an aggregated, extracellular form of tau that has been implicated in the transneuronal propagation of tau pathology. A Phase I RCT has been conducted to assess the safety and tolerability of single ascending doses of tilavonemab in 32 patients with PSPS (NCT02494024). In this study, tilavonemab was well tolerated and an open-label extension study was subsequently initiated to assess the long-term safety and tolerability (NCT03413319). Unfortunately, this study was prematurely terminated in July 2019, together with a 1-year Phase II RCT of tilavonemab (ARISE), in which two doses of the antibody were compared in 378 patients with PSPS (NCT02985879), as well as with a planned 4-year open-label extension (NCT03391765). Therefore, this anti-tau antibody was discontinued for PSPS after prespecified futility criteria were met at the second interim analysis. Trial results were subsequently published and confirmed target engagement by a decrease in CSF free tau and higher plasma total tau in treated patients, but tilavonemab showed no efficacy, although no treatment-related AEs were reported (H€oglinger et al., 2021).

PASSIVE TAU-BASED IMMUNOTHERAPY FOR TAUOPATHIES

Bepranemab (UCB0107, UCB 0107, antibody D) The only anti-tau monoclonal antibody still in clinical development for treating primary tauopathies (PSPS) is bepranemab. This is another anti-tau monoclonal antibody that targets amino acids 235–246 at the end of the second proline-rich region, just before the microtubulebinding domain. This mid-region of tau has also been implicated in the transneuronal propagation of aggregated tau. In 2018, preclinical studies indicated that bepranemab may inhibit the aggregation of tau (isolated from PSP or FTD tissue samples from humans) in vitro and the spread of tau pathology in vivo (Panza et al., 2020). A Phase I RCT has been conducted to determine the safety and tolerability of single ascending intravenous doses of bepranemab in healthy volunteers and to assess its pharmacokinetics in the blood and CSF as well as its ability to initiate anti-tau antibody generation and tau clearance (NCT03464227). The results have not yet been released, but a Phase I RCT in 25 patients with PSPS has been completed in November 2021 (NCT04185415). Participants received a predefined dose of bepranemab or placebo for 1 year, with a 4-month safety follow-up. The primary outcome was incidence of treatment-emergent AEs. In 2021, at the 15th International Conference on Alzheimer’s and Parkinson’s Diseases, no safety concerns have been reported. An open-label extension began in November 2020, to run for up to 5 years. Furthermore, in June 2021, a Phase II RCT on AD began (NCT04867616), randomizing 421 people with MCI or mild AD dementia to one of two doses of bepranemab or placebo for 80 weeks. The study will run until July 2025.

CONCLUSIONS Several tau-targeted passive immunotherapy approaches, which involve the administration of an anti-tau antibody, are in development for treating tauopathies. Studies in animals have suggested that the therapeutic efficacy of tau immunotherapy might depend on the tau region that is targeted and might not directly correlate with the reduction in tau pathology burden (Horie et al., 2021). Initially, tau N-terminus was the preferred target, because it produced the highest-affinity antibodies. The N-terminus can be cleaved from tau, and some truncated forms of tau have been implicated in tau spreading. However, recent clinical data suggested that antibodies binding the microtubule-binding region, which spans from amino acid residues 224–369, may be better at preventing aggregates from diffusion or targeting a phosphorylated epitope nearer the center of tau (Horie et al., 2021). The release of extracellular tau in synaptic clefts is largely responsible for neuronal cell-to-cell propagation and would be available for interception and removal by a monoclonal

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antibody. Moreover, antibodies binding the N-terminus, gosuranemab and tilavonemab, have had no success in Phase II trials to date for PSPS and have been discontinued for this disorder and AD. However, the resulting findings from the Phase II RCTs on semorinemab (Tauriel and Lauriet) were thought-provoking and suggested new alternative biological targets, as well as more multimodal approaches to addressing neurodegeneration in AD. The tau and Ab hypotheses have been proposed for many years in AD, and other assumed mechanisms such as neuroinflammation are also associated with these two proteins, suggesting combination therapeutic strategy, involving the target of neuroinflammation or considering genetic biomarkers such as APOE for risk stratification. Considering the central role of tau in tauopathies and its important role in AD progression, tau immunotherapy is still worth exploring. Since the underlying pathology of tauopathies consists of abnormal tau protein aggregates, treatments are being developed to interfere with the aggregation process or to promote the clearance of this protein. Anti-tau monoclonal antibodies should not only target tau protein in neuron cells but also inhibit tau diffusion outside the cells. This balance is difficult to maintain and adverse reactions with neuroinflammation may occur during treatment. Reasons for futility in RCTs include difficulties in earlier diagnosis of PSPS, especially preclinical stages, noneffective epitopes, and extracellular targeting (Jabbari and Duff, 2021). One possible alternate strategy for RCTs of potential disease-modifying therapies in tauopathies focused on MAPT mutation carriers who have known tau pathology and are relatively young (Moore et al., 2022), although carriers of an MAPT mutation are rare and familial PSPS is equally uncommon. Furthermore, advancement has been made concerning in vivo detection of tau, which mainly consists of neuroimaging, CSF, and blood markers. For example, very recently, brain-derived tau appeared to be a new blood-based biomarker that outperformed plasma total-tau and, unlike neurofilament light, showed specificity to AD (Gonzalez-Ortiz et al., 2023). These tau-based biomarkers may be auspicious candidates for early and differential diagnosis, disease progression prediction, pharmacodynamic and therapy mechanism interpretation, and RCT participants selection (Barthelemy et al., 2000).

CONFLICTS OF INTEREST The authors have no competing interests to disclose for the present commentary.

AUTHORS’ CONTRIBUTIONS Francesco Panza and Madia Lozupone: conceptualization and writing of the manuscript.

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PASSIVE TAU-BASED IMMUNOTHERAPY FOR TAUOPATHIES Liepelt I, Gaenslen A, Godau J et al. (2010). Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: clinical observations as a basis for power calculations and safety analysis. Alzheimers Dement 6: 70–74. Lindwall G, Cole RD (1984). Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem 259: 5301–5305. Ling H, Kovacs GG, Vonsattel JPG et al. (2016). Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology. Brain 139: 3237–3252. Litvan I, Phipps M, Pharr VL et al. (2001). Randomized placebo-controlled trial of donepezil in patients with progressive supranuclear palsy. Neurology 57: 467–473. LoPresti P, Szuchet S, Papasozomenos SC et al. (1995). Functional implications for the microtubule-associated protein tau: localization in oligodendrocytes. Proc Natl Acad Sci U S A 92: 10369–10373. Lozupone M, Imbimbo BP, Balducci C et al. (2023). Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer’s disease? Alzheimers Dement 19: 353–368. Mackenzie IR, Neumann M, Bigio EH et al. (2020). Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119: 1–4. Mendez MF, Shapira JS, McMurtray A et al. (2007). Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Am J Geriatr Psychiatr 15: 84–87. Mez J, Daneshvar DH, Kiernan PT et al. (2017). Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA 318: 360–370. Moore K, Convery R, Bocchetta M et al. (2022). A modified Camel and Cactus Test detects presymptomatic semantic impairment in genetic frontotemporal dementia within the GENFI cohort. Appl Neuropsychol Adult 29: 112–119. https://doi.org/10.1080/23279095.2020.1716357. Neve RL, Harris P, Kosik KS et al. (1986). Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Brain Res 387: 271–280. Novak P, Schmidt R, Kontsekova E et al. (2017). Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer‘s disease: a randomised, double-blind, placebocontrolled, phase 1 trial. Lancet Neurol 16: 123–134. O’Brien JT, Holmes C, Jones M et al. (2017). Clinical practice with anti-dementia drugs: a revised (third) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol 31: 147–166. Paholikova K, Salingova B, Opattova A et al. (2015). N-terminal truncation of microtubule associated protein tau dysregulates its cellular localization. J Alzheimers Dis 43: 915–926.

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Panza F, Logroscino G (2017). Anti-tau vaccine in Alzheimer‘s disease: a tentative step. Lancet Neurol 16: 99–100. Panza F, Lozupone M (2022). The challenges of anti-tau therapeutics in Alzheimer disease. Nat Rev Neurol 18: 577–578. Panza F, Solfrizzi V, Seripa D et al. (2016). Tau-centric targets and drugs in clinical development for the treatment of Alzheimer‘s disease. Biomed Res Int 2016: 3245935. Panza F, Imbimbo BP, Lozupone M et al. (2019). Diseasemodifying therapies for tauopathies: agents in the pipeline. Expert Rev Neurother 19: 397–408. Panza F, Lozupone M, Seripa D et al. (2020). Development of disease-modifying drugs for frontotemporal dementia spectrum disorders. Nat Rev Neurol 16: 213–228. Rascovsky K, Hodges JR, Knopman D et al. (2011). Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134: 2456–2477. Rosenmann H, Grigoriadis N, Karussis D et al. (2006). Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. Arch Neurol 63: 1459–1467. Sexton C, Snyder H, Beher D et al. (2022). Current directions in tau research: highlights from tau 2020. Alzheimers Dement 18: 988–1007. Shoeibi A, Olfati N, Litvan I (2018). Preclinical, phase I, and phase II investigational clinical trials for treatment of progressive supranuclear palsy. Expert Opin Investig Drugs 27: 349–361. Song C, Shi J, Zhang P et al. (2022). Immunotherapy for Alzheimer’s disease: targeting b-amyloid and beyond. Transl Neurodegener 11: 18. Spillantini MG, Goedert M (2013). Tau pathology and neurodegeneration. Lancet Neurol 12: 609–622. Spillantini MG, Goedert M, Crowther RA et al. (1997). Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci U S A 94: 4113–4118. Spillantini MG, Tolnay M, Love S et al. (1999). Microtubule-associated protein tau, heparan sulphate and alpha-synuclein in several neurodegenerative diseases with dementia. Acta Neuropathol 97: 585–594. Teng E, Manser PT, Pickthorn K et al. (2022). Safety and efficacy of semorinemab in individuals with prodromal to mild Alzheimer disease: a randomized clinical trial. JAMA Neurol 79: 758–767. Tsai RM, Boxer AL (2016). Therapy and clinical trials in frontotemporal dementia: past, present, and future. J Neurochem 138: 211–221. van Dyck CH, Swanson CJ, Aisen P et al. (2023). Lecanemab in early Alzheimer’s disease. N Engl J Med 388: 9–21. Yokoyama JS, Karch CM, Fan CC et al. (2017). Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia. Acta Neuropathol 133: 825–837.

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Index NB: Page numbers in italics refer to figures and tables.

A

AADvac1 196 614 Abciximab in Emergency Stroke Treatment Trial (AbESTT) 196 332 Aberrant splicing 196 49 Abnormal sexual behaviors, sleep-related 195 387 AbobotulinumtoxinA 196 540, 541, 550 Absolute refractory period 195 253–254 Academy of Neurology (AAN) 195 304 Acetazolamide 196 357–358 Acetylcholine esterase inhibitors 195 642–643, 646, 649 side-effects of 195 643 Acetylcholine-receptor-reactive T cells 195 641 Acetylcholine receptors (AChRs) 195 9, 266 antibodies 195 640 Acid maltase 195 234–235 Acquired demyelinating neuropathies 195 587–594 Actin, alpha, skeletal muscle 1 (ACTA1) 195 555 Action potential propagation 195 254 Activation gate 195 253–254 Active immunotherapeutics 196 614 Active standing, heart rate variability (HRV) with 195 307 Active zones (AZs) 195 336–338 Activities of daily living (ADLs) 195 56 Acute COVID-19 infection 195 160–161 Acute disseminated encephalomyelitis (ADEM) 196 109–110 Acute flaccid myelitis 196 111 Acute flaccid paralysis 196 151 Acute inflammatory demyelinating polyneuropathy (AIDP) acute axonal forms 195 734 acute motor axonal neuropathy 195 734 acute motor axonal sensory 195 734–735 acute motor conduction block neuropathy 195 735 clinical presentation of 195 733–735 electrodiagnostic criteria for 195 735–737 Guillain–Barr
e syndrome 195 733–739 reversible conduction failure 195 735, 735 Acute inflammatory demyelinating polyradiculoneuropathy 195 587, 619 mimics 195 623

Acute inflammatory demyelinating polyradiculoneuropathy (Continued) prevalence 195 619 recurrence rate 195 623–624 Acute inflammatory neuropathy. See Guillain-Barr
e syndrome (GBS) Acute intermittent porphyria (AIP) 195 211 Acute motor and sensory axonal neuropathy (AMSAN) 195 619 Acute motor axonal neuropathy (AMAN) 195 619 Acute paralytic poliomyelitis 195 730–731, 730 Acute pediatric stroke management 196 336 Acute quadriplegic myopathy (AQM) 195 709, 753–754, 757 Acute spinal cord ischemic disorders 195 729–730, 729 Acute spinal cord ischemic syndromes (ASCISs) 196 10 Acute transverse myelitis 196 150 Acute tropical myeloneuropathy 196 149–150 AD. See Alzheimer disease (AD) Adaptation, VOR 195 38 Adaptive immunity 195 136, 147, 196 368 Adaptive neuroplasticity 196 601 ADCAs. See Autosomal dominant cerebellar ataxia (ADCAs) A-delta (Ad) fibers 196 404 Adenosine triphosphatase (ATP) reactions 195 288 Adenylate cyclase 5 (ADCY5) 196 354 Adenylosuccinate synthase 1-related distal myopathies 195 501 a-adrenergic 1 receptors 196 417 Adrenocorticotropic hormone 196 238 Aducanumab 196 260–262 Adult Refsum disease 195 197 Adults acute stroke management in 196 329–336 anticoagulant therapy 196 331–332 antithrombotic therapy 196 331–332 neuroprotective therapy 196 334–335 neurovascular intervention and surgery 196 335–336 thrombolytic therapy 196 332–334 nerve biopsy indications in 195 293–294

Adults (Continued) onset mitochondrial diseases 195 564–565 pure motor stroke 196 321–325 cortical infarcts 196 325 internal capsule and lacunar infarction 196 323–325, 324–325 medullary infarction 196 322 midbrain infarction 196 322–323 overview 196 321–322 pontine infarction 196 322 Advanced acquired immunodeficiency syndrome (AIDS) 196 104 Adverse events (AEs) 196 615 Affordances limb apraxia 195 130 stable 195 130 Age-related primary tauopathies 196 612 Aging-related tau astrogliopathy (ARTAG) 196 257, 612 Agrin 195 9 Agrypnia excitata 196 285 AIDP. See Acute inflammatory demyelinating polyneuropathy (AIDP) AIM. See Autoimmune inflammatory myopathies (AIM) Alcohol abuse 196 306 Alcohol necrolyses 196 510 Alemtuzumab 196 137 Alien limb syndrome 196 449–450 Alpha-actinin gene (ACTN2) 195 500 Alpha-actinin-2-related distal myopathies 195 500 Alpha-2-agonists 196 466 a-Synuclein 196 175–176 Alpha-B crystallin 195 443 distal myopathies 195 501 Alpha dystroglycan related disorders B3GALNT1 195 480 FKTN and FKRP 195 479–480 genotype phenotype correlation 195 481–482 GTDC2 (POMGNT2) 195 480 ISPD 195 480 LARGE expression 195 479–480 LMNA 195 482 POMGNT1 gene 195 479 POMT1 and POMT2 genes 195 479 SEPN1 195 482 SGK196 195 481 subtypes 195 479–481 TMEM5 195 480–481

622 ALS. See Amyotrophic lateral sclerosis (ALS) Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischaemic Stroke (ATLANTIS) trials 196 333 Alzheimer disease (AD) 195 173–174, 215–216, 196 259–262, 267, 611–613 anti-amyloid agents for 196 261 clinical and biomarker diagnosis 196 259–260 gait dysfunction in abnormalities 196 268–269 APOE4 196 271 assessment methods 196 268–269 biomarkers 196 270–271 prognostic utility 196 269–270 pathology 196 259–260 risk for 196 267–268 treatment 196 260–262 Ambenonium chloride 195 642 Ambroxol 196 564 American Academy of Neurology (AAN) 195 329–330 4-Aminopyridine (4-AP) 196 139–140 Amplitude analysis of 195 276, 282, 283, 284 ratio 195 277 AMX0035 196 531 Amyloidosis 195 298, 298 Amyloid-related imaging abnormalities (ARIA) 196 260–262 Amyopathic dermatomyositis 195 427–428 Amyotonia congenita (Oppenheim) 195 402 Amyotrophic lateral sclerosis (ALS) 195 213–214, 283, 196 46, 72, 89, 150, 203–204, 523 adult familial 195 726 animal models of 195 142–143 axial FLAIR MRI 195 362 clinical presentation 196 206–207 diagnosis 196 207 diffusion tensor imaging 195 361–362 disease pathogenesis 196 215–219, 216 defective axonal cytoskeletal and transport 196 217–218 disrupted RNA metabolism 196 217 instability of mutant proteins 196 215–217 putative disease mechanisms 196 218–219 epidemiology 196 203–204 genetic basis of 196 207–215, 208–209, 210 Cu/Zn-superoxide dismutase 196 209–212 dynactin 196 214 fused in sarcoma 196 212 GLE1, RNA export mediator (GLE1) 196 214–215 optineurin (OPTN) 196 212–213 profilin-1 (PFN1) 196 215

INDEX Amyotrophic lateral sclerosis (ALS) (Continued) senataxin 196 214 ubiquilin 2 (UBQLN2) 196 215 valsolin-containing protein (VCP) 196 213–214 VAPB 196 215 genetic biomarkers 196 219–220 glia in 196 219 immune system in 195 142–143 incidence of 196 203–204 inflammation in 195 363 microbiota-gut-brain axis and motor systems in 195 149–150 molecular imaging techniques of neuroinflammation 195 362 and motor neuron disorders 196 223 MR spectroscopy 195 363 neuropathology 196 204–206, 205–206 paraneoplastic mechanisms 196 220–222 anti-HU/HUD 196 220–221 anti-RI/Nova1 196 221, 221 autoantibody-mediated 196 220–222 lymphoma-mediated 196 221–222 plus syndromes 196 204 single-voxel MR spectroscopy 195 362 sporadic 195 725–726 treatment 196 222–223 antisense oligonucleotides 196 222 microRNA 196 222 pluripotent stem cell therapy 196 222–223 T1-weighted structural imaging 195 361 Anakinra 196 526 Anatomic motor unit (A-MU) 195 271, 273 ANCA-associated vasculitides 195 686–689 Ancillary testing 196 180–182 Andersen-Tawil syndrome (ATS) 195 521, 526 acetazolamide 195 529 ECG in patient with 195 529 skeletal features 195 528 Angelman syndrome (AS) 195 233–234 Angiopoietins 1–4 196 577 Angiotensin converting enzyme (ACE) 196 334 Animal life 195 302 Animal models amyotrophic lateral sclerosis (ALS) 195 142–143 COVID-19 195 160 dystrophin-associated muscular dystrophy 195 469–471 Ankle-foot orthoses (AFO) 196 506 Ankle-foot-orthotic devices 196 79 Anoctamin-5 gene (ANO5) 195 501–502 Anoctamin 5-related distal myopathies 195 501–502 Anosmia 196 179, 192–193 ANS. See Autonomic nervous system (ANS)

Anterior cerebral artery (ACA) 196 314, 314 Anterior cingulate cortex (ACC) 195 119, 196 408–409 Anterior horn cells (AHC) 195 252, 196 203–204 Anterior horn syndrome 196 10 Anterior inferior cerebellar (AICA) 196 310–311 Anterior lobe 196 160 Anterior spinal artery (ASA) 196 307–308 Anterior spinal cord 196 10 Anterior thalamic radiation (ATR) 196 409–410 Anterior vermis (lobules I–V) 195 44 Anterolateral vessels 196 307–308 Anteromedial vessels 196 307–308 Antiaquaporin-4 (AQP4) 196 108 Anti-B-cell agents 195 447 Antibodies 195 641 detection 195 162 Antibody-associated nonparaneoplastic cerebellar ataxias 196 281–282, 282 Antibody-dependent cell-mediated cytotoxicity (ADCC) process 195 439–440 Antibody-mediated encephalitides 196 278–281, 280 Anticipatory postural adjustment (APA) 195 108, 115–116, 116 Anticoagulant therapy 196 331–332 Antigens, COVID-19 neurological illness 195 162 Anti-Hu IgG 196 241–242 Anti-IgLON5 disease 196 256–257, 286, 287–290, 288–289 Anti-Jo-1 syndrome 195 428 Anti-Ma2 antibodies 196 237 Anti-myelin-associated glycoprotein (anti-MAG) neuropathy 195 588, 624–626 Antimyelin oligodendrocyte glycoprotein (MOG) 196 108 Antineuronal nuclear antibody type 2 (ANNA-2) 196 233, 239 Antineutrophil cytoplasmic antibodies (ANCA) 195 658–659 Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) 195 653–654 history and examination 195 676–678 pediatric 195 655 vasculitides, tissue biopsy studies 195 679 Anti-NMDA receptor (NMDAR) encephalitis 196 278–280 Antipsychotics 196 464, 466 Antisense oligonucleotides (ASOs) 195 89, 196 52, 222 Antisynthetase syndromes (Anti-SS-OM) 195 425–426, 428, 444 clinical features 195 428 Anti-tau monoclonal antibody 196 614–615, 617

INDEX Antithrombotic therapy 196 331–332 Anti-TNFa 195 685 Aortitis 195 659–660 APA. See Anticipatory postural adjustment (APA) APOE4 196 271 Apolipoprotein E (APOE) 196 613 Applied neuroplasticity 196 601 Apraxia 196 451 AQM. See Acute quadriplegic myopathy (AQM) Aquaporin-4 (AQP4) 196 22, 127–128 Area 195 277 Area under the curve (AUC) 195 342 Argyrophilic grain disease (AGD) 196 255, 257, 612 Arimoclomol 196 528, 563 Aripiprazole 196 466 Arousals, confusional 195 386 Artemin 196 575 Arteriovenous fistula (AVF) 196 26–27 Arteriovenous malformations (AVM) 196 27–28 Ascorbic acid 195 328–329 Assisted coughing, congenital myopathies 195 553 Astrocytic plaques 196 255–256 Astrocytoma 196 16–18 Asymmetric clonic ending (ACE) 196 300–301, 301 Asymmetric tonic limb posturing 196 300 Asymptomatic carotid stenosis 196 306 Ataxia 195 570–572, 196 281 Friedreich 195 368–370, 369 hereditary 195 368 Ataxic gaits 196 268–269 Ataxin-2 195 226 Atherosclerotic plaque 196 324 Atonic seizures 196 299 ATPase Na+/K+ transporting subunit alpha 3 (ATP1A3) 196 354–355 ATS. See Andersen-Tawil syndrome (ATS) Attentional control 196 169 Atypical dopaminergic-resistant parkinsonian syndromes 196 612 Autism spectrum 196 169 Autoantibody 195 636 Autoimmune autonomic failure antemortem and postmortem pathology 195 90–91 diagnosis and outcome 195 92–93 ganglionopathy 195 91 mechanism of 195 89–90 neurophysiology 195 91–92 outcome and management 195 93–94 serology 195 92 Autoimmune CNS disorders and glial antibodies 196 283–285, 284 inhibitory synapsis 196 282–283 Autoimmune encephalitis 195 677–678 Autoimmune inflammatory myopathies (AIM) cancer and cancer immunotherapy and 195 435–436

