Stiff-Person Syndrome and Related Disorders: A Comprehensive, Practical Guide [1st ed.] 9783030430580, 9783030430597

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Stiff-Person Syndrome and Related Disorders A Comprehensive, Practical Guide Pichet Termsarasab Thananan Thammongkolchai Bashar Katirji

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Stiff-Person Syndrome and Related Disorders

Pichet Termsarasab Thananan Thammongkolchai Bashar Katirji

Stiff-Person Syndrome and Related Disorders A Comprehensive, Practical Guide

Pichet Termsarasab Division of Neurology Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok Thailand

Thananan Thammongkolchai Division of Neurology Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok Thailand

Bashar Katirji Department of Neurology University Hospitals Cleveland Medical Center Case Western Reserve University Cleveland, OH USA

ISBN 978-3-030-43058-0    ISBN 978-3-030-43059-7 (eBook) https://doi.org/10.1007/978-3-030-43059-7 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

We would like to dedicate this book to our families. For PT – to my partner, Ploy; parents, Boonreun and Veerachai; grandma, Lung and Prapai; and the Chomchai family. For TT – to my husband, PT, for all his support; my parents, Suchin and Waraporn; and my lovely sisters, Tahn and Pink. For BK – to my wife, Patricia, and my two children, Linda and Michael, as well as my parents, Malak and Zakarea.

Preface

Stiff-person syndrome (SPS), originally called stiff-man syndrome, is actually a group of disorders in which knowledge and understanding have been evolving rapidly in the past few decades. As one can appreciate from the name transition, this group of disorders affects men and women, thus the name change from “stiff-man syndrome” to “stiff-person syndrome.” With the rapid evolution in the neuroimmunology field, various different antibodies, in addition to anti-glutamic acid decarboxylase (anti-­GAD), with their associated phenotypes have been increasingly recognized. Hence, the name “stiff-person spectrum disorders (SPSD)” has emerged and is the most inclusive, because it includes various phenotypes in this group of disorders. Throughout this book, we use the term “SPSD” to clearly represent the entire group of SPS, not only classic SPS but also its variants. The relationship between antibodies and SPSD phenotypes is complex. Each individual antibody, such as the anti-GAD antibodies, may be associated with several SPSD phenotypes and other neurological phenotypes. Stiff-Person Syndrome and Related Disorders is the first book dedicated to this group of disorders. It serves as a single go-to resource that collects important knowledge about SPSD, from original descriptions to state-of-the-art information. Despite extensive knowledge accumulating in SPSD, the existing publications are mainly original papers, review articles, or book chapters. The authors’ clinical experiences are supplemented in this book, since knowledge in many areas in SPSD remains limited and expert opinions remain a useful resource. The book starts with a historical review of the evolution of SPSD. In the subsequent chapters, clinical overview including clinical phenomenology of SPSD, differential diagnoses, and clinically relevant basic science aspects, including neurochemistry and neuroimmunology, are discussed. Then, clinical phenotypes of SPSD and other associated phenotypes are detailed based on the antibody type, including anti-GAD and other antibodies. The progressive encephalomyelitis with rigidity and myoclonus syndrome is unique and highlighted in a dedicated chapter. With the complexity between the clinical phenotypes and immunophenotypes (types of antibodies), a summary of the practical approach is then discussed. This chapter is followed by chapters on treatment, as well as emergencies in SPSD in which significant morbidity or mortality may ensue if not identified and treated promptly. SPSD in the pediatric population and a closely

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related but different group of disorders, namely, peripheral nerve hyperexcitability syndromes and startle syndromes, are also detailed in individual chapters in this book. Stiff-Person Syndrome and Related Disorders would be of interest to neurologists as well as multiple neurologic subspecialists, including those specializing in movement disorders, neuromuscular disorders, epilepsy, and neuroimmunology. Trainees in neurology and any of the above fields will find this book enriching. In addition to neurologists, internists, rheumatologists, psychiatrists, and physiatrists, physical and occupational therapists may find this book useful as they may encounter patients with SPSD. This book will also serve as a resource for basic science researchers, including electrophysiologists, neurochemists, immunologists, or pathologists. Many challenges and gaps in the field of SPSD are identified from the currently available data, and we hope that this book will stimulate further research and studies to fill the gap in this field. Bangkok, Thailand Bangkok, Thailand Cleveland, OH, USA

Pichet Termsarasab Thananan Thammongkolchai Bashar Katirji

Acknowledgments

We would like to thank all of our patients. We would like to express thanks to all our mentors and colleagues. Their teaching and support helped all of us to be neurologists, clinicians, and writers. These include Kanokwan Boonyapisit, Catherine Cho, Robert B. Daroff, Steven J. Frucht, Paul E. Greene, John Leigh, Chanin Limwongse, David C. Preston, Teeratorn Pulkes, Tumtip Sangruchi, Barbara Shapiro, Kristina Simonyan, David Swope, Oscar M. Reinmuth, Winona Tse, Supoch Tunlayadechanont, Ruth H. Walker, and Asa J. Wilbourn. We also would like to thank Richard Lansing, Editorial Director, Clinical Medicine, Springer, and Diane Lamsback, Developmental Editor, for their support and help in getting this book successfully published.

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Contents

1 Historical Background of Stiff-Person Spectrum Disorders������������������   1 Historical Background ������������������������������������������������������������������������������    1 Criteria Evolution��������������������������������������������������������������������������������������    4 History of Variants in Stiff-Person Syndrome�������������������������������������������    6 Progressive Encephalomyelitis with Rigidity and Myoclonus��������������    6 Stiff-Limb Syndrome ����������������������������������������������������������������������������    6 Discovery of Antibodies����������������������������������������������������������������������������    7 Treatment History��������������������������������������������������������������������������������������    7 References��������������������������������������������������������������������������������������������������    8 2 Clinical Phenomenology of Stiff-Person Spectrum Disorders ��������������  11 Epidemiology��������������������������������������������������������������������������������������������   11 Differentiating Stiffness from Other Phenomenology ������������������������������   11 Classification of Stiff-Person Spectrum Disorders (SPSD) ����������������������   13 Classic Stiff-Person Syndrome (SPS)����������������������������������������������������   14 Stiff-Limb Syndrome (SLS)������������������������������������������������������������������   15 Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM)������������������������������������������������������������������������   15 Overlapping Syndrome��������������������������������������������������������������������������   16 Associated Clinical Features of SPSD������������������������������������������������������   16 Hyperekplexia and Stiff-Person Spectrum Disorders��������������������������������   16 Controversial SPS Variants and Terminology��������������������������������������������   17 References��������������������������������������������������������������������������������������������������   19 3 Differential Diagnosis of Stiff-Person Spectrum Disorders ������������������  21 Stiffness Due to Central Hyperexcitability������������������������������������������������   21 Stiffness Due to Peripheral Hyperexcitability ������������������������������������������   24 References��������������������������������������������������������������������������������������������������   25 4 Electrophysiology of Stiff-Person Spectrum Disorders��������������������������  27 The Role of Electrophysiology in Excluding Other Neuromuscular Causes of Muscle Stiffness������������������������������������������������������������������������   27 Electrophysiological Findings Useful in the Diagnosis of SPS����������������   29 Continuous Motor Unit Activity (CMUA)��������������������������������������������   30 Co-contraction of Agonist and Antagonist Muscles������������������������������   31 xi

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Loss of Vibration-Induced Inhibition of H-Reflexes������������������������������   32 Enhanced Exteroceptive Reflex ������������������������������������������������������������   33 Other Electrophysiological Studies��������������������������������������������������������   34 Summary����������������������������������������������������������������������������������������������������   34 References��������������������������������������������������������������������������������������������������   34 5 Neurochemistry of Inhibitory Synapses and Clinical Applications in Stiff-Person Spectrum Disorders��������������������������������������������������������������  37 GABA-ergic Synapses ������������������������������������������������������������������������������   37 Clinical Applications of GABA-ergic Synapses in Stiff-Person Spectrum Disorders and Associated Disorders������������������������������������������   42 Glycinergic Synapses��������������������������������������������������������������������������������   42 Clinical Applications of Glycinergic Synapses in Stiff-Person Spectrum Disorders and Associated Disorders������������������������������������������   43 References��������������������������������������������������������������������������������������������������   44 6 Immunopathogenesis of Stiff-Person Spectrum Disorders��������������������  47 Overview����������������������������������������������������������������������������������������������������   47 Antigenic Targets in Autoimmune Neurologic Disorders����������������������   47 General Principles of Autoimmunity ��������������������������������������������������������   49 Immunopathogenesis of Stiff-Person Spectrum Disorders with Focus on Anti-GAD-Associated Stiff-Person Spectrum Disorders����������������������   50 Is GAD65 Pathogenic Based on the Koch-Witebsky Postulates?��������������   52 Future Directions of Research on Immunopathogenesis of Stiff-Person Spectrum Disorders ����������������������������������������������������������   53 References��������������������������������������������������������������������������������������������������   53 7 Anti-Glutamic Acid Decarboxylase 65 (GAD65)-Associated Syndromes��������������������������������������������������������������������������������������������������  55 Laboratory Aspects of Anti-GAD65 Antibodies����������������������������������������   55 Phenotypic Spectrum of Anti-GAD Antibody Syndromes������������������������   58 Anti-GAD65-Associated Stiff-Person Spectrum Disorders (SPSD) ��������   58 Anti-GAD65-Associated Cerebellar Ataxia����������������������������������������������   61 Anti-GAD65-Associated Epilepsy������������������������������������������������������������   63 Anti-GAD65-Associated Neuropathy��������������������������������������������������������   64 Oncological Association of Anti-GAD65 Antibodies��������������������������������   65 Treatment Responses and Prognosis����������������������������������������������������������   67 References��������������������������������������������������������������������������������������������������   68 8 Antibodies in Stiff-Person Spectrum Disorders and Their Correlations with Clinical Phenotypes����������������������������������������������������  73 Frequency of Autoantibodies in Stiff-Person Spectrum Disorders (SPSD)��������������������������������������������������������������������������������������   74 Antibodies in Stiff-Person Spectrum Disorders (Other Than Anti-GAD): Basic Science and Clinical Aspects��������������������������������������   75 Anti-Amphiphysin Antibodies ��������������������������������������������������������������   75 Anti-GABAA Receptor (Anti-GABAAR) Antibodies����������������������������   80

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Anti-GABAA Receptor-Associated Protein (Anti-GABARAP) Antibodies����������������������������������������������������������������������������������������������   82 Anti-Gephyrin Antibodies����������������������������������������������������������������������   83 Anti-Glycine Transporter 2 (Anti-GlyT2) Antibodies ��������������������������   83 Anti-Glycine Receptor and Anti-Dipeptidyl-Peptidase-Like Protein 6 (Anti-DPPX) Antibodies��������������������������������������������������������   84 References��������������������������������������������������������������������������������������������������   84 9 Progressive Encephalomyelitis with Rigidity and Myoclonus ��������������  87 History��������������������������������������������������������������������������������������������������������   87 Clinical Features����������������������������������������������������������������������������������������   88 Electrophysiologic Findings����������������������������������������������������������������������   90 Antibodies Associated with Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM)������������������������������������������������������   91 Anti-Glycine Receptor Antibodies��������������������������������������������������������   91 Anti-Dipeptidyl-Peptidase-Like Protein 6 (Anti-DPPX) Antibodies �����  93 Prognosis and Treatment Responses����������������������������������������������������������   94 References��������������������������������������������������������������������������������������������������   94 10 Pediatric Stiff-Person Spectrum Disorders ��������������������������������������������  97 Prevalence��������������������������������������������������������������������������������������������������   97 Reported Cases in the Literature����������������������������������������������������������������   97 Clinical Phenotypes in Pediatric Stiff-Person Spectrum Disorders ����������   98 Autoantibodies in Pediatric Stiff-Person Spectrum Disorders������������������   99 Differential Diagnosis of Pediatric Stiff-Person Spectrum Disorders����������������������������������������������������������������������������������������������������   99 Treatment Strategies and Treatment Outcome������������������������������������������  100 References��������������������������������������������������������������������������������������������������  101 11 Diagnostic Approach in Stiff-Person Spectrum Disorders�������������������� 103 Complexity of Correlations Between Clinical Phenotypes and Immunophenotypes ����������������������������������������������������������������������������  103 Oncological Associations��������������������������������������������������������������������������  105 Practical Points for Antibody Testing in Stiff-Person Spectrum Disorders����������������������������������������������������������������������������������������������������  106 Future Directions ��������������������������������������������������������������������������������������  108 References��������������������������������������������������������������������������������������������������  109 12 Treatment of Stiff-Person Spectrum Disorders�������������������������������������� 111 General Management Principles of Stiff-Person Spectrum Disorders����������������������������������������������������������������������������������������������������  111 Symptomatic Therapies�����������������������������������������������������������������������������  112 Benzodiazepines������������������������������������������������������������������������������������  113 Baclofen ������������������������������������������������������������������������������������������������  114 Other Medications����������������������������������������������������������������������������������  115

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Specific Therapies��������������������������������������������������������������������������������������  116 Tumor Removal��������������������������������������������������������������������������������������  117 Immunotherapies������������������������������������������������������������������������������������  117 Proposed Treatment Algorithm������������������������������������������������������������������  125 Future Directions ��������������������������������������������������������������������������������������  127 References��������������������������������������������������������������������������������������������������  127 13 Emergencies in Stiff-Person Spectrum Disorders���������������������������������� 131 Acute Severe Exacerbation of Spasms and Rigidity and Status Spasticus in Stiff-Person Spectrum Disorders ������������������������������������������  131 Paroxysmal Autonomic Dysfunction and Autonomic Crisis in Stiff-Person Spectrum Disorders ����������������������������������������������������������  134 Acute Respiratory Failure in Stiff-Person Spectrum Disorders����������������  135 Treatment-Related Emergencies Including Baclofen Withdrawal Syndrome ������������������������������������������������������������������������������  136 Anesthetic Considerations in Stiff-Person Spectrum Disorders����������������  138 References��������������������������������������������������������������������������������������������������  138 14 Peripheral Nerve Hyperexcitability Syndromes������������������������������������� 141 Definitions of Peripheral Nerve Hyperexcitability Syndromes ����������������  141 Pathophysiology of Peripheral Nerve Hyperexcitability Syndromes��������  142 Clinical Syndromes of Peripheral Nerve Hyperexcitability����������������������  143 Isaacs Syndrome (Acquired Neuromyotonia, Idiopathic Generalized Myokymia)������������������������������������������������������������������������  143 Morvan Syndrome���������������������������������������������������������������������������������  145 Cramp-Fasciculation Syndrome������������������������������������������������������������  145 Limbic Encephalitis ������������������������������������������������������������������������������  145 Episodic Ataxia Type 1��������������������������������������������������������������������������  147 Others����������������������������������������������������������������������������������������������������  147 Electrodiagnostic Findings of Peripheral Nerve Hyperexcitability Syndromes��������������������������������������������������������������������������������������������������  147 Normal Muscle Insertional and Spontaneous Activity��������������������������  147 Abnormal Muscle Insertional and Spontaneous Activity in Peripheral Nerve Hyperexcitability Syndromes��������������������������������  149 Electrodiagnostic Differential Diagnosis ����������������������������������������������  151 Differential Diagnosis of Peripheral Nerve Hyperexcitability Syndromes��������������������������������������������������������������������������������������������������  154 Treatment of Peripheral Nerve Hyperexcitability Syndromes������������������  156 References��������������������������������������������������������������������������������������������������  156 15 Startle Syndromes�������������������������������������������������������������������������������������� 159 Normal Startle Reflex��������������������������������������������������������������������������������  160 Hyperekplexia��������������������������������������������������������������������������������������������  163 Hereditary Hyperekplexia����������������������������������������������������������������������  163 Sporadic Hyperekplexia������������������������������������������������������������������������  170

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Symptomatic Hyperekplexia������������������������������������������������������������������  170 Investigations of Hyperekplexia����������������������������������������������������������������  170 Treatment of Hyperekplexia����������������������������������������������������������������������  171 Neuropsychiatric Startle Syndromes����������������������������������������������������������  171 Culture-Specific Startle Syndromes������������������������������������������������������  172 Stimulus-Induced Disorders����������������������������������������������������������������������  173 References��������������������������������������������������������������������������������������������������  174 Index�������������������������������������������������������������������������������������������������������������������� 179

1

Historical Background of Stiff-Person Spectrum Disorders

Historical Background In the summer of 1924, two American neurologists at the Mayo Clinic in Rochester, Minnesota, Drs. Frederick P. Moersch and Henry V. Woltman (Fig. 1.1 [1, 2]), saw a farmer from Iowa, aged 49 years, who presented with “muscle stiffness and difficulty in walking.” His symptoms began insidiously 4 years prior and had worsened to the point that he could no longer work. The patient had “episodes of tightening of the muscles of his neck. Gradually these attacks had increased in frequency, in severity and in duration.” After a fall in 1923, they wrote, “His muscular condition had worsened. His neck muscles had remained rigid most of the time and his head could be brought forward only with great effort. Also, the abdominal muscles and, to a lesser degree, those of the lower part of the back and those of the thighs had partaken of this same stiffness or tightness. Moreover, the rigidity had been punctuated by intermittent and moderately painful spasms.” His neurological examination did not add much to the history, as they wrote, “Nothing helpful to diagnosis was learned from routine physical examination. On neurologic examination, the cranial nerves were found to be intact. The head was pulled down rigidly between the shoulders and, with the taut pectoral muscles, imparted an odd, hunched-over posture and an awkward, waddling gait. Both voluntary and passive movements of the trunk or lower extremities often precipitated, in the abdomen and legs abrupt spasm that might last minutes or even an hour. Intrinsic muscular strength was intact but was not always manageable. Muscle-stretch reflexes were normal; the plantar responses were flexor and sensation was unimpaired.” The patient’s sedimentation rate, blood, and urine were normal. Cerebrospinal fluid was normal. His head X-rays were normal, and spine X-rays showed “moderate hypertrophic arthritis and some kyphosis in the thoracic region.” Drs. Moersch and Woltman remarked, “We could not make a diagnosis but the unusual condition interested us no end and, to associate it with a memorable and descriptive term that could not be taken by anyone to be final, we nicknamed it the stiff-man syndrome.” © Springer Nature Switzerland AG 2020 P. Termsarasab et al., Stiff-Person Syndrome and Related Disorders, https://doi.org/10.1007/978-3-030-43059-7_1

