Myasthenia Gravis and Related Disorders (eBook)

Preface 6
Contents 7
Contributors 9
Series Editor Introduction 11
Color Plates 12
Neuromuscular Junction Physiology and Pathophysiology 13
1.1 INTRODUCTION 13
1.2 MOTOR NERVE PROPERTIES 13
1.2.1 Distal Motor Nerve Properties 13
1.2.2 The Nerve Terminal 14
1.2.2.1 Role of Ca2+ Channels in Transmitter Release 14
1.2.2.2 Synaptic Vesicle Fusion 15
1.3 THE SYNAPTIC CLEFT 16
1.3.1 Synatpic Cleft Acetylcholine Esterase 17
1.3.2 Alteration of AChE in Neuromuscular Diseases 17
1.3.3 Extracellular Matrix in the Synaptic Cleft 17
1.3.4 ACh-Binding Protein 18
1.4 POSTSYNAPTIC MEMBRANE SPECIALIZATION 18
1.4.1 How the NMJ Accommodates to Muscle Contraction 19
1.4.2 Postsynaptic Na+and AChR Channels 19
1.5 SAFETY FACTOR FOR NEUROMUSCULAR TRANSMISSION 20
REFERENCES 20
Acetylcholine Receptor Structure 25
2.1 INTRODUCTION 25
2.2 SIZE AND SHAPE OF ACHRS 26
2.3 STRUCTURES OF ACHR SUBUNITS 27
2.4 ORGANIZATION OF SUBUNITS IN ACHR SUBTYPES 31
2.5 ACETYLCHOLINE-BINDING SITES 33
2.6 CATION CHANNEL AND ITS GATE 35
2.7 ANTIGENIC STRUCTURE AND THE MAIN IMMUNOGENIC REGION (MIR) 35
2.8 INDUCTION OF THE AUTOIMMUNE RESPONSE TO ACHRS IN MG 38
2.9 AUTOIMMUNE MECHANISMS WHICH IMPAIR NEUROMUSCULAR TRANSMISSION IN MG AND EAMG 39
2.10 EFFECTS OF ACHR MUTATIONS IN CONGENITAL MYASTHENIC SYNDROMES 40
2.11 NEURONAL ACHR SUBTYPES AND FUNCTIONAL ROLES 42
2.12 AUTOIMMUNE IMPAIRMENT OF NEURONAL ACHRS 43
2.13 EFFECTS OF HUMAN NEURONAL ACHR MUTATIONS 44
REFERENCES 45
Immunopathogenesis of Myasthenia Gravis 54
3.1 INTRODUCTION 54
3.2 ANTI-ACHR Ab IN MG AND IN EXPERIMENTAL AUTOIMMUNE MG (EAMG) 54
3.3 EPITOPES RECOGNIZED BY ANTI-ACHR Ab IN MG AND EAMG 56
3.3.1 The MIR 56
3.3.2 The Cholinergic Site 56
3.3.3 Non-AChR Antigens 57
3.4 ANTI-ACHR CD4+ T-HELPER CELLS IN MG 58
3.4.1 Epitope Repertoire of Anti-AChR CD4+ T Cells in MG 59
3.4.2 CD4+ T Cells of MG Patients Recognize ‘‘Universal’’, Immunodominant AChR Epitopes 61
3.4.3 Unstable Recognition of AChR Epitopes by CD4+ T Cells of Ocular MG Patients 61
3.5 TCR Vbeta AND Valpha USAGE BY ANTI-ACHR CD4+ T CELLS OF MG PATIENTS 62
3.6 ROLES IN MG AND EAMG OF CYTOKINES SECRETED BY DIFFERENT CD4+ SUBSETS 64
3.7 CD8+ CELLS IN MG AND EAMG 67
3.8 THE THYMUS IN MG 68
3.8.1 AChR-Like Proteins Are Expressed in the Thymus 68
3.8.2 Thymus Cells That Express AChR Proteins 69
3.9 PATHOGENIC MECHANISMS OF MG 70
REFERENCES 72
Epidemiology and Genetics of Myasthenia Gravis 82
4.1 INTRODUCTION 82
4.2 EPIDEMIOLOGICAL ISSUES AND MYASTHENIA GRAVIS 82
4.2.1 Definition of Terms 82
4.2.2 Epidemiological Studies of Myasthenia Gravis 83