Autoimmune inflammatory myopathies (AIM) (Continued) corticosteroids 195 445 diagnosis and diagnostic workup 195 430–431 DM (see Dermatomyositis (DM)) electromyography 195 430 etiologies/triggering factors 195 435–436 idiopathic 195 425–426 intravenous immunoglobulin 195 445–447 magnetic resonance imaging 195 430 myotoxic drugs and 195 436 nonsteroidal immunosuppressive therapies 195 445 serum autoantibodies 195 430–431 serum muscle enzymes 195 430 viruses and 195 435 Autoimmune thyroiditis 195 646 Autoimmunity 196 369 Automatisms 196 298 Autonomic cardiovascular domain 196 187 Autonomic control 195 303 Autonomic dysfunction 196 196, 285 Autonomic dysreflexia 196 411 Autonomic function tests 195 303–310, 196 180–181, 180 Autonomic nervous system (ANS) 195 55–56, 301 aging 195 61–62 anatomy and physiology 195 302–303 animal life 195 302 autonomic control of bladder, bowel and sexual function 195 59 baroreflexes, autonomic, and baroreceptor failure 195 62–63 beat-to-beat blood pressure and vascular sympathetic control 195 307–308, 308 beat-to-beat BP induced by active and passive standing 195 309–310 components of 195 56–57 division of 195 302 great sympathetic nerve 195 302 heart rate variability (HRV) 195 304, 305 with active standing 195 307 with deep breathing 195 304–305, 306 at rest 195 307 with Valsalva maneuver 195 306–307 intercostal nerves 195 302 neuropathologic characterization 195 59–63 organic life 195 302 parasympathetic and sympathetic outflow 195 57–59 parasympathetic cholinergic system 195 56–57 parasympathetic ganglia 195 61 parasympathetic organization and output 195 58–59 sudomotor reflexes 195 310–312 sweat imprinting 195 311

623 Autonomic nervous system (ANS) (Continued) sympathetic skin response (SSR) 195 311–312, 312 thermoregulatory sweat test 195 310–311 sympathetic adrenergic system 195 57 sympathetic cholinergic system 195 56 sympathetic ganglia 195 60, 60 perivascular cuffing of 195 60 sympathetic noradrenergic system 195 56 sympathetic organization and output 195 58 tests of autonomic function 195 303–310 Valsalva maneuver, changes in beatto-beat BP induced by 195 308–309 vascular sympathetic control 195 307–308, 308 Vegetative Nervous System 195 302 Autophagy 195 224, 196 218 regulation of 195 208 Autosomal dominant (AD) 196 204 Autosomal dominant cerebellar ataxia (ADCAs) 195 199–202 ion channel dysfunction 195 200–202 noncoding repeat expansion/RNA toxicity 195 199–200 signal transduction 195 202 Autosomal recessive cerebellar ataxia 195 196–199 endosome and membrane vesicle trafficking 195 198 lipid and lipoprotein cell membrane and intracellular signaling 195 198 lysosomal metabolism 195 197–198 mitochondrial metabolism 195 197 nuclear DNA repair, replication, and genome stability 195 197 peroxisomal metabolism 195 197 protein translation 195 198 signal transduction 195 198–199 AVF. See Arteriovenous fistula (AVF) AVM. See Arteriovenous malformations (AVM) Axolemma 195 252, 253 Axon terminal/terminal bouton 195 254 Azathioprine 195 343–344, 644, 646–647, 682, 196 109, 112

B

Baclofen 196 140, 238, 507–508, 507 Bacterial myelitis 196 102–104 Bamlanivimab 195 169 Baroreflex 195 303 Basal ganglia 196 7, 409 frontal cortical connections with 195 119 movement disorders and 195 141–142 B-cell-receptors 196 368 Beat-to-beat blood pressure 195 307–308, 308

624 Becker muscular dystrophy (BMD) 195 348 Behavioral therapy 196 463–464 Behavioral variant of frontotemporal dementia (bvFTD) 196 255, 612 Behavior expression cortical control 195 110–114 corticofugal outputs 195 111 prefrontal cortex 195 110–112 role of 195 110–111 Behc¸et disease (BD) 195 653–654 Benign familial infantile-neonatal seizure (BFNIS) 196 360 Benign sleep myoclonus of infancy (BSMI) 195 392 Benzodiazepine 196 140, 238, 396, 509 Bepranemab 196 617 Beriberi 196 153 b-adrenergic receptors 196 417 b-blockers 196 396 Beta-glucosidase (GBA) 195 213 Bethlem myopathy 195 478 Bevacizumab 196 113 B3GALNT1 195 480 Bickerstaff brainstem encephalitis (BBE) 196 281 Bilateral diaphragm weakness 195 720 Bilharziasis 196 149–150 Biomarkers 196 270–271, 563 Birth defects 195 408 Bladder disorder 196 412–413 Blepharospasm 196 435, 544 Blood-brain barrier (BBB) 196 220, 369 Blood oxygen level-dependent (BOLD) activity 196 482 Blood pressure (BP) 195 302–303 Body schema 195 105–106, 116 Bone morphogenetic proteins (BMPs) 195 204–205, 196 576 BoNTs. See Botulinum neurotoxins (BoNTs) Bony spine, neuroanatomy 196 4–5 Borrelia burgdorferi 196 103, 317–319, 375–377, 381 Borreliosis 196 103 Botulinum neurotoxins (BoNTs) 196 95–96, 396, 426, 467, 509–510, 539–540 blepharospasm 196 544 cranial dystonia 196 544 dystonic head tremor 196 548 essential head tremor 196 548 essential tremor (ET) 196 546 essential voice tremor 196 548 oromandibular dystonia (OMD) 196 544 Parkinson rest tremor 196 549 task-specific dystonia (TSD) 196 544–545 tremor 196 546–548 Botulinum toxin A 196 140 Botulism 195 745–746 Bowel disorder diagnosis 196 412–413 differential diagnosis 196 415

INDEX Bradykinesia 196 289–290 Brain atrophy 196 123, 124 Brain Attack Coalition (BAC) 196 333 Brain-computer interfaces (BCI) 196 337 Brain-derived neurotrophic factor (BDNF) 195 223, 196 569–570, 572–573, 602 Brain hypomyelination 196 433–434 Brain injury 196 602–604 Brain microglia 196 369, 370 Brainstem and spinal cord corticofugal projections, functional organization of 195 113–114 disorders of 195 724–725 posture gait mechanisms in brainstem-spinal cord pathways 195 107–110 functional organization of 195 108 locomotor regions 195 107 locomotor system, functional organization of 195 109 spinal locomotor network 195 110 superior colliculus (SC) 195 109–110 Brain stem auditory evoked responses (BAER) 196 127 Brainstem encephalitis 196 237 Brainstem symptoms 196 283 Breastfeeding 195 647 Bronchogenic carcinoma 196 20 Brown-Sequard syndrome 196 11, 17, 20 Bruns-Garland syndrome 195 594 Bruxism 195 392–393 Buspirone 196 140

C

CACNA1S variants 195 527 Calcium activation, contraction and 195 7–8 Calcium voltage-gated channel auxiliary subunit beta 4 (CACNB4) 196 358–359 Calcium voltage-gated channel subunit alpha 1A (CACNA1A) 196 358 Calpainopathy 195 474–475 Cancer immunotherapy 195 435–436 Cannabidiol (CBD) 196 507, 508–509 Cannabinoids 196 508–509 Cannabis-based medicine 196 467 Carbamazepine (CBZ) 196 140, 348–351 Cardiac sympathetic neuroimaging 196 181 Cardioembolic infarction 196 319 Cardiovascular disease 196 306 Carotid Occlusion Surgery Study (COSS) 196 335 Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) 196 335 Carpal tunnel syndrome (CTS) 195 260 Casirivimab 195 169 Caspr2 antibodies 196 240 Cassava 196 154 Catathrenia sleep-related groaning 195 391 Catatonia 196 452 Catecholamine 196 181

Cauda equina syndrome 196 411 Caudal pontine tegmentum syndrome 196 309–310, 310 Caveolinopathy 195 474 Caveolin 3-related distal myopathies 195 502 Cavernous malformations 196 28 C5b-9 membranolytic attack complex (MAC) 195 436–437, 438 CB1 receptors 196 140 Celecoxib 196 525 Central cord syndrome 196 10 Central core disease (CCD) 195 533–534, 549 Central motor conduction time (CMCT) 196 13–14 Central nervous system (CNS) 195 186–187, 302–303 demyelinating diseases 196 22–24 MOG-antibody disease (MOGAD) 196 24 multiple sclerosis (MS) 196 23 NMO-spectrum disorders (NMOSD) 196 23–24 disorders 195 723–750 vasculitis 195 662 brain and meningeal biopsy 195 679–680 catheter angiography 195 665–666 computed tomography angiography 195 665 magnetic resonance angiography 195 665 MRI findings of 195 665 muscle and nerve and epidermal nerve fiber analysis 195 680 neuroradiological approach 195 663 Central pattern generators (CPGs) 195 104, 196 8 Centronuclear myopathy (CNM) 195 533–534 autosomal dominant 195 539 biopsy features 195 537 clinical features 195 538–539 disease pathogenesis 195 540 genetics 195 539 historical background 195 538 phenotype-genotype correlations 195 540 Cerebellar ataxia 196 268–269, 280 Friedreich ataxia 195 368–370, 369 hereditary ataxias 195 368 immune system in 195 142 Cerebellar circuitry 196 169–170 Cerebellar cognitive affective syndrome (CCAS) 196 168, 169 Cerebellar contribution, to error detection 195 117–118 Cerebellar cortex 196 160 Cerebellar-dependent mechanisms 195 47–48 Cerebellar motor syndrome (CMS) 196 168, 168 Cerebellar mutism 196 169 Cerebello-cortical circuits 196 167–168

INDEX Cerebellum 196 7, 310–311, 311 anatomy 196 160–162, 161–162 cellular physiology 196 162–165 complex spikes 196 162–164, 164 plasticity mechanisms 196 165 rebound depolarization and disinhibition 196 164 simple spikes 196 162–164, 164 cerebello-cortical circuits 196 167–168 cerebro-cerebellar structural connectivity 196 165–166, 166–167 circuitry 196 163 frontal cortical connections with 195 118 function 195 24 internal models 196 168–171, 170–171 MR imaging 195 25 Purkinje output 195 24 research 196 159–160 Cerebellum-brain inhibition (CBI) 196 167 Cerebral angiography 196 324–325 Cerebral autosomal-dominant arteriopathy with stroke and ischemic leukoencephalopathy (CADASIL) 196 306–307 Cerebral dopamine neurotrophic factor (CDNF) 196 578 Cerebral hemispheres 196 312–316, 314–315 Cerebral ischemia, and infarction 196 315–316 Cerebral palsy phenotype 196 73 Cerebro-cerebellar structural connectivity 196 165–166, 166–167 Cerebrospinal fluid (CSF) 195 619, 196 14, 181–182, 182, 188, 194, 259 Cerebrospinal fluid oligoclonal bands (CSF OCBs) 196 124, 135 Cerliponase alfa 196 561–562 Cervical vertebrae 196 4–5 C-fibers 196 404 CFTD. See Congenital fiber type disproportion (CFTD) Channelopathies, muscle myotonia 195 521–526 pediatric syndromes and variants 195 526 periodic paralysis 195 526–530 prevalence 195 521 Chaperone-assisted selective autophagy (CASA) 195 504 Charcot-Marie-Tooth (CMT) disease 195 190–191, 293–294, 320–329, 322, 326, 196 418. See also Hereditary neuropathy foot deformities in 195 321–326, 321 genetic basis of 195 323–325 neuropathy score 195 328 Charcot–Marie–Tooth Functional Outcome Measure (CMT-FOM) 195 327 Chemokines 196 578

Chest percussion and drainage 195 553 Childhood AIS Standardized Classification and Diagnostic Evaluation (CASCADE) 196 320 Childhood multiple sclerosis 196 130–131 clinical features 196 130 MOG serology 196 130–131 MRI findings 196 131 pediatric NMO 196 130–131 prognosis 196 131 Childhood muscular dystrophies classification 195 461–464 clinical approach 195 464 clinical recognition 195 464 electrodiagnostic studies 195 465 genetic classification of 195 472 genetic evaluation 195 465 imaging studies 195 465 integrated approach 195 466 laboratory approach 195 465–466 muscle biopsy 195 465–466 sarcolemmal membrane and enzymatic proteins 195 462–463 serum creatine kinase (CK) levels 195 465 treatment 195 482 Childhood spinal muscular atrophy 195 316–320, 317 classification 196 43–45 type 1 196 44, 45 type 2 196 44 type 3 196 44 type 4 196 44–45 disease-modifying molecular therapy 196 52–54 antisense oligonucleotide 196 52 nusinersen 196 52 onasemnogene 196 52–53 risdiplam 196 53–54 epidemiology 196 44 etiopathogenesis 196 48–50 electrophysiological biomarkers 196 50 epigenetic modifications 196 49–50 neurofilaments (NF) 196 49 neuroimaging 196 50 protein 196 48–49 SMN2 copy number 196 49 splicing regulators 196 49 genetics 196 46 history 196 43 laboratory evaluation of 196 45–46 management 196 50–51 natural history and prognosis 196 51–52 plus types 196 47 very severe 196 46–47 Childhood stroke 196 320–321 patterns and classification 196 320 pediatric inflammatory brain disease 196 321 Children, COVID-19 neurological illness in 195 163 Children’s postinfectious autoimmune encephalopathy (CPAE) 196 373–374

625 Chimeric/fusion proteins 196 563 China, myasthenia gravis with MuSK antibodies 195 637–638 Chlamydia pneumoniae 196 306 Chloride channel (ClC-1) 195 522–524, 524 Choking syndrome, sleep-related 195 394 Choline acetyltransferase (CHAT) deficiency 195 188 Cholinergic receptor nicotinic subunit alpha 4 (CHRNA4) 196 352 Cholinesterase inhibitors (ChE) 195 343, 196 260 Chorea 196 288–289 Chromosomal disorders 195 413 Chromosome 9 open reading frame 72 (C9orf72) gene 195 206, 196 211, 217, 524, 529 Chronic ataxic neuropathy 195 626 Chronic COVID illness Long-Hauler and Long 195 172–173 neurodegeneration 195 173–175 postacute sequela of 195 173 Chronic diarrhea 196 152 Chronic immune sensory polyradiculopathy (CISP) 195 625–626 Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 195 329–336, 329, 376–377, 587, 619–620 clinical presentation 195 625 CSF 195 627 cutaneous nerve biopsy 195 627–628 of early onset 195 629 electrodiagnostics 195 626–627, 628 etiopathogenesis 195 624 gammopathy and 195 626 laboratory evaluation 195 626–628 macrophage-mediated demyelination in 195 629 magnetic resonance imaging 195 627 mimics 195 626, 627 motor nerve demyelinating conduction criteria 195 628 nerve ultrasound demyelinating criteria 195 628 neuromuscular ultrasound 195 627 pathology 195 624–625 pathophysiology 195 624–625 prognosis 195 629–630 serology 195 626 subtypes of 195 619–620 treatment 195 628–629 variants 195 625–626, 625 Chronic progressive external ophthalmoplegia (CPEO) 195 572–573, 572 Chronic sensorimotor neuropathy 196 240 Chronic traumatic encephalopathy (CTE) 196 257–258, 485–486, 611–612 Chronic tropical myelopathy 196 150 Churg–Strauss syndrome (CSS) 195 293–294, 653–654

626 CIAW. See Critical illness-associated motor weakness (CIAW) CIDP. See Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Cigarette smoking 196 306 Cilgavimab 195 170 Ciliary neurotrophic factor (CNTF) 196 573–574 CIM. See Critical illness myopathy (CIM) CIP. See Critical illness polyneuropathy (CIP) Circulatory biomarkers 196 48 CLCN1 variants 195 522 Clomiphene citrate 196 417 Clonazepam 196 507, 509 Clonic seizures 196 296–297 Clonidine 196 466 Clostridium botulinum 196 539 Clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) genome editing platform 195 470–471, 196 529, 564 Clusterin 196 577 CMD. See Congenital muscular dystrophies (CMD) CMS. See Congenital myasthenic syndromes (CMS) CMT1A 195 610–611 CMT2A 195 613 CMT1B 195 611–612 CMT disease. See Charcot-Marie-Tooth (CMT) disease CMTX1 195 612 CNM-Au8 196 531 CNS. See Central nervous system (CNS) Cocaine-induced midline destructive lesions (CIMDL) 195 677 Coenzyme Q10 196 530–531 Cogan syndrome 195 653–654 Collagen VI-related disorders Bethlem myopathy 195 478 genotype phenotype correlation 195 478–479 Ullrich 195 477–478 Collapsing response-mediator protein-5 (CRMP-5) antibodies 196 113, 237 Collateral sprouting 196 34–35, 583–584 Common carotid artery (CCA) 196 312–314 Common data elements (CDEs) 195 315–316 Compensation and extravestibular sensory substitution 195 46–48 VOR 195 37–38 Competitive neuromuscular blocking agents 195 750 Complete stable remission (CSR) 195 341–342 Complex neurodegenerative disorders 196 74 Complex spikes 196 162–164, 164

INDEX Compound motor action potential (CMAP) 195 524 Compound muscle action potential (CMAP) 195 273, 318–319, 196 50 duration 195 709 Compressive myelopathies 196 101 Computerized tomography (CT) 196 149 Concussion Symptom Inventory (CSI) 196 480–481 Conduction block electrophysiological criteria for 195 593 motor neuropathy with 195 590 partial motor 195 591–592 Conduction velocity 195 257 Confusional arousals 195 386 Congenital fiber type disproportion (CFTD) 195 409–410 biopsy features 195 537 clinical features 195 544 definition 195 543 genetics 195 544–545 historical background 195 543–544, 544 phenotype-genotype correlations 195 545 Congenital muscular dystrophies (CMD) 195 408, 534–536 biochemical basis 195 476 classification 195 476 genotype phenotype correlation 195 477 LAMA2 195 476–477 Congenital myasthenic syndromes (CMS) 195 185–186, 188–190, 338–339, 534–536, 648–650 classification 195 648, 648 clinical features 195 648–649 CMS6 195 410 CMS9 195 411 CMS10 195 411 CMS11 195 411 CMS22 195 411 defect in protein glycosylation 195 190 diagnosis 195 649 endplate development and maintenance defects 195 189–190 epidemiology 195 648 future perspectives 195 650 management 195 649 pathogenesis 195 649 postsynaptic defects 195 188–189 presynaptic defects 195 188 synaptic space defects 195 188 Congenital myopathies 195 402–403, 407, 409, 530 approach to diagnosis 195 546–550 assessment 195 552 assisted coughing 195 553 biopsy features 195 537 chest percussion and drainage 195 553 clinical clues to 195 546–550, 546 clinical features 195 534 cores 195 548 counseling 195 554 effective peak cough flow 195 552

Congenital myopathies (Continued) fiber type disproportion 195 549, 549 genetic basis of 195 535 glossopharyngeal breathing 195 553 histopathology vs. genetics 195 534 internal nuclei 195 549–550 lung and chest expansion 195 552 maintenance of respiratory muscle strength and endurance 195 554 management of patients 195 551–554 minicores 195 548–549 muscle histopathology 195 547–550, 547 muscle imaging 195 550 muscle magnetic resonance imaging 195 550, 551 muscle ultrasound 195 536, 550 natural history 195 545–546 nemaline bodies (rods) 195 547–548, 548 neonates and infants 195 546–547 noninvasive intermittent positive pressure ventilation 195 553 older children 195 547 oximetry monitoring and biofeedback 195 553–554 respirator interventions 195 552–553 serum creatine kinase (CK) elevation 195 536 subtypes 195 536–545 treatment of respiratory insufficiency 195 553–554 types of 195 533 ventilation and air distribution 195 552 ventilatory assessment and support 195 551–554 Congenital myotonic dystrophy 195 486–488, 534–536 CTCF1 site methylation 195 488 early investigations 195 486 genetic basis 195 486–487 molecular mechanism 195 487–488 parental transmission 195 487 with respiratory failure and arthrogryposis 195 486 Constipation 196 179 Constraint-induced movement therapy (CIMT) 196 337, 602 Continuous positive airway pressure (CPAP) therapy 196 604 Contraction calcium activation of 195 7–8 cross-bridge cycle 195 5–6, 6 definition 195 3–4 mechanisms 195 5–6 Contractures 195 402–403, 409, 412 Contrast-enhanced magnetic resonance angiography (CE-MRA) 196 15 Convalescent plasma transfusion 195 171 Conventional MRI 196 15 Core myopathy disease biopsy features 195 537 clinical features 195 541–542 disease pathogenesis 195 542–543 genetics 195 542