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1  Historical Background of Stiff-Person Spectrum Disorders

Frederick P. Moersch, MD

Henry W. Woltman, MD

Fig. 1.1  Frederick P. Moersch, MD and Henry W. Woltman, MD. These two authors originally described stiff-person syndrome in 1956. (Photograph of Moersch reprinted from Amadio [1], Copyright 1992, with permission from Elsevier. Photograph of Woltman reproduced with permission from Corbin and Kernohan [2])

They had very little to offer for treatment. They wrote, “In the absence of a diagnosis, and without knowledge of specific treatment, we observed the effects of bromides, of intramuscular administration of magnesium sulfate and of sedation with barbiturates, but these helped only temporarily. Warm baths, massage and passive exercises, the patient said, increased his comfort in walking and the length of time that he could walk. He was advised to continue physical therapy at home.” They did not see or examine this patient again but they communicated with him in 1927. They marked in their report that “there had been slight periods of improvement but, if anything, his condition had worsened and he no longer left his home for a walk. The spasms had increased in frequency and he had difficulty in feeding himself.” They last communicated with him in 1932. Per the patient report, they transcribed: “the stiffness had lessened and muscular spasms were fewer than they had been. He could be on his feet but he was weak and could take only a few steps unassisted” [3]. In 1956, Drs. Moersch and Woltman reported this patient and 13 others seen at the Mayo Clinic in the Proceedings of the Staff Meetings of the Mayo Clinic. The title of the publication was “progressive fluctuating muscular rigidity and spasms (“stiffman” syndrome): Report of a case and observations in 13 other cases” [3]. Prior to 1956, Ornsteen had reported one case of stiff-man presentation, a man with stiffness at the age of 40 [4]. Intermittent pain and disability were noted. However, Ornsteen did a muscle biopsy and concluded the diagnosis of myositis fibrosa instead.

Historical Background

3

In 1991, Blum and Jankovic suggested the preferred name, “stiff-person syndrome (SPS)”, instead of “stiff-man syndrome”, since the disease affects both men and women. Since then, the name SPS has become the accepted name for this entity [5]. The timeline of historical events in SPS is shown in Fig. 1.2 [3, 6–18].

Fig. 1.2  Timeline of significant discovery in stiff-person spectrum disorders [3, 6–18]. PERM progressive encephalomyelitis with rigidity and myoclonus, anti-GAD anti-glutamic acid decarboxylase antibodies, SPS stiff-­ person syndrome, PLEX plasma exchange, IVIG intravenous immunoglobulin, SLS stiff-limb syndrome, anti-GABARAP anti-­ GABAA receptor associated protein antibodies, anti-DPPX dipeptidyl-peptidase-like protein-6

Clinical discovery Antibody discovery Treatment discovery 1956

First description by Moersch & Woltman

1963

Treated SPS by diazepam successfully

1967

First criteria by Gordon et al

1971

First PERM case reported

1988

Anti-GAD discovered by Solimena et al

1989

Criteria by Lorish et al. Treated SPS by PLEX successfully

1993

Anti-amphiphysin discovered by Folli et al

1994

Treated SPS by IVIG successfully

1997

First SLS case reported

2000

Anti-gephyrin discovered by Butler et al

2006

Anti-GABARAP discovered by Raju et al

2008

Anti-Glycine discovered by Hutchinson et al

2009

Criteria by Dalakas et al

2013

Anti-DPPX discovered by Boronat et al

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1  Historical Background of Stiff-Person Spectrum Disorders

SPS remains a relatively novel entity. Patients with SPS suffer from muscle rigidity, especially of axial muscle, causing pain and significant disability. Most of the patients were previously labeled as having psychogenic or functional disease owing to relatively normal physical examination, laboratory, and imaging.

Criteria Evolution After the first reported series in 1956, there were more than 100 cases reported with stiff-man syndrome, reflecting an increase in the awareness of this disease among physicians. The first criteria were proposed by Gordon et al. in 1967 [7]. They included clinical and, neurophysiological criteria, as well as laboratory findings from literature in the 10-year period after Moersch and Woltman’ initial publication. However, anti-glutamic acid decarboxylase (anti-GAD) antibody, which was not discovered by that time, was not included in the laboratory findings. Gordon et al. also clarified in more detail the neurophysiological findings reported in the literature. They defined it as “persistent tonic contraction reflected in constant firing even at rest.” This electrical and contractile activity would disappear after myoneural block, motor nerve block, or general anesthesia. They highlighted that the changes occurring after neurologic blocking agents are essential, because Isaacs described a similar case with muscle rigidity and stiffness; however, motor unit action potentials were not abolished with general anesthesia and not totally with motor nerve block. Later, several authors called the finding as continuous motor unit activity (CMUA) [19]. This activity had been described by Moersch, Woltman, Gordon, and others [3, 6, 7, 20–22]. Lorish et al. proposed another criteria in 1989 that included seven clinical, physical examination, and neurophysiological criteria [10]. Even though the data of anti-­ GAD antibody from Solimena et al. were published in 1988 [9], these criteria did not include laboratory criteria, concluding at that time that there were insufficient data since they report antibody from only one patient. During that period, clinicians identified patients who did not fit Gordon’s or Lorish’s criteria, often referring to them as “atypical stiff-person syndrome”. In 1997, Brown and Marsden reported cases of focal stiff-person syndrome or “stiff-limb syndrome” [23]. Barker et al. reported case series and different categories of stiff-­person syndrome in 1998 [24]. They divided the spectrum into typical stiff-person syndrome, progressive encephalopathy with rigidity and myoclonus (PERM), and stiff-limb syndrome (or a focal form of the disorders). In 1999, Brown and Marsden published their case series and included clinical, immunological, and pathological features. They also proposed another similar classification (see Chap. 2), defined into classic form and stiff-man plus syndromes, which was further divided into two subgroups: subacute (PERM) and chronic (brainstem form including jerking stiff-man syndrome) and spinal form (stiff-limb syndrome) [25]. In 2009, Dalakas classified clinical features of SPS [17]. His clinical criteria are shown in Table 1.1.

Criteria Evolution

5

Table 1.1  Comparison between criteria by Gordon, Lorish, and Dalakas [7, 10, 17] Gordon et al. [7] 1. Prodromes: Episodic aching and tightness of the axial musculature 2. Progression: Symmetrical continuous stiffness involves most of the limb, trunk, and neck musculature, involving both agonist and antagonist muscles 3. Painful spasm: Paroxysmal muscle spasm described as tetanic and titanic. Precipitated by noise, jar, active or passive motion of a limb, and emotion 4. Sleep: Rigidity is abolished by sleep 5. Intellect: Intact Normal motor and sensory exam Difficulty in active movement Reflexes may be increased

Lorish et al. [10] 1. Insidious onset and slow progression of symptoms 2. Muscular tightness, stiffness and rigidity involving neck, paraspinal and abdominal muscles 3. Rigidity involves both agonist and antagonist muscles 4. Intermittent severe spasms in affected muscles, precipitated by unexpected movements or noises (simply by being jarred or touched) or occasionally by fear or apprehension 5. Severe pain associated with the spasms

Dalakas [17] 1. Muscular rigidity in the limbs and axial (trunk) muscles, prominent in the abdominal and thoracolumbar paraspinals 2. Continuous co-contraction of agonist and antagonist muscles, confirmed clinically and electrophysiologically 3. Episodic spasms precipitated by unexpected noises, tactile stimuli, or emotional upset 4. Absence of any other neurologic diseases that could explain stiffness and rigidity

Not applicable

Laboratory testing

Not applicable

Normal motor and sensory exam Reflexes can be increased Muscles are tight, and have rock-hard, board-like quality Slow and very cautious gait Not applicable

Electrodi­ agnostic finding

1. Persistent tonic contraction in constant firing even at rest and attempt at relaxation cannot alter the discharge 2. Normal motor unit action potentials

Positive anti-glutamic acid decarboxylase (GAD)65 (or amphiphysin) antibodies assessed by immunocytochemistry, Western blot, or radioimmunoassay 1. Continuous motor unit Not applicable activity at rest and attempts to relax 2. No other abnormalities on electromyography

Clinical manifestations

Physical examination

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1  Historical Background of Stiff-Person Spectrum Disorders

History of Variants in Stiff-Person Syndrome Progressive Encephalomyelitis with Rigidity and Myoclonus In 1971, Kasperek reported a case with stiffness and painful spasm initially similar to description in SPS; however, the patient worsened with gaze palsies and peripheral polyneuropathy [8]. Despite of the diazepam trial, patient unfortunately died 11  months after onset of stiffness. Autopsy showed evidence of subacute encephalomyelitis affecting the lower brainstem and spinal cord. In 1973, Lhermitte reported additional two cases with similar presentation and raised the possibility of a new entity [26]. In 1976, Whiteley reported another two cases and proposed the term “progressive encephalomyelitis with rigidity (PER)” [27]. Whiteley found that Campbell and Garland had reported patients with PER presentation in 1956 and named the disorder “subacute myoclonic spinal neuronitis” instead [28]. The pathology in these cases was striking and different from classic stiff-person syndrome. All of them reported evidence of inflammation, initially concerned for viral infection, in the lower brainstem. Neuroimaging data was not well described until the late 1900s. In 1989, McCombe reported T2 hyperintensity on MRI throughout the length of the cervical cord and lower brainstem, correlating with T1 hypointensity in the same regions, in a patient with progressive encephalomyelitis with rigidity [29]. This patient underwent biopsy in the area of MRI changes, which showed perivascular cuffing with mononuclear cells, accompanied by destruction of myelin and axon. This finding was consistent with an inflammatory process which supported the theory of autoimmune disorder at that time. Meinck et al. first added “myoclonus” in the name of PER to become “progressive encephalomyelitis with rigidity and myoclonus (PERM)” [30]. However, the name was interchangeably called either PER or PERM, mostly PER, until 2010 when PERM has become the more popular and preferred term. Barker et al. first lumped SPS and related disorders including PER together [24]. Similar classification was also reported by Brown and Marsden in 1999 [25].

Stiff-Limb Syndrome Focal SPS was first reported by Brown in 1997 [23]. They described four cases with stiffness confined to the lower extremity only. The term “stiff-leg syndrome” was suggested as a variant of SPS based on clinical and electrodiagnostic evidences. In 1998, Barker reported a case series of 23 patients with SPS [24]. Of them, 13 had stiffness only in either upper or lower extremity without truncal stiffness and named “stiff-limb syndrome.” In the same year, Saiz et  al. also reported two cases with stiff-leg syndrome [31], while Fiol et  al. in 2001 published on “focal stiff-person syndrome” [32]. Since then stiff-limb syndrome has been recognized as a focal form of SPS.

Treatment History

7

Discovery of Antibodies Anti-GAD antibody was first discovered by Solimena et al. in 1988 [9]. This was based on the hypothesis of continuous alpha motor unit activity in SPS and the impairment of the suprasegmental or spinal inhibitory systems which is mediated through γ-aminobutyric acid (GABA). The authors obtained serum and Cerebrospinal fluid (CSF) from one patient with SPS and type 1 diabetes mellitus and tested for immunochemistry in association with GABA-ergic neuron. They identified the autoantibody to glutamic acid decarboxylase (GAD), the enzyme responsible for the biosynthesis of GABA in the serum and CSF, and confirmed staining patterns in mouse brains by patient’s antibodies. They also identified similar positive staining to GAD in the pancreatic beta cells. In 1990, Solimena and De Camilli et al. published a larger series of patients [33]. They confirmed that anti-GAD was found in up to 60% of SPS patients. Anti-GAD was also found in the stiff-person variants. In 1991, Burn et al. reported a case with PERM phenotype with positive anti-GAD antibody [34]. Anti-GAD was identified in two distinct isoforms: GAD65 and GAD67. These two proteins are translated from two different genes and both are expressed in the brain [35]. In 1993, Butler et al. found that antibodies in SPS selectively recognized GAD65 isoform [36]. In 1993, Folli et al., from the same group of Solimena and De Camilli, reported antibody linked to paraneoplastic SPS [12]. At that time, they identified a 128-kd based antibody in the CSF of three patients with breast cancer and SPS. In all three patients, anti-GAD antibody was negative. In 1993, De Camilli et al. uncovered that this 128-kd based antibody is anti-­amphiphysin [37]. Since then, it is estimated that 5% of patients with SPS have a strong association with cancer, especially breast cancer. In 2000, Butler found another antibody which was later called anti-gephyrin in paraneoplastic stiff-person syndrome [14]. Since 2000, multiple antibodies had been identified in association with SPS, e.g., anti-GABAA receptor-­associated protein (anti-GABARAP) [15], anti-glycine receptor [16], and anti-dipeptidyl-peptidase-like protein 6 (anti-DPPX) antibodies [18]. Although anti-glycine receptor antibody is the main antibody associated with PERM, it may also be positive in classic SPS. For example, Carvajal-Gonzales et al. found 2 out of 45 patients (4%) with SPS with positive anti-glycine receptor antibody [38]. Despite these important discoveries, the most common antibody associated with SPS remains the antiGAD65 antibody.

Treatment History The first successful treatment of SPS with diazepam was published by Howard in 1963 (Fig. 1.2) [6]. He reported significant improvement in stiffness and spasms. This finding supported the hypothesis for pathophysiology of stiff-person syndrome as either hyperexcitation of central catecholaminergic neurons or inhibition of GABA-ergic neurons. In 1989, Vicari et al. reported one patient with SPS who was

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1  Historical Background of Stiff-Person Spectrum Disorders

successfully treated with plasma exchange [11]. However in the same year, Harding et  al. reported two patients who did not improve with plasma exchange [39]. In 1994, Amato et al. and Karlson et al. reported separately that intravenous immunoglobulin (IVIG) improved both subjective and functional outcomes in their three patients combined [13, 40]. Karlson’s patients were bedridden and were able to walk after IVIG therapy. In the past decade, multiple case reports described the use of immunosuppressive therapies in SPS including rituximab with variable outcome. Eventually, in 2017 Dalakas et al. published a double-blind, placebo-controlled trial of rituximab in stiff-person syndrome which demonstrated no significant difference compared to placebo [41]. This will be discussed futher in detail in Chap. 12.

References 1. Amadio PC. The Mayo Clinic and carpal tunnel syndrome. Mayo Clin Proc. 1992;67(1):42–8. https://doi.org/10.1016/s0025-6196(12)60278-x. 2. Corbin KB, Kernohan JW.  Henry William Woltman, M.D., 1889–1964. Neurology. 1965;15:413–4. https://doi.org/10.1212/wnl.15.4.413. 3. Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin. 1956;31(15):421–7. 4. Ornsteen AM. Chronic generalized fibromyositis. Ann Surg. 1935;101(1):237–45. https://doi. org/10.1097/00000658-193501000-00024. 5. Blum P, Jankovic J.  Stiff-person syndrome: an autoimmune disease. Mov Disord. 1991;6(1):12–20. https://doi.org/10.1002/mds.870060104. 6. Howard FM Jr. A new and effective drug in the treatment of the stiff-man syndrome: preliminary report. Proc Staff Meet Mayo Clin. 1963;38:203–12. 7. Gordon EE, Januszko DM, Kaufman L. A critical survey of stiff-man syndrome. Am J Med. 1967;42(4):582–99. https://doi.org/10.1016/0002-9343(67)90057-5. 8. Kasperek S, Zebrowski S. Stiff-man syndrome and encephalomyelitis. Report of a case. Arch Neurol. 1971;24(1):22–30. https://doi.org/10.1001/archneur.1971.00480310050004. 9. Solimena M, Folli F, Denis-Donini S, Comi GC, Pozza G, De Camilli P, et al. Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med. 1988;318(16):1012–20. https://doi.org/10.1056/ NEJM198804213181602. 10. Lorish TR, Thorsteinsson G, Howard FM Jr. Stiff-man syndrome updated. Mayo Clin Proc. 1989;64(6):629–36. https://doi.org/10.1016/s0025-6196(12)65339-7. 11. Vicari AM, Folli F, Pozza G, Comi GC, Comola M, Canal N, et al. Plasmapheresis in the treatment of stiff-man syndrome. N Engl J Med. 1989;320(22):1499. 12. Folli F, Solimena M, Cofiell R, Austoni M, Tallini G, Fassetta G, et al. Autoantibodies to a 128-­ kd synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med. 1993;328(8):546–51. https://doi.org/10.1056/NEJM199302253280805. 13. Amato AA, Cornman EW, Kissel JT.  Treatment of stiff-man syndrome with intravenous immunoglobulin. Neurology. 1994;44(9):1652–4. https://doi.org/10.1212/wnl.44.9.1652. 14. Butler MH, Hayashi A, Ohkoshi N, Villmann C, Becker CM, Feng G, et al. Autoimmunity to gephyrin in stiff-man syndrome. Neuron. 2000;26(2):307–12. 15. Raju R, Rakocevic G, Chen Z, Hoehn G, Semino-Mora C, Shi W, et  al. Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain. 2006;129(Pt 12):3270–6. https://doi.org/10.1093/brain/awl245. 16. Hutchinson M, Waters P, McHugh J, Gorman G, O’Riordan S, Connolly S, et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology. 2008;71(16):1291–2. https://doi.org/10.1212/01.wnl.0000327606.50322.f0.