4.2.3 Current Trends in the Epidemiology of Myasthenia Gravis 83
4.2.4 Seronegative and Muscle-Specific Kinase Antibody-Related Myasthenia Gravis 85
4.2.5 Genetics of MG 86
4.2.6 Proof of Inheritance 86
4.3 CANDIDATE GENES 87
4.3.1 HLA Complex 87
4.3.2 AChR as a Self-Antigen and Other HLA Genes 87
4.3.3 Other Candidate Genes 88
REFERENCES 88
Clinical Presentation and Epidemiology of Myasthenia Gravis 90
5.1 DEFINITION AND CLASSIFICATION 90
5.2 CLINICAL MANIFESTATIONS 90
5.2.1 Ocular 90
5.2.2 Bulbar 91
5.2.3 Limb, Trunk and Respiratory 94
5.2.4 Muscle Atrophy 95
5.2.5 Clinical Classifications and Quantitative Tests 97
5.2.6 Cognitive Involvement 97
5.2.7 The Course of the Disease 98
5.2.8 Exacerbating Factors 99
5.3 EPIDEMIOLOGY 100
5.3.1 Incidence and Prevalence 100
5.3.2 Age, Gender and Classification 100
5.3.3 Acquired Infantile MG 101
5.3.4 Myasthenia Gravis in the Elderly 101
5.3.5 Myasthenia Gravis and Thymoma 101
5.3.6 The Incidence of Autoimmune Diseases in MG 101
5.3.7 Genetic Predisposition 102
5.3.8 Differential Diagnosis 102
REFERENCES 102
Ocular Myasthenia 106
6.1 INTRODUCTION 106
6.2 EPIDEMIOLOGY 106
6.3 BASIS FOR OCULAR MUSCLE INVOLVEMENT BY MYASTHENIA GRAVIS 106
6.4 CLINICAL PRESENTATION 107
6.5 DIAGNOSTIC TESTING 107
6.6 PROGRESSION TO GENERALIZED MYASTHENIA GRAVIS 110
6.7 TREATMENT 111
References 112
Thymoma-Associated Paraneoplastic Myasthenia Gravis 116
7.1 INTRODUCTION 116
7.2 HISTOPATHOLOGY OF THE THYMUS IN MG 117
7.2.1 Thymic Lympho-follicular Hyperplasia (TFH) 117
7.2.2 Thymus Histology in Late-Onset MG (LOMG) 118
7.2.3 Thymomas and Paraneoplastic MG 118
7.3 PATHOGENETIC CONCEPTS IN SEROPOSITIVE MG 118
7.3.1 Pathogenesis of MG in Thymic Lympho-follicular Hyperplasia (TFH) 118
7.3.2 Pathogenesis of Thymoma-Associated (Paraneoplastic) MG 120
7.3.2.1 Genetic Features Contributing to Paraneoplastic MG 120
7.3.2.2 Molecular and Functional Features Contributing to Paraneoplastic MG 121
7.3.2.3 Shared Features Among MG-Associated Thymomas 121
7.3.3 A Pathogenetic Model of Paraneoplastic Myasthenia Gravis 121
7.3.4 Etiological Triggers of Paraneoplastic MG 122
7.3.5 Major Unresolved Questions in Paraneoplastic MG 123
REFERENCES 124
Electrodiagnosis of Neuromuscular Junction Disorders 129
8.1 INTRODUCTION 129
8.2 BASIC CONCEPTS OF NEUROMUSCULAR TRANSMISSION 129
8.2.1 Quantum 129
8.2.2 End-Plate Potential 129
8.2.3 Safety Factor 130
8.2.4 Calcium Influx into the Terminal Axon 130
8.2.5 Compound Muscle Action Potential 130
8.3 ELECTRODIAGNOSTIC TESTS IN NEUROMUSCULAR JUNCTION DISORDERS 130
8.3.1 Routine Motor Nerve Conduction Studies 130