INDEX Core myopathy disease (Continued) historical background 195 540–541 phenotype-genotype correlations 195 542 ryanodine 1 (RYR1) gene mutations 195 541 RYR1 and SEPN1 mutations 195 542 Coronavirus-2 infection. See Severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) Cortex occipitotemporal 195 131 parietal 195 128 primary motor 195 131 ventral premotor 195 128 Cortical control, behavior expression 195 110–114 corticofugal outputs 195 111 prefrontal cortex 195 110–112 role of 195 110–111 Cortical function, reorganization of 196 327–328, 329 Cortical infarcts 196 325 Cortical silent period (CSPs) 196 484–485 Corticobasal degeneration (CBD) 196 255–256 Corticobasal syndrome (CBS) 196 612 Corticobulbar fibers 196 6–7 Corticofugal projections, functional organization of 195 113–114 Corticoreticular projections 195 108, 113, 116 Corticospinal tract (CST) 195 18, 21–22, 361–363, 362, 196 77–78, 328–329, 330 degeneration 196 204 fibers 196 6–7 Corticosteroids (CS) 195 332–334, 343, 680–682, 196 103–104, 112–113, 136, 150, 237–238, 240, 372 and autoimmune inflammatory myopathies 195 445 COVID-19 195 170–171 dose 195 342 COVID-19 infection 195 624, 709 acute infection 195 160–161 adult CNS vasculitis 195 672–673 in adults 195 162–163 animal models 195 160 antigens 195 162 bamlanivimab and etesevimab 195 169 casirivimab and imdevimab 195 169 childhood CNS vasculitis 195 672 in children 195 163 chronic COVID illness Long-Hauler and Long 195 172–173 neurodegeneration 195 173–175 postacute sequela of 195 173 clinical and neuropathological findings of 195 166 clinicopathological correlation 195 165–167 convalescent plasma transfusion 195 171 corticosteroids 195 170–171

COVID-19 infection (Continued) cytokine storm 195 163–164 detecting antibodies to 195 162 diagnostic testing 195 161–162 disease definitions 195 160 epidemiology 195 159–160 Guillain–Barr
e syndrome 195 620 hydroxychloroquine 195 168 immunotherapy 195 168–171 interleukin-6 inhibition 195 171 intravenous immune globulin therapy 195 171 monoclonal antibodies 195 168–170 multisystem inflammatory syndrome in children 195 671–672 neurological illness 196 374, 375 neurological presentation 195 162–163 neuropsychiatric illness 195 175 postinfectious autoimmunity CNS vasculitis 195 670–673 remdesivir 195 168 sotrovimab 195 169–170 susceptibility to infection 195 160 tixagevimab and cilgavimab 195 170 triggering causes of AIM 195 435 vaccination 195 172 variants 195 168 viral RNA by RT-PCR 195 161–162 weakness associated with 195 760–761 zoonotic origin 195 159–160 CPEO. See Chronic progressive external ophthalmoplegia (CPEO) C-peptide 196 574 Cramps, hereditary neuropathy 195 614–615 Cranial arteritis 195 656 Cranial dystonia 196 544 Craniopharyngioma 196 311–312 Creatine 196 530–531 Critical illness-associated motor weakness (CIAW) 195 707 brainstem disorders 195 724–725 central nervous system disorders 195 723–750 encephalopathy 195 723–724 lateral medullary syndrome 195 724–725 medial medullary syndrome 195 724 medullary infarction 195 724–725 motor neuron disease adult familial amyotrophic lateral sclerosis 195 726 hereditary motor neuron disease 195 726–729 infantile and childhood spinal muscular atrophy 195 726–727 progressive muscular atrophy 195 727–729, 728 sporadic amyotrophic lateral sclerosis 195 725–726 neuromuscular assessment 195 710–718 cerebrospinal fluid analysis 195 717 compound muscle action potential waveforms 195 713

627 Critical illness-associated motor weakness (CIAW) (Continued) direct muscle stimulation 195 715–717 electrophysiological studies 195 711–717 history and physical examination 195 710–711 laboratory evaluation 195 711–718 motor unit number estimation 195 717 muscle and nerve biopsy 195 717–718 needle electromyography 195 712–713 nerve conduction studies 195 711–712 neuroimaging 195 711 quantitative motor unit potential analysis 195 713–715 repetitive nerve stimulation 195 712 specialized electrophysiologic studies 195 713–717 respiratory assessment bedside evaluation 195 719–722 dermal myelinated nerves 195 719 diaphragm studies 195 720–722 electrophysiology 195 720–722 imaging 195 720 phrenic nerve conduction studies 195 721, 721–722 pulmonary function testing 195 719–720 spinal cord disorders acute spinal cord ischemic disorders 195 729–730, 729 lumbosacral plexus disorders 195 731–733 poliomyelitis 195 730–731, 730 Critical illness myopathy (CIM) 195 707, 714, 751 bedside examination 195 754 electrophysiological studies 195 754–755 histological studies 195 754 nerve and muscle histopathology 195 755–756 recommendations 195 756, 756 severity of 195 753 Critical illness polyneuropathy (CIP) 195 707, 716, 750–753, 750–751 bedside examination 195 752 electrophysiologic studies 195 752 nerve and muscle histopathology 195 752, 753 pathophysiology 195 756–758 prognosis 195 752–753, 758–760 recommendations 195 756 treatment 195 760 Cross-bridge cycle 195 5–6, 6 CRYAB mutations 195 501 Cryoglobulinemic vasculitis 195 653–654 CS. See Corticosteroids (CS) CST. See Corticospinal tract (CST) Curtain sign 195 338, 338

628 Cu/Zn-superoxide dismutase (SOD1) 195 207–208, 196 209–212 CX3CL1 (fractalkine) 195 136–137 Cyclic AMP (cAMP) 196 581 Cyclophosphamide 195 646–647, 682 Cyclosporine 195 645, 196 109 Cystatin B 195 221 Cysteine-rich neurotrophic factor (CNRF) 196 578 Cytokines 195 137, 196 368–370, 577–578 signaling 196 141 storm 195 163–164 Cytotoxic T cells 196 242–244

D DADS. See Distal acquired demyelinating symmetric (DADS) Dalfampridine 196 95–96, 139–140 Danon disease 196 558 Dantrolene 196 140, 507, 509 Deep brain stimulation (DBS) 196 467–468 Deep breathing, heart rate variability (HRV) with 195 304–305, 306 Deep tendon reflexes (DTRs) 196 44, 75 Defecation disorders 196 413–414 Defective autophagy 196 218 Defective axonal cytoskeletal and transport 196 217–218 Delay line, isolation by 195 274, 275 D9-tetrahydrocannabinol (D9THC) 196 507, 508–509 Dementia with Lewy bodies (DLB) 196 175, 190–195 clinical features 196 192–193 diagnostic criteria 196 192 epidemiology 196 191–192 genetics 196 191 nonmotor features 196 192–193 paraclinical testing 196 193–194 analysis of cerebrospinal fluid 196 194 autonomic testing 196 193–194 imaging techniques 196 193, 194 plasma catecholamines 196 194 skin biopsy 196 194 pathology 196 191 pathophysiology 196 190–191 treatment 196 194–195 Demyelinating conduction block (DMCB) 195 259–260, 260 Demyelinating conduction slowing (DMCS) 195 259–260 Demyelination 195 203 Dentatorubral-pallidoluysian atrophy (DRPLA) 195 231 Depolarization phase 195 253 Depolarization threshold 195 253 Derived metrics 195 277 Dermatomyositis (DM) 195 425–426 anti-B-cell agents 195 447 associated antibodies 195 431 characteristic clinical features 195 426–427, 427

INDEX Dermatomyositis (DM) (Continued) historical background 195 426 immunopathology 195 436–439, 437, 439 IVIg on muscle strength 195 447 on skin manifestations 195 446 muscle biopsy 195 431, 432 necrotizing autoimmune myositis 195 439–440 new biologics 195 447–448 shared clinical features 195 426 Desmin-related distal myopathies 195 502 Deutetrabenazine 196 467 Developmental delay 196 74 Dexpramipexole 196 530–531 DGC. See Dystrophin-glycoprotein complex (DGC) Diabetes mellitus (DM) 196 306, 418–419 Diabetic amyotrophy 195 594 Diabetic lumbosacral radiculoplexus neuropathy (DLRPN) 195 594 3,4-Diaminopyridine 195 649 Diazepam 196 507, 509 Dietary cyanide intoxication, neurologic disorders with 196 154–155 Diffuse axonal injury (DAI) 196 475–476 Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) 196 333 Diffusion tensor imaging (DTI) 196 165 Diffusion weighted imaging (DWI) 196 319 Digital subtraction angiography (DSA) 196 15–16 Dihydrolipoamide S-acetyltransferase (DLAT) 196 353–354 Dihydropyridine receptor (DHPR) 195 8 Dimethyl fumarate 196 137 Diplopia 195 639, 645 Direct immunofluorescence 195 296 Disability outcome measures 195 332 Disease-modifying therapy (DMT) 196 136–137 Disheveled, Egl-10, and Pleckstrin domain containing 5 (DEPDC5) 196 352 Distal acquired demyelinating symmetric (DADS) 195 587–589 characteristics 195 587–588 classifications 195 588 clinical presentation 195 588 diagnostic evaluation 195 588 prognosis 195 589 treatment 195 588–589 Distal CIDP. See Distal acquired demyelinating symmetric (DADS) Distal Hereditary Motor Neuropathies (dHMN) 195 609 Distal latency 195 256–257 Distal myopathies 195 461–462, 484–486 adenylosuccinate synthase 1-related 195 501 alpha-actinin-2-related 195 500 alpha-B crystallin-related 195 501

Distal myopathies (Continued) anoctamin 5-related 195 501–502 caveolin 3-related 195 502 clinical presentation 195 500 desmin-related 195 502 diagnosis of 195 511–512 DNAJB6-related 195 503 dysferlin-related 195 503 early/juvenile onset recessive 195 510 filamin C-related 195 503–504 forms of 195 497 genetically defined 195 498–499 genetic myopathies with distal phenotype at onset 195 511 GNE-related 195 504 HSPB8-related 195 504 KLHL9-related 195 511 laing early-onset 195 465, 484 LIM domain-binding protein 3-related 195 504–505 management and treatment 195 512 Matrin-3-related 195 505 Miyoshi 195 485–486 myoglobulin-related myopathy 195 511 myosin heavy chain beta-related 195 505–506, 506 myotilin-related 195 506 nebulin-related 195 506–507 perilipin-4–related 195 507 ryanodyne receptor 1-related 195 507 sequestosome 1 and tia-related digenic 195 507 small muscle protein X-linked-related 195 507–508 TIA1-related 195 508–509 titin-related 195 509–510 valosin-containing protein-related 195 510–511 Distal nebulin myopathy 195 506–507 Distal response 195 255, 256 Distal vibration perception, mild impairment of 196 75 DLB. See Dementia with Lewy bodies (DLB) DM. See Dermatomyositis (DM) DNAJB6-related distal myopathies 195 503 Dominant negative effects 195 210–211 Dominant Optic Atrophy (DOA) 195 194 Dopamine 195 386, 196 417 Dopamine-responsive dystonia (DRD) 196 436–437 Doppler ultrasonography 196 307 Dorsal arteriovenous fistula 196 26 Dorsal column 196 74 Dorsiflexion 196 75 Dorso-dorsal stream 195 128, 131 Double-seronegative MG 195 338–339 Down’s syndrome 196 611–612 DSA. See Digital subtraction angiography (DSA) Duchenne muscular dystrophy (DMD) 195 347–350, 461 carriers 195 212

INDEX Dynactin (DCTN1) 195 209–210, 196 214, 217–218 Dysarthria 196 74 Dysferlinopathy 195 475 Dysferlin-related distal myopathies 195 503 Dysmetria 196 168–169 Dystonia 195 570, 196 186–187, 255, 541–545 -ataxia syndromes 196 438 blepharospasm 196 544 classification 196 428–429, 430–431 clinical clues 196 426–427 clinical presentation 196 427 combined dystonia 196 436–438 dopamine-responsive dystonia (DRD) 196 436–437 dystonia-ataxia syndromes 196 438 dystonia parkinsonism 196 436 myoclonus dystonia 196 437 paroxysmal dyskinesias 196 437–438 cranial dystonia 196 544 defined 196 500 isolated 195 151 isolated dystonia 196 429–436 adult-onset focal/segmental dystonia 196 435 early-onset generalized dystonia 196 432–435 red flags 196 435–436 laboratory evaluation 196 427–428 oromandibular dystonia (OMD) 196 544 overview 196 425 parkinsonism 196 436 pathogenesis 196 429, 430–431 phenomenology 196 425–426 task-specific dystonia (TSD) 196 544–545 Dystonic head tremor 196 548 Dystrophin-associated muscular dystrophy animal models 195 469–471 clinical aspects 195 466–467 electrodiagnosis 195 467 genotype phenotype correlation 195 468–469 incidence 195 466 laboratory diagnosis 195 467–468 muscle biopsy 195 467–468 serum creatine kinase 195 467 treatment 195 469–471 Dystrophin-glycoprotein complex (DGC) 195 187, 346–347, 348, 466 DYT6 196 433 DYT24-ANO3 196 435 DYT12-ATP1A3 196 436–437 DYT25-GNAL 196 435 DYT-HPCA 196 435 DYT-KMT2B 196 433 DYT16-PRKRA 196 433 DYT1-TOR1A 196 432–433

E EA. See Episodic ataxias (EA) Early/juvenile onset recessive distal myopathies 195 510

Eating disorder, sleep-related 195 386–387 Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) 196 333 Eculizumab 195 346 Edaravone 196 530 Efference copy signal 195 43, 47 Ehlers-Danlos syndrome (EDS) 195 407, 412–413 Elastomeric garments 196 511 Electrocardiogram (ECG) 195 304 Electrodiagnostic (EDX) techniques of demyelination and axon loss 195 259–261 manifestations of 195 251 Electroencephalography (EEG) 195 195, 196 319 Electromyography (EMG) 196 328 Electrophysiological biomarkers 196 50 Electrophysiologic motor unit (E-MU) 195 273 isolation 195 274–275 delay line 195 274, 275 photography 195 274 template matching 195 274–275, 275 metric changes with 195 281 normal aging 195 281 pathology 195 281 metrics 195 275–277 routine 195 273–274, 274 viewing and assessment 195 273–275 Eliglustat 196 562 Emery–Dreifuss muscular dystrophy (EDMD) 195 482–483, 483 Emotional control 196 169 Emotional valence, in freezing 195 119–120 Empty beds 195 316–317 E-MU. See Electrophysiologic motor unit (E-MU) Encephalopathy 195 723–724 Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial 196 335 Endocannabinoid signaling 196 140–141 Endoneurium 195 296 Endoplasmic reticulum (ER) network morphology 195 203–204 stress 196 218 Endosomal dynamics 195 204 Endosome 195 198 Endplate activity 195 254, 266 Endplate current (EPC) 195 336–338 Endplate potential (EPP) 195 10, 185–186, 336–338 Enhanced stop-codon read-through 196 564 E-norm 195 279–280 Enoyl-CoA hydratase, short chain 1 (ECHS1) 196 353–354 Enterovirus A71 196 104 Enterovirus D68 196 104 Environmental dependency syndrome 196 450

629 Enzyme enhancement therapy (EET) 196 562 Enzyme-linked immunosorbent assay (ELISA) 196 149–150 Enzyme replacement therapy (ERT) 196 558, 560–561 Eosinophilic granulomatosis with polyangiitis (EGPA) 195 653–654 Ependymomas 196 18–19 Epidermal growth factor (EGF) 196 576 Epidermal nerve fibers (ENFs) 195 185 Epididymitis 196 413 Epidural abscesses 196 102–103 Epigenetics, genomic imprinting and 195 233–234 Epilepsy 196 417 Epilepsy, progressive myoclonic 1A (EPM1A) 195 221 Epileptic spasm (ES) 196 297 Epinephrine 195 303 Episodic ataxias (EA) 196 347, 349–350, 356–360 type 1 196 357 type 2 196 357–358 type 3 196 358 type 4 196 358 type 5 196 358–359 type 6 196 359 type 7 196 359 type 8 196 359 type 9 196 359–360 Episodic weakness 195 521 periodic paralysis 195 526–527 during pregnancy 195 530 Epstein-Barr virus (EBV) infection 196 120 Erectile function 196 415–417 E-reference 195 279–280 Erythropoietin (EPO) 196 576–577 Essential tremor (ET) 195 141–142, 196 546 clinical presentation 196 391–393 diagnosis 196 393–394 epidemiology 196 390–391 genetics 196 390–391 head tremor 196 548 history 196 389–390 natural history 196 391–393 overview 196 389, 396 pathophysiology 196 394–396 treatment 196 396 voice tremor 196 548 Etesevimab 195 169 Ethanol 196 396 European Carotid Surgery Trial (ECST) 196 335 European Cooperative Acute Stroke Study (ECASS) trials 196 333 European Federation of Neurological Societies (EFNS) 195 329–330 European League against Rheumatism (EULAR) 195 654 European Stroke Prevention Study 2 (ESPS2) 196 331

630 Evidence-based approaches, of stroke recovery 196 336–337 Evoked retinal ganglion (ERG) cell 195 194 Exafference 195 40 Excessive fragmentary hypnic myoclonus (EFHM) 195 392 Exercise multiple sclerosis (MS) 196 140 spasticity 196 506 Exome sequencing analysis 196 528–529 Extensor digitorum brevis (EDB) muscle 195 331 External ophthalmoplegia, minicore with 195 409 External urethral sphincter (EUS) 196 403–404 Extracellular amyloid plaques 196 260 Extracorporeal shock wave therapy (ECSWT) 196 511 Extradural–intradural spinal AVMs 196 27 Extrapolated metrics 195 278–279, 280 near-fiber count 195 279 near-fiber jiggle 195 279 near-fiber motor unit jiggle 195 279 Extra-vestibular information 195 46–47 Extravestibular sensory substitution, compensation and 195 46–48 Extrinsic factors 195 147

F

Fabry disease (FD) 196 558, 561 Facial expression, frontal lobe motor syndromes 196 452 Faciobrachial dystonic seizures (FBDS) 196 280–281 Facioscapulohumeral dystrophy (FSHD) 195 461–462 Facioscapulohumeral muscular dystrophy 195 462 FALS. See Familial amyotrophic lateral sclerosis (FALS) Familial amyloid polyneuropathies 195 193–194, 196 418 Familial amyotrophic lateral sclerosis (FALS) 195 205–210 C9orf72 gene 195 206 CU/ZN-superoxide dismutase (SOD1) 195 207–208 dynactin (DCTN1) 195 209–210 fused in sarcoma (FUS) 195 207 optineurin (OPTN) 195 208–209 TAR DNA-binding protein 43 (TARDBP) 195 206–207 valsolin-containing protein (VCP) 195 209 Familial dysautonomia (FD) 195 84–89, 410 Fascio-scapular myopathies 195 484 Fast axonal transport 196 253 Fatigue defined 196 120–121 hereditary neuropathy 195 614–615 FD. See Fiber density (FD)

INDEX Feet weakness 195 502, 509. See also Tibial muscular dystrophy (TMD) Fencing position (M2e) sign 196 300 Fiber density (FD) 195 277–278, 278, 284 Fiber type 1 195 549. See also Congenital fiber type disproportion (CFTD) Fiber type disproportion 195 409–410, 549, 549 Fibrillation potentials 195 266 Fibroblast growth factor (FGF) 196 575–576 Fibroblast growth factor 14 (FGF14) 196 360 Filamin C-related distal myopathies 195 503–504 Fingolimod (FTY720) 196 137, 526 FKTN and FKRP 195 479–480 Flocculonodular lobe 196 160 Flocculus and ventral paraflocculus 195 42–44 Flocculus/paraflocculus 196 160 Fluid-attenuated inversion recovery (FLAIR) 196 280, 319 fMRI. See Functional magnetic resonance imaging (fMRI) Focal cerebral arteriopathy (FCA) 195 666–667 Forced groping 196 448–449 Forced vital capacity (FVC) 196 51 Forkhead box G1 (FOXG1) 196 355 Forward-shifted foot strike 196 75 Fowlers syndrome 195 210 Fragile X syndrome (FXS) 195 221 Freezing emotional valence in 195 119–120 of gait (FOG) 195 103 slow walking and 195 111–112 Friedreich ataxia (FRDA) 195 220 Frontal gait 196 268–269 disorders 195 103–104 Frontal lobe motor syndromes apraxia 196 451 catatonia 196 452 clinical neurologic signs forced groping 196 448–449 gegenhalten 196 448 grasp reflexes 196 448–449 other primitive reflexes 196 449 paratonia 196 448 spasticity 196 448 facial expression 196 452 gait disorders 196 452 motor behavioral phenomena alien limb syndrome 196 449–450 environmental dependency 196 450 imitation behavior 196 450 motor impersistence 196 451 perseveration 196 451 stereotypies 196 451 utilization behavior 196 450 overview 196 443–444 prefrontal cortex 196 447 premotor cortex 196 445–446 primary motor cortex 196 444–445

Frontal lobe motor syndromes (Continued) supplementary motor area (SMA) 196 446–447 Frontotemporal dementia (FTD) 196 91, 253–255, 451, 612 Frontotemporal lobar degeneration (FTLD) 196 253 FTD. See Frontotemporal dementia (FTD) FTLD-Tau 196 612, 614 Functional electrical stimulation (FES) 196 511 Functional magnetic resonance imaging (fMRI) 196 126–127, 326, 328 Fungal myelitis 196 105 Fused in sarcoma (FUS) 195 207, 196 212, 253 F waves 195 262, 263 technique 195 281

G

Gabapentin 196 140, 396, 507, 508 Gain-of-function (GOF) CUG tract 195 232 polyalanine tract expansion 195 232–233 polyglutamine tract expansion 195 221–231 toxic 195 212 Gait 196 75 abnormalities 196 287–288 assessment 196 269–270 disorders 196 452 integration 196 8 Gait control, frontal lobe cholinergic (ACh) systems 195 105 cortical sensory-motor information processing 195 105–107 dopaminergic (DA) systems 195 105 parieto-temporo-occipital cortices 195 106 posture-gait control, fundamental framework of 195 104–105, 104 Gait dysfunction in Alzheimer’s disease abnormalities 196 268–269 APOE4 196 271 assessment methods 196 268–269 biomarkers 196 270–271 prognostic utility 196 269–270 Gait initiation, mechanisms of 195 117 Galveston orientation and amnesia test (GOAT) 196 486 Gamma-aminobutyric acid type A receptor subunit alpha 1 (GABRA1) 196 355 Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2) 196 355 g-amino butyric acid type B receptors (GABAB) 196 484–485 Ganglionopathy 195 91 Gap junction beta-1 protein (GJB1) gene 195 610 Gastric achlorhydria 196 152 Gastrointestinal domain 196 187–188 Gastrointestinal dysfunction 196 179