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17. Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009;11(2):102–10. 18. Boronat A, Gelfand JM, Gresa-Arribas N, Jeong HY, Walsh M, Roberts K, et al. Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol. 2013;73(1):120–8. https://doi.org/10.1002/ana.23756. 19. Isaacs H.  A syndrome of continuous muscle-fibre activity. J Neurol Neurosurg Psychiatry. 1961;24(4):319–25. https://doi.org/10.1136/jnnp.24.4.319. 20. Olafson RA, Mulder DW, Howard FM. “Stiff-man” syndrome: a review of the literature, report of three additional cases and discussion of pathophysiology and therapy. Mayo Clin Proc. 1964;39:131–44. 21. Trethowan WH, Allsop JL, Turner B. The “stiff-man” syndrome. A report of two further cases. Arch Neurol. 1960;3:448–56. 22. Werk EE Jr, Sholiton LJ, Marnellrt. The “stiff-man” syndrome and hyperthyroidism. Am J Med. 1961;31:647–53. https://doi.org/10.1016/0002-9343(61)90147-4. 23. Brown P, Rothwell JC, Marsden CD. The stiff leg syndrome. J Neurol Neurosurg Psychiatry. 1997;62(1):31–7. https://doi.org/10.1136/jnnp.62.1.31. 24. Barker RA, Revesz T, Thom M, Marsden CD, Brown P.  Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry. 1998;65(5):633–40. https://doi.org/10.1136/jnnp.65.5.633. 25. Brown P, Marsden CD.  The stiff man and stiff man plus syndromes. J Neurol. 1999;246(8):648–52. 26. Lhermitte F, Chain F, Escourolle R, Chedru F, Guilleminault C, Francoual M. [A further case of tetanus-like contracture distinct from the stiff man syndrome. Pharmacological and neuropathological study of a case of predominantly spinal encephalomyelitis]. Rev Neurol (Paris). 1973;128(1):3–21. 27. Whiteley AM, Swash M, Urich H.  Progressive encephalomyelitis with rigidity. Brain. 1976;99(1):27–42. https://doi.org/10.1093/brain/99.1.27. 28. Campbell AM, Garland H.  Subacute myoclonic spinal neuronitis. J Neurol Neurosurg Psychiatry. 1956;19(4):268–74. https://doi.org/10.1136/jnnp.19.4.268. 29. McCombe PA, Chalk JB, Searle JW, Tannenberg AE, Smith JJ, Pender MP.  Progressive encephalomyelitis with rigidity: a case report with magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry. 1989;52(12):1429–31. https://doi.org/10.1136/jnnp.52.12.1429. 30. Meinck HM, Ricker K, Hulser PJ, Schmid E, Peiffer J, Solimena M.  Stiff man syndrome: clinical and laboratory findings in eight patients. J Neurol. 1994;241(3):157–66. https://doi. org/10.1007/bf00868343. 31. Saiz A, Graus F, Valldeoriola F, Valls-Sole J, Tolosa E. Stiff-leg syndrome: a focal form of stiff-man syndrome. Ann Neurol. 1998;43(3):400–3. https://doi.org/10.1002/ana.410430322. 32. Fiol M, Cammarota A, Rivero A, Pardal A, Nogues M, Correale J.  Focal stiff-person syndrome. Neurologia. 2001;16(2):89–91. 33. Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med. 1990;322(22):1555–60. https://doi.org/10.1056/NEJM199005313222202. 34. Burn DJ, Ball J, Lees AJ, Behan PO, Morgan-Hughes JA. A case of progressive encephalomyelitis with rigidity and positive antiglutamic acid decarboxylase antibodies [corrected]. J Neurol Neurosurg Psychiatry. 1991;54(5):449–51. https://doi.org/10.1136/jnnp.54.5.449. 35. Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ.  Two genes encode distinct glutamate decarboxylases. Neuron. 1991;7(1):91–100. https://doi. org/10.1016/0896-6273(91)90077-d. 36. Butler MH, Solimena M, Dirkx R Jr, Hayday A, De Camilli P. Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies in stiff-man syndrome. J Exp Med. 1993;178(6):2097–106. https://doi.org/10.1084/jem.178.6.2097.

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37. De Camilli P, Thomas A, Cofiell R, Folli F, Lichte B, Piccolo G, et al. The synaptic vesicle-­ associated protein amphiphysin is the 128-kD autoantigen of stiff-man syndrome with breast cancer. J Exp Med. 1993;178(6):2219–23. https://doi.org/10.1084/jem.178.6.2219. 38. Carvajal-Gonzalez A, Leite MI, Waters P, Woodhall M, Coutinho E, Balint B, et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain. 2014;137(Pt 8):2178–92. https://doi.org/10.1093/brain/awu142. 39. Harding AE, Thompson PD, Kocen RS, Batchelor JR, Davey N, Marsden CD.  Plasma exchange and immunosuppression in the stiff man syndrome. Lancet. 1989;2(8668):915. https://doi.org/10.1016/s0140-6736(89)91568-7. 40. Karlson EW, Sudarsky L, Ruderman E, Pierson S, Scott M, Helfgott SM. Treatment of stiff-­ man syndrome with intravenous immune globulin. Arthritis Rheum. 1994;37(6):915–8. 41. Dalakas MC, Rakocevic G, Dambrosia JM, Alexopoulos H, McElroy B.  A double-blind, placebo-controlled study of rituximab in patients with stiff person syndrome. Ann Neurol. 2017;82(2):271–7. https://doi.org/10.1002/ana.25002.

2

Clinical Phenomenology of Stiff-Person Spectrum Disorders

Stiff-person spectrum disorders (SPSD) often pose a diagnostic challenge in clinical practice. The symptoms and signs mimic other more common disorders including musculoskeletal, neuromuscular, and rheumatologic disorders as well as dystonia. Patients with SPS often have co-existing neuropsychiatric disorders including depression and anxiety and may be misdiagnosed as a functional nerologic disorder. Patients are often evaluated by multiple physicians before the correct diagnosis is made; the delay in diagnosis is partly the source of patients’ frustration. In this chapter, the clinical features of SPSD, including classic SPS and its variants, will be covered.

Epidemiology The true incidence and prevalence of all stiff-person spectrum disorders (SPSD), including classic stiff-person syndrome (SPS) and its variants, are not known. For classic SPS, the incidence is estimated to be one case per million per year, and the estimated prevalence is one to two cases per million [1]. Nevertheless, SPSD are likely underdiagnosed [2].

Differentiating Stiffness from Other Phenomenology The first crucial step in making the diagnosis of SPSD is identification of the correct phenomenology, “stiffness,” which contributes to the main clinical feature of SPS and its variants. While SPSD is often under-recognized, it is also important not to overdiagnose. On several occasions, patients referred to the authors with the

Electronic Supplementary Material The online version of this chapter (https://doi. org/10.1007/978-3-030-43059-7_2) contains supplementary material, which is available to authorized users. © Springer Nature Switzerland AG 2020 P. Termsarasab et al., Stiff-Person Syndrome and Related Disorders, https://doi.org/10.1007/978-3-030-43059-7_2

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diagnosis of “SPS” turned out to have other diagnoses such as functional neurologic disorder or dystonia. Here, we will discuss how to differentiate stiffness in SPSD from spasticity, cramps, and dystonia. Stiffness in SPSD is characterized by muscle rigidity in the axial musculature or extremities. This correlates with the electrophysiological hallmark of continuous co-contraction of agonist and antagonist muscles. When examining the muscle tone of patients with SPSD, the examiner may feel the “tightness” or “resistance” during passive movements of the affected body parts. This “tightness” may be called by some physicians as “hypertonia,” and the “resistance” is called as “rigidity.” Although “rigidity” in SPSD and parkinsonian disorders shares some common clinical features, it is not identical. In both groups of disorders, the examiner may feel uniformly increased tone against resistance. In parkinsonian disorders, prominent pain is usually not a feature when passively moving the body parts, whereas in SPSD, pain during the examination may be prominent and sometimes limit the ability to perform full examination. In addition, cogwheel rigidity due to tremor superimposed on rigidity is not a feature in SPSD. Spasticity is an increased muscle tone which is an essential feature of upper motor neuron (aka pyramidal) dysfunction. It is distinctive from hypertonia since the markedly increased muscle tone in spasticity leads to abnormal posturing of body parts especially extremities at rest which may be overcome by passive movements. This is also different from joint contracture, where there is limited range of active and passive motion around the joint, and passive movements cannot overcome the abnormal posturing back to the fully normal position. Finally, another important feature of spasticity is a velocity-dependent increase in resistance during the examination, often easily appreciated by the examiner. Cramps are very severe muscle spasms which are extremely painful. Cramps typically occur exclusively in an episodic fashion. In contrast, stiffness in SPSD is typically less severe than cramps and occurs in continuous fashion (presence of baseline stiffness) with superimposed episodic exacerbation of painful spasms. Cramps usually occur in a single or few limb muscles at a time, whereas stiffness in SPS often involves axial and limb muscles. In stiff-limb syndrome, although only limb muscles may be involved, the stiffness is more widespread (i.e., the entire limb or multiple distal limb muscles). Electrophysiologically, cramps are spontaneous, high-frequency, typically 20–150  Hz, runs of regularly discharging one or more motor unit action potentials. Dystonia may sometimes be difficult to differentiate from SPSD (Video 2.1). Some patients with SPSD may be misdiagnosed as dystonia [3], and the reverse also occurs [4]. In fact, SPS is considered to be one of dystonia mimics or pseudodystonia. Dystonia is usually more prominent during voluntary activation of that body part, and less prominent at rest. SPSD, in contrast, usually appear the same at rest and with activation. In other words, dystonia tends to be more mobile during different parts of the examination. Other features of dystonia, when present, may help differentiating it from stiffness in SPSD, including sensory tricks or geste antagoniste, mirror dystonia, motor overflow, null point (the position

Classification of Stiff-Person Spectrum Disorders (SPSD)

13

where dystonia is minimal or markedly improved), and dystonic tremor [5]. One useful examination technique is asking the patient to run or walk backward. In dystonia, the affected body parts such as the trunk or lower limbs may improve when walking backward or running (called “state function”) [6], whereas in SPSD, the severity of the affected body parts is fixed and does not change with these maneuvers. Due to commonly co-existing anxiety, patients with SPSD tend to be reluctant to walk or walk in deliberate manner, whereas walking in dystonia patients is usually limited mainly by the severity of dystonia. Exaggerated startle or head retraction reflex, when present, helps in the diagnosis of SPSD. Myotonia, as seen in dystrophic and non-dystrophic myotonias, often presents with muscle stiffness. There are some features that distinguish myotonia from stiffness of SPSD. Myotonia is usually worst at the initiation of limb or hand movement, improves with activity, and is not painful. On examination, there is grip or eyelid myotonia as well as percussion myotonia. Needle electromyography (EMG) shows myotonic discharges and sometimes low-amplitude, short-duration and polyphasic muscle action potentials (MUAPs). These are specific findings not seen in SPSD (see Chap. 14). Finally, peripheral nerve hyperexcitability of Isaacs or Morvan syndromes often manifests with generalized muscle stiffness, which persists during sleep. This is usually associated with slowness of movement and often muscle hypertrophy. On inspection, there is frequently continuous muscle twitching and undulation (bag of worms). Signs of dysautonomia including hyperhidrosis, sialorrhea, piloerection, and abdominal pain are frequent. Needle EMG reveals a variety of spontaneous activities including fasciculations, myokymic discharges, and neuromyotonic discharges. A significant number of these patients have elevated serum voltage-gated potassium channel-complex antibodies. These clinical, needle EMG and serological findings distinguish these disorders from SPSD (see Chap. 14).

Classification of Stiff-Person Spectrum Disorders (SPSD) Although there has been no consensus on the classification of SPSD, we propose the classification that can be useful in clinical practice (Table 2.1).

Table 2.1  Our proposed classification of stiff-person spectrum disorders. The terms “jerking SPS” and “SPS-plus” have been used confusingly in the literature. Please refer to the section “Controversial SPS Variants and Terminology” for further discussion 1. Classic stiff-person syndrome 2. Variant stiff-person syndrome  2.1 Stiff-limb syndrome (SLS)  2.2 Progressive encephalomyelitis with rigidity and myoclonus (PERM)  2.3 Overlapping syndrome

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2  Clinical Phenomenology of Stiff-Person Spectrum Disorders

Classic Stiff-Person Syndrome (SPS) Classic SPS is a form of SPS most commonly seen in clinical practice. Classic SPS is characterized by muscle rigidity that typically involves axial musculature, especially in the thoracic and lumbar levels, as well as proximal legs. The onset is usually insidious, and the symptoms typically develop over a period of several months or years. Patients usually have superimposed episodic painful spasms, in addition to ongoing muscle rigidity present at baseline. The superimposed episodic spasms are often aggravated by unexpected external stimuli such as auditory, tactile, or visual stimuli, or emotional upset. Truncal stiffness may give rise to a “wooden-like” (aka “statue-like” or “log-­ like”) appearance. Patients with truncal involvement typically have hyperlordosis of the spine. Transverse skin creases can also be observed at the back, but this feature is not specific since it can also be seen in normal population. Some patients may have frequent falls while in this posture with lack of appropriate defense mechanism leading to injury [7]. Myoclonic jerks can co-exist with muscle spasms in SPS, or some muscle spasms may have jerky appearance resembling myoclonus, sometimes referred to as “jerking” SPS. It is not uncommon or surprising that many patients with SPS are misdiagnosed with functional (aka psychogenic) neurologic disorders. This may be due to multiple reasons. First, the clinical presentation of SPS is under-recognized by medical and healthcare personnel. Many patients consult multiple physicians including general practitioners, orthopedists, and neurologists. Not uncommonly, patients initially present with chronic back pain, but no specific causes can be identified on extensive work-up. Second, many patients with SPS often have co-existing psychiatric illness such as phobia, anxiety, and depression. Third, patients may exhibit prominent fear of falls, severe dysautonomia, or painful spasm crises. This may mislead clinicians to the incorrect diagnosis of functional neurologic disorders. Neuropsychiatric features in SPS include anxiety, depression, and phobia such as agoraphobia on situation-specific phobia, obsession, talkativeness, and frequent repetitions [2]. Specific phobia was found in 44% of SPS patients in one study [8]. Although these are considered comorbidities of SPS, a small study suggested that fear and anxiety in SPS were likely attributed to the disease itself, and not due an underlying pre-existing psychiatric disorder before the development of the disease [9]. Exclusionary features of classic SPS include pyramidal and extrapyramidal features, lower motor neuron signs, sphincter dysfunction, and sensory impairment [10]. Among all pyramidal signs, only hyperreflexia is an accepted finding. This diagnostic criteria of classic SPS have evolved over the years parallel to the discovery of autoantibodies in SPS, and our understanding of pathophysiology and treatment response. Two of the diagnostic criteria were proposed by Dalakas et al. In 1999–2000, Dalakas et al. proposed the original criteria for SPS [11, 12]. In this criteria, there were only four clinical criteria which remained the first four in the updated version. Positive anti-glutamic acid decarboxylase 65 (anti-GAD65) was not included. In the revised version of the criteria by Dalakas et al. in 2009, positive

Classification of Stiff-Person Spectrum Disorders (SPSD)

15

Table 2.2  Dalakas diagnostic criteria of SPS [2] 1. Muscular rigidity in the limbs and axial (trunk) muscles, prominent in the abdominal and thoracolumbar paraspinals 2. Continuous co-contraction of agonist and antagonist muscles, confirmed clinically and electrophysiologically 2. Episodic spasms precipitated by unexpected noises, tactile stimuli, or emotional upset 4. Absence of any other neurologic disease that could explain stiffness and rigidity 5. Positive anti-glutamic acid decarboxylase (GAD)65 or amphiphysin antibodies assessed by immunocytochemistry, Western blot, or radioimmunoassay 6. Clinical response to benzodiazepinesa a

The sixth criterion was added later, and not included in the original criteria

antibodies including anti-GAD65 and anti-amphiphysin were added as the fifth criterion (Table 2.2) [2]. Later, clinical response to benzodiazepines was added as the sixth criterion. These two added criteria are considered to be minor criteria [1]. These criteria are mainly applied to classic SPS. For example, a stiff-limb syndrome variant where only extremities are involved would not fulfill the first criterion. In addition, with more advances in neuroimmunology and explosion of antibody identification, other antibodies besides anti-GAD65 and anti-amphiphysin may be associated with classic SPS.