8.3.2 Conventional Needle Electromyography 130
8.3.2.1 Moment-to-Moment Variation Instability of Motor Unit Action Potentials 130
8.3.2.2 Short-Duration, Low-Amplitude, and Polyphasic MUAPs 131
8.3.2.3 Fibrillation Potentials 131
8.3.3 Repetitive Nerve Stimulation 131
8.3.3.1 Principles 131
8.3.3.2 Techniques 131
8.3.3.3 Findings 132
8.3.3.4 Measurements 134
8.3.4 Single-Fiber EMG 136
8.3.4.1 Principles 136
8.3.4.2 Techniques 136
8.3.4.3 Measurements 138
8.3.4.4 Findings 139
8.4 NEUROMUSCULAR DEFECT FINDINGS IN NEUROMUSCULAR JUNCTION DISORDERS 140
8.4.1 Myasthenia Gravis 140
8.4.1.1 Baseline Motor Nerve Conduction Studies 141
8.4.1.2 Slow Repetitive Nerve Stimulation 141
8.4.1.3 Rapid Repetitive Nerve Stimulation and Post-exercise Facilitation 141
8.4.1.4 Single-Fiber EMG 142
8.4.1.5 Conventional Needle EMG 144
8.4.2 Lambert-Eaton Syndrome 144
8.4.2.1 Baseline Motor Nerve Conduction Studies 145
8.4.2.2 Rapid Repetitive Nerve Stimulation and Post-exercise Facilitation 145
8.4.2.3 Slow Repetitive Nerve Stimulation 145
8.4.2.4 Single-Fiber EMG 145
8.4.2.5 Conventional Needle EMG 145
8.4.3 Botulism 145
8.4.3.1 Baseline Motor Nerve Conduction Studies 147
8.4.3.2 Rapid Repetitive Nerve Stimulation and Post-exercise Facilitation 147
8.4.3.3 Slow Repetitive Nerve Stimulation 147
8.4.3.4 Single-Fiber EMG 147
8.4.3.5 Conventional Needle EMG 148
8.4.4 Congenital Myasthenic Syndromes 148
8.4.5 Electrodiagnostic Strategy in a Patient with Suspected Neuromuscular Junction Disorder 148
8.5 NEUROMUSCULAR DEFECT FINDINGS IN OTHER NEUROMUSCULAR DISORDERS 149
8.5.1 Amyotrophic Lateral Sclerosis 149
8.5.2 Miller-Fisher Syndrome 149
8.5.3 Guillian-Barré Syndrome 149
REFERENCES 150
Autoantibody Testing in the Diagnosis and Management of Autoimmune Disorders of Neuromuscular Transmission and Related Diseases 152
9.1 INTRODUCTION 152
9.2 SPECTRUM OF ANTIBODIES TO TARGETS AT THE NMJ AND ASSOCIATED MOLECULES 152
9.3 IDENTIFYING A PATHOGENIC ROLE FOR ANTIBODIES IN ANTIBODY-MEDIATED DISORDERS 153
9.4 DISEASE PHENOTYPES IN AUTOIMMUNE MYASTHENIC DISORDERS 153
9.5 HETEROGENEITY AND PATHOPHYSIOLOGICAL EFFECTS OF AChR ANTIBODIES 154
9.5.1 Binding Antibodies Measured by Immunoprecipitation 155
9.5.2 Blocking Antibodies 156
9.5.3 Assays to Detect Modulating Antibodies 156
9.5.4 Other Autoantibodies 156
9.6 AUTOIMMUNE MG IN ASSOCIATION WITH THYMOMA 156
9.6.1 Striated Muscle Antibody Assays 157
9.7 LATE-ONSET MG NOT ASSOCIATED WITH A DETECTABLE THYMOMA 157
9.8 ROLE OF ANTIBODIES IN DIAGNOSIS AND TREATMENT IN PATIENTS WITH MG 157
9.9 SERONEGATIVE (SN) MG 158