INDEX Gaucher disease (GD) 195 213 type 1 196 560–561 Gaze 195 31–32, 36 Gazing and orienting posture 195 114–115 GBS. See Guillain-Barr
e syndrome (GBS) GCA. See Giant cell arteritis (GCA) Gegenhalten 196 448 Gene defect, assignment of 195 234–235 Genentech Tau Probe 1 (GTP1) 196 615–616 Gene therapy 195 350, 650, 196 564 Genetic biomarkers 195 213–216, 196 219–220 Alzheimer disease 195 215–216 amyotrophic lateral sclerosis (ALS) 195 213–214 synucleinopathies 195 214–215 tauopathies 195 215 Genetic disorder 196 59 Genetic heterogeneity 195 210–211 Genetic modifiers 195 212–213 Genetic myopathies with distal phenotype at onset 195 498–499, 511 Genetic neurological disorders 195 187–210 congenital myasthenic syndrome (CMS) 195 188–190 familial amyotrophic lateral sclerosis 195 205–210 hereditary cerebellar ataxia 195 196–202 hereditary spastic paraplegia 195 202–205 mitochondrial disorders 195 194–196 muscular dystrophy 195 187–188 peripheral neuropathy 195 190–194 Genetic sequencing strategies 195 210 Genetic therapy 195 404 Genitourinary dysfunction 196 179 Genome-wide association studies (GWAS) 195 137–139, 196 614 Genomic imprinting, and epigenetics 195 233–234 Genotype phenotype correlation 195 478–479 Giant cell arteritis (GCA) 195 653–654 large vessel vasculitis 195 656 temporal artery biopsy 195 679 Glasgow Coma Scale (GCS) score 196 486 Glatiramer acetate (GA) 196 137, 525 GLE1, RNA export mediator (GLE1) 195 217–218, 196 214–215 Glia, in amyotrophic lateral sclerosis 196 219 Glial antibodies, autoimmune CNS disorders and 196 283–285, 284 Glial cell line-derived neurotrophic factor (GDNF) 196 574–575 Glial fibrillary acidic protein (GFAP) 196 277–278, 284–285, 482–483 Gliomas 196 17 Globoid cell (Krabbe) leukodystrophy 195 406–407 Globular glial tauopathy (GGT) 196 256

Glossopharyngeal breathing, congenital myopathies 195 553 Glucagon-like peptide (GLP-1) 196 578 Glucocerebrosidase (GBA1) enzyme 196 564 Glutamate 196 141 Glutamate ionotropic receptors (iGluRs) 196 141 Glutamic acid decarboxylase (GAD) 196 233–234, 277–278, 282 Glutaminergic fibers 196 6–7 Glycyl-tRNA synthetase 1 195 218 GNE-related distal myopathies 195 504 GOF. See Gain-of-function (GOF) Golgi method 196 159–160 Gosuranemab 196 616 Gower’ sign 195 347–348, 349 G protein subunit alpha O1 (GNAO1) 196 355 Grand mal seizure. See Tonic-clonic (T-C) seizure Granular layer 196 160 Granulomatosis with polyangiitis (GPA) 195 653–654 Granulomatous angiitis 195 663 Granulomatous angiitis of the nervous system (GANS) 195 654 Grasp 195 127–129 reflexes 196 448–449 Great sympathetic nerve 195 302 Group atrophy 195 291 Growth factors clinical trials motor neuron disease 196 585 other 196 585–586 polyneuropathy 196 585 clinical use 196 586 delivery 196 578–579 and human disease experimental motor disorders 196 581–582 nerve regeneration 196 582–583 other 196 584–585 Parkinson’s disease (PD) 196 582 peripheral neuropathies 196 583–584 limitations 196 586 signaling cascades 196 579–581 GTDC2 (POMGNT2) 195 480 GTP cyclohydrolase 1 (GCH1) 196 353 Guadeloupean Parkinsonism 196 258 Guam Parkinsonism-dementia complex 196 258 Guanfacine 196 466 Guillain-Barr
e syndrome (GBS) 196 151, 236–237, 240, 411 acute inflammatory demyelinating polyneuropathy 195 733–739 axonal forms of 195 619 clinical presentation 195 621 CSF 195 621 diagnostic approach 195 738 electrodiagnostic criteria for 195 621–622, 735–737, 736–737 etiopathogenesis 195 620 incidence of 195 620

631 Guillain-Barr
e syndrome (GBS) (Continued) laboratory evaluation 195 621–622 mimics 195 622, 623 pathology 195 620–621 pathophysiology 195 620–621 prognosis 195 624 recommendations in ICU 195 738 respiratory management 195 738 serology 195 621 treatment 195 622–624 variants 195 621, 622 Gut microbiota abnormalities in Parkinson disease 195 146 in ALS patients 195 150 human 195 143 influence of 195 144 manipulation of 195 143–144 pathological role of 195 143

H

Haldane rule 195 468–469 Hammersmith Functional Motor Scale-Expanded (HFMSE) 195 319 Hand movement limb apraxia 195 128 affordances 195 130 imitation deficits 195 129 localization 195 129–130 object use deficits 195 130 parietal control of 195 127 Hand weakness 195 502, 508. See also Welander myopathy Haploinsufficiency 195 211 acute intermittent porphyria (AIP) 195 211 juvenile GM2 gangliosidosis 195 211 Tay-Sachs disease (TSD) 195 211 Harvard Cooperative Stroke Registry 196 321 HCA. See Hereditary cerebellar ataxia (HCA) HD. See Huntington disease (HD) Head motion, encoding of 195 33 Heart rate variability (HRV) 195 304, 305 with active standing 195 307 with deep breathing 195 304–305, 306 at rest 195 307 with Valsalva maneuver 195 306–307 Heat shock proteins (HSP) 196 563 Hematopoietic stem cell transplantation (HSCT) 196 558, 560 Hemorrhage 196 19 Henoch-Sch€ onlein purpura (HSP) 195 653–654 Hepatocyte growth factor (HGF) 196 577 Hereditary cerebellar ataxia (HCA) 195 186–187, 196–202 Hereditary connective tissue disorders Ehlers–Danlos syndrome 195 412–413 Marfan syndrome 195 413 Hereditary motor neuron disease 195 726–729

632 Hereditary motor neuronopathy (HMN) 195 191 Hereditary neuropathy CMT1A 195 610–611 CMT2A 195 613 CMT1B 195 611–612 CMTX1 195 612 cramps 195 614–615 fatigue 195 614–615 management 195 614–615 mood disorders 195 614–615 pain 195 614–615 prevalence 195 609 rehabilitation therapy 195 614 (SORD)-ASSOCIATED CMT 195 613 surgical treatment 195 614 Hereditary sensory and autonomic neuropathies (HSANs) 195 192–193, 410 autonomic nervous system 195 86 classification of 195 84 genetics 195 85 postmortem studies 195 85–86 sensory nervous system 195 85–86 Hereditary spastic paraplegias (HSPs) 195 202–205, 203, 196 59–71, 80, 90, 92–95 axon pathfinding 195 202–203 bone morphogenic proteins (BMPs) signaling 195 204–205 classification 196 72 clinical aspects and disease course 196 74–76 clinical presentation 196 72–74 definitions 196 72 demyelination 195 203 diagnosis 196 76–77, 76 endoplasmic reticulum network morphology 195 203–204 endosomal dynamics 195 204 epidemiology 196 72 functions of 196 80 genetic basis 196 78–79 genetic counseling 196 78 genetic testing 196 77 genetic types of 196 59, 60–71 lipid synthesis and metabolism 195 204 medications 196 79 mitochondrial function 195 205 motor transport 195 205 narrow-based stance 196 75 neuroimaging 196 77 neuropathology 196 78 neurophysiology 196 77 orthotics 196 79 physical therapy 196 79–80 simplex cases 196 72 spasticity treatment 196 79 symptoms 196 74 treatment and prognosis 196 79–80 uncomplicated 196 74 upper extremities 196 75–76 weakness 196 74 Herpes simplex virus-1 (HSV-1) 196 104 Herpes simplex virus-2 (HSV-2) 196 104

INDEX Heteroplasmy 195 184 High-density lipoproteins (HDL) 196 306 High-dose corticosteroids 195 646 High-dose methotrexate chemotherapy 196 22 High frequency (HF) bands 195 307 Hip flexion 196 75 Hippocampus in etiopathogenesis of pediatric neuropsychiatric disorders 196 377–380 gross anatomy 196 378 microscopic anatomy 196 379 Histone deacetylase (HDAC) inhibitors 196 563 Hodgkin lymphoma (HL) 196 221–222 Homocysteine 196 306 Homoplasmy 195 184 Horner syndrome 196 307–308 H reflex studies 195 261, 262 HRV. See Heart rate variability (HRV) HSANs. See Hereditary sensory and autonomic neuropathies (HSANs) HSPB8-related distal myopathies 195 504 HSPs. See Hereditary spastic paraplegias (HSPs) Human T-cell leukemia virus type 1 (HTLV-1) 196 150 Human T-cell lymphotropic virus type 1 (HTLV-1) 196 104–105 Hunter syndrome 196 558 Huntingtin (HTT) gene 195 141 Huntington disease (HD) 195 141, 221 diffusion tensor imaging 195 366 inflammation in 195 368 microbiota-gut-brain axis and motor systems in 195 149 molecular imaging 195 366–368 T1-weighted structural imaging 195 366, 367 Hurler syndrome 196 558, 564 Hydrocephalus 196 17 Hydroxychloroquine 195 168 2-Hydroxypropyl-bcyclodextrin (HPBCD) 196 564 Hyperkalemic periodic paralysis (HyperPP) 195 521, 526, 527 Hyperkinetic seizures 196 298–299 Hyperlipidemia 196 306 HyperPP. See Hyperkalemic periodic paralysis (HyperPP) Hyperreflexia 196 75 Hypersensitivity vasculitis 195 657–658 Hypertension 196 306 Hypertonia 196 499–500 Hypnic jerks 195 391–392 Hypochlorhydria 196 152 Hypocomplementemic urticarial vasculitis (HUV) 195 653–654 Hypokalemic periodic paralysis (HypoPP) 195 521, 526, 527 HypoPP. See Hypokalemic periodic paralysis (HypoPP) Hypothalamus 196 409

Hypotonia clinical inspection 195 402–403 clues to differential cause 195 403–419 CNS-related 195 406 congenital myopathies 195 408–410 historical background 195 401–402 in infants 195 403 neonatal and infantile etiology 195 404 genetic basis of 195 405–406 and neurodevelopment 195 567 neurogenetic disorders 195 408 neuromuscular etiology 195 401

I IBM. See Inclusion-body myositis (IBM) ICU. See Intensive care unit (ICU) ICU-associated weakness (ICUAW) with COVID-19 195 760–761 GBS 195 738 myopathies 195 750–761 ICUAW. See ICU-associated weakness (ICUAW) I-cubed (I3) 196 369 Idiopathic brachial plexopathy. See Neuralgic amyotrophy Idiopathic myelitis 196 111 Idiopathic orthostatic hypotension (IOH) 195 73 IFN-b-1a 196 137 IgA vasculitis (IgAV) 195 653–654 Imaging motor recovery 196 326, 327 Imdevimab 195 169 Imitation behavior 196 450 Immune globulin 195 334–335 Immune modulatory therapy 195 738–739 Immune system in amyotrophic lateral sclerosis 195 142–143 basal ganglia-related movement disorders 195 141–142 in cerebellar ataxias 195 142 in development and physiology 195 136–137 in motor pathology 195 137–143 overview of 195 136 in Parkinson disease and atypical Parkinsonian syndromes 195 137–141, 140 role of 195 138–139 Immunoglobulin, vs. corticosteroids 195 335 Immunoglobulin m-binding protein 2 (IGHMBP2) 195 218 Immunoperoxidase 195 288–289 Immunosuppressive drug treatment 195 644 Immunotherapy 195 168–171 Impairment outcome measures 195 332 Imprinting control regions (ICRs) 195 233 Imprinting mutation 195 233–234 Inclusion-body myositis (IBM) 195 283, 292–293, 293, 425–426, 429 alemtuzumab 195 448–449 anakinra and canakinumab 195 449

INDEX Inclusion-body myositis (IBM) (Continued) antithymocyte globulin 195 449 autoimmune features of 195 441 beta-interferon 1a 195 449 clinical features 195 429–430, 429 comment of failed immunotherapy 195 449 cross-talk of inflammatory and degenerative elements 195 443–444 degenerative features 195 442–443 factors favoring inflammationautoimmunity 195 443–444 immunopathology 195 440–441 intravenous immunoglobulin 195 448 mechanisms in 195 442 MHC-1/CD8 complex in 195 434 muscle biopsy 195 434 nonimmune agents 195 449–450 nonimmune factors in 195 442–444 oxandrolone 195 449 primary degenerative disease with secondary inflammatory features 195 444 step-by-step therapeutic approach 195 445–448 supportive therapies 195 450 treatment 195 445 treatment trials in 195 448–450 IncobotulinumtoxinA 196 540, 541–543, 545–546, 548–550 Incremental stimulation technique 195 280 Induced pluripotent stem cell (iPSC) technology 196 222–223 Infantile convulsions with choreoathetosis (ICCA) syndrome 196 348 Infantile hypotonia etiology 195 404 genetic basis of 195 405–406 Infantile-onset hereditary spastic paraplegias 196 73 Infantile onset spinal muscular atrophy 196 44 Infantile spasms (IS) 195 568 Infarction 196 10 Infectious myelitis 196 101–105, 103 bacterial myelitis 196 102–104 fungal myelitis 196 105 parasitic 196 105 viral myelitis 196 104–105 Inflammatory neuropathy acute (see Guillain-Barr
e syndrome (GBS)) INCAT score 195 626–627 sensory 195 625–626 Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale 195 332, 333 Inflammatory Rasch-built Overall Disability Scale (I-RODS) 195 332 Inflammatory signaling, mitigation of 195 208 Infliximab 196 112

Infusion-related adverse events (IRAE) 196 561 Inherited Neuropathy Consortium (INC) 195 326–327 Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) 195 85 Innate immunity 195 147 Insertional activity 195 264–266 Insidiously progressive spastic gait 196 73 Insomnia 196 285 Insula 196 408 Insulin 196 574 Insulin-like growth factor I (IGF-I) 195 136–137 Insulin-like growth factors (IGFs) 196 574 Insulin receptors (IRs) 196 574 Intellectual impairment 196 74 Intensive care unit (ICU) ICUAW (see ICU-associated weakness (ICUAW)) period of care in 195 707 Intercellular adhesion molecule (ICAM)-I 195 437–438 Intercostal nerves 195 302 Interleukin-1b (IL-1b) 196 136, 141, 370 Interleukin-6 (IL-6) inhibition 195 171 Intermittent theta burst stimulation 196 603 Internal capsule infarction 196 323–325, 324–325 Internal carotid artery (ICA) 196 312–314 Internal nuclei, congenital myopathies 195 549–550 International normalized ration (INR) 196 331 International Pediatric Stroke Study (IPSS) 195 667, 196 320 International Stroke Trial (IST) 196 331 Internode 195 297 Intracellular signaling 195 198 Intracranial hemorrhage (ICH) 196 305–306 Intraepidermal nerve fiber density 195 298–299 Intramedullary AVMs 196 27–28 Intrathecal baclofen (ITB) 196 510–511 Intrathecal phenol 196 511 Intravenous immunoglobulin (IVIg) therapy 195 345–346, 645–646, 656, 196 102–104, 109–111, 237–238, 240, 242–244, 372–373 autoimmune inflammatory myopathies 195 445–447 COVID-19 195 171 dermatomyositis on muscle strength 195 447 on skin manifestations 195 446 Intrinsic factors 195 147 Invasive microelectrode 196 600–601 Ion channel dysfunction 195 200–202 Iron supplementation 195 390

633 Ischemia 196 10 spinal cord cervical region 196 11–12 lumbar region 196 12 thoracic region 196 12 Ischemic inflammatory and autoimmune factors 195 674–675 Ischemic penumbra 196 320 Ischemic Stroke System 196 336 Isolated dystonia 196 429–436 Isolated motor phenomena in sleep 195 391–394 Isoniazid 196 140 Isoprenoid synthase domain-containing protein (ISPD) 195 480 IVIg therapy. See Intravenous immunoglobulin (IVIg) therapy

J

Jamaican optic neuropathy 196 154–155 Janus kinase/signal transducer and activator of transcription (JAK/ STAT) pathway 196 581 Jiggle 195 277 Jitter 195 278, 279, 284 Junctional folds (JFs) 195 9–10 Juvenile GM2 gangliosidosis 195 211 Juvenile myasthenia gravis 195 637

K

Kabuki syndrome 195 210 Kaplan-Maier method 195 346 Karwinskia calderoni 196 151 Karwinskia humboldtiana 196 151 Kawasaki disease (KD) 195 653–654 KCNJ2 gene 195 527 Kearns-Sayre syndrome (KSS) 195 194–195 Kennedy disease 195 223 King-Devick (K-D) test 196 483–484 Kir2.1 potassium channel 195 528 Kiss-and-hop fashion technique 196 252 KLHL9 gene 195 511 KLHL9-related distal myopathies 195 511 Knee adduction, and incomplete extension 196 75 Knife-edge atrophy 196 255 Konzo 196 154 Krabbe disease 196 560

L

Lacunar infarction 196 323–325, 324–325 Laing distal myopathy 195 465, 484 Lambert-Eaton myasthenic syndrome (LEMS) 195 338–339, 635, 744–745, 196 233, 235, 241 Lamin A/C (LMNA) 195 482 Laminin 2 (LAMA2) gene 195 476–477 Laminopathy 195 474 LARGE expression 195 479–480 Large vessel vasculitides (LVV) 195 653–654 Laryngoscopy 196 188 Laryngospasm 195 526 sleep-related 195 393–394

634 Lateral medullary infarction 196 309 Lateral medullary syndrome 195 724–725 Lateral pontine arteries 196 308–309 Lateral vessels 196 307–308 Lausanne Stroke Registry 196 307 Leber hereditary optic neuropathy (LHON) 195 574 Leber optic atrophy modifier (LOAM) 195 183–184 Lecanemab 196 260–262 Leflunomide 195 682 Leg tremor 196 392 LEMS. See Lambert-Eaton myasthenic syndrome (LEMS) Length of stay (LOS) 196 329–330 Lennox–Gastaut syndrome (LGS) 196 295–296 Lenticulostriate arteries 196 312 Leprosy 196 150 LETM. See Longitudinally extensive transverse myelitis (LETM) Leukemia inhibitory factor (LIF) 196 577–578 Levodopa therapy 196 436 Lewy body disorders 196 190–195, 611–612 LGMD. See Limb-girdle muscular dystrophy (LGMD) Limb and respiratory muscles, weakness of neuromuscular assessment 195 710–718 cerebrospinal fluid analysis 195 717 compound muscle action potential waveforms 195 713 direct muscle stimulation 195 715–717 electrophysiological studies 195 711–717 history and physical examination 195 710–711 laboratory evaluation 195 711–718 motor unit number estimation 195 717 muscle and nerve biopsy 195 717–718 needle electromyography 195 712–713 nerve conduction studies 195 711–712 neuroimaging 195 711 quantitative motor unit potential analysis 195 713–715 repetitive nerve stimulation 195 712 specialized electrophysiologic studies 195 713–717 respiratory assessment bedside evaluation 195 719–722 dermal myelinated nerves 195 719 diaphragm studies 195 720–722 electrophysiology 195 720–722 imaging 195 720 phrenic nerve conduction studies 195 721, 721–722 pulmonary function testing 195 719–720

INDEX Limb apraxia 195 128 affordances 195 130 anatomy of 195 128 imitation deficits 195 129 localization 195 129–130 object use deficits 195 130 Limb-girdle muscular dystrophy (LGMD) 195 211, 461–462, 196 44 calpainopathy 195 474–475 caveolinopathy 195 474 clinical aspects 195 471 dysferlinopathy 195 475 electrodiagnosis 195 471 genotype phenotype correlation 195 474–476 imaging studies 195 471–473 laboratory diagnosis 195 471–474 laminopathy 195 474 muscle biopsy 195 473–474 myotilinopathy 195 474 sarcoglycanopathy 195 475 serum creatine kinase 195 471 subtypes of 195 471 treatment 195 475–476 Limbic encephalitis 196 237, 280 Limbic subsystems 196 380 LIM domain-binding protein 3-related distal myopathies 195 504–505 Lingual fasciculation 195 725 Lipid 195 198 synthesis 195 204 Lipoprotein cell membrane 195 198 Lipoprotein-receptor-related protein 4 (LRP4) antibodies 195 641 LMN. See Lower motor neuron (LMN) Lobar atrophy 196 255 Locomotion, vertebrate control of 195 103 Locus coeruleus (LC) 195 383 LOF. See Loss-of-function (LOF) Long exercise testing (LET), periodic paralysis 195 527–528 Longitudinally extensive transverse myelitis (LETM) 196 109, 111 Long-term depression (LTD) 196 165, 599–600 Long-term plasticity 196 165 Long-term potentiation (LTP) 196 165, 599–600 Losartan Intervention For Endpoint (LIFE) trial 196 334 Loss-of-function (LOF) 195 212 in repeat expansion 195 220–221 Low-density lipoprotein (LDL) 196 306 Lower motor neuron (LMN) 195 252, 196 46, 89, 91 features 195 18 neurophysiological studies of 195 17–18 syndrome 195 18 system 195 25 Lower urinary tract dysfunction 196 410 Low frequency (LF) bands 195 307 LRPN. See Lumbosacral radiculoplexus neuropathies (LRPN) Lumbar vertebrae 196 4–5

Lumbosacral and cervical radiculoplexus neuropathy 195 675–676 Lumbosacral plexus disorders 195 731–733 acute peripheral neuropathy 195 733–740 clinical and electrodiagnostic features 195 731–732 lumbosacral radiculoplexus neuropathy 195 732–733, 732 Lumbosacral radiculoplexus neuropathies (LRPN) 195 587, 594–596, 692–693, 732–733, 732 Lung and chest expansion, congenital myopathies 195 552 LUT control 196 407 Lyme disease 196 103, 411 Lyme neuroborreliosis 196 375–377 Lymphoma 196 21–22 Lyonization 195 212 Lysosomal metabolism 195 197–198 Lysosomal storage disorders (LSDs) 196 557–558 biomarkers 196 563 clinical features 196 559 defect 196 559 enzyme enhancement therapy (EET) 196 562 enzyme replacement therapy (ERT) 196 558, 560–561 gene therapy 196 564 hematopoietic stem cell transplantation (HSCT) 196 558, 560 investigational therapeutic options 196 562–564 mRNA-based therapy 196 564 newborn screening (NBS) 196 560 substrate reduction therapy (SRT) 196 562 therapeutic options 196 558–564, 560 Lystedt laws 196 487