Stiff-Limb Syndrome (SLS) SLS is considered to be a focal form of SPSD where only extremities are involved with no or only minimal truncal involvement (Video 2.2). The data about SLS remain scant in the literature. The lower extremities are more commonly affected than the upper extremities. Thus, the term “stiff-leg syndrome” has also been used in literature. Brown and Marsden suggested to use the term “stiff-limb syndrome” to cover the entire spectrum of this variant. Distal part of the extremity is usually affected, but proximal involvement or involvement of the entire extremity without gradient can also be seen. In one case series of 23 patients with SPSD, SLS represented 15% of all patients [13]. Stiffness, rigidity, and episodic painful spasm are present, similar to classic SPS, but only extremities are involved without involvement of the trunk. Patients with SLS can have a marked delay in diagnosis. Psychiatric comorbidities as well as fear of falls can also be present, similar to classic SPS.

 rogressive Encephalomyelitis with Rigidity P and Myoclonus (PERM) PERM is a variant of SPS within the domain of SPSD with a primary pathology in the brainstem. Patients with PERM typically present with subacute encephalopathy within several days or weeks, along with generalized rigidity, especially in the axial musculature. Another characteristic feature that can also serve as an important diagnostic clue is brainstem myoclonus. Given the origin in the brainstem, myoclonic

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2  Clinical Phenomenology of Stiff-Person Spectrum Disorders

jerks in PERM typically involve cranial and neck musculature; however, they can often spread to truncal and limb muscles as well. The myoclonic jerks are sensitive to auditory and tactile stimuli. Patients may also have exaggerated startle. Autonomic features such as diaphoresis and hyperthermia can also be seen [14]. PERM variant is discussed in detail in Chap. 9.

Overlapping Syndrome Overlapping syndrome is referred to the co-existing neurologic features that may accompany the clinical features of SPSD, including cerebellar ataxia in 10%, epilepsy in 10–20%, or limbic encephalitis [15, 16]. Unfortunately, there is no consensus definition of the accepted neurological features within the overlapping syndrome. At present, at least cerebellar ataxia, epilepsy, and limbic encephalitis are recognized features in the existing literature [15]. While other autoimmune diseases such as type 1 diabetes and thyroid disorders are known co-existing disorders in SPSD, patients who have SPSD along with these autoimmune disorders are not classified as overlapping syndrome, since they are not neurological disorders.

Associated Clinical Features of SPSD SPSD, especially classic SPS which has been most studied, may have associated clinical features in addition to ataxia, epilepsy, and limbic encephalitis, as mentioned above. Autoimmunity can co-exist in SPSD, and these include type 1 diabetes (aka insulin-dependent diabetes mellitus [IDDM]) in 30–40% of SPSD cases [11], thyroid diseases including Hashimoto thyroiditis and Graves’ disease in 10%, pernicious anemia in 5%, as well as vitiligo, celiac disease, myasthenia gravis, autoimmune retinopathy and scleritis, and systemic lupus erythematosus [1, 16, 17]. IDDM has a strong association with an anti-GAD antibody, and this is further discussed in Chap. 7.

Hyperekplexia and Stiff-Person Spectrum Disorders Hyperekplexia is characterized by an exaggerated startle response to various stimuli such as auditory, tactile, or visual. It is considered to be a form of brainstem myoclonus. Hyperekplexia is classified into three main groups: hereditary, sporadic, and symptomatic (see Chap. 15). This central nervous system hyperexcitability is related to abnormality in glycinergic transmission within the brainstem. Patients with SPSD may exhibit exaggerated startle responses or clinical features resembling hyperekplexia. One obvious example is the exaggerated startle responses and myoclonic jerks after auditory or tactile stimuli seen in PERM variant. In contrast, patients with hyperekplexia also have a clinical feature of stiffness. For instance, in hereditary hyperekplexia, babies have continuous muscle stiffness and a short period of worsening muscle stiffness. Repetitive stimulation such as nose tapping can lead to exacerbation of muscle stiffness and respiratory depression, and this should be

Controversial SPS Variants and Terminology

17

avoided. Glycine is a common substrate among these disorders. Hereditary hyperekplexia is due to mutations of the genes encoding protein or receptors related to glycinergic transmission [18], the most common of which are mutations in the α1 subunit of the glycine receptor. PERM can be attributed to an anti-glycine receptor antibody [19]. This demonstrates a parallel between an autoimmune disorder and hereditary hyperekplexia affecting the same protein. Thus, while exaggerated startle responses and stiffness are overlapping features between SPSD and hereditary hyperekplexia, SPSD is an autoimmune disorder, not genetic. Furthermore, stiffness in SPSD is continuous but can be exacerbated, whereas stiffness in adult (symptomatic or genetic) hyperekplexia occurs only after startling stimuli. Both hyperekplexia and SPSD can be categorized under the same umbrella of “startle syndromes,” but SPSD is typically classified in a (startling) stimulus-­induced disorder, rather than “hyperekplexia,” subcategory. Startle syndromes, as well as the comparison between SPSD, hereditary hyperekplexia, and other forms of hyperekplexia, are discussed in detail in Chap. 15.

Controversial SPS Variants and Terminology Two terms that have been used most confusingly in the literature and clinical practice are “jerking SPS” and “SPS-plus.” Brown and Marsden classified SPS (called “stiff-man syndrome” at that time) as follows [20]: –– Stiff man syndrome –– Stiff man plus syndromes 1. Subacute (death within 3 years, long tract signs present): ‘progressive encephalomyelitis with rigidity’ 2. Chronic (survival >3 years, long tract signs absent/few): • Brainstem form, includes the ‘jerking stiff man syndrome’ • Spinal form, ‘stiff limb syndrome’… According to this classification, “jerking stiff-man syndrome” represents a chronic brainstem form of SPSD, or could simply be viewed as a PERM variant with survival greater than 3  years. However, many clinicians later use the term “jerking SPS” when SPS manifests with prominent co-existing myoclonus or myoclonic-like component that render SPS appear jerky, regardless of the time course. It is now known that patients with PERM may survive longer than 3 years, if appropriately treated. Since jerkiness occurs in the SLS variant as well as the PERM variant and classic SPS, we suggest not using the term “jerking SPS” as a final diagnosis. Nevertheless, the term “jerky” can still be used to expand the phenomenological description of stiffness in some patients. Another confusing terminology is “SPS-plus.” According to Brown and Marsden, SPS-plus is defined as when there is at least one of the following clinical features: • Rigidity and abnormal posturing of one or more limbs that includes the hand or foot • Myoclonus involving all four limbs

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• • • • • •

2  Clinical Phenomenology of Stiff-Person Spectrum Disorders

Brainstem signs Long tract signs Lower motor neuron signs Cognitive changes, especially memory impairment Autonomic failure/sphincter involvement Cerebrospinal fluid pleocytosis

In another publication by Martinez-Hernandez and colleagues, SPS-plus is defined as “patients with all or partial elements of PERM: brainstem dysfunction, myoclonus, upper or lower motor neuron symptoms, sensory deficits, sphincter or autonomic dysfunction, seizures, and cognitive changes” [15]. Although similar to the previous definition proposed by Brown and Marsden, these two definitions are not identical. Rigidity in the limb is endorsed in the criteria proposed by Dalakas, and this can be simply classified as classic SPS when apparent axial involvement is also present. In addition, myoclonus may be seen in several SPS variants, brainstem signs are typically seen in the PERM variant, and long tract signs may be present in classic SPS and several variants. Therefore, we suggest to avoid using the term “SPS-plus.” The term “overlapping syndrome” can be used when ataxia, epilepsy, or limbic encephalitis co-exists, as mentioned above. Consensus definition of these terms would be very useful for clinical practice and advancing research in this field in the future. Table 2.3 compares the Brown and Marsden classification with our proposed classification, and Table 2.4 provides pearls and pitfalls in the diagnosis of SPSD. Table 2.3 Comparison between Brown and Marsden classification and our proposed classification Brown and Marsden classification Stiff-man syndrome Stiff-man plus syndrome  Subacute: progressive encephalomyelitis with rigidity  Chronic    Brainstem form: jerking stiff-man syndrome    Spinal form: stiff-limb syndrome

Our proposed classification Classic SPS PERM variant —a see remark below SLS variant

Abbreviations: PERM progressive encephalomyelitis with rigidity and myoclonus, SLS stiff-limb syndrome, SPS stiff-person syndrome a Jerking SPS is mainly seen in PERM variant, but can also be seen in SLS, classic SPS, or overlapping syndrome Table 2.4  Pearls and pitfalls in the diagnosis of stiff-person spectrum disorders Keep a low index of suspicion especially in patients with back or limb pain Psychiatric comorbidities of SPSD such as anxiety and depression are not uncommon and often misdiagnosed as functional neurologic disorder Prominent pain and deliberate slowness can be misleading features in SPSD SPSD is a clinical diagnosis in combination with an appropriate biomarker Continuous motor unit activities (CMUAs), although described as a characteristic electrophysiologic feature of SPSD, are not a specific finding and may be seen with poor relaxation, spasticity, and extrapyramidal disorders (see Chap. 4)

References

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References 1. Baizabal-Carvallo JF, Jankovic J.  Stiff-person syndrome: insights into a complex autoimmune disorder. J Neurol Neurosurg Psychiatry. 2015;86(8):840–8. https://doi.org/10.1136/ jnnp-2014-309201. 2. Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009;11(2):102–10. 3. Stone D, Kaye L, Wicklund M, Malaty I. Stiff person syndrome masquerading as more common movement disorders (P5.024). Neurology. 2017;88(16 Supplement):P5.024. 4. Balint B, Meinck HM, Bhatia KP.  Axial dystonia mimicking stiff person syndrome. Mov Disord Clin Pract. 2016;3(2):176–9. https://doi.org/10.1002/mdc3.12249. 5. Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord. 2013;28(7):863–73. https:// doi.org/10.1002/mds.25475. 6. Frucht SJ.  The definition of dystonia: current concepts and controversies. Mov Disord. 2013;28(7):884–8. https://doi.org/10.1002/mds.25529. 7. Blum P, Jankovic J.  Stiff-person syndrome: an autoimmune disease. Mov Disord. 1991;6(1):12–20. https://doi.org/10.1002/mds.870060104. 8. Henningsen P, Meinck HM.  Specific phobia is a frequent non-motor feature in stiff man syndrome. J Neurol Neurosurg Psychiatry. 2003;74(4):462–5. https://doi.org/10.1136/ jnnp.74.4.462. 9. Ameli R, Snow J, Rakocevic G, Dalakas MC.  A neuropsychological assessment of phobias in patients with stiff person syndrome. Neurology. 2005;64(11):1961–3. https://doi. org/10.1212/01.WNL.0000163984.71993.FE. 10. Espay AJ, Chen R.  Rigidity and spasms from autoimmune encephalomyelopathies: stiff-­ person syndrome. Muscle Nerve. 2006;34(6):677–90. https://doi.org/10.1002/mus.20653. 11. Dalakas MC, Fujii M, Li M, McElroy B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology. 2000;55(10):1531–5. https://doi.org/10.1212/ wnl.55.10.1531. 12. Levy LM, Dalakas MC, Floeter MK. The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid. Ann Intern Med. 1999;131(7):522–30. https://doi.org/10.7326/0003-4819-131-7-199910050-00008. 13. Barker RA, Revesz T, Thom M, Marsden CD, Brown P.  Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry. 1998;65(5):633–40. https://doi.org/10.1136/jnnp.65.5.633. 14. Campbell AMG, Garland H.  Subacute myoclonic spinal neuronitis. J Neurol Neurosurg Psychiatry. 1956;19(4):268–74. https://doi.org/10.1136/jnnp.19.4.268. 15. Martinez-Hernandez E, Arino H, McKeon A, Iizuka T, Titulaer MJ, Simabukuro MM, et al. Clinical and immunologic investigations in patients with stiff-person spectrum disorder. JAMA Neurol. 2016;73(6):714–20. https://doi.org/10.1001/jamaneurol.2016.0133. 16. Meinck HM, Thompson PD.  Stiff man syndrome and related conditions. Mov Disord. 2002;17(5):853–66. https://doi.org/10.1002/mds.10279. 17. Rakocevic G, Floeter MK.  Autoimmune stiff person syndrome and related myelopa thies: understanding of electrophysiological and immunological processes. Muscle Nerve. 2012;45(5):623–34. https://doi.org/10.1002/mus.23234. 18. Tijssen MAJ, Rees MI. Hyperekplexia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, et al., editors. GeneReviews (R): Seattle; 1993. [updated 2012 Oct 4]. 19. Carvajal-Gonzalez A, Leite MI, Waters P, Woodhall M, Coutinho E, Balint B, et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain. 2014;137(Pt 8):2178–92. https://doi.org/10.1093/brain/awu142. 20. Brown P, Marsden CD.  The stiff man and stiff man plus syndromes. J Neurol. 1999;246(8):648–52.

3

Differential Diagnosis of Stiff-Person Spectrum Disorders

Several disorders may mimic stiff-person spectrum disorders (SPSD). Some movement disorder phenomenology such as dystonia and parkinsonism (rigidity) may easily be mistaken as stiffness associated with SPSD. Differentiation between these phenomenologies and stiffness in SPSD was discussed in Chap. 2. In this chapter, we will discuss disorders where stiffness is present. The etiologies of disorders with stiffness are extensive, but are classified into two main categories: (1) stiffness due to central hyperexcitability and (2) stiffness due to peripheral hyperexcitability. In addition, some musculoskeletal or rheumatologic disorders such as ankylosing spondylitis may lead to impaired truncal movements mimicking SPSD [1]. Thorough musculoskeletal and systemic examinations usually provide clues to differentiate these disorders from SPSD.

Stiffness Due to Central Hyperexcitability Central etiologies of stiffness are summarized in Table  3.1. Focal lesions of the spinal cord have been reported to produce stiffness in the limbs. The lesions can be intrinsic spinal cord tumor [2, 3], syringomyelia [4], and vascular etiologies [5]. Infectious/parainfectious etiologies include acute poliomyelitis [6], borreliosis [7], or acute or chronic tetanus [8]. An example of toxic etiology is strychnine poisoning [9] (Fig. 3.1), which is not common in current clinical practice but is an important mimic of tetanus (Fig. 3.2). Stiffness in tetanus typically involves extensor truncal and jaw or lower cranial muscles, giving rise to opisthotonic posturing and trismus (aka locked jaw or risus sardonicus). In strychnine poisoning, stiffness involves the body regions similar to tetanus including extensor truncal and lower cranial muscles. Nevertheless, the history in strychnine poisoning is a key, since the signs and symptoms typically occur 15–30  minutes after exposure. Strychnine can be contaminated in illicit drugs such as heroin and cocaine where it is used to cut as white powder [10] or wine where it is intentionally mixed. Strychnine acts as a

© Springer Nature Switzerland AG 2020 P. Termsarasab et al., Stiff-Person Syndrome and Related Disorders, https://doi.org/10.1007/978-3-030-43059-7_3

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22 Table 3.1 Etiologies of stiffness due to central hyperexcitability

3  Differential Diagnosis of Stiff-Person Spectrum Disorders Focal spinal cord lesions  Tumor  Syringomyelia  Vascular anomalies Toxic, infectious, parainfectious causes  Strychnine poisoning  Tetanus Autoimmune causes  LGI1-associated faciobrachial dystonic seizures Paroxysmal movement disorders  Paroxysmal kinesigenic dyskinesia (PKD)  Paroxysmal non-kinesigenic dyskinesia (PNKD)  Paroxysmal exercise dystonia (PED)   Secondary paroxysmal kinesigenic dyskinesias   Paroxysmal tonic spasm in multiple sclerosis   Other structural spinal cord lesions Episodic ataxia

Fig. 3.1  The molecular structure of strychnine

competitive inhibitor of postsynaptic glycine receptor in the spinal cord, thereby causing central hyperexcitability. Stiff-person syndrome (SPS) has also been reported as post-infectious phenomena such as after West Nile virus infection [11]. Autoimmune disorders may lead to either central or peripheral hyperexcitability, or both. For central hyperexcitability, leucine-rich glioma-inactivated 1 (LGI1) antibody can lead to faciobrachial dystonia seizure (FBDS) [13], which mimics stiff-­ limb syndrome (SLS). The differentiating features of FBDS are typical distribution involving usually unilateral face and arm, and brief duration of the paroxysmal events, typically not longer than a few seconds. LGI1 antibody is associated with voltage-gated potassium channel and thereby is considered to be a part of the voltage-­gated potassium channel complex (VGKC-complex). Another antibody

Stiffness Due to Central Hyperexcitability

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Fig. 3.2  Tetanus in a neonate. This baby has severe generalized stiffness with opisthotonos. (Reprinted from Thwaites and Thwaites [12], Copyright 2013, with permission from Elsevier)

directed to another part of the VGKC-complex is CASPR2, which can lead to neuromyotonia, a form of peripheral hyperexcitability [14]. This will be discussed further later in this chapter. Paroxysmal movement disorders may also mimic SPSD, especially the SLS variant. The key differentiating feature of these disorders from SPSD is their paroxysmal nature of the events, in contrast to persistent stiffness in SPSD.  The phenomenology in these paroxysmal movement disorders includes dystonia, chorea, choreoathetosis, mixed, and sometimes other phenomenology that cannot be simply classified as convention phenomenology, hence called “dyskinesia.” These paroxysmal movement disorders are classified into two main categories, primary (genetic/sporadic or unknown) and secondary, e.g., in the setting of demyelinating disorders or spinal cord pathologies. Age at onset is an important clue, since secondary etiologies should be considered first when paroxysmal movement

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3  Differential Diagnosis of Stiff-Person Spectrum Disorders

disorders occur after late teens, while primary paroxysmal dyskinesias typically start in early childhood. Important secondary causes of paroxysmal movement disorders are multiple sclerosis and neuromyelitis optica spectrum disorders where paroxysmal tonic spasms of the limbs occurs [15, 16]. Neuroimaging especially MRI of the spine should be obtained to exclude other spinal cord pathologies such as intrinsic spinal cord tumor [17]. Primary paroxysmal dyskinesias are further classified based on triggers into three subcategories. Paroxysmal kinesigenic dyskinesia (PKD) is triggered by sudden movements (“kinesigenic” triggers). PKD may be preceded by auras such as sensory phenomena including paresthesia. The episodes of PKD are usually brief, less than 1 minute (typically less than 30 seconds), and may occur up to 10–100 times a day. Mutations in the PRRT2 gene encoding proline-rich transmembrane protein 2 contribute to approximately 40% of patients with PKD [18, 19]. Paroxysmal non-kinesigenic dyskinesia (PNKD) is not triggered by sudden movements and can occur spontaneously without triggers. However, PNKD episodes can be precipitated by caffeine, alcohol, and stress. The episodes of PNKD are typically longer than those of PKD, minutes to hours, and occur less frequently. Mutations in the PNKD (aka MR1) gene encoding myofibrillogenesis regulator 1 gene have been identified in some cases [20]. Paroxysmal exercise-induced dyskinesia (PED) is triggered by exercise. The duration and frequency of episodes can vary, but may be similar to those of PNKD. Glucose transporter 1 (GLUT1) deficiency syndrome has been identified in many PED patients [21], and this is important to recognize as it is treatable with ketogenic diet. Episodic ataxia is another paroxysmal movement disorder that is not often confused with SPS, given ataxia as its main phenomenology. Episodic ataxia, which is paroxysmal, also differs from anti-GAD-associated cerebellar ataxia, which is persistent.