9.9.1 Plasma Exchange and Passive Transfer 158
9.9.2 Functional and Binding Studies 158
9.9.3 Antibodies to a Candidate Antigen 158
9.10 LAMBERT-EATON SYNDROME AND CEREBELLAR ATAXIA 159
9.10.1 Plasma Exchange and Passive Transfer 159
9.10.2 Functional and Binding Studies 160
9.10.3 Radioimmunoprecipitation Assays 160
9.11 ACQUIRED NEUROMYOTONIA 160
9.11.1 Plasma Exchange and Passive Transfer 160
9.11.2 Functional and Binding Assays 160
9.12 STIFF PERSON SYNDROME 162
9.13 CONCLUSIONS 162
REFERENCES 162
Treatment of Myasthenia Gravis 166
10.1 INTRODUCTION 166
10.2 PATIENT EDUCATION AND EVALUATION 167
10.3 TREATMENTS 168
10.3.1 Cholinesterase Inhibitors 169
10.3.2 Corticosteroids 170
10.3.3 Azathioprine 171
10.3.4 Cyclosporine 172
10.3.5 Mycophenolate Mofetil 173
10.3.6 Tacrolimus 173
10.3.7 Plasma Exchange 174
10.3.8 Intravenous Immunoglobulin 174
10.3.9 Other Immunosuppressive Treatments 175
10.4 SPECIFIC CLINICAL SITUATIONS 176
10.4.1 Myasthenia Gravis and Pregnancy 176
10.4.2 Treatment of the Myasthenia Gravis Patient with Thymoma 176
10.4.3 Juvenile Myasthenia Gravis 176
10.4.4 The Treatment-Resistant Patient 177
10.4.5 Experimental Treatments for Myasthenia Gravis 177
REFERENCES 178
Neurocritical Care of Myasthenic Crisis 183
11.1 INTRODUCTION 183
11.2 PATHOPHYSIOLOGY 183
11.2.1 Precipitants 183
11.2.2 Respiratory Abnormalities 184
11.2.3 Oropharyngeal Dysfunction 184
11.2.4 Clinical Presentation and Evaluation 184
11.2.5 Differential Diagnosis 186
11.3 MANAGEMENT 186
11.3.1 General 186
11.3.2 Ventilatory Management 187
11.3.3 Ventilator Weaning 187
11.3.4 Treatment of Neuromuscular Dysfunction 188
11.3.5 Outcome of Myasthenic Crisis 189
REFERENCES 190
Thymectomy for Non-thymomatous MG 192
12.1 INTRODUCTION 192
12.2 TOTAL THYMECTOMY IS INDICATED 192
12.3 SURGICAL ANATOMY OF THE THYMUS 193
12.4 RESECTIONAL POTENTIAL OF THE SURGICAL TECHNIQUES 194
12.4.1 Combined Transcervical and Transsternal Thymectomy 194
12.4.2 Transsternal Thymectomies 194
12.4.3 Transcervical Thymectomies 197
12.4.4 Videoscopic-Assisted Thymectomies 197
12.5 PROBLEMS IN THE ANALYSIS OF THYMECTOMY FOR MG 198
12.5.1 Data Analysis 198
12.5.2 Other Pitfalls of the Analysis of Results 199
12.6 THE RESULTS OF THYMECTOMY 200
12.6.1 Introduction 200
12.6.2 Thymectomy Versus Medical Management 201
12.6.3 Comparative Results Following Thymectomy 201
12.7 INDICATIONS FOR THYMECTOMY 203
12.8 SELECTING THE THYMECTOMY TECHNIQUE 204
12.9 RE-OPERATION 205
12.10 TRACHEOSTOMY: TIMING AND TECHNIQUE 206
12.11 SURGICAL MANAGEMENT OF THYMOMA 207
12.12 PERI-OPERATIVE PATIENT MANAGEMENT 207