M

Macrolide antibiotics 196 102–103 Macrophage stimulating protein (MSP) 196 577 Magnetic resonance imaging (MRI) 195 331, 196 12–13, 50, 149 childhood multiple sclerosis 196 131 multiple sclerosis (MS) 196 122–123, 123, 125–126 primary lateral sclerosis (PLS) 196 91–92 Magnetic resonance spectroscopy (MRS) 196 126 Maladaptive neuroplasticity 196 601 Mammalian target of rapamycin (mTOR) 196 580 Marfan syndrome (MFS) 195 407, 413 Marr-Albus-Ito theory 196 165 Masitinib 196 531 Maternally inherited Leigh syndrome (MILS) 195 184 Matrin-3-related distal myopathies 195 505

INDEX McManis protocol 195 527–528 Mechanical thrombectomy 196 335 Medial medullary infarction 196 309 Medial medullary syndrome 195 724 Medical Research Council (MRC) 195 184, 196 317 Medical Scientific Advisory Board (MSAB) 195 340 Medications 196 79 hereditary spastic paraplegias (HSPs) 196 79 neurogenic erectile dysfunction 196 419 Tourette syndrome (TS) 196 465 Medium vessel vasculitides (MVV) 195 653–654 Medulla 196 307–308, 308 Medullary infarction 195 724–725, 196 322 Meige syndrome 196 435 Memantine 196 260 Membrane attack complex (MAC) 195 346 Membrane vesicle trafficking 195 198 Meningiomas 196 19–20 Mesencephalic astrocyte-derived neurotrophic factor (MANF) 196 578 Mesencephalic locomotor region (MLR) 195 107 Mesenchymal stem cells 196 223 Messenger ribonucleic acid (mRNA) 196 209 Metabolic disorders 195 402–403 Metabolism 195 204 Metabolomics 195 145–147, 150–151 Metabotropic glutamate receptor type 1 (mGluR1) 196 282 Metachromatic leukodystrophy (MLD) 195 406–407, 196 560 Metastases 196 20–21 Methotrexate 195 645–647, 682, 196 109, 112 Methylation 196 49–50 Methylcobalamin 196 531 Methylprednisolone 196 109 Metoclopramide 196 96 MG. See Myasthenia gravis (MG) MG Activity of Daily Living (ADL) Profile 195 342 MG Composite (MGC) score 195 342 MGFA. See Myasthenia Gravis Foundation of America (MGFA) MG-specific quality of life 195 342 MGUS. See Monoclonal gammopathy of undetermined significance (MGUS) Microbiome milieu 196 368 Microbiota-gut-brain axis and motor systems 195 143–151 in amyotrophic lateral sclerosis (ALS) 195 149–150 in Huntington disease (HD) 195 149 intrinsic and extrinsic factors 195 147 in nondegenerative “network” movement disorders 195 150–151

Microbiota-gut-brain axis and motor systems (Continued) in Parkinson disease (PD) 195 145–149, 146, 148–149 Microglia 195 136–137, 196 260 Microglia, brain interactions 196 369–370 MicroRNA (miR) 196 222 Microscopic polyangiitis (MPA) 195 653–654 Microtubule-associated proteins (MAP) 196 252 Microtubule-associated protein tau (MAPT) 196 613 Microtubule-binding domains (MTBDs) 196 613 Microvasculitis (MV) 195 654 Microzones 196 162 Micturition disorders 196 411 Midbrain 196 311–312, 312 infarction 196 322–323 nuclei 196 409 Middle cerebral artery (MCA) 196 315, 316 Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) 196 332–333 Middle tegmental pontine syndrome 196 309, 310 Midkine (MK) 196 577 Mid-pontine basilar syndromes 196 310 Miglustat 196 562 Mild cognitive impairment (MCI) 196 613 Mild traumatic brain injury (mTBI) 196 475–477 clinicopathologic correlation 196 482–486 definitions 196 477–478 epidemiology 196 478–479 history 196 475–477, 479–480 laboratory evaluation 196 480–481 management 196 486 neuroradiologic approaches 196 481–482 physical examination 196 479–480 prognosis 196 486 public health policy and impact 196 486–490 community level 196 488–489 interpersonal level 196 489–490 intrapersonal level 196 489–490 school policy 196 487–488 socioecological framework (SEF) 196 486–490 state legislation 196 487 Miniature endplate potentials (MEPPs) 195 254, 266 Minicores with external ophthalmoplegia 195 409 myopathy 195 548–549 structured 195 548–549 Minimal clinically important difference (MCID) 195 335 Minimal manifestations 195 341–342 Minipolymyoclonus 196 44 Minocycline 196 525

635 Mirror neuron system 195 21 Mirror therapy 196 337 Mitochondrial aspartyl-tRNA synthetase 2 (DARS2) 196 360 Mitochondrial diseases 195 194–196 acute neurological presentations 195 576 adult-onset 195 564–565 ataxia 195 571–572 chronic neurological presentations 195 576 chronic progressive external ophthalmoplegia 195 572–573, 572 diagnostic investigation 195 575–576 dystonia 195 570 genetics 195 566–567 hypotonia and neurodevelopment 195 567 management 195 576–577 mitochondrial epilepsy of childhood 195 567–568 movement disorders 195 570 myoclonus 195 570 myopathy 195 572–573 neuroimaging findings 195 569 neurological manifestations of 195 567–575 neuropathy 195 573–574 optic neuropathies 195 574–575 Parkinsonism 195 571 pediatric-onset 195 564–565 prevalence 195 563 stroke-like episodes 195 568–570 Mitochondrial encephalomyopathies 195 194–196 Kearns-Sayre syndrome (KSS) 195 194–195 mitochondrial encephalomyopathy, lactic acidosis, with stroke-like episodes (MELAS) 195 195–196 myoclonus epilepsy and ragged red fibers (MERRF) 195 195 Mitochondrial encephalomyopathy, lactic acidosis, with stroke-like episodes (MELAS) 195 195–196, 567–568, 570, 576 Mitochondrial epilepsy of childhood 195 567–568 Mitochondrial function 195 205 Mitochondrial metabolism 195 197 Mitochondrial myopathy 195 292, 292 Mitofusin-2 (MFN2) gene 195 610, 613 Miyoshi distal myopathy 195 485–486 MMN. See Multifocal motor neuropathy (MMN) MNDs. See Motor neuron diseases (MNDs) Mobile Universal Lexicon Evaluation System (MULES) 196 483–484 Modifiers 195 212–213 MOGAD. See Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)

636 MOG-antibody disease (MOGAD) 196 24, 283–284 Molecular genetics 195 318, 348 Molecular layer 196 160 Molecular profiling 196 19 Monoaminergic pathways 195 107 Monoamines 195 303 Monocarboxylate transporter type 8 (MCT8) 196 355 Monoclonal antibodies, COVID-19 195 168–170 Monoclonal gammopathy 195 590 Monoclonal gammopathy of undetermined significance (MGUS) classification 195 589 clinical presentation 195 589–590 definition 195 589 diagnostic evaluation 195 590 IgM 195 589–590 management approach 195 591 pathophysiology 195 589 prognosis 195 590–591 treatment 195 590 Mood disorders, hereditary neuropathy 195 614–615 Morphometric analysis 195 289, 294–295 Morvan syndrome 196 285–287, 286 Mossy fiber-granule cell synapses, plasticity of 196 165 Motor cortex dorsomedial premotor cortex 195 21 force and speed control 195 20 local circuitries of 195 19–20 motor learning 195 20 motor program 195 20–21 organization and function 195 19 sensory feedback 195 20 supplementary motor area (SMA) 195 21 Motor disorders 196 581–582 Motor dysfunction 196 120–121 Motor function, recovery of 196 326 Motor impersistence 196 451 Motor learning 196 600–601, 603 Motor nerve conduction studies 195 255–257 Motor neuron diseases (MNDs) 195 316–320, 196 28, 45–46, 89, 236, 239, 585 adult familial amyotrophic lateral sclerosis 195 726 childhood spinal muscular atrophy 195 316–320, 317 classification 195 316 molecular genetics 195 318 natural history 195 318–319 neuropathology 195 316–317, 317–318 randomized controlled trials (RCTs) 195 319–320 hereditary 195 726–729 hereditary motor neuron disease 195 726–729 of infancy and childhood 195 412

INDEX Motor neuron diseases (MNDs) (Continued) infantile and childhood spinal muscular atrophy 195 726–727 neurodegeneration 196 93–94 poliomyelitis 196 32–33 primary lateral sclerosis (PLS) 196 32 progressive muscular atrophy (PMA) 195 727–729, 728, 196 30–32 spinal muscular atrophy (SMA) 196 28–30 sporadic amyotrophic lateral sclerosis 195 725–726 Motor neurons 195 252 Motor neuropathies, rheumatological disease 195 598–601, 599 rheumatoid arthritis peripheral neuropathy 195 600–601 Sj€ ogren’s syndrome peripheral neuropathy 195 598–600 Motor pathology, immune system in 195 137–143 Motor seizure semiology atonic seizures 196 299 automatisms 196 298 clinical manifestations 196 296 clonic seizures 196 296–297 epileptic spasm (ES) 196 297 future perspective 196 301 with high lateralizing values 196 299–301 asymmetric clonic ending (ACE) 196 300–301, 301 asymmetric tonic limb posturing 196 300 fencing position (M2e) sign 196 300 unilateral dystonia 196 300 version 196 299–300 hyperkinetic seizures 196 298–299 myoclonic seizures 196 297–298 negative motor phenomena 196 299 overivew 196 295, 301–302 tonic–clonic (T-C) seizure 196 297 tonic seizures 196 295–296 Motor-sensory axonal degeneration 196 78 Motor sequela chronic traumatic encephalopathy (CTE) 196 485–486 motor control 196 485 motor performance 196 484–485 posture 196 484 vestibular 196 484 visual 196 483–484 Motor symptoms in nonparaneoplastic CNS disorders with neural antibodies 196 277–278, 279 antibody-associated nonparaneoplastic cerebellar ataxias 196 281–282, 282 antibody-mediated encephalitis 196 278–281, 280 glial antibodies, autoimmune CNS disorders and 196 283–285, 284

Motor symptoms in nonparaneoplastic CNS disorders (Continued) inhibitory synapsis, autoimmune CNS disorders and 196 282–283 sleep dysfunction, antibody-associated CNS disorders with 196 285–290 Motor systems evolution of 195 19 functional, in brain and spinal cord 195 18 Motor tone 195 402 Motor transport 195 205 Motor unit 195 289 anatomy of 195 11 fast fatigable (FF) 195 12 fast fatigue resistant (FR) 195 12 firing rates 195 13 force-frequency relationship 195 13 properties 195 11–12 recruitment 195 12–13 slow (S) 195 12 Motor unit action potentials (MUAPs) amplitude 195 267 duration 195 267–268 morphology 195 267 onset frequency 195 268–269 phases and turns 195 268 recruitment ratio 195 269 spatial recruitment 195 268–269 spectrum of 195 268 stability 195 269 temporal recruitment 195 268–269 Motor unit number estimations (MUNE) 195 280–281, 284, 318–319, 196 29, 46 F-wave technique 195 281 incremental stimulation technique 195 280 multipoint stimulation technique 195 281 MUNIX 195 281 Poisson distribution technique 195 281 spike triggered averaging technique 195 281 Movement disorders 195 570, 196 287–288 Movement sensors 196 337 mRNA-based therapy 196 564 MS. See Multiple sclerosis (MS) MSA. See Multiple system atrophy (MSA) mTBI. See Mild traumatic brain injury (mTBI) MUAPs. See Motor unit action potentials (MUAPs) Multicore disease 195 548–549 Multifocal motor neuropathy (MMN) clinical criteria 195 592 clinical presentation 195 591–592 diagnostic evaluation 195 592–593 prevalence 195 591 prognosis 195 594 treatment 195 593 Multimechanical Embolus Retrieval in Cerebral Ischemia (MERCI) Trial 196 335–336

INDEX Multiminicore disease (MmD) 195 533–534 Multiple sclerosis (MS) 195 311–312, 371–372, 372, 196 23, 24, 108, 150, 417 childhood 196 130–131 clinical motor dysfunction 196 120–121 clinicopathologic spectrum 196 134 course 196 121–122, 122 diagnosis 196 121–127, 138 functional MRI (fMRI) 196 126–127 magnetic resonance imaging (MRI) 196 122–123, 123, 125–126 magnetic resonance spectroscopy (MRS) 196 126 transcranial magnetic stimulation (TMS) 196 126–127 epidemiology 196 119–121 etiopathogenic factors 196 119–121 gross pathology 196 131–132 immunopathology 196 132–136 inflammatory infiltrates in 196 135 microscopic pathology 196 131–132 myelin oligodendrocyte glycoproteinIgG1-associated disorder (MOGAD) 196 129–130 neurodegeneration 195 175 neuromyelitis optica spectrum disorders (NMOSD) 196 127–128 overview 196 119 pharmacotherapy 196 136–142 assessing motor disability 196 137–139 disease-modifying therapy 196 136–137 rehabilitation adaptive equipment 196 139 exercise 196 140 neural plasticity 196 140–142 symptomatic therapy 196 139–140 remyelinated lesions in 196 135 signs 196 121 symptoms 196 121 variants 196 127–131 Multiple Sclerosis Functional Composite (MSFC) 196 137–139 Multiple system atrophy (MSA) 195 311–312, 196 175–177, 184–190, 288, 418 ataxia of gait 195 68 autonomic failure 195 71–72, 72 classification 195 69–71 clinical features 196 185–187 diagnostic criteria for 196 185–186, 186 motor features of 196 186–187 nonmotor features 196 187 survival 196 187 diagnosis of 195 70 epidemiology 196 185 features 195 70 genetics 196 185 glial cytoplasmic inclusions 195 69 hot cross bun sign 195 72 laboratory assessment 195 72

Multiple system atrophy (MSA) (Continued) motor symptoms 196 188 multidisciplinary approach 196 188 nonmotor symptoms 196 189 paraclinical testing 196 187–188 analysis of cerebrospinal fluid 196 188 autonomic cardiovascular domain 196 187 brain imaging 196 188 cardiac sympathetic neuroimaging 196 188 plasma catecholamines 196 187 skin biopsy 196 188 thermoregulatory domain 196 187 urogenital, gastrointestinal, and respiratory domains 196 187–188 vs. Parkinson’s disease 195 71 pathology 196 184–185 pathophysiology 195 69, 196 184 vs. primary autonomic failure 195 71 symptom management 196 188–190 treatment 196 188–190 disease-modifying approaches 196 189–190, 189 motor symptoms 196 188 multidisciplinary approach 196 188 nonmotor symptoms 196 189 symptom management 196 188–190 Multipoint stimulation technique 195 281 MUNE. See Motor unit number estimations (MUNE) MUNIX 195 281 Muscle abnormalities 195 290 Muscle activation, reduced speed of 196 75 Muscle biopsies 195 287–299 indications for 195 287–288 reactions to injury 195 290–293, 291, 297–298 skin biopsy 195 298–299 techniques 195 288 tissue processing 195 288–298 nerve biopsies 195 293–294 reactions to injury 195 290–293, 291, 297–298 structure of normal nerve 195 296–297 structure of normal skeletal muscle 195 289–290, 289 techniques 195 294–296, 295 Muscle cells 195 254–255 Muscle channelopathies myotonia 195 521–526 pediatric syndromes and variants 195 526 periodic paralysis 195 526–530 prevalence 195 521 Muscle fiber 195 254–255 types 195 6–7 Muscle-fiber conduction velocity (MFCV) 195 709 Muscle histopathology, congenital myopathies 195 547–550, 547

637 Muscle imaging, congenital myopathies 195 550 Muscle lengthening 196 511–512 Muscle magnetic resonance imaging, congenital myopathies 195 550, 551 Muscle-specific kinase (MuSK) antibodies 195 640–641 myasthenia gravis (MG) with 195 637–638 Muscle tissue 195 288 Muscle ultrasound, congenital myopathies 195 536, 550 Muscle weakness 195 638, 641 Muscular dystrophy 195 187–188, 346–350 childhood 195 472 congenital biochemical basis 195 476 classification 195 476 genotype phenotype correlation 195 477 LAMA2 195 476–477 Duchenne muscular dystrophy (DMD) 195 347–350 classification 195 347–348 molecular genetics 195 348 natural history 195 348–349 randomized controlled trials (RCTs) 195 349–350 dystrophin-associated animal models 195 469–471 clinical aspects 195 466–467 electrodiagnosis 195 467 genotype phenotype correlation 195 468–469 incidence 195 466 laboratory diagnosis 195 467–468 muscle biopsy 195 467–468 serum creatine kinase 195 467 treatment 195 469–471 emery–Dreifuss 195 482–483, 483 facioscapulohumeral 195 462 limb-girdle 195 461–462 calpainopathy 195 474–475 caveolinopathy 195 474 clinical aspects 195 471 dysferlinopathy 195 475 electrodiagnosis 195 471 genotype phenotype correlation 195 474–476 imaging studies 195 471–473 laboratory diagnosis 195 471–474 laminopathy 195 474 muscle biopsy 195 473–474 myotilinopathy 195 474 sarcoglycanopathy 195 475 serum creatine kinase 195 471 subtypes of 195 471 treatment 195 475–476 Miyoshi 195 461–462 oculopharyngeal 195 461–462, 464 rigid spine-1 (RSMD1) 195 482 sarcomeric and nuclear proteins 195 463

638 Muscular infantilism. See Nemaline, myopathy Musician’s dystonia 196 545 MuSK antibodies. See Muscle-specific kinase (MuSK) antibodies Mutation-targeted pharmacotherapy ACTA1 195 555 MTM1 195 555–556 RYR1 195 554–555 SEPN1 195 554 Myasthenia gravis (MG) 195 336–346, 337, 635–647, 740–744, 196 235 Activity of Daily Living (ADL) 195 342 classification 195 635–637, 636, 742, 743 clinical features 195 638–639 clinical overview 195 338 clinical presentation 195 741 clinical status 195 742–743 clinical status and outcome measures 195 340–342 clinical testing 195 639 comorbidity 195 646 composite score 195 342 corticosteroid dose and area under the curve 195 342 crisis 195 637, 645–646 diagnosis 195 641–642, 741 differential diagnosis 195 741 epidemiology 195 637–638 future perspectives 195 647 immunomodulation 195 636 immunosuppression 195 636 induction of long-term improvement 195 744 induction of short-term improvement 195 743–744 management 195 642–645 with muscle-specific kinase (MuSK) antibodies 195 637–638 natural history 195 339–340 neuromuscular transmission 195 740–741 nosology 195 742 nosology and classification 195 338–339 outcome measures 195 742–743 overview 195 336–338 pathogenesis 195 640–641, 640 patient involvement 195 647 pregnancy and neonatal phase 195 646–647 quality of life 195 342 risk factors 195 639–640 serology 195 742 thymectomy 195 744 thymus role 195 741 treatment 195 342–346 azathioprine 195 343–344 cholinesterase inhibitors (ChE) 195 343 corticosteroids 195 343 eculizumab 195 346 intravenous immune globulin (IVIg) 195 345–346

INDEX Myasthenia gravis (MG) (Continued) mycophenolate mofetil 195 344 plasma exchange (PE) 195 345–346 rituximab 195 344 thymectomy 195 346, 347 Myasthenia Gravis Foundation of America (MGFA) 195 340 clinical classification 195 340 postintervention status 195 341–342 Myasthenia gravis manual muscle testing (MG-MMT) 195 342 Mycobacterium leprae 196 150 Mycobacterium tuberculosis 196 103–104 Mycophenolate 196 109 mofetil 195 344, 645–647, 682, 196 112 Mycoplasma pneumoniae 196 102–103 Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) 195 371–373, 373, 196 110–111, 129–130, 277–278 advanced imaging techniques 195 373–374 sarcoidosis 195 374 Myelin protein zero (MPZ) gene 195 611–612 Myelopathies 196 101, 102 demyelinating myelopathies 195 371–372 spinal cord infarction 195 370, 371 Myeloperoxidase (MPO) 195 658–659 Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome 195 570 Myoclonic seizures 196 297–298 Myoclonus 195 570 dystonia 196 437 Myoclonus epilepsy and ragged red fibers (MERRF) 195 195 Myofibrillar myopathy 195 506 Myofibrils 195 254–255 Myoglobulin-related myopathy 195 511 Myopathies 195 290–292, 572–573 vs. fatigue 195 284 congenital 195 530, 747–750, 747 critical illness weakness in ICU 195 750–761 differential diagnosis 195 747–748 metabolic 195 746, 747 mutation-targeted pharmacotherapy 195 749–750 natural history 195 748 respiratory management 195 748–749 rhabdomyolysis 195 746 Myosin heavy chain beta-related distal myopathies 195 505–506, 506 Myosin S1 structure 195 5 Myotilinopathy 195 474 Myotilin-related distal myopathies 195 506 Myotonia chloride channel (ClC-1) 195 524 CLCN1 variants 195 522 clinical features 195 521–522 diagnosis 195 523–525 electrophysiology 195 524

Myotonia (Continued) Fournier pattern I, SCN4A variant 195 525 laboratory investigation 195 523–525 management 195 525–526 molecular genetics 195 522–523 pathogenic mechanisms 195 522–523 to periodic paralysis and congenital myopathy 195 522 sodium channel (Nav1.4) channel 195 524 symptoms of 195 522, 523, 526 Myotonia congenita (MC) 195 521 Myotonic dystrophy 196 611–612 congenital 195 486–488 CTCF1 site methylation 195 488 early investigations 195 486 genetic basis 195 486–487 molecular mechanism 195 487–488 parental transmission 195 487 with respiratory failure and arthrogryposis 195 486 Myotoxic drugs and autoimmune inflammatory myopathies 195 436 Myotubularin 1 (Mtm1) 195 555–556

N NAM. See Necrotizing autoimmune myositis (NAM) Natalizumab 196 137 National Human Genome Research Institute 195 184 National Institute of Health Stroke Scale (NIHSS) 196 317, 318 National Institute of Neurological Disorders and Stroke (NINDS) 195 315–316 Navigation 195 31–32, 48–49 NCS. See Nerve conduction studies (NCS) Near-fiber count 195 279 Near fiber electromyography 195 272, 278–279 Near-fiber jiggle 195 279 Near-fiber motor unit jiggle 195 279 Nebulin-related distal myopathies 195 506–507 Necroptosis, blockade of 195 208 Necrosis 195 292–293 Necrotizing autoimmune myositis (NAM) 195 425–426 clinical features 195 428–429 features of 195 433 immunopathology 195 439–440 MHC-1/CD8 complex in 195 434 muscle biopsy 195 432 Needle EMG examination 195 263–269 Negative motor phenomena 196 299 Negative phase duration 195 257 Nemaline 195 409 bodies (rods) 195 547–548, 548 myopathy biopsy features 195 537 children with 195 538 clinical phenotype 195 537 disease pathogenesis 195 538

