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Contributors | p. xv |
The Anatomy and Molecular Architecture of the Neuromuscular Junction | p. 1 |
Basic Concepts | p. 1 |
The Innervation of Muscle | p. 3 |
The Presynaptic Region | p. 3 |
The Nerve Terminal | p. 4 |
Giant Synaptic Vesicles | |
Coated Vesicles | |
Dense-core Vesicles | |
Small Clear Synaptic Vesicles | |
Vesicular ACh Uptake | |
Synaptic Vesicle Pools | |
Synaptic Vesicles Move to and Dock at die Active Zones | |
Exocytotic Machinery | |
SNARE Complex | |
Priming of Docked Synaptic Vesicles | |
Synaptotagmin-1 | |
Steps in Exocytosis | |
Other Proteins Modulating Exocytosis | |
Presynaptic Cytoskeletal Components | |
The Active Zone and die Voltage-Gated Ca2+ Channels | |
Voltage-gated K+ Channels of die Presynaptic Membrane | |
Endocytotic Events and die Formation of New Synaptic Vesicles | |
The Synaptic Space | p. 15 |
Synaptic Basal Lamina | |
Asymmetric AChE | |
Collagen XIII | |
Synaptic Laminins | |
The Postsynaptic Region | p. 16 |
The Junctional Folds and Their Cytoskeletal Components | |
AChRs on the Junctional Folds | |
The Saturating Disk Model of Neuromuscular Transmission | |
Regulation of die Distribution and Subunit Composition of AChR | |
The Postsynaptic Cytoskeleton | |
The Junctional Sarcoplasm | |
AChR Syndiesis and Degradation | |
Signaling Mechanisms at the Neuromuscular Junction | p. 25 |
Agrin, MuSK, and LRP4 | |
Dok-7 and Its Downstream Activators Crk, Crk-L, and Tidl | |
The Neuregulin/ARIA Signaling Pathway | |
Electrodiagnosis of Myasthenic Disorders | p. 37 |
Introduction | p. 37 |
Standard Motor Nerve Conduction Studies | p. 38 |
Repetitive Compound Muscle Action Potentials | |
Repetitive Nerve Stimulation Studies | p. 39 |
The Safety Margin of Neuromuscular Transmission | |
Pseudofacilitation vs. True Facilitation | |
Drug Effects | |
Choice of Muscles and Stimulation Sites | |
Troubleshooting Technical Problems | |
Special Considerations in Infants and Young Children | |
What Constitutes an Adequate Repetitive Stimulation Examination? | |
Needle Electromyography | p. 46 |
The Properties of Motor Unit Potentials | |
MUP Changes Observed in Myasthenic Disorders | |
Single-Fiber Electromyography | |
Electrodiagnostic Findings in Specific Myasthenic Disorders | p. 47 |
Autoimmune Myasthenia Gravis | |
Lambert-Eaton Syndrome | |
Botulism | |
Congenital Myasthenic Syndromes | |
The Immunopathogenesis of Myasthenia Gravis | p. 60 |
Introduction | p. 60 |
Immunological Principles | p. 61 |
Basic Properties of B Cells and T Cells | |
The Intrathymic Differentiation of T Cells | |
Tolerance and Autoimmunity | |
Antigen Recognition by B Cells and Antibodies | |
Antigen Recognition by T Cells | |
Cooperation of B Cells and Helper T Cells | |
Myasthenia with Thymic Hyperplasia | p. 70 |
Early Notions on the Role of the Thymus in MG | |
Intrathymic Myoid Cells and AChR | |
Key Tenets of "Intrathymic Pathogenesis" | |
Intrathymic Antigen Presentation | |
Thymic Autoantibody Production | |
Intrathymic Germinal Centers and B Cells | |
Human MG Thymus Grafted into SCID Mice | |
Two-Step Model of Intrathymic Autosensitization | |
"Promiscuous" Expression of Autoantigens by Medullary Thymic Epithelial Cells | |
Role of Regulatory T Cells (Treg) | |
Possible -Role of Viruses | |
Myasthenia Gravis with Thymoma | p. 74 |
Epidemiology | |
Classification of Thymomas | |
Thymoma Features Associated with MG | |
Autoantibodies in Thymoma-Associated MG | |
Pathogenesis of Thymoma-Associated MG | |