12.13 HOSPITAL MORBIDITY AND MORTALITY 208
12.14 OUTCOMES RESEARCH 209
12.15 RECOMMENDATIONS 210
12.16 EPILOGUE 210
REFERENCES 211
Lambert-Eaton Syndrome 216
13.1 INTRODUCTION 216
13.2 HISTORY 216
13.3 PATHOGENESIS 217
13.3.1 Physiology of Neuromuscular Transmission 217
13.3.2 Pathophysiology of Neuromuscular Transmission in LES 218
13.3.3 Immunopathophysiology of LES 220
13.4 EPIDEMIOLOGY 221
13.5 CLINICAL PRESENTATION 222
13.5.1 Symptoms and Signs 222
13.5.2 Natural History 223
13.6 DIAGNOSIS 223
13.6.1 Clinical Manifestations 223
13.6.2 Electrodiagnostic Studies 224
13.6.3 Serological Tests 224
13.6.4 Differential Diagnosis 225
13.7 TREATMENT 226
13.7.1 Symptomatic Treatment 226
13.7.1.1 Cholinesterase Inhibitors 226
13.7.1.2 Guanidine 226
13.7.1.3 3,4-Diaminopyridine 226
13.7.2 Treatment of the Associated Neoplasm 227
13.7.3 Immunotherapy 227
REFERENCES 228
Acquired Neuromyotonia 233
14.1 INTRODUCTION 233
14.2 CLINICAL FEATURES OF NMT AND RELATED SYNDROMES 233
14.2.1 Clinical Manifestations 233
14.2.2 Electrophysiological Features 234
14.3 SERUM AND CEREBROSPINAL FLUID TESTS 235
14.4 PHYSIOLOGICAL BASIS OF EXCITABILITY OF MOTOR AXONS IN NMT PATIENTS 235
14.4.1 Clinical and Experimental Evidence for an Autoimmune Basis 236
14.4.1.1 Associated Autoimmune Syndromes 236
14.4.1.2 Response to Immunotherapies 236
14.4.1.3 Passive Transfer of Immunoglobulins to Mice 236
14.5 ANTIBODIES TO VGKC 237
14.5.1 Other Possible Autoantibodies in NMT 239
14.6 VGKC ANTIBODIES IN OTHER MUSCLE DISEASES 239
14.7 CENTRAL NERVOUS SYSTEM ABNORMALITIES IN NMT 240
14.7.1 Morvan’s Syndrome 240
14.7.2 Limbic Symptoms Without Overt Neuromyotonia 241
14.8 TREATMENT OF NMT 241
REFERENCES 242
Congenital Myasthenic Syndromes 245
15.1 INTRODUCTION 245
15.2 MOLECULAR GENETIC CLASSIFICATION 245
15.3 DIAGNOSTIC METHODS 246
15.4 PRESYNAPTIC CONGENITAL MYASTHENIC SYNDROMES 247
15.4.1 Congenital Myasthenic Syndrome with Episodic Apnea 247
15.4.1.1 Clinical Features 247
15.4.1.2 Molecular Basis 247
15.5 SYNAPTIC CONGENITAL MYASTHENIC SYNDROME 248
15.5.1 Endplate Acetylcholinesterase Deficiency 248
15.5.1.1 Clinical Features 248
15.5.1.2 Molecular Basis 248
15.6 POSTSYNAPTIC CONGENITAL MYASTHENIC SYNDROMES 249
15.6.1 Genetic Disorders of the AChR 249
15.6.2 AChR Deficiency due to Mutations in the AChR Subunits 249
15.6.2.1 Clinical Features 249
15.6.2.2 Molecular Basis 250
15.7 KINETIC ABNORMALITIES OF THE ACHR 250
15.7.1 Slow-Channel Congenital Myasthenic Syndrome 250
15.7.1.1 Clinical Features 250
15.7.1.2 Molecular Basis 250
15.7.2 Fast-Channel Congenital Myasthenic Syndrome 252