Stiffness Due to Peripheral Hyperexcitability Hyperexcitability in the peripheral nervous system may be of peripheral nerve or skeletal muscle origin (Table 3.2). This is discussed further in detail in Chap. 14. Peripheral nerve hyperexcitability (PNH) syndromes include Isaacs syndrome, Morvan syndrome, and cramp-fasciculation syndrome may mimic SPSD both clinically and electrophysiologically. PNH syndromes may involve the extremities, usually distally such as hands as in Isaacs syndrome. Patients with Morvan syndrome also have central nervous system manifestations or encephalopathy. Both Isaacs and Morvan syndromes have been associated with anti-CASPR2 antibodies, one of the anti-VGKC-complex antibodies [14]. Electrophysiologically, neuromyotonic discharges associated with the PNH syndromes may be mistaken as continuous motor unit activities (CMUA) in SPSD. However, neuromyotonic discharges are characterized by very high frequency, typically 150–300 Hz spontaneous firing of motor unit action potentials (MUAPs), giving rise to “dive-bombing” or “pinging” sound.

References Table 3.2  Etiologies of stiffness due to peripheral hyperexcitability

25 Peripheral nerve hyperexcitability syndromes  Isaacs syndrome  Morvan syndrome  Cramp-fasciculation syndrome Disorders of skeletal muscle membrane hyperexcitability  Myotonic dystrophies  Myotonia congenita  Paramyotonia congenita  Myotonia in periodic paralysis  Schwartz-Jampel syndrome  Rippling muscle disease

Myokymic discharges, a slower firing of grouped MUAPs, are also often present in PNH syndromes. One clue to differentiate stiffness in SPSD from the one in PNH syndromes is the body distribution. In classic SPS, axial regions especially the trunk are involved, whereas in PNH syndromes, the limbs especially distal regions are usually affected. Also, stiffness often involves the entire limb in SLS, rather than predominantly distal limb. In addition, undulating muscle movements (“bags of worms”) from myokymia, when present, are a very useful clue to differentiate PNH syndromes from SPSD where there is only stiffness without undulating muscle movements. Similarly, in cramp-fasciculation syndrome, fasciculations usually in multifocal distribution can serve as an important clinical clue to differentiate this disorder from SPSD. Identification of fasciculation potentials on electrophysiologic testing will help confirm the diagnosis. Skeletal muscle membrane hyperexcitability includes various disorders as listed in Table 3.2 and Chap. 14. Presence of clinical and electrical myotonia helps differentiate myotonic disorders from SPSD.  Clinical myotonia may be induced by handgrip or percussion which then leads to delayed relaxation of muscles. Rippling muscle disease can be paraneoplastic or genetic due to mutations in the CAV3 gene encoding caveolin-3 [22]. Rippling of muscles, as the name implies, will help differentiate SPSD from rippling muscle disease.

References 1. Taurog JD, Chhabra A, Colbert RA.  Ankylosing spondylitis and axial spondyloarthritis. N Engl J Med. 2016;374(26):2563–74. https://doi.org/10.1056/NEJMra1406182. 2. Rushworth G, Lishman WA, Hughes JT, Oppenheimer DR. Intense rigidity of the arms due to isolation of motoneurones by a spinal tumour. J Neurol Neurosurg Psychiatry. 1961;24:132–42. https://doi.org/10.1136/jnnp.24.2.132. 3. Lourie H. Spontaneous activity of alpha motor neurons in intramedullary spinal cord tumor. J Neurosurg. 1968;29(6):573–80. https://doi.org/10.3171/jns.1968.29.6.0573. 4. Tarlov IM. Rigidity in man due to spinal interneuron loss. Arch Neurol. 1967;16(5):536–43. https://doi.org/10.1001/archneur.1967.00470230088012. 5. Davis SM, Murray NM, Diengdoh JV, Galea-Debono A, Kocen RS. Stimulus-sensitive spinal myoclonus. J Neurol Neurosurg Psychiatry. 1981;44(10):884–8. https://doi.org/10.1136/ jnnp.44.10.884.

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6. Denny-Brown D, Foley JM. Effect of poliomyelitis on the function of the motor neuron. Arch Neurol Psychiatr. 1950;64:145–55. 7. Martin R, Meinck HM, Schulte-Mattler W, Ricker K, Mertens HG.  Borrelia burgdorferi myelitis presenting as a partial stiff man syndrome. J Neurol. 1990;237(1):51–4. https://doi. org/10.1007/bf00319670. 8. Bhatt AD, Dastur FD. Relapsing tetanus (a case report). J Postgrad Med. 1981;27(3):184–6. 9. Hardin JA, Griggs RC.  Diazepam treatment in a case of strychnine poisoning. Lancet. 1971;2(7720):372–3. https://doi.org/10.1016/s0140-6736(71)90085-7. 10. Otter J, D’Orazio JL. Strychnine toxicity. Treasure Island, FL: StatPearls; 2019. 11. Hassin-Baer S, Kirson ED, Shulman L, Buchman AS, Bin H, Hindiyeh M, et al. Stiff-person syndrome following West Nile fever. Arch Neurol. 2004;61(6):938–41. https://doi.org/10.1001/ archneur.61.6.938. 12. Thwaites GE, Thwaites CL. Tetanus. In: Thwaites GE, Thwaites CL, editors. Hunter’s tropical medicine and emerging infectious disease. 9th ed. New York: W.B. Saunders; 2013. p. 508–10. 13. Irani SR, Michell AW, Lang B, Pettingill P, Waters P, Johnson MR, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol. 2011;69(5):892–900. https://doi.org/10.1002/ana.22307. 14. Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-­ associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain. 2010;133(9):2734–48. https://doi.org/10.1093/brain/awq213. 15. Tranchant C, Bhatia KP, Marsden CD. Movement disorders in multiple sclerosis. Mov Disord. 1995;10(4):418–23. https://doi.org/10.1002/mds.870100403. 16. Usmani N, Bedi G, Lam BL, Sheremata WA.  Association between paroxysmal tonic spasms and neuromyelitis optica. Arch Neurol. 2012;69(1):121–4. https://doi.org/10.1001/ archneurol.2011.832. 17. Marrufo M, Politsky J, Mehta S, Morgan JC, Sethi KD. Paroxysmal Kinesigenic Segmental Myoclonus due to a spinal cord glioma. Mov Disord. 2007;22(12):1801–3. https://doi. org/10.1002/mds.21635. 18. Erro R, Sheerin UM, Bhatia KP. Paroxysmal dyskinesias revisited: a review of 500 genetically proven cases and a new classification. Mov Disord. 2014;29(9):1108–16. https://doi. org/10.1002/mds.25933. 19. Huang XJ, Wang T, Wang JL, Liu XL, Che XQ, Li J, et al. Paroxysmal kinesigenic dyskinesia: clinical and genetic analyses of 110 patients. Neurology. 2015;85(18):1546–53. https://doi. org/10.1212/WNL.0000000000002079. 20. Lee HY, Xu Y, Huang Y, Ahn AH, Auburger GW, Pandolfo M, et al. The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum Mol Genet. 2004;13(24):3161–70. https://doi.org/10.1093/hmg/ddh330. 21. Suls A, Dedeken P, Goffin K, Van Esch H, Dupont P, Cassiman D, et al. Paroxysmal exercise-­ induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain. 2008;131(Pt 7):1831–44. https://doi.org/10.1093/brain/awn113. 22. Betz RC, Schoser BG, Kasper D, Ricker K, Ramirez A, Stein V, et  al. Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease. Nat Genet. 2001;28(3):218–9. https://doi.org/10.1038/90050.

4

Electrophysiology of Stiff-Person Spectrum Disorders

The diagnosis of stiff-person spectrum disorders (SPSD) is often made based on clinical manifestations and is often supported by elevated serum antibodies that are closely linked to the disorder. Electrophysiological studies often serve as an adjunctive tool to assist the clinician in making the diagnosis of classic stiff-person syndrome (SPS) or one of its variants. The role of electrophysiology is mostly to exclude other neuromuscular disorders manifesting with muscle stiffness and cramps. The value of electrophysiology in the confirmation of SPS is dubious and may require additional non-­conventional testing that may not be readily available. Multiple electrophysiological modalities are used in SPSD including routine needle electromyography (EMG), abnormal monosynaptic reflexes, and abnormal exteroceptive reflexes. In this chapter, we discuss the reported and disputed electrophysiological findings in the diagnosis of SPSD. Most previous studies focus on classic SPS but this may also be applied to an SLS variant. When SPS is mentioned in this chapter, it is generally referred to classic SPS.

 he Role of Electrophysiology in Excluding Other T Neuromuscular Causes of Muscle Stiffness Clinical electromyography (EMG) includes two main components: nerve conduction studies and needle electromyography (EMG). EMG study is often used to localize lesions along the neuraxis. More specifically, the study assesses disorders affecting exclusively the peripheral nervous system including the large fiber sensory system and lower motor neuron (from anterior horn cell to muscle) [1]. Given the basic principle of clinical EMG, routine sensory and motor nerve conduction studies (NCS) are unremarkable in SPS since the pathophysiology is central and mostly due to dysfunction of the inhibitory system [2]. In patients

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Table 4.1  Stiff-person syndrome mimics with abnormal electrophysiologic findings differing from continuous motor unit activity (CMUA) Disorders mimicking SPS Tetanus Cramp Peripheral nerve hyperexcitability syndromes (e.g., Isaacs and Morvan syndromes) Myotonic disorders (e.g., myotonic dystrophies)

Abnormal electrophysiologic findings Absence of the silent period Cramp potentials Neuromyotonic discharges Doublets Triplets Myokymic discharges Myotonic discharges Myopathic units on voluntary activation

with SPS and an associated type 1 diabetes mellitus, NCS may be abnormal due to an underlying diabetic peripheral polyneuropathy. Routine needle EMG is normal in SPS. Hence, the major role of this study is to exclude mimics of SPS.  More specifically, needle EMG mostly help in excluding other causes of muscle stiffness which are often considered in the differential diagnosis of SPS.  These include the peripheral nerve hyperexcitability syndromes (e.g., Isaacs and Morvan syndromes), myotonic disorders (e.g., myotonic dystrophies), or rippling muscle disease (please refer to Chap. 14 for details). In SPS, there is no detectable needle EMG abnormality that could be attributed to lower motor neuron, neuromuscular junction, or muscle dysfunction. Abnormal insertional or spontaneous activities seen on needle EMG that would dismiss the diagnosis of SPS include fibrillation potentials, myotonic discharges, myokymic discharges (including doublets, triplets, and multiplets), and neuromyotonic discharges (Table 4.1). During voluntary activation, configuration of motor unit action potentials (MUAPs) is normal in SPS. Hence, abnormal MUAP morphology is not compatible with the diagnosis of SPS, unless there is an associated neuromuscular finding such as peripheral polyneuropathy or radiculopathy. These abnormalities include mostly longduration, high-amplitude, and polyphasic MUAPs (seen with neurogenic disorders), or short-duration, low-amplitude, and polyphasic MUAPs (seen with myopathic disorders). Tetanus is another disorder which sometimes imitates SPS.  Tetanus may present with stiffness, though the presentation is more acute in onset with rapid progression. Examining the silent period of the lower motor neuron is an electrophysiological modality which may differentiate tetanus from SPS. The silent period is a short and transient disappearance of voluntary EMG activity in a contracting muscle following stimulation. It is a direct result of the stretch reflex, causing a pause in muscle-­spindle discharge [3, 4]. In a normal subject, the constant voluntary motor unit activity pauses transiently (duration 5–60 ms) following electrical stimulation to the nerve supplying the particular muscle or mechanical stimulation directly to the muscle itself (Fig.  4.1) [5]. This silent period is absent in tetanus; however, it is normal in SPS [4].

Electrophysiological Findings Useful in the Diagnosis of SPS

a

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R Jaw jerk

0.2 mV L

b

10 msec

R

Masseteric silent period L

c

R

Masseteric inhibitory reflex

L

Fig. 4.1  Silent period. (a) Jaw jerk. (b) Silent period recording from the masseter muscles induced by mechanical tapping to the chin. (c) Silent period or inhibitory reflex from the same muscle but induced by electrical stimuli to the mentalis nerve. (Reprinted from Valls-Sole [5], Copyright 2012, with permission from Elsevier)

Electrophysiological Findings Useful in the Diagnosis of SPS Continuous motor unit activity (CMUA) is considered the most characteristic electrophysiologic findings in SPS, though its value is limited. There are also other useful electrophysiologic studies including co-contraction of agonist and antagonist muscles, loss of vibration-induced inhibition of H-reflexes, enhanced exteroceptive reflexes, among others. These requires special techniques, and are not routinely performed in most electrophysiologic laboratories.

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a

b Fig. 4.2  Needle electromyography with continuous motor unit activity (CMUA). This shows needle electromyography testing in the rectus abdominis muscles. In the beginning (a), the trace showed continuous motor unit activity, which was exacerbated by clapping (∗). (b) The motor unit activity subsides after diazepam 10 mg intravenous injection. (Reproduced with permission from Folli et al. [7])

Continuous Motor Unit Activity (CMUA) Moersch and Woltman in their original publication reported on findings on needle EMG [6]. Five of their 14 cases had needle EMG performed; in all 5, the needle EMG reported voluntary activity that resembled normal MUAPs. Later, it was noted that the muscle activity associated with stiffness in patients with SPS is unremitting and does not disappear despite patient’s effort to relax the examined muscle. This was referred to as “continuous motor unit activity” (CMUA). CMUA is, hence, defined as “continuous muscle activity with inability to suppress the contraction at rest or by attempting to relax.” CMUA is associated with normal MUAPs without any complex morphology. It is seen in muscles showing stiffness and spasms with a predilection to axial, paraspinal, and proximal muscles. Typically, CMUA is significantly reduced during sleep and following general or spinal anesthesia. It is also abolished with the use of benzodiazepines (such as diazepam), baclofen, and other GABA-ergic agents (Fig.  4.2) [7]. This feature supports the pathophysiology of dysfunction of central inhibition [8]. The value of assessing CMUA in the confirmation of the diagnosis of SPS has significant limitations. The morphology and pattern of recruitment of MUAPs seen in CMUA are indistinguishable from normal voluntary muscle contraction. More

Electrophysiological Findings Useful in the Diagnosis of SPS

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importantly, CMUA recorded during routine needle EMG in SPS cannot be differentiated from ongoing motor unit activity generated by patient’s poor relaxation or other hypertonic disorders including dystonia, spasticity, and rigidity [9, 10].