INDEX Nemaline (Continued) genetics 195 537–538 historical background 195 537 Met283Lys mutation 195 548 phenotype-genotype correlations 195 538 Neocerebellum 196 160 Neonatal hypotonia etiology 195 404 genetic basis of 195 405–406 Neonatal myasthenia 195 637 Nerve biopsies 195 293–294 Nerve conduction studies (NCS) amplitude 195 255–256 mixed 195 259 negative area under the curve (AUC) 195 256 sensory 195 251–252, 257–259 surface recording electrodes 195 256 utility of motor NCS 195 257 Nerve regeneration 196 582–583 Nerve root innervation 195 265 Neuralgic amyotrophy 195 596–598 Neural plasticity 196 140–142 cytokine signaling 196 141 endocannabinoid signaling 196 140–141 receptor signaling 196 141–142 Neuroanatomy bony spine 196 4–5 spinal cord 196 5 vasculature 196 5–6 Neurocysticercosis 196 105 Neurodegenerative autonomic failure 195 63–84 autonomic reflex screen and composite autonomic score 195 67 autonomic symptom assessment and disability 195 65 cardiac radioisotopic denervation imaging 195 67 central and peripheral autonomic components 195 63, 64 clinical and laboratory autonomic assessment 195 65–67 electrodiagnostic studies 195 67 head-up tilt table testing 195 66 heart rate response to deep breathing 195 66 multiple system atrophy 195 65 orthostatic hypotension 195 64–65 Parkinson’s disease with autonomic failure 195 65 pure autonomic failure (PAF) 195 65 quantitative sudomotor axonal reflex test 195 65 skin biopsy 195 67 supine and standing catecholamine levels 195 67 thermoregulatory sweat test 195 66 Valsalva maneuver 195 66–67 Neurodevelopment disorders 196 74 Neurofibrillary tangles (NFT) 196 252, 611–612 Neurofilaments (NF) 196 49

Neurogenetic motor disorders assignment of gene defect 195 234–235 clinical clues of 195 184–187 central nervous system (CNS) 195 186–187 peripheral nervous system (PNS) 195 185–186 defects in RNA processing 195 216–219 GLE1, RNA export mediator (GLE1) 195 217–218 glycyl-tRNA synthetase 1 195 218 immunoglobulin m-binding protein 2 (IGHMBP2) 195 218 Nova1 195 218–219 senataxin 195 217 survival motor neuron 195 216–217 genetic biomarkers 195 213–216 Alzheimer disease (AD) 195 215–216 amyotrophic lateral sclerosis (ALS) 195 213–214 synucleinopathies 195 214–215 tauopathies 195 215 genetic neurological disorders 195 187–210 congenital myasthenic syndrome (CMS) 195 188–190 familial amyotrophic lateral sclerosis (FALS) 195 205–210 hereditary cerebellar ataxia (HCA) 195 196–202 hereditary spastic paraplegia (HSP) 195 202–205 mitochondrial disorders 195 194–196 muscular dystrophy 195 187–188 peripheral neuropathy 195 190–194 genetic sequencing strategies 195 210 genomic imprinting and epigenetics 195 233–234 phenotypical gene expression 195 210–213 dominant negative effects and genetic heterogeneity 195 210–211 genetic modifiers 195 212–213 haploinsufficiency 195 211 loss-of-function (LOF) 195 212 lyonization 195 212 penetrance 195 211–212 toxic gain-of-function 195 212 repeat expansions diseases (REDs) 195 219–233, 219 Neurogenic atrophy 195 290 Neurogenic erectile dysfunction cause 196 419 Charcot-Marie-Tooth (CMT) disease 196 418 diabetes mellitus 196 418–419 epilepsy 196 417 familial amyloid polyneuropathies 196 418 medications 196 419 multiple sclerosis (MS) 196 417 multiple systems atrophy (MSA) 196 418

639 Neurogenic erectile dysfunction (Continued) Parkinson’s disease 196 417–418 spinal cord injury 196 417 Neurogenic orthostatic hypotension 196 178–179 Neuroimaging of motor disorders CNS motor disorders 195 361–370 diffusion tensor imaging 195 359–360 magnetic resonance imaging 195 359–360, 360 MR spectroscopy 195 361 PET 195 360–361 PNS disorders 195 374–377 SPECT 195 360–361 Neuroinflammation therapies 196 524–526 Neurological disability score (NDS) 195 332–333 Neuromuscular assessment 195 710–718 cerebrospinal fluid analysis 195 717 compound muscle action potential waveforms 195 713 direct muscle stimulation 195 715–717 electrophysiological studies 195 711–717 history and physical examination 195 710–711 laboratory evaluation 195 711–718 motor unit number estimation 195 717 muscle and nerve biopsy 195 717–718 needle electromyography 195 712–713 nerve conduction studies (NCS) 195 711–712 neuroimaging 195 711 quantitative motor unit potential analysis 195 713–715 repetitive nerve stimulation 195 712 specialized electrophysiologic studies 195 713–717 Neuromuscular diseases 195 315, 342 Neuromuscular electrodiagnosis 195 251 Neuromuscular junction (NMJ) 195 254, 272, 277, 635 components of 195 9 disorders of 195 290, 740–746 Neuromuscular reference centers (NRC) 195 330 Neuromyelitis optica spectrum disorders (NMOSD) 195 371–373, 372, 196 109, 127–128 with aquaporin-4 antibodies 196 277–278 motor symptoms in 196 283–284 Neuromyotonia 195 635, 196 285–287 and Morvan syndrome 196 240 Neuronal apoptosis inhibitory protein (NAIP) 196 46 Neuronal coding in alert animals 195 32–34 Neuronal cytoplasmic inclusions (NCIs) 196 204–205 Neurons 195 252 Neuropathology 195 316–317, 317–318 Laboratory 195 294

640 Neuropathy 195 573–574 axonal 195 571 clinical findings 195 573–574 Leber hereditary optic 195 574 optic 195 570, 574–575 peripheral 195 571 sensorimotor 195 574 Neuropathy, Ataxia and Retinitis pigmentosa (NARP) 195 184 Neurophysiological tests 195 641 Neurophysiology 196 13, 77 Neuroplasticity 196 599–601 adaptive 196 601 applied neuroplasticity 196 601 learning and 196 603–604 maladaptive 196 601 rehabilitation and 196 601–603 Neuroprotective effects, founder and 195 213 Neuroprotective therapy 196 334–335 Neuropsychiatric circuits, and networks 196 371–372 Neuropsychiatric comorbidity 196 410 Neuropsychiatric disorders 196 460–461 Neuropsychiatric illness 195 175 Neuropsychiatric symptoms (NPS) 196 613–614 Neurorehabilitation 196 601–603 Neurosarcoid myelitis 195 374 Neurosyphilis 196 103 Neurotransmission 195 10–11 Neurotransmitter 196 498 Neurotrophin-3 (NT-3) 196 573 Neurotrophin 4/5 (NT-4/5) 196 573 Neurotrophin growth factor (NGF) 196 569–572 brain-derived neurotrophic factor (BDNF) 196 569–570, 572–573 neurotrophin-3 (NT-3) 196 573 neurotrophin 4/5 (NT-4/5) 196 573 Neurovascular intervention and surgery 196 335–336 Neurturin 196 575 Newborn screening (NBS) 196 560 Niemann-Pick disease-type C 196 611–612 Nifedipine 196 96 Nitric oxide 196 417 Nitrous oxide exposure 196 113–114 N-methyl-D-aspartate (NMDA) receptors 196 142 encephalitis 196 237–238 NMJ. See Neuromuscular junction (NMJ) NMOSD. See Neuromyelitis optica spectrum disorders (NMOSD) NMO-spectrum disorders (NMOSD) 196 23–24 Nocturnal leg cramps 195 393 Nocturnal panic attacks 195 394 Nodulus/uvula, posterior cerebellar vermis 195 44–46 Noncoding repeat expansion 195 199–200 Noncompressive myelopathies 196 101 transverse myelitis (TM) (see Transverse myelitis (TM))

INDEX Nondegenerative “network” movement disorders, microbiota-gut-brain axis and motor systems in 195 150–151 Nondiabetic LRPN (NDLRPN) 195 594 Nondystrophic myotonias (NDM) 195 521 SCN4A-related NDMs 195 523 Non-Hodgkin lymphoma (NHL) 196 221–222 Noninfectious myelitis 196 105–111, 106–107, 107–108 acute disseminated encephalomyelitis (ADEM) 196 109–110 among children and adults 196 106–107 idiopathic myelitis 196 111 multiple sclerosis 196 108 myelin oligodendrocyte glycoproteinantibody-associated disease 196 110–111 neuromyelitis optica spectrum disorders (NMOSD) 196 109 Noninvasive intermittent positive pressure ventilation, congenital myopathies 195 553 Noninvasive spinal cord imaging 196 12–13 Nonlinear & spike timing codes 195 34–36 Nonmotor symptoms 196 189 Non-neurotrophin growth factors angiopoietins 1–4 196 577 bone morphogenetic proteins (BMPs) 196 576 cerebral dopamine neurotrophic factor (CDNF) 196 578 ciliary neurotrophic factor (CNTF) 196 573–574 clusterin 196 577 cysteine-rich neurotrophic factor (CNRF) 196 578 cytokines 196 577–578 epidermal growth factor (EGF) 196 576 erythropoietin (EPO) 196 576–577 fibroblast growth factor (FGF) 196 575–576 glial cell line-derived neurotrophic factor (GDNF) 196 574–575 glucagon-like peptide (GLP-1) 196 578 hepatocyte growth factor (HGF) 196 577 insulin and insulin-like growth factors (IGFs) 196 574 mesencephalic astrocyte-derived neurotrophic factor (MANF) 196 578 midkine (MK) 196 577 osteopontin 196 577 platelet-derived growth factor (PDGF) 196 576 pleiotrophin (PTN) 196 577 transforming growth factors (TGFbs) 196 576 vascular endothelial growth factor (VEGF) 196 577 Nonprimary tauopathies 196 611–612 Nonprogressive spastic gait 196 73

Nonrapid eye movement sleep (NREM) 196 604 Nonsteroidal immunosuppressive therapies, and autoimmune inflammatory myopathies 195 445 Nonsystemic peripheral nerve vasculitides (NPNV) 195 673–676 Nonsystemic vasculitic neuropathy 195 691–692 Norepinephrine 195 303, 196 417 Normal aging 195 281 Normal nerve, structure of 195 296–297 Normal skeletal muscle, structure of 195 289–290, 289 Normative data 195 279–280, 280 NorthAmerican Symptomatic Carotid Endarterectomy Trial (NASCET) 196 335 Northern France tauopathy 196 258 Northern Manhattan Stroke Study (NOMASS) 196 305–306 Nosology 195 709–710 and classification 195 338–339 Nova1 195 218–219 Novel coronavirus-2 2019 (COVID-19) pandemic. See COVID-19 infection NREM sleep parasomnias confusional arousals 195 386 sleep-related abnormal sexual behaviors 195 387 sleep-related eating disorder 195 386–387 sleep terrors 195 386 sleep walking 195 386 Nuclear DNA repair, replication, and genome stability 195 197 Nuclei neurons 195 33 Nusinersen 195 319, 196 52 Nutritional deficiency 196 151–152 Nutritional neuropathy 196 152

O Obsessive-compulsive disorder (OCD) 196 370–371, 378–380 implications for 196 378–380 Occupational therapy 195 649 OCD. See Obsessive-compulsive disorder (OCD) Ocrelizumab 196 137 Ocular myasthenia gravis 195 644 Ocular toxicity 196 153 Oculomotor apraxia disorder 195 197 Oculopharyngeal muscular dystrophy (OPMD) 195 232, 461–462, 464 Oculopharyngodistal myopathies 195 511 Older children, congenital myopathies in 195 547 Oligoclonal bands (OCBs) 196 123–124 OnabotulinumtoxinA 196 541–543, 546, 548–550 Onasemnogene 195 319–320, 196 52–53 One and done therapy 196 222 Oneiric stupor 196 285

INDEX Online Mendelian Inheritance of Man (OMIM) 196 356–357 Onset latency 195 256–257 Optic neuritis (ON) 196 111 Optic neuropathies 195 574–575, 196 152–153 diagnostic investigation 195 575–576 dominant optic atrophy (DOA) 195 574–575 Leber hereditary optic neuropathy 195 574 Optineurin (OPTN) 195 208–209, 196 212–213, 218 Optokinetic after-nystagmus (OKAN) test 196 484 Oral cannabis extract (OCE) 196 140–141 Organic life 195 302 Organophosphorous pesticides 196 153 Orientation log (O-log) 196 486 Orienting posture, mechanisms of 195 115–116 Orofacial-lingual dyskinesias 196 278 Oromandibular dystonia (OMD) 196 435, 544 Orthostatic hypotension 195 82, 196 178–179 nonpharmacologic therapy 195 88 pharmacologic therapy 195 88 transient surges with everyday activities 195 88 treatment of 195 88 Orthotics 196 79 Osteopontin 196 577 Osteosclerotic myeloma 195 626 Outliers 195 349 Overall disability sum score (ODSS) 195 332 Overall neuropathy limitation score (ONLS) 195 327 Overlap myositis 195 425–428 with Jo-1 antibodies, muscle biopsy 195 431–432 Oxidative phosphorylation (OXPHOS) 195 566 Oxidative stress (OS) therapies 196 530–531 Oximetry monitoring and biofeedback, congenital myopathies 195 553–554 Oxybutynin 196 96

P PAF. See Pure autonomic failure (PAF) Pain, hereditary neuropathy 195 614–615 Paleocerebellum 196 160 PAN. See Polyarteritis nodosa (PAN) PANDAS 196 372–373 Pandemic, COVID-19. See COVID-19 infection PANS. See Pediatric acute-onset neuropsychiatric syndrome (PANS) Paraffin 195 292–294 Parallel arteries 196 310 Parallel visuomotor processing 195 128

Paramyotonia congenita (PMC) 195 521 Paraneoplastic cerebellar degeneration (PCD) 196 236 Paraneoplastic encephalomyelitis (PEM) 196 236–237 Paraneoplastic mechanisms 196 220–222 Paraneoplastic motor disorders (PNDs) clinical syndromes brainstem encephalitis 196 237 chronic sensorimotor neuropathy 196 240 Guillain-Barr
e syndrome (GBS) 196 240 Lambert–Eaton myasthenic syndrome 196 241 limbic encephalitis 196 237 motor neuron syndromes 196 239 neuromyotonia and Morvan syndrome 196 240 NMDA receptor encephalitis 196 237–238 paraneoplastic cerebellar degeneration (PCD) 196 236 paraneoplastic encephalomyelitis (PEM) 196 236–237 paraneoplastic myelopathy 196 238 paraneoplastic opsoclonus-myoclonus ataxia (POMA) 196 238 paraneoplastic sensory neuronopathy 196 240 stiff-person syndrome (SPS) 196 238 subacute motor neuronopathy 196 239–240 subacute sensorimotor neuropathy 196 240 clinicopathologic features 196 233 epidemiology 196 235–236 examples 196 231–233 historical perspective 196 233–235 immunopathogenesis 196 241–242 laboratory evaluation 196 241 with motor system involvement 196 232 neural-specific autoantibody 196 243 overview 196 231 prognosis 196 242–245 treatment 196 242–245 Paraneoplastic myelitis 196 113 Paraneoplastic myelopathy 196 238 Paraneoplastic opsoclonus-myoclonus ataxia (POMA) 195 218–219, 196 221, 238 Paraneoplastic sensory neuronopathy 196 240 Paraneoplastiques 196 220 Paraproteinemic neuropathy. See Monoclonal gammopathy of undetermined significance (MGUS) Parasomnias, NREM sleep confusional arousals 195 386 sleep-related abnormal sexual behaviors 195 387 sleep-related eating disorder 195 386–387

641 Parasomnias, NREM sleep (Continued) sleep terrors 195 386 sleep walking 195 386 Parasympathetic cholinergic system 195 56–57 Parasympathetic ganglia 195 61 Parasympathetic nervous system (PaNS) 195 55–56 Paratonia 196 448 Parietal lobe 195 127, 130–131 Parkinson disease (PD) 195 135, 311–312, 196 175, 177, 190–195, 256, 417–418, 582 autonomic and neuropathological correlations 195 79–81 autonomic failure in 195 79–81 autonomic symptoms in 195 78–79 clinical features 196 192–193 clinical immunotherapy 195 141 diagnostic criteria 196 192 epidemiology 196 191–192 genetics 196 191 hypothalamic functional connectivity in 195 80 immune system in 195 137–141, 140 Lewy bodies in hypothalamic nuclei 195 81 microbiota-gut-brain axis and motor systems in 195 145–149, 146, 148–149 multiple system atrophy vs. 195 71 neurodegeneration 195 174–175 nonmotor features 196 192–193 paraclinical testing 196 193–194 analysis of cerebrospinal fluid 196 194 autonomic testing 196 193–194 imaging techniques 196 193, 194 plasma catecholamines 196 194 skin biopsy 196 194 pathology 196 191 pathophysiology 196 190–191 in primary lateral sclerosis (PLS) patients 196 90–91 rigidity 196 500 treatment 196 194–195 Parkinsonian syndromes, atypical 195 140 Parkinsonism 195 571, 196 150, 289–290 axial T2 FLAIR MRI 195 364 diffusion imaging 195 364 iron-sensitive MR imaging 195 366 molecular imaging techniques 195 363–364 neuromelanin-sensitive MR 195 365 Parkinson rest tremor 196 549 Paroxysmal dyskinesia (PxD) 196 347–356, 349–350, 437–438 paroxysmal exercise-induced dyskinesia (PED) 196 353–354, 438 paroxysmal kinesigenic dyskinesia (PKD) 196 348–352 paroxysmal nonkinesigenic dyskinesia (PNKD) 196 352–353 pathophysiologic framework 196 355–356

642 Paroxysmal movement disorders 196 347–348 Paroxysmal nonkinesigenic dyskinesias I (PNKD1) 196 437–438 Parsonage–Turner syndrome. See Neuralgic amyotrophy Passive tau-based immunotherapy, for tauopathies bepranemab 196 617 disease-modifying approaches for 196 613–614 gosuranemab 196 616 primary tauopathies 196 612 semorinemab 196 615–616 tau protein structure and function 196 613 tilavonemab 196 616 Pathogenic B-cell activation 196 135 PCNSV. See Primary CNS vasculitides (PCNSV) PD. See Parkinson disease (PD) PE. See Plasma exchange (PE) Pediatric acute-onset neuropsychiatric syndrome (PANS) 196 373–377 with postinfectious immune mechanisms 196 374 Pediatric infection-triggered autoimmune neuropsychiatric disorders (PITANDS) 196 372 Pediatric inflammatory brain disease 196 321 Pediatric neuropsychiatric disorders brain milieu 196 369–370 blood-brain barrier (BBB) 196 369 brain microglia 196 369, 370 cytokines 196 369–370 COVID-19 neurological illness 196 374, 375 etiopathogenesis 196 377–380 immune system 196 368 adaptive immunity 196 368 autoimmunity 196 369 Lyme neuroborreliosis 196 375–377 microbiome milieu 196 368 obsessive-compulsive disorder (OCD) implications for 196 378–380 PANDAS 196 372–373 pediatric acute-onset neuropsychiatric syndrome (PANS) 196 373–377 with postinfectious immune mechanisms 196 374 Tourette syndrome (TS) 196 370–372 definition of 196 371 immunopathogenic factors 196 372 neuropsychiatric circuits and networks 196 371–372 treatment of 196 372 Pediatric-onset mitochondrial diseases 195 564–565 Pediatric Rheumatology European Society (PRES) 195 654 Pediatric Rheumatology International Trials Organization (PRINTO) 195 654 Pediatric syndromes and variants 195 526

INDEX Pediatric transverse myelitis 196 111 Pedigree analysis, muscular dystrophy 195 464 Penetrance 195 211–212 Penumbra Pivotal Stroke Trial 196 335 Percutaneous transluminal angioplasty and stenting (PTAS) 196 335 Perfusion weighted imaging (PWI) 196 319 Periaqueductal gray (PAG) 196 405–408 Perilipin-4–related distal myopathies 195 507 Perindopril Protection Against Recurrent Stroke Study (PROGRESS) 196 334 Perineurial cells 195 296 Periodic acid-Schiff (PAS) 195 185, 288 Periodic limb movement disorder (PLMD) 195 391 Periodic paralysis (PP) calcium channel (Cav1.1) 195 528 clinical features 195 526–527 diagnosis 195 527–529 genetic testing 195 528 Kir2.1 potassium channel 195 528 laboratory investigation 195 527–529 management 195 529–530 molecular genetics 195 527 neurophysiology 195 527–528 pathogenic mechanisms 195 527 SCN4A variant 195 530 Peripheral myelin protein 22 (PMP22) gene 195 610–611 Peripheral nerve block 196 510 Peripheral nerve demyelination, electrodiagnostic criteria for 195 332 Peripheral nerve hyperexcitability (PNH) 196 240 Peripheral nerve imaging 195 374–377 focal mononeuropathies 195 375 hereditary and acquired inflammatory demyelinating neuropathies 195 376–377 plexopathy 195 375–376 Peripheral nerve stimulation 196 603 Peripheral nerve vasculitis (PNV) 195 654 classification 195 676 Peripheral nervous system (PNS) 195 185–186 spinal column and 195 253 Peripheral neuromuscular system organization of 195 252 pertinent anatomy and physiology 195 252–254 Peripheral neuropathy 195 190–194, 293–294, 320–336, 196 75, 77–78, 150, 583–584 Charcot–Marie–Tooth (CMT) disease 195 190–191, 320–329, 322, 326 assessment tools for 195 327 classification 195 321–326 natural history 195 326–327 randomized controlled trials (RCTs) 195 328–329