15.7.2.1 Clinical Features 252
15.7.2.2 Molecular Basis 252
15.8 MUTATIONS AFFECTING ACHR CLUSTERING AND SYNAPTIC STRUCTURE 252
15.8.1 AChR Deficiency due to RAPSN Mutations 252
15.8.1.1 Clinical Features 252
15.8.1.2 Molecular Basis 253
15.8.2 Congenital Myasthenic Syndrome with Proximal Weakness due to Mutations in DOK7 254
15.8.2.1 Clinical Features 254
15.8.2.2 Molecular Basis 254
15.8.3 Prenatal Hereditary Myasthenia due to Mutations in CHRNG 256
15.8.3.1 Clinical features 256
15.8.3.2 Molecular Basis 256
15.8.4 Rare Postsynaptic Congenital Myasthenic Syndromes 256
REFERENCES 257
Toxic Neuromuscular Transmission Disorders 260
16.1 INTRODUCTION 260
16.2 PHARMACOLOGICAL NEUROTOXICITY 261
16.2.1 Antibiotics 261
16.2.2 Cardiovascular Drugs 262
16.2.3 Cholesterol-Lowering Agents 263
16.2.4 Magnesium 263
16.2.5 Recreational Drugs 264
16.2.6 Rheumatologic Drugs 264
16.2.7 Other 264
16.2.7.1 Interferon Alpha 264
16.2.7.2 Botulinum Neurotoxin 265
16.3 BIOLOGICAL NEUROTOXINS 265
16.3.1 Botulism 265
16.3.2 Envenomation 266
16.3.2.1 Arthropods 266
16.3.2.2 Spider Bites 267
16.3.2.3 Tick Paralysis 267
16.3.2.4 Scorpion Bites 269
16.3.2.5 Snakebites 269
16.3.2.6 Marine Toxins 270
16.3.2.7 Plant Toxins 271
16.4 OCCUPATIONAL NEUROTOXINS 271
16.4.1 Heavy Metals 271
16.4.2 Organophosphate and Carbamate Poisoning 272
16.4.2.1 Pesticides 273
16.4.2.2 Agents of War and Terrorism 273
16.4.2.3 Pathophysiology 274
16.4.2.4 Treatment 274
REFERENCES 275
The Impact of Myasthenia Gravis on Mood, Cognitive Function, and Quality of Life 283
17.1 INTRODUCTION 283
17.2 THE EFFECTS OF PSYCHOLOGICAL HEALTH ON DISEASE 283
17.3 THE IMPACT OF MG ON THE PSYCHOLOGICAL AND SOCIAL HEALTH OF PATIENTS 285
17.3.1 Psychological Health in MG 285
17.4 COGNITION AND MENTAL FATIGUE IN MG 288
17.4.1 Neuropsychological Function in MG 289
17.4.2 Fatigue in Myasthenia Gravis 289
17.4.3 The Relationship Between Fatigue and Cognition in Myasthenia Gravis 290
17.5 FACTORS THAT SUPPORT PSYCHOLOGICAL HEALTH IN MYASTHENIA GRAVIS 291
17.5.1 Perceived Control 291
17.5.2 Uncertainty in Illness 292
17.5.3 Illness Intrusiveness 292
17.5.4 Social Support 293
17.6 SUMMARY 293
REFERENCES 294
Myasthenia Gravis: Classification and Outcome Measurements 297
18.1 INTRODUCTION 297
18.2 CLINICAL CLASSIFICATION OF MG 297
18.3 QUANTITATIVE MG SCORE (QMG) 299
18.4 MYASTHENIA GRAVIS MANUAL MUSCLE TEST (MG-MMT) 300
18.5 MYASTHENIC MUSCLE SCORE (MMS) 300
18.6 MG ACTIVITY OF DAILY LIVING PROFILE (MG-ADL) 301
18.7 FATIGUE TESTING 301
18.8 MGFA THERAPY STATUS 302
18.9 MGFA POSTINTERVENTION STATUS (PIS) 303
REFERENCES 304
Index 307