Co-contraction of Agonist and Antagonist Muscles In a normal subject, motor unit activity is seen during voluntary muscle contraction. For a particular joint movement to occur, contraction of an agonist muscle along with an increase in the length of antagonist muscle generates proper movement around the joint. When contraction occurs in both agonist and antagonist, it is called co-contraction. In the normal situation, co-contraction is important for joint stability [11]. Co-contraction can also be generated volitionally in normal subjects for a short period during joint flexion or extension [12]. Co-contraction occurring outside the appropriate circumstances is a common finding observed in patients with SPS [13]. Motor unit activity recording may be done simultaneously from both agonist and antagonist muscles of affected region using two or more muscles (Fig.  4.3) [14]. Tibialis anterior/gastrocnemius and

Agonist

Antagonist

SPS

Agonist

Antagonist

Normal

500 ms

Fig. 4.3  Co-contraction of agonist and antagonist muscles in SPS. The upper pair of traces showed needle EMG recording of muscle contraction in agonist and antagonist. Arrow represents voluntary action of the antagonist muscles. The contraction in agonist persists in spite of voluntary action of the antagonist muscles. For comparison, in the normal control as shown in the lower pair, the contraction disappears in the agonist muscles after voluntary contraction occurs in the antagonist muscles. (Reproduced with permission of John Wiley and Sons from Rakocevic and Floeter [14])

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Table 4.2  Advantages and disadvantanges of needle and surface electromyography (EMG) recording in the assessment of co-contraction Recording Needle EMG Surface EMG

Advantage Less artifacts Clear baseline Less painful More feasible for simultaneous recording from many sites

Disadvantage Painful Cost of needle More artifacts

EMG; electromyography

quadriceps/hamstrings are the most commonly used muscle pairs in the lower extremity. Biceps/triceps are commonly recorded in the upper extremity. Paraspinal and rectus abdominis are useful to assess axial muscles. Co-contraction of agonist and antagonist muscles may be recorded with either needle or surface EMG, using an at least two-channel equipment. Needle EMG has an obvious advantage in recording the motor unit activity within muscle itself and has dramatically less artifact. Since simultaneous recording from both agonist and antagonist muscles including possibly axial muscles is required, multiple needle electrodes are needed to be inserted simultaneously with several EMG channels activated. This may be painful and not technically feasible. Hence, surface EMG is an alternative and definitely less invasive. Multiple surface recordings could be placed at once without inducing pain. The disadvantage of surface recording is skin impedance, 60  Hz artifact, and movement artifacts that would interfere with the recording and may mask components of CMUA (Table 4.2). It is also possible to record using both techniques. The limitations of simultaneous recording from agonist and antagonist muscles looking for co-contraction are somehow similar to the limitations of CMUA assessment recording from individual muscles during routine needle EMG. Co-contraction seen in SPS patients may be indistinguishable from similar muscle activity generated volitionally in normal subjects [12]. More importantly, co-contraction is not specific since it is also seen in many other central nervous disorders associated with increased or abnormal muscle tone, including dystonia, severe spasticity, and severe rigidity [9, 10].

Loss of Vibration-Induced Inhibition of H-Reflexes H-reflex (H for Hoffman) is a true monosynaptic reflex. H-reflexes may be obtained from either soleus or flexor carpi radialis muscles, stimulating the tibial or radial nerves, respectively. Group IA sensory fibers constitute the afferent arc which activates the alpha motor neurons that in turn generate the efferent arc of the reflex through their motor axons. In normal situation, H-reflex appears with submaximal stimulation. Once the nerve is under supramaximal stimulation, H-reflex disappears. Vibration of the Achilles tendon inhibits the tibial H-reflex in normal subjects. In SPS, there is loss of vibration-induced inhibition of monosynaptic H-reflex, and the

Electrophysiological Findings Useful in the Diagnosis of SPS

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H-reflex appears with submaximal stimulation and continues to be present with supramaximal stimulations [15, 16]. Although this procedure is a useful sign of loss of central inhibition, it is technically challenging since it requires a specialized equipment; hence, it is not commonly done in clinical practice.

Enhanced Exteroceptive Reflex Exteroceptive reflexes are polysynaptic reflexes which could be elicited by a variety of peripheral stimulations, including either tactile, auditory, or visual stimuli. Exteroceptive reflexes are preferably done by percutaneous electrical stimulation of mixed or sensory nerves such as median nerve at the wrist or tibial nerve at the ankle. The nerve is stimulated usually in train of four or five pulses with intensity two to three times stronger than the sensory threshold or slightly above threshold to cause muscle contraction. Recording could include a single muscle or, preferably, several muscles simultaneously using surface or needle electrodes and multichannel equipment. Commonly examined muscles include the quadriceps, tibialis anterior, and gastrocnemius in the lower limb, the biceps and triceps in the upper limb, and paraspinal axial muscles. Exteroceptive reflexes are enhanced in SPS (Fig.  4.4) [14]. This is similar in concept to the loss of vibration-induced H-reflex. These exaggerated polysynaptic reflexes from non-painful stimuli spread as reflex spasms into remote muscles that are not close to the site of stimulation, and not involved in  local spinal reflexes. Examples include reflex spasms in the quadriceps or lumbar paraspinal muscles

Fig. 4.4  Enhanced exteroceptive reflex. Traces recording tibialis anterior, hamstrings, quadriceps, and L3 paraspinal muscles. Four-pulse electrical stimulation was given to the sural nerve which elicited contraction of both two flexors (tibialis anterior and hamstrings) and also spread abnormally to the extensor (quadriceps) and paraspinal muscles. (Reproduced with permission of John Wiley and Sons from Rakocevic and Floeter [14])

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after stimulating the median nerve at the wrist. The enhancement is seen as an initial EMG burst at a short latency (50–80 ms) followed by a long period of tonic activity and a large amplitude burst of tonic decrescendo activity. The second long burst is not seen in normal situation [13, 15]. Exteroceptive reflexes are difficult to accomplish in clinical practice and often require multichannel setup which may not be available in many EMG laboratories. A survey of 58 North American neuromuscular specialists and members of the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) revealed that only 3 of the 58 utilize this technique in the diagnosis of SPS [12].

Other Electrophysiological Studies The blink reflexes, specifically the R2 components, are enhanced in SPS [15]. These are also exteroceptive polysynaptic reflexes. Transcranial magnetic stimulation shows enlarged motor evoked potential in SPS patients compared to control, suggesting central hyperexcitability and loss of inhibition [17].

Summary Electrophysiology is only an adjunctive tool to support the diagnosis of SPS and may require specialized setup. The first step is to perform NCS and routine needle EMG which is most useful in excluding SPS mimics. Then, CMUA should be sought after since it is a key feature of SPS on needle EMG. This is best achieved by simultaneous recording from agonist and antagonist muscles looking for co-­ contraction. Other confirmatory findings using specialized electrophysiologic tests may be performed, including loss of vibration-induced inhibition of H-reflexes and enhanced exteroceptive reflexes. These findings confirm the presence of central hyperexcitability.

References 1. Katirji B. The scope of the EMG examination. In: Electromyography in clinical practice: a case study approach. 3rd ed. New York: Oxford University Press; 2018. p. 3. 2. Preston DC, Shapiro BE. Basic electromyography: analysis of motor unit action potential. In: Electromyography and neuromuscular disorders: clinical-electrophysiologic correlations. 3rd ed. London/New York: Elsevier Saunders; 2013. p. 247. 3. Erkelens CJ, Bosman F.  Reflex sensitivity of human jaw-closing muscles during the silent period following a jaw jerk. Arch Oral Biol. 1983;28(11):1059–65. https://doi. org/10.1016/0003-9969(83)90063-8. 4. Poncelet AN. Blink reflexes and the silent period in tetanus. Muscle Nerve. 2000;23(9):1435–8. https://doi.org/10.1002/1097-4598(200009)23:93.0.co;2-i. 5. Valls-Sole J.  The blink reflex and other cranial nerve reflexes. In: Aminoff MJ, editor. Aminoff’s electrodiagnosis in clinical neurology. 6th ed. Philadelphia: Saunders; 2012. p. 426.

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6. Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin. 1956;31(15):421–7. 7. Folli F, Prioletta A, Quattrini A, Galardi G. Stiff-man syndrome. In: Katirji B, Kaminski HJ, Ruff RL, editors. Neuromuscular disorders in clinical practice. 2nd ed. New York: Springer; 2014. p. 1465–77. 8. Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009;11(2):102–10. 9. Adler CH, Crews D, Hentz JG, Smith AM, Caviness JN.  Abnormal co-contraction in yips-­ affected but not unaffected golfers: evidence for focal dystonia. Neurology. 2005;64(10):1813–4. https://doi.org/10.1212/01.WNL.0000162024.05514.03. 10. Farmer SF, Sheean GL, Mayston MJ, Rothwell JC, Marsden CD, Conway BA, et al. Abnormal motor unit synchronization of antagonist muscles underlies pathological co-contraction in upper limb dystonia. Brain. 1998;121(Pt 5):801–14. https://doi.org/10.1093/brain/121.5.801. 11. Gorkovenko AV, Sawczyn S, Bulgakova NV, Jasczur-Nowicki J, Mishchenko VS, Kostyukov AI.  Muscle agonist-antagonist interactions in an experimental joint model. Exp Brain Res. 2012;222(4):399–414. https://doi.org/10.1007/s00221-012-3227-0. 12. Li Y, Thakore N. An appraisal of electrodiagnostic studies in stiff person syndrome. J Clin Neuromusc Dis. In press. 13. Espay AJ, Chen R.  Rigidity and spasms from autoimmune encephalomyelopathies: stiff-­ person syndrome. Muscle Nerve. 2006;34(6):677–90. https://doi.org/10.1002/mus.20653. 14. Rakocevic G, Floeter MK.  Autoimmune stiff person syndrome and related myelopa thies: understanding of electrophysiological and immunological processes. Muscle Nerve. 2012;45(5):623–34. https://doi.org/10.1002/mus.23234. 15. Meinck HM, Ricker K, Hulser PJ, Solimena M. Stiff man syndrome: neurophysiological findings in eight patients. J Neurol. 1995;242(3):134–42. https://doi.org/10.1007/bf00936885. 16. Martinelli P, Nassetti S, Minardi C, Macri S, Ippoliti M. Electrophysiological evaluation of the stiff-man syndrome: further data. J Neurol. 1996;243(7):551–3. https://doi.org/10.1007/ bf00886879. 17. Sandbrink F, Syed NA, Fujii MD, Dalakas MC, Floeter MK. Motor cortex excitability in stiff-­ person syndrome. Brain. 2000;123(Pt 11):2231–9. https://doi.org/10.1093/brain/123.11.2231.

5

Neurochemistry of Inhibitory Synapses and Clinical Applications in Stiff-Person Spectrum Disorders

Antibodies targeting various antigenic targets at presnaptic or postsynaptic sites of two main inhibitory synapses, namely, γ-aminobutyric acid (GABA)-ergic and glycinergic synapses, are associated with stiff-person spectrum disorders (SPSD). This chapter covers basic neurochemistry of these two synapses.

GABA-ergic Synapses GABA is a major inhibitory neurotransmitter with ubiquitous distribution throughout the brain and the spinal cord. GABA is important in maintaining balance between excitation and inhibition within the central nervous system. A GABA-ergic synapse is mainly formed by a presynaptic terminal, which is an axon terminal, releasing GABA, and a postsynaptic site which has GABA receptors. The synaptic cleft lies between the presynaptic and postsynaptic sites. In addition, there is also adjacent glial cells, especially astrocytes, that can also uptake GABA via a GABA transporter and help promote clearance of GABA from the synaptic cleft. At the presynaptic neuron, GABA is synthesized from glutamate. The metabolic pathway of GABA synthesis is called “GABA shunt” (Fig. 5.1) [1]. Synthesis of GABA requires a substrate from Krebs cycle, α-ketoglutarate, and GABA can be shunted back to Krebs cycle via succinate. Firstly, α-ketoglutarate, one of the substrates in Krebs cycle, is catalyzed by the enzyme α-ketoglutarate transaminase (aka GABA-T) to glutamate. Glutamate is then decarboxylated by the enzyme glutamic acid decarboxylase (GAD) into GABA. GABA is metabolized by GABA-T into succinic semialdehyde, which can subsequently turn into succinate back into the Krebs cycle by the enzyme succinic semialdehyde dehydrogenase (SSADH). There are two isoforms of the GAD enzyme in the presynaptic terminal, GAD65 and GAD67. GAD65 and GAD67 have molecular weights of 65 and 67 kDa, respectively. GAD65 has a primary role in the synthesis of GABA for presynaptic vesicles, whereas GAD67 is for non-vesicular GABA synthesis within the cytoplasm. GAD67 © Springer Nature Switzerland AG 2020 P. Termsarasab et al., Stiff-Person Syndrome and Related Disorders, https://doi.org/10.1007/978-3-030-43059-7_5

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5  Neurochemistry of Inhibitory Synapses and Clinical Applications in Stiff-Person…

Fig. 5.1  γ-Aminobutyric acid (GABA) shunt. Synthesis of GABA requires a substrate from Krebs cycle, α-ketoglutarate, and GABA can be shunted back to Krebs cycle via succinate. GABA-T α-ketoglutarate transminase, GAD glutamic acid decarboxylase, SSADH succinic semialdehyde dehydrogenase

is constitutively active. When a surge or pulse release of GABA is required, GAD65 becomes active, and GABA is released from the presynaptic vesicles [2]. Both GAD65 and GAD67 have three main domains: N-terminal domain, middle pyridoxal 5′-phosphate (PLP) domain, and C-terminal domain (Fig.  5.2a). The amino acid sequence homology is 25% in the N-terminal domain and 74% in the middle PLP and C-terminal domains [3]. As mentioned above, GAD65 has a closely related role with presynaptic vesicles. The N-terminal domain has a segment that binds to the presynaptic vesicles. In addition, there is also a separate proteolytic cleavage site in the N-terminal domain. GAD65 is typically activated after the binding of PLP, and this occurs in the middle PLP domain. Depending on conformation, antigenic targets within the GAD65 molecule can be conformational or linear. Anti-­ GAD65 antibody is positive in approximately 80% of patients with insulin-­ dependent or type 1 diabetes [4]. In contrast, anti-GAD67 antibody is found in only a small number of patients with type 1 diabetes, and this may represent cross-­ reactivity from anti-GAD65 antibody [5]. There are some differences in antigenic targets of anti-GAD65 antibodies between SPS and type 1 diabetes. Generally antigenic epitopes, areas within protein molecules that are recognized and bound by antibodies (immunoglobulins), can be either linear or conformational (Fig.  5.2b). The linear epitope is continuous amino acid sequences which can still be recognized by the antibody even after the protein is denatured or digested. In contrast, the conformational epitope contains discontinuous amino acid sequences which, after denaturation or digestion, are no longer recognized by the antibody. In SPS, linear epitopes in the N-terminal domain are unique targets for anti-GAD65 antibodies, but these are not targets in type 1 diabetes [6] (Fig. 5.2a). In addition, conformational epitopes in the C-terminal and downstream portion of the middle PLP domains are other targets of anti-GAD65 in SPS.  However, the conformational epitopes in

GABA-ergic Synapses

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a

b

Fig. 5.2  Differences between the two isoforms of glutamic acid decarboxylase (GAD), GAD67 and GAD65. (a) Three main domains within GAD67 and GAD65 molecules. Antibody-binding sites and type(s) of the antigenic epitopes (either linear or conformational or both) in stiff-person syndrome (SPS, in red) and type 1 diabetes (T1D, in green) are demonstrated. (b) Two types of antigenic epitopes. The linear epitope is continuous, and hence still recognized by the antibody after denaturation or digestion. The conformational epitope is discontinuous, and hence no longer recognized by the antibody after denaturation or digestion. Ab antibody, GAD glutamic acid decarboxylase, PLP pyridoxal 5′-phosphate, T1D type 1 diabetes

these regions are targets that are not specific to SPS, but are also targets of antiGAD65 in type 1 diabetes. Finally, linear epitopes at the C-terminal and downstream portion of the middle PLP domains are other targets for anti-GAD65 in type 1 diabetes but not in SPS.

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5  Neurochemistry of Inhibitory Synapses and Clinical Applications in Stiff-Person…

Fig. 5.3 GABAA receptor. The receptor is comprised of five subunits. Each subunit of GABAA receptor has four transmembrane domains

After the release of GABA into the synaptic cleft, GABA binds to GABA receptors. There are two main classes of GABA receptors: GABAA and GABAB. GABA receptors are present at both synaptic and extra-synaptic sites. The receptors at the synaptic sites are responsible for “synaptic (or phasic) inhibition” after a pulsatile release of GABA from the presynaptic sites. In contrast, tonic inhibition occurs at extra-synaptic sites from steady and low concentration of GABA [7]. GABAA receptors are pentamers that form a chloride channel. They are classified within a superfamily of “Cys-loop” ligand-gated ion channel receptors which also include the nicotinic acetylcholine receptor and the serotonergic 5-HT3 receptor [8]. “Cys-loop” refers to a loop formed between two cysteine residues that are linked together with a disulfide bond. This loop is in the N-terminal of the extracellular domain of GABAA receptors (Fig. 5.3). Each GABAA receptor is comprised of five subunits, hence called pentamer. Each subunit has four transmembrane domains. The N-terminal starts as an extracellular domain which also has a Cys-loop. In one GABAA receptor, there are two α and two β subunits, as well as one remaining subunit which is most commonly a γ subunit, but can also be other types. Each type of subunits may have more than one member. For example, α subunits have six different members, α1–α6. However, the α subunits within the same GABAA receptor are typically of identical subtype, so are the β subunits. The homology is 75–90% among each member in the same type of subunits and 20–30% among different types of subunits [9]. This reflects the diversity that gradually develops during an evolution and the preserved homology. Common combinations of subunits that form one GABAA receptor include α1β2γ2, α3β3γ2, and α2β3γ2. For example, the α1β2γ2 GABAA receptor is comprised of two α1, two β2 and one γ2 subunits.

GABA-ergic Synapses

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From the top view of a single GABAA receptor, the second transmembrane domain of each subunit forms a lumen or pore that serves as a chloride channel. The ligand binding pockets, including two GABA and one benzodiazepine binding pocket, lie in the border between two subunits. Once GABA binds to the GABA binding pocket, the chloride channel is opened, and chloride influxes into the cell. Hyperpolarization from the influx of the negatively charged ion (i.e., chloride) leads to postsynaptic inhibition. The opening frequency and duration of the chloride channel can be modulated by various pharmacological agents. Bicuculline reduces both opening frequency and duration of the channel. Benzodiazepines bind to the benzodiazepine-binding pockets and increase the opening frequency of the channel, but not duration. In contrast, barbiturates bind to the allosteric site and increase the opening duration of the channel. There are anchoring molecules or proteins that hold GABAA receptors at the synapses and prevent lateral sliding or movements. One example is gephyrin, a protein that anchors an α subunit of a GABAA receptor, especially α1, α2, and α3, to intracellular cytoskeleton, namely microtubules and microfilaments (Fig.  5.4).