Peripheral neuropathy (Continued) chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 195 329–336, 329 clinical presentation 195 329 diagnosis and treatment guidelines 195 329–332 disability outcome measures 195 332 impairment outcome measures 195 332 overview 195 329 randomized clinical trials (RCTs) 195 332–336 revised diagnostic criteria 195 331 revised electrodiagnostic criteria 195 331–332, 333 diagnostic evaluation 195 590 familial amyloid polyneuropathy 195 193–194 hereditary sensory and autonomic neuropathy (HSAN) 195 192–193 Peripheral Neuropathy Society (PNS) 195 329–330 Perivasculitis (PV) 195 654 Peroral pyridostigmine 195 642 Peroxisomal metabolism 195 197 Persephin 196 575 Pharmacodynamics (PD) 196 53–54 Pharmacokinetics (PK) 196 53–54 Pharmacologic chaperone (PC) 196 562 Pharmacologic remission 195 341–342 Pharmacotherapy 196 464–467, 465 Phenobarbital 196 396 Phenol necrolyses 196 510 Phenotypical gene expression 195 210–213 dominant negative effects and genetic heterogeneity 195 210–211 genetic modifiers 195 212–213 haploinsufficiency 195 211 loss-of-function (LOF) 195 212 lyonization 195 212 penetrance 195 211–212 toxic gain-of-function 195 212 Phosphatase and tensin homolog (PTEN) 196 579–580 Physiological fragmentary (partial) hypnic myoclonus (PFHM) 195 392 Physiotherapy 195 649, 196 79–80, 506 Pick’s disease (PiD) 196 255 Picornaviruses 196 104 PI3K-pAkt pathway 196 579 Pinealoma 196 311–312 Plasma catecholamines 196 187, 194 Plasma exchange (PE) 195 335–336, 345–346, 646, 196 109, 111, 113, 237–238, 242–244, 372 Plasticity mechanisms 196 165 Platelet-derived growth factor (PDGF) 196 576 Pleiotrophin (PTN) 196 577 PLS. See Primary lateral sclerosis (PLS) Pluripotent stem cell therapy 196 222–223 PM. See Polymyositis (PM)

INDEX PMA. See Progressive muscular atrophy (PMA) PNDs. See Paraneoplastic motor disorders (PNDs) Poisson distribution technique 195 281 Polioencephalitis 196 32 Poliomyelitis 195 730–731, 730, 196 32–33 Poliovirus 196 104 infections 196 32 Polyarteritis nodosa (PAN) 195 653–654 childhood PAN (cPAN) 195 655–656 with prominent motor involvement 195 655–656 small vessel vasculitides 195 656–657 vasculitides, tissue biopsy studies 195 679 Polyminimyoclonus 196 44 Polymyositis (PM) 195 425–426 autoimmune features of 195 441 clinical features 195 428 immunopathology 195 440–441 muscle biopsy 195 432–434, 433 Polyneuropathy 196 585 Polysomnography 196 188, 194 POMGNT1 gene 195 479 Pompe disease 196 561 POMT1 and POMT2 genes 195 479 Pons 196 308–310 Pontine infarction 196 322 Pontine micturition center (PMC) 196 405–408 Pontocerebellar hypoplasia (PCH) 196 47 Porphyria 195 739–740 Positioning 196 506 Positron emission tomography (PET) 196 92, 259, 326, 615–616 Positron emission tomography (PET), and PET fused to magnetic resonance imaging (PET-MRI) in COVID-19-associated PANS and PASC 196 375 in neuroborreliosis-associated PANS 196 376 in PANDAS 196 373 in Tourette syndrome 196 371–372 Postconcussion Symptom Scale (PCSS) 196 480–481 Postconcussion syndrome (PCS) 196 476 Posterior and inferior cerebellar artery (PICA) 196 310 Posterior cerebral artery (PCA) 196 315, 315 Posterior communicating artery (PoCA) 196 312 Posterior fossa syndrome 196 169 Posterior lobe 196 160 Posterior spinal artery (PSA) syndrome 196 11 Postganglionic axons 195 303 Postinfectious autoimmunity CNS vasculitis, COVID-19 pandemic 195 670–673 Postinfectious immune response 195 160–161

Postpolio muscular atrophy 195 731 Postsynaptic defects 195 188–189 Posttraumatic amnesia (PTA) 196 477 Postural reflexes, adaptation and compensation of 195 41 Postural tachycardia syndrome (POTS) 195 310 Posture 195 34, 41 Posture gait mechanisms anticipatory postural adjustment (APA) 195 115–116 by BG 195 117–120 brainstem-spinal cord pathways 195 107–110 by cerebellum 195 117–120 cortical mechanisms, human posture–gait control 195 114–116 DA neurons 195 118–119 by emotional systems 195 117–120 first step 195 116 functional organization of 195 108 gazing and orienting posture 195 114–115 locomotor regions 195 107 locomotor system, functional organization of 195 109 spinal locomotor network 195 110 superior colliculus (SC) 195 109–110 upright standing posture 195 114 during walking 195 104 Post-Varicella angiopathy (PVA) 196 336 Postvoid residual (PVR) 196 185 Potassium calcium-activated channel subfamily M alpha 1 (KCNMA1) 196 352–353 Potassium voltage-gated channel subfamily A member 1 (KCNA1) 196 357 PP. See Periodic paralysis (PP) Prader–Willi syndrome (PWS) 195 233–234 Pramipexole 196 530–531 Praziquantel 196 149–150 Precision medicine 196 262 Prednisolone 195 644, 646–647 Prednisone 195 343, 349–350, 196 238 Prefrontal cortex (PFC) 196 409 behavior expression 195 110–112 role of 195 110–111 slow walking and FOG by disturbances 195 111–112 Pregabalin 196 507, 508 Premotor cortex functional organization of 195 112–113 premotor–corticoreticular system, posture–gait control 195 113 rostral and caudal premotor regions 195 112–113 Presynaptic defects 195 188 PReventiOn regimen For Effectively avoiding Second Strokes (PRoFESS) 196 334–335 Primary acetylcholine receptor deficiency 195 649

643 Primary age-related tauopathy (PART) 196 257, 612 Primary angiitis 195 664 Primary CNS vasculitides (PCNSV) 195 654 in adults 195 660–663, 689–690 in children 195 660–663, 690–691 Primary intramedullary spinal lymphoma 196 21 Primary lateral sclerosis (PLS) 196 32, 206–207 clinical description 196 90–91 differential diagnosis 196 90, 92–93, 93 electrophysiology 196 91 genetics 196 94–95 motor neuron disease (MND) 196 93–94 neurodegeneration 196 93–94 neuroimaging MRI 196 91–92 positron emission tomography (PET) 196 92 neuropathology 196 91 overview 196 89–90 Parkinson disease (PD) patients with 196 90–91 phenotype 196 73 treatment 196 95–96 Primary progressive aphasia (PPA) 196 612 Primary progressive multiple sclerosis (PPMS) 196 92 Primary sensorimotor zone 196 166 Primary tauopathies 196 251–257, 254, 611–612, 614–615, 615, 617 aging-related tau astrogliopathy (ARTAG) 196 257 anti-IGLON5 196 256–257 argyrophilic grain disease (AGD) 196 257 corticobasal degeneration 196 255–256 frontotemporal dementia 196 253–255 globular glial tauopathy (GGT) 196 256 Pick’s disease (PiD) 196 255 primary age-related tauopathy (PART) 196 257 progressive supranuclear palsy (PSP) 196 256 Primidone 196 140, 396 Primitive reflexes 196 449 Procerus sign 196 256 Profilin-1 (PFN1) 196 215, 218 Progresses with external ophthalmoplegia (PEO) 195 534–536 Progressive autonomic failure 196 176 Progressive encephalomyelitis with rigidity and myoclonus (PERM) 196 277–278, 283 Progressive muscular atrophy (PMA) 195 727–729, 728, 196 30–32, 206–207 Progressive myoclonic epilepsy-1A (EPM1A) 195 221 Progressive supranuclear palsy (PSP) 196 256, 287–288, 451, 612

644 Proline rich transmembrane protein 2 (PRRT2) 196 348–351, 355–356 Propranolol 196 140, 396 Proprioception 195 46–47 Propriospinal myoclonus (PSM) at sleep wake transition 195 392 Protein aggregation 196 527–528 glycosylation, defect in 195 190 homeostasis 195 224 translation 195 198 Proteinase 3 (PR3) 195 658–659 Protein misfolding cyclic amplification (PMCA) 196 181–182 Protein-O-mannose kinase (POMK) gene 195 481 Proximal response 195 255, 256 Pseudo-hypertrophic DMD 195 484 Psychosis spectrum 196 169 Ptosis 195 638, 639 Pulse therapy 196 136 Punch drunk syndrome 196 485–486 Pure autonomic failure (PAF) 195 73–78, 196 176–184, 184 ancillary testing 196 180–182 analysis of cerebrospinal fluid 196 181–182, 182 autonomic function tests 196 180–181, 180 cardiac sympathetic neuroimaging 196 181 catecholamine 196 181 evaluation of end-organ damage 196 181 gastrointestinal studies 196 181 laboratory testing 196 181 neuroendocrine 196 181 skin biopsy 196 181 urodynamic studies 196 181 baroreflex failure autonomic storms 195 86–87 bladder dysfunction 195 83–84 bowel dysfunction 195 83–84 chemoreflex failure 195 87 clinical features 196 178–180, 178 anosmia 196 179 dream enactment behavior 196 179 gastrointestinal dysfunction 196 179 genitourinary dysfunction 196 179 neurogenic orthostatic hypotension 196 178–179 supine hypertension 196 178–179 thermoregulatory dysfunction 196 179 diagnosis 195 75 epidemiology 196 178 gastrointestinal dysfunction 195 82–83 genetics 196 177–178 historical turning points 195 73–75 laboratory studies 195 75 natural history and prognosis 195 75–78 neurophysiology of 195 86–87 orthostatic hypotension 195 82 pathology 196 177 pathophysiology 196 177

INDEX Pure autonomic failure (PAF) (Continued) postmortem clinicopathological features 195 74 prognosis 195 87–88 prospective cohort studies selection 195 75 sexual dysfunction 195 83–84 tilt table testing 195 76 treatment 196 182–184 care team 196 182 prognosis and phenoconversion 196 183–184 symptom management 196 183 treatment and management of failure 195 81–84, 82 Valsalva maneuver 195 77 Purkinje cell layer 196 160 Purkinje neurons 196 160, 162–164 PxD. See Paroxysmal dyskinesia (PxD) Pyridostigmine 195 646–647 Pyruvate Dehydrogenase Complex (PDC) 196 353–354 Pyruvate dehydrogenase complex component X (PDHX) 196 353–354 Pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) 196 353–354

Q QEMG. See Quantitative electromyography (QEMG) QSART. See Quantitative sudomotor axonal reflex test (QSART) Quadriparesis 196 74 Quantitative electromyography (QEMG) 195 271–273, 272 amyotrophic lateral sclerosis (ALS) 195 283 anatomic motor unit (A-MU) 195 273 electrophysiologic motor unit (E-MU) metrics 195 273, 275–277 motor unit number estimations (MUNE) 195 280–281, 284 motor unit viewing and assessment 195 273–275 myopathy vs. fatigue 195 284 normative data 195 279–280, 280 radiculopathy 195 283 routine 195 283–284 single-fiber electromyography 195 277–279, 284 statistical motor unit and muscle characterization 195 281–282, 282 turns and amplitude, analysis of 195 282, 283 Quantitative MG scale 195 340–341, 341 Quantitative sudomotor axon reflex test (QSART) 195 304, 312, 196 180–181

R

Rabies 196 151 Radiation therapy-related myelitis 196 113 Radiculopathy 195 283

Radiculoplexus neuropathies lumbosacral radiculoplexus neuropathy 195 594–596 neuralgic amyotrophy 195 596–598 Randomized controlled trials (RCTs) 195 319–320, 328–329, 332–336, 349–350 ascorbic acid 195 328–329 corticosteroids 195 332–334 immunoglobulin 195 334–335 vs. corticosteroids 195 335 nusinersen 195 319 onasemnogene 195 319–320 plasma exchange 195 335–336 prednisone 195 349–350 risdiplam 195 320 Rapid eye movement (REM) 196 256, 280–281 RAR-related orphan receptor (ROR) alpha 195 225 Rasagiline 196 530–531 Ras/ERK pathway 196 581 RCTs. See Randomized controlled trials (RCTs) Reaching 195 48 Reafference 195 40–41 Real-time quaking-induced conversion (RT-QuIC) analysis 195 214–215 Receptor signaling 196 141–142 Recessive hereditary cerebellar ataxias 195 196 Recurrent isolated sleep paralysis (RISP) 195 387 REDs. See Repeat expansions diseases (REDs) Regional cerebral blood flow (rCBF) 196 328 Rehabilitation hereditary neuropathy 195 614 and neuroplasticity 196 601–603 Relapsing-remitting pattern (RRMS) 196 120, 123 brain MRI imaging cortical lesions 196 126 clinicopathological spectrum 196 131–132, 133 disease-modifying therapy (DMT) 196 137 Remak cells 195 297 Remdesivir, COVID-19 195 168 REM sleep behavior disorder (RBD) 195 387 REM sleep parasomnias 195 387 Repeat expansions diseases (REDs) 195 219–233, 219 gain-of-function (GOF) CUG tract 195 232 polyalanine tract expansion 195 232–233 polyglutamine tract expansion 195 221–231 loss-of-function (LOF) in 195 220–221 Repetitive nerve stimulation (RNS) 195 338, 641, 643, 196 50

INDEX Repetitive nerve stimulation studies (RNSS) 195 254, 263, 263–264 Repolarization phase 195 253 Respirator interventions, congenital myopathies 195 552–553 Respiratory assessment bedside evaluation 195 719–722 dermal myelinated nerves 195 719 diaphragm studies 195 720–722 electrophysiology 195 720–722 imaging 195 720 phrenic nerve conduction studies 195 721, 721–722 pulmonary function testing 195 719–720 Respiratory domain 196 187–188 Respiratory insufficiency, treatment of 195 553–554 Respiratory muscle strength and endurance, congenital myopathies 195 554 Respiratory muscles weakness neuromuscular assessment 195 710–718 cerebrospinal fluid analysis 195 717 compound muscle action potential waveforms 195 713 direct muscle stimulation 195 715–717 electrophysiological studies 195 711–717 history and physical examination 195 710–711 laboratory evaluation 195 711–718 motor unit number estimation 195 717 muscle and nerve biopsy 195 717–718 needle electromyography 195 712–713 nerve conduction studies 195 711–712 neuroimaging 195 711 quantitative motor unit potential analysis 195 713–715 repetitive nerve stimulation 195 712 specialized electrophysiologic studies 195 713–717 respiratory assessment bedside evaluation 195 719–722 dermal myelinated nerves 195 719 diaphragm studies 195 720–722 electrophysiology 195 720–722 imaging 195 720 phrenic nerve conduction studies 195 721, 721–722 pulmonary function testing 195 719–720 Respiratory sinus arrhythmia (RSA) 195 304 Resting activity insertional activity 195 264–266 snap-crackle-pop 195 265–266 Resting membrane potential (RMP) 195 252–253 Restless leg syndrome (RLS) 195 387–391 causes of secondary RLS 195 389 differential diagnosis of 195 388

Restless leg syndrome (RLS) (Continued) epidemiology 195 389 ICSD definition 195 388 management 195 390–391 mechanisms 195 389 pharmacological treatments 195 390 refractory 195 391 Reticulospinal tract (RST) 195 107, 108 Retinal ganglion cells (RGCs) 195 183–184 Reversible conduction failure 195 735, 735 Rhabdomyolysis 195 746 Rheumatoid arthritis peripheral neuropathy 195 600–601 Rheumatoid vasculitis 195 601 Rheumatological disease, motor neuropathies 195 598–601, 599 rheumatoid arthritis peripheral neuropathy 195 600–601 Sj€ ogren’s syndrome peripheral neuropathy 195 598–600 Rhythmic movement disorders (RMDs) 195 393 Ribonucleic acid (RNA) 195 293 Rigid spine muscular dystrophy-1 (RSMD1) 195 482 Riley-Day syndrome 195 410 Riluzole 196 523–524, 530–531 RimabotulinumtoxinB 196 540, 541 RIPK1 196 526 Risdiplam 195 320, 196 53–54 Risperidone 196 464–466 Rituximab 195 344, 645–647, 684–685, 196 237–238 Rivaroxaban 196 331 RLS. See Restless leg syndrome (RLS) RNA metabolism 196 217, 528–529 RNA processing, defects in 195 216–219 GLE1, RNA export mediator (GLE1) 195 217–218 glycyl-tRNA synthetase 1 195 218 immunoglobulin m-binding protein 2 (IGHMBP2) 195 218 Nova1 195 218–219 senataxin 195 217 survival motor neuron 195 216–217 RNA toxicity 195 199–200 RNSS. See Repetitive nerve stimulation studies (RNSS) Robotics 196 337 Rods. See Nemaline, bodies (rods) Rostral tegmental pontine syndrome 196 309, 309 Routine metrics 195 276–277, 276, 277 derived metrics 195 277 amplitude ratio 195 277 area 195 277 duration 195 276 phases and turns 195 276 recruitment 195 276 size index 195 277 jiggle 195 277 Routine quantitative electromyography 195 283–284 amyotrophic lateral sclerosis (ALS) 195 283

645 Routine quantitative electromyography (Continued) myopathy vs. fatigue 195 284 radiculopathy 195 283 Ryanodine receptors (RyRs) 195 543 Ryanodyne receptor 1-related distal myopathies 195 507 RYR1 195 554–555

S

Saccadic eye movements 195 108, 115 Sacral segments 195 302–303 Saku disease 196 153 Salience network 196 408 Saltatory conduction 195 260 Sarcoglycanopathy 195 475 Sarcoidosis 195 374, 196 112 Sarcolemma 195 252 Sarcoma, fused in 196 212 SARS-CoV-2. See Severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) SCA36 196 217 Scapuloperoneal dystrophy 195 461–462 Schistosoma haematobium 196 105, 149–150 Schistosoma mansoni 196 105 Schistosomiasis 196 105, 149–150 Schmahmann syndrome (SS) 196 169 Schwann cells 195 297 SCI. See Spinal cord injury (SCI) SCN4A variant loss of function 195 526 NDMs 195 523 periodic paralysis 195 530 Scoliosis 196 51 Secondary tauopathies 196 259–262, 611–612, 614–615, 615 Segmental necrosis 195 292–293, 292 Selective dorsal rhizotomy (SDR) 196 512 Selenoprotein N (SEPN1) 195 482, 542–543, 554 Self-motion 195 31–33, 41–46 Semiquantitative electromyography 195 283 Semithin sections (STS) 195 292–294, 295 Semorinemab 196 615–616 Senataxin 195 217, 196 214 Sensorimotor apraxia executive apraxia 195 131–132 localization 195 129 optic ataxia 195 128–129 tactile apraxia 195 128, 131 Sensorineural deafness 196 153 Sensory ataxias 196 268–269 Sensory loss 196 317 Sensory nerve conduction studies amplitude 195 258, 258 latency 195 258–259 measurements 195 257–259 orthodromic vs. antidromic techniques 195 259 technique 195 257 utility 195 259 Sensory Organization Test (SOT) 196 484

646 Sequestosome 1 and tia-related digenic distal myopathies 195 507 Sequestosome gene (SQTM1) 195 507 Serial casting 196 506 Serotonin 195 303, 196 417 Severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) 196 105. See also COVID-19 infection Sexsomnia 195 387 SGK196 195 481 Short exercise testing (SET), myotonia 195 524 Shy-Drager syndrome. See Multiple system atrophy (MSA) Signal transduction 195 198–199, 202 Simple spikes 196 162–164, 164 Single-fiber electromyography (SFEMG) 195 277–279, 284, 338 analysis of turns and amplitude 195 284 extrapolated metrics 195 278–279, 280 fiber density 195 277–278, 278, 284 jitter studies 195 278, 279, 284 motor unit number estimations (MUNE) 195 284 Size index 195 277 Sj€ogren’s syndrome peripheral neuropathy 195 598–600 Skeletal muscle biopsy 196 46 function 195 3, 8 hierarchy of, structural 195 4 myosin S1 structure 195 5 structure 195 4–5 Skin biopsy 195 298–299, 196 181, 188, 194 Sleep bruxism 195 392–393 Sleep disorders 196 187 Sleep disturbances 196 287 Sleep dysfunction, antibody-associated CNS disorders with 196 285–290 Sleep motor control 195 383–386, 384 Sleep-related eating disorder 195 386–387 Sleep-related motor disorders abnormal swallowing syndrome 195 394 choking syndrome 195 394 laryngospasm 195 393–394 sleep talking 195 393 Sleep talking 195 393 Sleep walking 195 386 SMA. See Spinal muscular atrophy (SMA) Small molecule kinetin 195 89 Small muscle protein X-linked-related distal myopathies 195 507–508 Small nuclear ribonucleoprotein polypeptide N (SNRPN) gene 195 534–536 Small-vessel CNS vasculitides 195 668–670 in children and adults 195 669 Small vessel vasculitis (SVV) 195 653–654 SMN2 copy number 196 49 Smoking 195 645

INDEX Smoothing effect 196 167–168 Snap-crackle-pop 195 265–266 Sneer sign 195 338, 339 Social skill set 196 169 Socioecological framework (SEF) 196 486–490 SOD1 196 527–528 Sodium channel myotonia (SCM) 195 521, 524 Sodium voltage-gated channel subunit alpha 2 (SCN2A) 196 360 Sodium voltage-gated channel subunit alpha 8 (SCN8A) 196 352 Solute carrier family 1 member 3 (SLC1A3) 196 359 Solute carrier family 2 member 1 (SLC2A1) 196 353 Solute carrier family 16 member 2 (SLC16A2) 196 355 Somatosensory evoked potentials (SSEPs) 196 13, 77 Somatosensory evoked responses (SSER) 196 127 Somnambulism. See Sleep walking Somniloquy 195 393 SORD-associated CMT 195 613 Sotrovimab, COVID-19 195 169–170 Spastic ataxia phenotype 196 73 Spasticity 196 74, 90, 92–93, 95–96, 448, 549–550 adaptive changes 196 498–499 assessment 196 503 biomechanical assessment 196 503 clinical assessment 196 503 education 196 503–504 goal setting 196 503–504 physiological assessment 196 503 self-management 196 503–504 definition 196 120–121, 497–498 and hypertonia 196 499–500 impact of 196 502 impairments 196 500 management 196 504–512 injectable therapies 196 509–511 pharmacological management 196 506–509 physiotherapy interventions 196 506 potential physical adjuncts 196 511 surgical interventions 196 511–512 movement dysfunction 196 502 negative features 196 501–502 pain 196 502–503 pathophysiology 196 498–503 positive features 196 501 reticulospinal (RST) damage 196 498 spinal cord inhibition 196 498 treatment 196 79 trigger factor management 196 504 Spastic paraplegia 196 74, 121 with distal muscle wasting 196 74 Speech therapy 195 649 Sphingosine 1-phosphate (S1p) 196 142 Spike-time-dependent plasticity (STDP) 196 165, 599–600