Fig. 5.4  Various antigenic targets in stiff-person spectrum disorders located around the GABA-­ ergic and glycinergic synapses. At the GABA-ergic synapse (left), there are (1) glutamic acid decarboxylase (GAD) and (2) amphiphysin at the presynaptic site, as well as (3) GABAA receptor (GABAAR), (4) GABAA receptor-associated protein (GABARAP), and (5) gephyrin at the postsynaptic site. At the glycinergic synapse (right), there are (7) glycine transporter 2 (GlyT2) at the presynaptic site, as well as (6) glycine receptor (GlyR) and (5) gephyrin at the postsynaptic site. Note that gephyrin is present in both GABA-ergic and glycinergic synapses

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Gephyrin also has a role in clustering of glycine receptors and some subtypes of GABAA receptors [10]. GABAA receptor-associated protein (GABARAP) links GABAA receptors with intracellular cytoskeleton and also plays a role in clustering of GABAA receptors [11]. GABAB receptors are different from GABAA receptors. GABAB receptors are heterodimer: they have two subunits, R1 and R2. In contrast to GABAA receptors which are ligand-gated ion channel receptors, GABAB receptors are coupled with G protein. Baclofen, a muscle relaxant commonly used to treat spasticity and dystonia, is a GABAB receptor agonist.

 linical Applications of GABA-ergic Synapses in Stiff-Person C Spectrum Disorders and Associated Disorders Autoantibodies targeting GAD at the presynaptic GABA-ergic nerve terminals or GABAA receptors, gephyrin, and 14 kDa GABARAP at the postsynaptic sites are associated with stiff-person spectrum disorders (Fig. 5.4). Mutations in the GPHN gene encoding gephyrin may lead to hereditary hyperekplexia. Furthermore, in peripheral non-neuronal tissues, gephyrin has a role in synthesis of molybdenum cofactor. Therefore, mutations of the GPHN gene can also cause molybdenum cofactor deficiency.

Glycinergic Synapses Glycinergic synapses have some similarities to GABA-ergic synapses. However, there are several distinctive features. Glycine, similar to GABA, is one of the two major inhibitory neurotransmitters within the central nervous system, especially the spinal cord and brainstem. In the presynaptic nerve terminals, glycine is synthesized from an amino acid, serine, by the enzyme serine hydroxymethyltransferase (SHMT). In order to convert serine to glycine, tetrahydrofolate simultaneously converts to N5, N10-methylene tetrahydrofolate (Fig. 5.5). Once glycine is synthesized, it is then packaged into vesicles within the presynaptic nerve terminals. This packaging step is relied on

Fig. 5.5  Glycine synthesis. Glycine is synthesized from serine by the serine hydroxymethyltransferase (SHMT) enzyme with tetrahydrofolate as a cofactor

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vesicular inhibitory amino acid transporter (VIAAT) which is also used for packaging of GABA into vesicles [12]. Thus, this transporter is also called vesicular GABA transporter (vGAT). The release of vesicular glycine from presynaptic nerve terminals is mediated by influx of calcium. Once released into synaptic clefts, glycine then binds to glycine receptors. Glycine receptors are also Cys-loop ligand-gated ion channel receptors which are within the same superfamily as GABAA receptors. The clearance of glycine is mainly by two types of glycine transporters, GlyT1 and GlyT2 [13]. GlyT1 is mainly found at astrocytes in the central nervous system, and functions in clearing glycine from postsynaptic sites. This is similar to GABA transporters at astrocytes which also has a role in clearance of GABA from synaptic clefts. GlyT2 is mainly found in the brainstem and spinal cord and has a role in transporting glycine back into the presynaptic nerve terminal which will then repackage back into presynaptic vesicles. Glycine receptors, similar to GABA receptors, have five subunits, called pentameric receptors [14]. Five subunits together form a chloride channel. Each subunit consists of four transmembrane domains. Unlike GABA receptors, subunits of glycine receptors have only α and β types. There are four types of α subunits (α1, α2, α3, α4) and only one type of β subunit. In neonatal period, α subunits are mainly α2 and α4, while α1 is mainly present in adults. In adults, the stoichiometry (or proportion of each subunit) is typically a combination of three α1 and two β subunits, or four α1 and one β subunits. Being a small amino acid, one molecule of glycine is a ligand with low binding energy. For the activation of the glycine receptor, up to three molecules of glycine are required. Other amino acids can be a ligand to activate glycine receptors. These include β-alanine, taurine, L-alanine, L-serine, and proline [9]. After the activation of the glycine receptors by these ligands, there is opening of the channel and influx of chloride. This will then lead to hyperpolarization and inhibitory effects. Similar to GABA receptors, gephyrin is an anchoring protein present in the cytoplasm of postsynaptic glycinergic synapses (Fig.  5.4) [10]. It anchors a glycine receptor with intracellular cytoskeleton such as microtubules and microfilaments in order to prevent lateral sliding of the receptors. It also has a role in clustering of glycine receptors.

 linical Applications of Glycinergic Synapses in Stiff-Person C Spectrum Disorders and Associated Disorders Strychnine is a glycine receptor antagonist [15]. Thus, strychnine poisoning can lead to glycine receptor dysfunction and loss of inhibitory responses within the central nervous system, which in turn leads to clinical features similar to SPS [16]. Autoantibodies to glycine typically cause a phenotype of progressive encephalomyelitis with rigidity and myoclonus (PERM), a variant of SPS primarily involving the brainstem [17]. PERM patients usually have hyperekplexia, which is a form of

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brainstem myoclonus. Anti-GlyT2 antibody was reported in two patients with SPSD who also had co-existing anti-GAD antibodies [18]. Interestingly, abnormalities of these proteins can also be found in hereditary hyperekplexia. For example, this disorder can be due to mutations in the GLRA1 gene encoding the α1 subunit of the glycine receptor [19], the GLRB gene encoding the β subunit [20], and the SLC6A5 gene encoding GlyT2 [21]. These demonstrate genetic counterparts of autoimmune hyperekplexia involving similar molecules related to glycinergic synapses. Hyperekplexia is discussed further in detail in Chap. 15.

References 1. Tillakaratne NJ, Medina-Kauwe L, Gibson KM.  Gamma-Aminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues. Comp Biochem Physiol A Physiol. 1995;112(2):247–63. https://doi.org/10.1016/0300-9629(95)00099-2. 2. Ali F, Rowley M, Jayakrishnan B, Teuber S, Gershwin ME, Mackay IR. Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies. J Autoimmun. 2011;37(2):79–87. https://doi.org/10.1016/j.jaut.2011.05.005. 3. Baizabal-Carvallo JF, Jankovic J.  Stiff-person syndrome: insights into a complex autoimmune disorder. J Neurol Neurosurg Psychiatry. 2015;86(8):840–8. https://doi.org/10.1136/ jnnp-2014-309201. 4. Baekkeskov S, Landin M, Kristensen JK, Srikanta S, Bruining GJ, Mandrup-Poulsen T, et al. Antibodies to a 64,000 Mr human islet cell antigen precede the clinical onset of insulin-­ dependent diabetes. J Clin Invest. 1987;79(3):926–34. https://doi.org/10.1172/JCI112903. 5. Hagopian WA, Michelsen B, Karlsen AE, Larsen F, Moody A, Grubin CE, et al. Autoantibodies in IDDM primarily recognize the 65,000-M(r) rather than the 67,000-M(r) isoform of glutamic acid decarboxylase. Diabetes. 1993;42(4):631–6. https://doi.org/10.2337/diab.42.4.631. 6. Kim J, Namchuk M, Bugawan T, Fu Q, Jaffe M, Shi Y, et al. Higher autoantibody levels and recognition of a linear NH2-terminal epitope in the autoantigen GAD65, distinguish stiff-­ man syndrome from insulin-dependent diabetes mellitus. J Exp Med. 1994;180(2):595–606. https://doi.org/10.1084/jem.180.2.595. 7. Farrant M, Nusser Z.  Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci. 2005;6(3):215–29. https://doi.org/10.1038/nrn1625. 8. Nys M, Kesters D, Ulens C. Structural insights into Cys-loop receptor function and ligand recognition. Biochem Pharmacol. 2013;86(8):1042–53. https://doi.org/10.1016/j.bcp.2013.07.001. 9. Olsen RW, Betz H. GABA and glycine. In: Siegel GJ, Albers RW, Brady ST, Price DL, editors. Basic neurochemistry. 7th ed. Massachusetts: Elsevier; 2006. p. 291–301. 10. Groeneweg FL, Trattnig C, Kuhse J, Nawrotzki RA, Kirsch J. Gephyrin: a key regulatory protein of inhibitory synapses and beyond. Histochem Cell Biol. 2018;150(5):489–508. https:// doi.org/10.1007/s00418-018-1725-2. 11. Chen ZW, Olsen RW.  GABAA receptor associated proteins: a key factor regulat ing GABAA receptor function. J Neurochem. 2007;100(2):279–94. https://doi. org/10.1111/j.1471-4159.2006.04206.x. 12. Gasnier B.  The loading of neurotransmitters into synaptic vesicles. Biochimie. 2000;82(4):327–37. https://doi.org/10.1016/s0300-9084(00)00221-2. 13. Gomeza J, Ohno K, Betz H.  Glycine transporter isoforms in the mammalian central nervous system: structures, functions and therapeutic promises. Curr Opin Drug Discov Devel. 2003;6(5):675–82.

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14. Burgos CF, Yevenes GE, Aguayo LG.  Structure and pharmacologic modulation of inhibitory glycine receptors. Mol Pharmacol. 2016;90(3):318–25. https://doi.org/10.1124/ mol.116.105726. 15. Young AB, Snyder SH.  Strychnine binding associated with glycine receptors of the central nervous system. Proc Natl Acad Sci U S A. 1973;70(10):2832–6. https://doi.org/10.1073/ pnas.70.10.2832. 16. Otter J, D’Orazio JL. Strychnine toxicity. [Updated 2019 Mar 26]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2019. Available from: https://www.ncbi.nlm.nih. gov/books/NBK459306/. 17. Carvajal-Gonzalez A, Leite MI, Waters P, Woodhall M, Coutinho E, Balint B, et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain. 2014;137(Pt 8):2178–92. https://doi.org/10.1093/brain/awu142. 18. Balint B, Blöcker I, Unger M, Stoecker W, Probst C, Komorowski L. Antibody spectrum in stiff person syndrome and related disorders. In: 19th International Congress of Parkinson’s Disease and Movement Disorders, 2015. Wiley-Blackwell 111 River St, Hoboken 07030-5774, NJ USA; 2015. p. S263–S. 19. Shiang R, Ryan SG, Zhu YZ, Hahn AF, O’Connell P, Wasmuth JJ. Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nat Genet. 1993;5(4):351–8. https://doi.org/10.1038/ng1293-351. 20. Rees MI, Lewis TM, Kwok JB, Mortier GR, Govaert P, Snell RG, et al. Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Hum Mol Genet. 2002;11(7):853–60. https://doi.org/10.1093/ hmg/11.7.853. 21. Rees MI, Harvey K, Pearce BR, Chung SK, Duguid IC, Thomas P, et al. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet. 2006;38(7):801–6. https://doi.org/10.1038/ng1814.

6

Immunopathogenesis of Stiff-Person Spectrum Disorders

The pathogenesis of stiff-person spectrum disorders (SPSD) has been closely linked to autoimmunity. However, despite decades after the discovery of anti-GAD65, the first antibody related to SPSD, the exact role of anti-GAD65 in the pathogenesis of SPSD, remains unclear. In this chapter, we discuss the framework of pathogenesis of SPSD with the main focus on the classic stiff-person syndrome (SPS), controversies, and current supportive and arguing evidence. These vague areas in the field may stimulate further thoughts and works to elucidate clearer pathomechanisms of SPSD in the future.

Overview Antigenic Targets in Autoimmune Neurologic Disorders In general, autoimmune neurologic disorders are classified into three main categories, based on the location of antigenic targets (Fig. 6.1 and Table 6.1) [1]. The first category is disorders with intracellular antigenic targets, called onconeuronal antigens. Since antigens are inside the cells, antibodies that are present in blood or cerebrospinal fluid are generally not pathogenic but serve as biomarkers. Disorders in this category typically have high association with cancer and have poor response to immunotherapies. Examples of antibodies in this category include anti-Hu (aka anti-neuronal nuclear antigen 1 or ANNA-1), anti-Ri (aka anti-neuronal nuclear antigen 2 or ANNA-2), anti-Yo (aka anti-Purkinje cell cytoplasmicantibody type 1 or anti-PCA1). The second category of autoimmune neurologic disorders is disorders with antigenic targets at neuronal cell surface proteins, typically at postsynaptic sites. Antibodies have direct interaction or binding with these antigens. Therefore, these antibodies are pathogenic and also serve as biomarkers. Disorders in this category generally have relatively lower association with cancer, and better responses to immunotherapies, when compared to the disorders in the first category. Examples of © Springer Nature Switzerland AG 2020 P. Termsarasab et al., Stiff-Person Syndrome and Related Disorders, https://doi.org/10.1007/978-3-030-43059-7_6

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b

c

Fig. 6.1  Three main categories of antigenic targets in autoimmune neurologic syndromes. These include (a) Onconeuronal antigens, in blue, (b) Cell surface proteins, in red, and (c) Intracellular synaptic antigens, in blue Table 6.1  Antigenic targets in stiff-person spectrum disorders (SPSD) classified according to three main categories based on locations of the antigens Onconeuronal antigen N/A

Cell surface protein Glycine receptor DPPX GABAA receptor

Intracellular synaptic protein Presynaptic Postsynaptic Gephyrin GAD GABARAP Amphiphysin GlyT2

The most common antibodies are anti-GAD antibodies which target intracellular presynaptic antigens. None of antibodies associated with SPSD targets onconeuronal antigen Abbreviations: DPPX dipeptidyl-peptidase-like protein 6, GABARAP GABAA receptor-associated protein, GAD glutamic acid decarboxylase, GlyT2 glycine transporter 2, N/A not applicable (none)

antibodies in this category include anti-N-methyl-D-aspartate (NMDA) receptor, anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, anti-glycine receptor, and anti-GABAA receptor antibodies. The third category is autoimmune neurologic disorders where antigenic targets are intracellular, similar to the first category but located at the synaptic sites. It remains unclear whether the pathophysiology is T-cell mediated as in the first category or antibody-mediated as in the second category. This third category has overlapping features between the first and second categories. For example, while antigenic targets are located inside the cells as in the first category, disorders in this group usually have low association with cancer and good response to immunotherapies. The classic example of antibodies in this category is anti-glutamic acid decarboxylase (anti-GAD) antibodies, the most common antibodies associated with SPSD. The antigenic target is the GAD enzyme, a presynaptic protein located intracellularly. However, the anti-GAD antibody syndromes typically have low association with cancer and respond well to immunotherapies. Many authors may incorporate the anti-GAD antibodies into the second category above and called disorders with antibodies to cell surface “and synaptic proteins.” In our view, anti-­ GAD antibodies are unique and should possibly be classified as a separate third

General Principles of Autoimmunity

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category. Anti-amphiphysin antibodies also belong to this third category. Amphiphysin is a presynaptic intracellular antigen. Unlike anti-GAD65-associated SPSD, anti-amphiphysin-associated SPSD typically have high association with cancer. Our understanding of the pathophysiology of disorders in this third category is relatively incomplete, compared to the first two categories, and further research is highly needed to fill the current knowledge gap. The antigenic targets for other autoantibodies associated with SPSD such as anti-gephyrin and anti-GABAA receptor-­associated protein (anti-GABARAP) are intracellular synaptic proteins, but unlike GAD and amphiphysin, the antigens are at postsynaptic sites. It remains unclear whether these antibodies should be categorized to the third category, or should be distinguished into another different unique category.

General Principles of Autoimmunity The main processes attributed to autoimmunity are failure of self-tolerance and activation of self-reactive lymphocytes (Fig.  6.2) [2]. With regard to defective self-­ tolerance, genetic susceptibility, especially related to the human leukocyte antigen complex (HLA, a major histocompatibility complex [MHC] in humans), plays a role in this step. This will be discussed further below. Autoimmunity may be triggered by environmental stimuli such as infections. Before activation of self-reactive lymphocytes, there is generally activation of antigen-­presenting cells (APCs). Activation of APC may be triggered by tissue injury, local inflammation (or innate immune response), and/or infection. Infection can trigger immune responses by two main mechanisms: bystander activation and molecular mimicry (Fig. 6.3).

Fig. 6.2  General overview of autoimmunity. Autoimmunity can occur due to both genetic susceptibility and environmental stimuli, which trigger immune responses including activation of antigen-­ presenting cells (APCs)

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Fig. 6.3  Infection can trigger immune responses by two main mechanisms. Bystander activation (in which local antigen-presenting cells [APCs] are activated by microbial agents) is shown in the top panel, and molecular mimicry is shown in the bottom panel. APC antigen-presenting cell, DC dendritic cell

First, bystander activation is a process that microbial agents trigger local APCs within the tissue to present self-antigen to self-reactive T-cells that are non-specific. The second mechanism, molecular mimicry, is a process that antigens within microbial agents are similar to antigens within body tissue. In this circumstance, antigens within microbial agents, not self-antigen, are presented directly to self-reactive T-cells. Activated T-cells will then target self-antigens within self-tissues that have molecular mimicry to the antigens of microbial agents. One of the key differences between these two mechanisms is that the antigens presented to self-reactive T-cells are self-antigens in bystander activation while, in molecular mimicry, the presented antigens, are microbial agents themselves. It is important to note that infection can also cause local inflammation which then will induce local innate immune responses, recruitment of leukocytes, and subsequently cell-mediated immune responses including activation of tissue APCs.

I mmunopathogenesis of Stiff-Person Spectrum Disorders with Focus on Anti-GAD-Associated Stiff-Person Spectrum Disorders Here we focus the main discussion on the immunopathogenesis of the anti-GAD-associated SPSD, especially the classic SPS. In order to understand the immunopathogenesis specifically related to the anti-GAD-associated SPSD, the general immunologic principles can be applied, and the discussion follows the abovementioned steps. “SPS,” when mentioned in most literature, has been referred to the classic SPS phenotype, and the data or results may not be applied to other phenotypes of SPSD.

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The etiologies or triggers of defective self-tolerance in the classic SPS remain to be elucidated, as in most autoimmune disorders. With regard to genetic susceptibility, SPS is genetically associated with HLA-DQB1∗0201 and HLA-DRB1∗0301 [3, 4]. Each of these HLA alleles was reported to be present in 70% of the SPS patients in two case series. In one of these series, 62.5% of the SPS patients without an HLA-DQB1∗06 allele had diabetes, while only 20% of the SPS patients with an HLA-DQB1∗06 had diabetes [3]. Therefore, the presence of HLA-DQB1∗0602 allele was suggested to be protective for development of diabetes in SPS patients. Infection triggers activation of APC and self-reactive lymphocytes. Several infections have been proposed in the pathogenesis of SPS, and these include cytomegalovirus [5] and West Nile virus [6]. Enteroviruses especially coxsackievirus B4 has been linked to anti-GAD65 antibodies in type 1 diabetes [7–9]. There has been evidence suggestive of molecular mimicry between cytomegalovirus and the GAD antigen. GAD65-specific T-cells have cross-reactivity with a peptide of the human cytomegalovirus (hCMV) major DNA-binding protein [5]. In addition to molecular mimicry, bystander activation of autoreactive T-cells to the GAD antigen by viral infection has also been proposed [10]. Autoreactive T-cells are activated in the periphery. However, epitope regions of the GAD protein where these T-cells react differ between anti-GAD-associated SPS and type 1 diabetes, to GAD fragments 81–171 and 313–403  in the former vs. 161–243 and 473–555 in the latter [11]. In SPS, there are both Th1 and Th2 responses which produces interferon γ (IFNγ) and interleukin 4 (IL-4), respectively. In contrast, Th1 response mainly takes place in type 1 diabetes [12]. In general, Th1 response leads to cytokine, in particular IFNγ production, which in turn activates macrophages. Th2 response leads to different cytokine production including IL-4, IL-5, IL-6, and IL-10 which is important in B-cell activation and subsequent antibody production. With regard to the antibody production, there is also difference of anti-GAD immunoglobulin subclasses between SPS and type 1 diabetes. IgG1 is a common main immunoglobulin subclass found in sera of both SPS and type 1 diabetes; however, in SPS, IgG2, IgG3, IgG4, and IgE may be detected in low levels [13]. It remains unclear whether SPS is predominantly B-cell- or T-cell-mediated (aka humoral immunity vs. cell-mediated immunity). However, both are likely involved in the pathogenesis of SPS. While intrathecal production of anti-GAD65 antibody supports the main role of B-cells in the pathogenesis, there is also some evidence of T-cell contribution. One study demonstrated that GAD65-specific CD4+ T-cells alone could cause an encephalomyelitis-like response in mice [14]. Th2 response which is associated with downstream B-cell activation and antibody production serves as an evidence supporting a role of B-cells in SPS. The interaction between T and B-cells in SPS remains to be elucidated. In order to cause an autoimmunity within the central nervous system (CNS), anti-GAD antibody has to be present intrathecally. There is an evidence showing that GAD65-specific T-cells can be cloned in the cerebrospinal fluid (CSF) of patients with marked intrathecal synthesis of GAD65 IgG [15]. Therefore, GAD65specific T-cells are in the intrathecal compartment in conjunction with clonally expanded B-cells which produce anti-GAD antibody in the CSF. The frequent presence of CSF oligoclonal bands in much higher titers, compared to serum, supports

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the intrathecal synthesis of anti-GAD65 antibody [16]. Nevertheless, the mechanism of GAD65-specific T-cell activation and interaction with B-cells within the intrathecal compartment remains unknown. It is important to note that the immunopathogenesis discussed above is relevant to anti-GAD-associated SPS. Nevertheless, other antibodies associated with SPSD may have different immunopathogenesis.

Is GAD65 Pathogenic Based on the Koch-Witebsky Postulates? According to Koch-Witebsky postulates, an antibody is considered pathogenic in an autoimmune disorder when certain criteria are fulfilled (Table 6.2) [17]. However, many antibodies that are clearly associated with autoimmune disorders and most likely pathogenic still do not fulfill all criteria in Koch-Witebsky postulates. While some antibodies fulfill these criteria, others, such as anti-Yo (aka anti-PCA1), do not; however, their pathogenic roles are widely accepted in clinical practice. One important question is whether anti-GAD65 antibody found in SPS patients directly causes the disease or is just a coincidental finding. When considering anti-­ GAD antibodies using Koch-Witebsky postulates, the antibody is usually found in high titers in SPS patients. While positive anti-GAD65 antibodies maybe found in 8% of healthy individuals, titers are typically low [18]. Further details regarding seropositivity of anti-GAD65 antibodies in SPSD and other disorders especially type 1 diabetes is discussed in Chap. 7. GAD65 is its known antigenic target. There have been several animal studies showing that passive transfer of anti-GAD antibody causes phenotypes similar to SPS in humans. For example, Manto and colleagues demonstrated that injections of purified IgG from patients with anti-GAD antibody into the lumbar paraspinal region of rats induced electrophysiologic findings similar to what seen in human SPS including continuous motor unit activity with repetitive discharges, abnormal exteroceptive reflexes, and increased anterior horn cell excitability evidenced by increased F-wave/M-response ratio [19]. Geis and colleagues found that passive transfer of IgG from SPS patients with anti-­ GAD65 antibody into intrathecal space of rats resulted in anxiety and agoraphobia phenotypes, similar to the neuropsychiatric features (anxiety, depression, and agoraphobia) seen in humans with SPS. In humans, maternal passive transfer of antiGAD65 antibodies did not lead to phenotypes of congenital stiff-person syndromes [20]. There has also been evidence of active transfer of anti-GAD. Chang and colleagues demonstrated that sera of mice after immunization with GAD65 showed characteristic immunoreactivity pattern of anti-GAD antibody (intracellular Table 6.2 Koch-Witebsky postulates. Fulfillment of all criteria proves that an antibody is pathogenic for an autoimmune disorder

1. The antibody is found in patients, but not healthy control 2. The antibody interacts with target antigen 3. There is evidence of passive transfer 4. There is evidence of active transfer 5. Reduction in antibody titers leads to improvement in clinical symptoms 6. The phenotype is comparable to genetic and pharmacological models

References

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binding) [21]. Although sera of these mice also had autoantibodies binding to the surface of cultured cerebellar neurons, phenotypes of SPS including abnormal behaviors were not seen in these mice. In contrast, anti-GAD antibody titers are not always correlated with clinical severity or disease progression [22], evidence arguing against pathogenic roles of anti-GAD antibody, according to Koch-Witebsky postulates. Finally, one important conundrum is that GAD has an intracellular location but there has been no evidence demonstrating uptake of anti-GAD antibody by the presynaptic nerve terminals, nor has been evidence that GAD antigen moves to cell surface in order to have an interaction with the antibody.

 uture Directions of Research on Immunopathogenesis F of Stiff-Person Spectrum Disorders GAD65 is an intracellular antigen but anti-GAD-associated SPS behaves as autoimmune neurologic syndromes to cell surface receptors (e.g., less or no association with cancer and relatively good response to immunotherapies). In our opinion, future research should focus on how anti-GAD antibody interacts with the intracellular GAD65 antigen. Hypotheses include that (1) the antibody enters the cell to have interactions with the antigen intracellularly; (2) the antigen, at some point during the process, reaches the cell surface, referred to as “moonlighting” [23], to have interactions with the antibody; or (3) the antibody and the antigen have interaction via other different mechanisms such as via other intermediate processes. The answer to this question will give us clearer insights into the pathogenicity of anti-GAD antibodies. Furthermore, the antibodies related to SPSD have been expanding. Even in classic SPS, there are also other associated antibodies such as anti-amphiphysin and anti-GABARAP. More studies of these antibodies, including their exact pathogenic mechanisms, how they are attributed to different phenotypes of SPSD, and whether there are interactions between these antibodies including with anti-GAD antibodies, will shed further light on our understanding in the immunopathogenesis and treatment of SPSD.

References 1. Lancaster E, Dalmau J. Neuronal autoantigens–pathogenesis, associated disorders and antibody testing. Nat Rev Neurol. 2012;8(7):380–90. https://doi.org/10.1038/nrneurol.2012.99. 2. Abbas AK, Lichtman AH, Pillai S. Immunologic tolerance and autoimmunity. In: Abbas AK, Lichtman AH, Pillai S, editors. Cellular and molecular immunology. 9th ed. Philadelphia: Elsevier; 2018. p. 325–50. 3. Pugliese A, Solimena M, Awdeh ZL, Alper CA, Bugawan T, Erlich HA, et al. Association of HLA-DQB1∗0201 with stiff-man syndrome. J Clin Endocrinol Metab. 1993;77(6):1550–3. https://doi.org/10.1210/jcem.77.6.8263140. 4. Dalakas MC, Fujii M, Li M, McElroy B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology. 2000;55(10):1531–5. https://doi.org/10.1212/ wnl.55.10.1531. 5. Hiemstra HS, Schloot NC, van Veelen PA, Willemen SJ, Franken KL, van Rood JJ, et  al. Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen

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glutamic acid decarboxylase. Proc Natl Acad Sci U S A. 2001;98(7):3988–91. https://doi. org/10.1073/pnas.071050898. 6. Hassin-Baer S, Kirson ED, Shulman L, Buchman AS, Bin H, Hindiyeh M, et al. Stiff-person syndrome following West Nile fever. Arch Neurol. 2004;61(6):938–41. https://doi.org/10.1001/ archneur.61.6.938. 7. Atkinson MA, Bowman MA, Campbell L, Darrow BL, Kaufman DL, Maclaren NK. Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-­ dependent diabetes. J Clin Invest. 1994;94(5):2125–9. https://doi.org/10.1172/JCI117567. 8. Hyoty H. Enterovirus infections and type 1 diabetes. Ann Med. 2002;34(3):138–47. 9. Tong JC, Myers MA, Mackay IR, Zimmet PZ, Rowley MJ. The PEVKEK region of the pyridoxal phosphate binding domain of GAD65 expresses a dominant B cell epitope for type 1 diabetes sera. Ann N Y Acad Sci. 2002;958:182–9. https://doi.org/10.1111/j.1749-6632.2002. tb02966.x. 10. Filippi CM, von Herrath MG.  Viral trigger for type 1 diabetes: pros and cons. Diabetes. 2008;57(11):2863–71. https://doi.org/10.2337/db07-1023. 11. Lohmann T, Hawa M, Leslie RD, Lane R, Picard J, Londei M.  Immune reactivity to glutamic acid decarboxylase 65  in stiffman syndrome and type 1 diabetes mellitus. Lancet. 2000;356(9223):31–5. https://doi.org/10.1016/S0140-6736(00)02431-4. 12. Lohmann T, Londei M, Hawa M, Leslie RD.  Humoral and cellular autoimmune responses in stiff person syndrome. Ann N Y Acad Sci. 2003;998:215–22. https://doi.org/10.1196/ annals.1254.024. 13. Baizabal-Carvallo JF, Jankovic J.  Stiff-person syndrome: insights into a complex autoimmune disorder. J Neurol Neurosurg Psychiatry. 2015;86(8):840–8. https://doi.org/10.1136/ jnnp-2014-309201. 14. Burton AR, Baquet Z, Eisenbarth GS, Tisch R, Smeyne R, Workman CJ, et al. Central nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells. J Immunol. 2010;184(9):4863–70. https://doi.org/10.4049/jimmunol.0903728. 15. Skorstad G, Hestvik AL, Vartdal F, Holmoy T. Cerebrospinal fluid T cell responses against glutamic acid decarboxylase 65  in patients with stiff person syndrome. J Autoimmun. 2009;32(1):24–32. https://doi.org/10.1016/j.jaut.2008.10.002. 16. Skorstad G, Hestvik AL, Torjesen P, Alvik K, Vartdal F, Vandvik B, et  al. GAD65 IgG autoantibodies in stiff person syndrome: clonality, avidity and persistence. Eur J Neurol. 2008;15(9):973–80. https://doi.org/10.1111/j.1468-1331.2008.02221.x. 17. Witebsky E, Rose NR, Terplan K, Paine JR, Egan RW.  Chronic thyroiditis and auto immunization. J Am Med Assoc. 1957;164(13):1439–47. https://doi.org/10.1001/ jama.1957.02980130015004. 18. Walikonis JE, Lennon VA. Radioimmunoassay for glutamic acid decarboxylase (GAD65) autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus. Mayo Clin Proc. 1998;73(12):1161–6. https://doi.org/10.4065/73.12.1161. 19. Manto MU, Laute MA, Aguera M, Rogemond V, Pandolfo M, Honnorat J.  Effects of anti-­ glutamic acid decarboxylase antibodies associated with neurological diseases. Ann Neurol. 2007;61(6):544–51. https://doi.org/10.1002/ana.21123. 20. Nemni R, Caniatti LM, Gironi M, Bazzigaluppi E, De Grandis D.  Stiff person syndrome does not always occur with maternal passive transfer of GAD65 antibodies. Neurology. 2004;62(11):2101–2. https://doi.org/10.1212/01.wnl.0000127446.61806.2f. 21. Chang T, Alexopoulos H, Pettingill P, McMenamin M, Deacon R, Erdelyi F, et  al. Immunization against GAD induces antibody binding to GAD-independent antigens and brainstem GABAergic neuronal loss. PLoS One. 2013;8(9):e72921. https://doi.org/10.1371/ journal.pone.0072921. 22. Rakocevic G, Alexopoulos H, Dalakas MC. Quantitative clinical and autoimmune assessments in stiff person syndrome: evidence for a progressive disorder. BMC Neurol. 2019;19(1):1. https://doi.org/10.1186/s12883-018-1232-z. 23. Irani SR. ‘Moonlighting’ surface antigens: a paradigm for autoantibody pathogenicity in neurology? Brain. 2016;139(Pt 2):304–6. https://doi.org/10.1093/brain/awv364.

7

Anti-Glutamic Acid Decarboxylase 65 (GAD65)-Associated Syndromes

The classic stiff-person syndrome (SPS) is mainly associated with anti-glutamic acid decarboxylase (anti-GAD) antibodies. Conversely, anti-GAD antibodies are attributed to not only SPS phenotypes but also other neurologic syndromes including cerebellar ataxia, limbic encephalitis and epilepsy, among others. The two most common neurologic phenotypes associated with anti-GAD antibodies are classic SPS and cerebellar ataxia. In this chapter, we discuss a group of disorders, which may be together called “GAD-opathies,” with broad range of phenotypes, all associated with elevated anti-GAD antibodies.

Laboratory Aspects of Anti-GAD65 Antibodies As mentioned in the previous chapters, anti-GAD65 antibodies are not specific to SPS and may also be found in type 1 diabetes mellitus. Anti-GAD65 antibody is positive up to 80–90% of patients with SPS [1–3] and 70–80% of patients with type 1 diabetes mellitus [4, 5]. GAD is an enzyme that is also present in pancreatic cells. In addition, anti-GAD65 antibodies can also be positive in neuronal ceroid lipofuscinosis (aka Batten disease) [6, 7] and other autoimmune disorders without central nervous system involvement such as autoimmune thyroiditis (in both diabetic and non-diabetic patients) [8–10] and autoimmune polyendocrine (polyglandular) syndrome [11, 12]. However, levels of the anti-GAD65 antibody titers differ between SPS and other disorders [13, 14]. In SPS, the titer is typically very high, greater than 20  nmol/L and typically greater than 100  nmol/L by immunoprecipitation assay (IPA). In contrast, GAD65 antibodies are typically positive in a low titer in type 1 diabetes mellitus and other autoimmune disorders.

Electronic Supplementary Material The online version of this chapter (https://doi. org/10.1007/978-3-030-43059-7_7) contains supplementary material, which is available to authorized users. © Springer Nature Switzerland AG 2020 P. Termsarasab et al., Stiff-Person Syndrome and Related Disorders, https://doi.org/10.1007/978-3-030-43059-7_7

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Table 7.1  Laboratory techniques in detection of anti-GAD65 antibodies and general cut-off values for normal and “high levels or titers” Laboratory technique Radioimmunoassay (RIA) Enzyme-linked immunosorbent assay (ELISA) Immunohistochemistry (then confirmed by RIA or Western blot) Intrathecal synthesis Indirect immunofluorescence (by using mouse tissue)

Unit Normal value nmol/L 1000– 2000 No clear cut-off >1

None