Spike triggered averaging technique 195 281 Spinal abscesses 196 102–103 Spinal and bulbar muscular atrophy (SBMA) 195 223–224 Spinal arteriovenous fistula 196 26–27 Spinal column, and peripheral nervous system 195 253 Spinal cord. See also Brainstem and spinal cord arterial blood supply 196 5 arteriovenous malformations (AVMs) 196 27–28 damage 196 112–113 disorders acute spinal cord ischemic disorders 195 729–730, 729 lumbosacral plexus disorders 195 731–733 poliomyelitis 195 730–731, 730 ischemic disorders, acute 195 729 local functions of 195 23–24 motor learning 195 24 motor unit activity 195 22–23 neuroanatomy 196 5 neuroimaging of 195 370–374 overview 196 3 segmental arterial supply 196 6 spinal descending motor pathways 195 21–22 spinal sensory input 195 23 tuberculosis of 196 103–104 tumors (see Tumors, spinal cord) Spinal cord infarction (SCI) 195 371 stroke 196 25–28 arteriovenous fistula (AVF) 196 26–27 arteriovenous malformations (AVM) 196 27–28 cavernous malformations 196 28 vascular malformations 196 26–28 Spinal cord injury (SCI) 196 9–12, 417 depression 196 34 intramedullary insults 196 33–34 muscle and motor neuron excitability 196 34 neural plasticity, implications for 196 34–35 collateral sprouting 196 34–35 regeneration 196 35 pathology 196 410–411 short- and long-term potentiation 196 34 spinal cord syndromes in longitudinal axis 196 11–12 in transverse plane 196 10–11 Spinal cord motor disorder diagnosis 196 12 advanced MRI techniques 196 15 cerebrospinal fluid (CSF) analysis 196 14 conventional MRI 196 15 digital subtraction angiography (DSA) 196 15–16 neurophysiology 196 13

INDEX Spinal cord motor disorder (Continued) noninvasive spinal cord imaging 196 12–13 transcranial magnetic stimulation (TMS) 196 13–14 vascular imaging 196 14–16 history 196 12 physical examination 196 12 spinal motor control 196 6–8 gait integration 196 8 supraspinal connections 196 6–8 Spinal cord syndromes 196 11–12 ischemia of cervical region 196 11–12 of lumbar region 196 12 of thoracic region 196 12 in transverse plane 196 10–11 anterior horn 196 10 anterior spinal cord 196 10 brown-sequard 196 11 centromedullary 196 10–11 posterior spinal artery (PSA) syndrome 196 11 transverse complete spinal cord syndrome 196 11 Spinal digital subtraction angiography (SpDSA) 196 15 Spinal intramedullary AVM 196 27–28, 28 Spinal muscular atrophy (SMA) 195 401, 412, 534–536, 196 28–30 classification of 195 316 infantile and childhood 195 726–727 Spinal vascular malformations (SVMs) 196 15 Spinocerebellar ataxia (SCA) 195 186–187 Spinocerebellar tract (SCT) 195 117, 196 166 Spirochete 196 103 Spontaneous activity 195 266 Sporadic amyotrophic lateral sclerosis 196 204 Sport Concussion Assessment Tools (SCAT) 196 480–481 Sports-related concussion (SRC) 196 475 clinicopathologic correlation 196 482–486 definitions 196 477–478 epidemiology 196 478–479 features 196 480 grading scale 196 481 history 196 475–477, 479–480 laboratory evaluation 196 480–481 management 196 486 neuroradiologic approaches 196 481–482 physical examination 196 479–480 prognosis 196 486 public health policy and impact 196 486–490 community level 196 488–489 interpersonal level 196 489–490 intrapersonal level 196 489–490 school policy 196 487–488

Sports-related concussion (SRC) (Continued) socioecological framework (SEF) 196 486–490 state legislation 196 487 sideline evaluation 196 481 symptoms 196 480 SSR. See Sympathetic skin response (SSR) Stable affordances 195 130 Staphylococcus pneumoniae 196 102–103 Statistical motor unit, and muscle characterization 195 281–282, 282 Steering 195 48–49 Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial 196 335 Stereotypies 196 451 Steroids 196 110 Stiff-person syndrome (SPS) 196 238, 277–278, 283 Strachan syndrome 196 152–153 Streptococcus aureus 196 102–103 Stretching 196 506 Striatum 196 312 Stridor 195 526 Stroke 195 311–312, 196 305 acute pediatric stroke management 196 336 acute stroke management, in adults 196 329–336 adult pure motor 196 321–325 childhood 196 320–321 classification 196 320 epidemiology 196 305–307 laboratory evaluation 196 317–320 -like episodes 195 568–570 neurovascular topography and clinical deficits 196 307–316 patients history 196 316 patients physical examination 196 317 prognosis and outcome 196 325–329 recovery, rehabilitation modalities of 196 336–337 recurrence 196 326 spinal cord infarction (SCI) 196 25–28 arteriovenous fistula (AVF) 196 26–27 arteriovenous malformations (AVM) 196 27–28 cavernous malformations 196 28 vascular malformations 196 26–28 Stroke Prevention in Reversible Ischemia Trial (SPIRIT) 196 331 Structure mammalian vestibular system 195 32 Subacute inflammatory demyelinating polyradiculoneuropathy (SIDP) 195 623–624 Subacute motor neuronopathy (SMN) 196 233, 239–240 Subacute myelo-optic neuropathy (SMON) 196 150 Subacute sclerosing panencephalitis 196 611–612

647 Subacute sensorimotor neuropathy 196 240 Subarachnoid hemorrhage (SAH) 196 305–306 Subcutaneous immunoglobulin (SCIg) 195 645 Sublatero-dorsal tegmental nucleus (SLD) 195 383–385 intermittent firing 195 385 motor sleep pathways 195 384 Substrate reduction therapy (SRT) 196 562 Sudden unexpected death in epilepsy (SUDEP) 196 297 Sudomotor reflexes 195 310–312 Superficial radial sensory response 195 255 Superior cerebellar artery (SCA) 196 308–310 Superoxide dismutase-1 (SOD1) 196 203, 215–216, 218 Supine hypertension 196 178–179 Supplementary motor area (SMA) 195 21 Supplementary sensorimotor area (SSMA) seizures 196 296 Supportive therapy 195 645 Supramodal zone 196 166 Sural nerve biopsy 196 152–153 Surfeit locus protein 1 (SURF1) 195 567 Survival motor neuron (SMN) 195 216–217 Survival motor neuron 1 (SMN1) gene 196 46–47 Swallowing syndrome, sleep-related abnormal 195 394 Sweat imprinting 195 311 Sydenham’s chorea (SC) 196 372 Sylvian aqueduct syndrome 196 311 Sympathetic nervous system (SNS) 195 55–56, 303 Sympathetic skin response (SSR) 195 304, 311–312, 312 Symptomatic drug treatment 195 642 Symptomatic therapy 196 139–140 Synaptic plasticity 195 137, 196 136 Synaptic space defects 195 188 Synucleinopathies 195 214–215, 196 175–176, 196 Syphilis 196 317–319 Systemic disorders paraneoplastic myelitis 196 113 radiation therapy-related myelitis 196 113 sarcoidosis 196 112 systemic lupus erythematosus (SLE) 196 112–113 toxic-metabolic vascular mimickers 196 113–114 Systemic lupus erythematosus (SLE) 196 112–113

T

Tabes dorsalis 196 103 Tachycardia 196 297 Tacrolimus 195 645 Taenia solium 196 105

648 Takayasu arteritis (TAK) 195 653–654, 196 336 Taping 196 511 TAR DNA-binding protein (TARDBP) 196 211–212, 216–217 TAR DNA-binding protein 43 (TARDBP) 195 206–207 TAR DNA-binding protein of 43kDa (TDP-43) 196 253 Target fibers 195 291 Target region sequencing (TRS) 195 210 Task-specific dystonia (TSD) 196 544–545 Task-specific phobia 196 283 Tauopathies 195 215, 196 251–252 environmental exposures 196 257–258 chronic traumatic encephalopathy (CTE) 196 257–258 progressive supranuclear palsy (PSP) 196 258 and motor symptoms 196 254 primary 196 253–257, 254 secondary 196 259–262 structure and function 196 252–253 normal tau 196 252 pathological tau 196 252–253, 253 Tau protein, strucure and function of 196 613 Tay-Sachs disease (TSD) 195 211 TDP-43 196 527 Teased nerve fiber analysis 195 295–296, 296 Tectospinal tract (TST) 195 107 Telmisartan Randomized AssessmeNt Study in aCE-iNtolerated subjects with cardiovascular Disease (TRANSCEND) trials 196 334–335 Template matching method, isolation by 195 274–275, 275 Temporal lobe (and medial temporal lobe), in etiopathogenesis of pediatric neuropsychiatric disorders 196 377–380 Teriflunomide 196 137 Terrors, sleep 195 386 Tetrabenazine 196 467 Tetrahydrocannabinol (THC) 196 140–141 Thalamus 196 312, 313, 409 Thalidomide 196 150 Thermoregulatory domain 196 187 Thermoregulatory dysfunction 196 179 Thermoregulatory sweat test 195 310–311 Thiamine 196 153 Thiamin pyrophosphokinase 1 (TPK1) 196 360 Thiocyanate 196 154 Thoracic vertebrae 196 4–5 Thrombolytic therapy 196 332–334 Thymectomy 195 346, 347, 644, 744 of myasthenia gravis (MG) 195 644 Thymoma 195 636–637, 641, 644 Thymus 195 641, 642, 741

INDEX TIA1-related distal myopathies 195 508–509 Tibial muscular dystrophy (TMD) 195 509, 509 Tilavonemab 196 616 Titin gene (TTN) 195 509–510 Titin-related distal myopathies 195 509–510 Tixagevimab 195 170 Tizanidine 196 140, 507, 508 TMS. See Transcranial magnetic stimulation (TMS) TNF receptor-1 (TNF-R1) 196 142 Tobacco alcohol amblyopia 196 154–155 Tocilizumab 196 526 Toe walking 196 75 Tofersen 196 531 Tonic-clonic (T-C) seizure 196 297 Tonic seizures 196 295–296 Topiramate 196 396, 467 Tourette syndrome (TS) 195 142, 196 370–372 clinical characteristics 196 458 comorbidities illicit substance use 196 461 neuropsychiatric disorders 196 460–461 quality of life 196 461 sleep disturbances 196 461 definitions 196 371, 458 diagnostic criteria 196 458–459 differential diagnosis 196 459–460 epidemiology 196 458–459 immunopathogenic factors 196 372 natural history 196 459 neuropsychiatric circuits and networks 196 371–372 overview 196 457–458 pathophysiology 196 462–463 risk factors 196 462 treatment 196 372, 463–468 behavioral therapy 196 463–464 deep brain stimulation (DBS) 196 467–468 medications 196 465 pharmacotherapy 196 464–467, 465 Toxic-metabolic vascular mimickers 196 113–114 Toxic neuropathy 196 153 Transcranial electrical stimulation 196 167 Transcranial magnetic stimulation (TMS) 196 13–14, 126–127, 167, 326, 482, 599–603 Transcranial motor stimulation (TMS) 196 328 Transcutaneous electrical stimulation (TENS) 196 511 Transforming growth factors (TGFbs) 196 576 Transmembrane capacitance (TMC) 195 252–253 Transmembrane potential (TMP) 195 252 Transmembrane protein 5 (TMEM5) 195 480–481

Transmembrane protein 151A (TMEM151A) 196 351–352 Transmembrane voltage (TMV) 195 252 Transverse complete spinal cord syndrome 196 11 Transverse myelitis (TM) 196 20–21, 25, 150 infectious myelitis 196 101–105, 103 bacterial myelitis 196 102–104 fungal myelitis 196 105 parasitic 196 105 viral myelitis 196 104–105 noninfectious myelitis 196 105–111, 106–107, 107–108 acute disseminated encephalomyelitis (ADEM) 196 109–110 among children and adults 196 106–107 idiopathic myelitis 196 111 multiple sclerosis 196 108 myelin oligodendrocyte glycoproteinantibody-associated disease (MOGAD) 196 110–111 neuromyelitis optica spectrum disorders, (NMOSD) 196 109 systemic disorders paraneoplastic myelitis 196 113 radiation therapy-related myelitis 196 113 sarcoidosis 196 112 systemic lupus erythematosus (SLE) 196 112–113 toxic-metabolic vascular mimickers 196 113–114 and vaccines 196 111–112 Trauma-associated sleep disorder (TASD) 195 392 Traumatic brachial plexopathy 195 376 Trazadone 196 140 Treatment Satisfaction Questionnaire for Medication (TSQM) 195 349–350 Tremor 196 545 botulinum toxin treatment 196 546–548 dystonic head tremor 196 548 essential head tremor 196 548 essential tremor (ET) 196 546 essential voice tremor 196 548 Parkinson rest tremor 196 549 Treponema pallidum 196 103, 317–319 Triad structure 195 7, 7 Trial of ORG 10172 in Acute Stroke Treatment (TOAST) 196 320 Trimodal evoked responses 196 127 Tri-ortho-cresyl phosphate intoxication 196 153 Triple stimulation technique (TST) 196 13–14 Tropical amblyopia 196 154–155 Tropical ataxic neuropathy (TAN) 196 154 Tropical myelopathy 196 149–150 Tropical neuropathy 196 150–153, 151 Tropical spastic paraparesis (TSP) 196 150 chronic tropical myelopathy 196 150 tropical spastic paraparesis 196 150

INDEX Tropical spastic paraparesis (TSP) (Continued) neurologic disorders with dietary cyanide intoxication 196 154–155 toxic neuropathy 196 153 tropical myelopathy 196 149–150 acute tropical myeloneuropathy 196 149–150 transverse myelitis 196 150 tropical neuropathy 196 150–153 Beriberi 196 153 Strachan syndrome 196 152–153 Tuberculosis, of spinal cord 196 103–104 Tumor necrosis factor (TNF) 196 136 Tumors, spinal cord 196 16 classification 196 16–17 gliomas 196 17 astrocytomas 196 17–18 ependymomas 196 18–19 lymphoma 196 21–22 meningiomas 196 19–20 metastases 196 20–21 Turns, analysis of 195 282, 283, 284

U

Ubiquilin 2 (UBQLN2) 196 215 Ubiquitin C-terminal hydrolase–L1 (UCHL1) 196 482–483 Ubiquitin proteasome system (UPS) 196 48, 218 Ubiquitin protein ligase E3 component N-recognition 4 (UBR4) 196 359 Ullrich myopathy 195 477–478 Ultrasound (US) 196 50 UMN. See Upper motor neuron (UMN) Uncomplicated spastic paraplegia syndrome 196 73 Unified Huntington’s Disease Rating Scale (UHDRS) 195 222 Unified Multiple System Atrophy Rating Scale (UMSARS) 196 190 Unilateral dystonia 196 300 Unilateral thalamotomy 196 140 Uniparental disomy 195 233–234 Unipolar brush cell (UBC) 196 159–160 United States Food and Drug Administration (FDA) 196 260–262 Universal Cerebellar Transform (UCT) 196 169 Upper motor neuron (UMN) 195 252, 196 89–90, 95 neurophysiological studies of 195 17–18 syndrome 195 18, 196 305, 497–498 Upright standing posture mechanisms of 195 114 postural control 195 114 Urate 196 530–531 Urination, control of 196 403–410 central control 196 405–410 anterior cingulate cortex (ACC) 196 408–409 anterior thalamic radiation (ATR) 196 409–410 basal ganglia 196 409

Urination, control of (Continued) hypothalamus 196 409 insula 196 408 midbrain nuclei 196 409 periaqueductal gray (PAG) 196 405–408 pontine micturition center (PMC) 196 405–408 prefrontal cortex (PFC) 196 409 salience network 196 408 thalamus 196 409 lower urinary tract dysfunction 196 410 neuropsychiatric comorbidity 196 410 Urodynamics 196 413 Urogenital domain 196 187–188 US Food and Drug Administration (FDA) 196 613 Utilization behavior 196 450

V

Vaccination, COVID-19 195 172 Vaccines 196 111–112 Vagal preganglionic fibers 195 302–303 Vaginal delivery 195 647 Valbenazine 196 467 Valosin-containing protein-related distal myopathies 195 510–511 Valsalva maneuver (VM) changes in beat-to-beat BP induced by 195 308–309, 309–310 heart rate variability (HRV) with 195 306–307 Valsolin-containing protein (VCP) 195 209, 196 213–214 VAPB 196 215 Variable affordances 195 130 Variable vessel vasculitis (VVV) 195 653–654 Variation of uncertain significance (VOUS) 195 299 Varicella-zoster virus (VZV) infection 196 104 Vascular cell adhesion molecule (VCAM)I 195 437–438 Vascular effects of Infection in Pediatric Stroke (VIPS) 195 667, 196 320 Vascular endothelial growth factor (VEGF) 196 219–220, 577 Vascular imaging 196 14–16 Vascular inflammatory alteration 196 103 Vascular malformations 196 26–28 Vascular myelopathies 196 114 Vascular sympathetic control 195 307–308, 308 Vascular system 196 4 Vasculitic neuropathy 195 293–294 Vasculitides with nervous system involvement 195 654 tissue biopsy studies in 195 679–680 Vasculitis 195 298, 299 definition 195 653–654 hypersensitivity 195 657–658 laboratory evaluation 195 678–680, 678 treatment 195 680–693

649 Vegetative Nervous System 195 302 Ventilation and air distribution, congenital myopathies 195 552 Ventilatory assessment and support, congenital myopathies 195 551–554 Ventral arteriovenous fistula 196 26 Ventro-dorsal stream 195 128–129, 131 Ventromedial medulla (VMM) 195 383–385 Vermal anterior lobes 196 160 Vermal posterior lobes 196 160 Vertebral artery 196 307–308 Very severe spinal muscular atrophy 196 46–47 Vesicular monoamine transporter 2 inhibitors 196 467 Vestibular cerebellum 195 41–46, 42 Vestibular motor control anterior vermis (lobules I–V) 195 44 cerebellar-dependent mechanisms 195 47–48 compensation and extravestibular sensory substitution 195 46–48 dynamic range of 195 35 encoding of head motion 195 33 extra-vestibular information 195 46–47 flocculus and ventral paraflocculus 195 42–44 navigation 195 48–49 neuronal coding in alert animals 195 32–34 nodulus/uvula, posterior cerebellar vermis 195 44–46 nonlinear & spike timing codes 195 34–36 nuclei neurons 195 33 postural reflexes, adaptation and compensation of 195 41 reaching 195 48 steering 195 48–49 structure mammalian vestibular system 195 32 vestibular cerebellum 195 41–46 organization of 195 42 vestibulo-ocular reflex 195 36–38 adaptation and compensation of 195 38 functions 195 37 pathways 195 38, 39, 46 rotational 195 37 vestibulospinal reflex pathways 195 39–41, 40 VIII cranial nerve 195 31–32 voluntary behavior 195 48–49 Vestibular nuclei 196 159–160, 162 Vestibular prosthetic development 195 35 Vestibulo-cerebellar syndrome (VCS) 196 169 Vestibulocerebellum 196 160 Vestibulo-ocular reflex 195 36–38 adaptation and compensation of 195 38 functions 195 37 pathways 195 38, 39, 46 rotational 195 37

650 Vestibulospinal reflex pathways 195 39–41, 40 Vestibulospinal tract (VST) 195 107 VIII cranial nerve 195 31–32 Viral illnesses 196 411 Viral myelitis 196 104–105 Viral RNA 195 161–162 Virtual reality (VR) 196 337 Visual evoked potentials (VEPs) 195 194 Visual evoked responses (VER) 196 127 Vitamin B 196 151–152 Vitamin B12 deficiency 196 411 Vitamin deficiency 196 154 Vitamin E 196 151–152 VM. See Valsalva maneuver (VM) Vocal cord and pharyngeal distal myopathy (VCPDM) 195 505 Voluntary activity 195 266–269 Voluntary behavior 195 48–49 Vomiting attacks with autonomic crises 195 89 and hypertensive crises 195 88–89

W

Wake-up stroke 196 332 Walking, sleep 195 386 Wallenberg medullary syndrome 196 310 Wallerian degeneration 195 261 Warfarin-Aspirin Recurrent Stroke Study (WARSS) 196 331 Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Trial 196 331

INDEX Weakness of limb and respiratory muscles neuromuscular assessment 195 710–718 cerebrospinal fluid analysis 195 717 compound muscle action potential waveforms 195 713 direct muscle stimulation 195 715–717 electrophysiological studies 195 711–717 history and physical examination 195 710–711 laboratory evaluation 195 711–718 motor unit number estimation 195 717 muscle and nerve biopsy 195 717–718 needle electromyography 195 712–713 nerve conduction studies (NCS) 195 711–712 neuroimaging 195 711 quantitative motor unit potential analysis 195 713–715 repetitive nerve stimulation 195 712 specialized electrophysiologic studies 195 713–717 respiratory assessment bedside evaluation 195 719–722 dermal myelinated nerves 195 719 diaphragm studies 195 720–722 electrophysiology 195 720–722 imaging 195 720

Weakness of limb and respiratory muscles (Continued) phrenic nerve conduction studies 195 721, 721–722 pulmonary function testing 195 719–720 Welander distal myopathy 195 508–509, 508 Werdnig-Hoffmann disease 196 44 West Indian amblyopia 196 154–155 West Nile virus 196 104 Wet beriberi 196 153 Whole-exome sequencing (WES) 195 210 Whole-genome sequencing (WGS) 195 210 Wiechers–Johnson syndrome 195 266 Willis–Ekbom disease 195 387 WNT (Wingless-related integration site)-catenin pathway 196 581 World Health Organization (WHO) 196 150

X

X-linked arthrogryposis (SMAX2) 196 47

Y Yale Global Tic Severity Scale (YGTSS) 196 371

Z

Zika virus 196 104 Zoonotic origin, COVID-19 195 159–160