Models of Tolerance Breakdown in TAMG | |
B Cell Responses In Myasthenia Gravis | p. 78 |
General Features of Anti-AChR Antibodies | |
Epitopes Recognized by Anti-AChR Antibodies | |
Anti-Striational Antibodies | |
"MuSK-positive" and "Seronegative" Myasthenia | |
T Cell Responses in Myasthenia Gravis | p. 81 |
AChR-Specific T Cells | |
Antigenic Epitopes Recognized by AChR-Specific T Cells | |
Cooperation Between B Cells and T Cells In MG | p. 82 |
Pathogenic Effects of the Anti-Achr Antibodies | p. 83 |
Summary | p. 84 |
Natural History of Myasthenia Gravis | p. 90 |
The History and "Natural" History of Myasthenia Gravis | p. 90 |
Epidemiology | p. 92 |
Onset | p. 92 |
Ocular Myasthenia | p. 93 |
Generalized Myasthenia Gravis | p. 94 |
Time Between Onset and Generalized Manifestations | |
Signs and Symptoms | |
Exacerbation | |
Remission | |
Course | |
Mortality | |
Specific Clinical Situations | p. 99 |
MuSK-Myasdienia Gravis | |
Pregnancy | |
Neonatal Myasthenia Gravis | |
Age-Related Issues for Myasthenia Gravis | p. 100 |
Familial Incidence of Myasthenia Gravis | p. 101 |
Disorders Associated with Myasthenia Gravis | p. 101 |
Thymoma | |
Thyroid Disorders | |
Odier Autoimmune Diseases | |
Summary | p. 102 |
The Diagnosis of Myasthenia Gravis and Other | |
Disorders of Neuromuscular Transmission | p. 108 |
Introduction and Historical Background | p. 108 |
Clinical Presentation | p. 109 |
Myasthenia Gravis | |
MG Caused by Antibodies to Muscle-Specific Protein Kinase (MuSK-MG) | |
Physical Findings | p. 111 |
Myasthenia Gravis | |
MuSK-MG | |
Differential Diagnosis | p. 113 |
Differential Diagnosis of Ptosis | |
Differential Diagnosis of Diplopia | |
Differential Diagnosis of Dysarthria and Dysphagia | |
Differential Diagnosis of Isolated Respiratory Muscle Weakness | |
Differential Diagnosis of Fatigue | |
Differential Diagnosis of Mimicking Disorders | |
Diagnostic Studies for Myasthenia Gravis | p. 116 |
Edrophonium Test | |
Antibody Tests | |
Electrodiagnostic Testing | |
Ocular Cooling (Ice-Pack Test) | |
Comparison of Diagnostic Techniques | |
Other Diagnostic Tests | |
6. Therapy of Myasthenia Gravis | p. 130 |
Introduction | p. 130 |
Pathogensis of MG | p. 130 |
Immune Pathogenesis of MG | |
Origin of MG | p. 131 |
Treatment of MG | p. 132 |
Prehminaries | |
Treatment Strategies | |
Treating MG in Special Situations | p. 145 |
Ocular Myasthenia | |
Management of Associated Conditions Co-morbidities | |
Drug Interactions | |
Pregnancy and Neonatal MG | |
Myasdienic Crisis | |
Future Prospects for Treatment of MG | p. 148 |
The Paradox of Difficulty in Obtaining Approval of MG Treatments | |
Conclusions | p. 150 |
The Lambert-Eaton Myasthenic Syndrome | p. 156 |
History | p. 156 |
Clinical Features | p. 157 |
Symptoms | |
Physical findings | |
Cancer-Associated Lems (Ca-Lems) | p. 157 |
Non-Cancer Associated or Autoimmune Lems (Nca-Lems) | p. 158 |
Epidemiology | p. 159 |
Pathophysiology and Immunopathology | p. 159 |
Electrodiagnostic Findings | p. 161 |
Repetitive Nerve Stimulation Testing Needle Electromyography (EMG) | |
Single-fiber Electromyography | |
Electromyograpbic Quantitation of severity | |
Serological Testing | p. 165 |
Voltage-gated Calcium Channel Antibodies | |
SOX1 Antibodies | |
Other Tests | p. 166 |
Differential Diagnosis | p. 166 |
MG/LEMS Overlap | p. 167 |
Treatment | p. 167 |
Cancer | |
Symptomatic Treatment | |
Immunotherapy | |
Agents That May Worsen Lems | p. 168 |
Prognosis | p. 169 |
Summary | p. 169 |
Congenital Myasthenic Syndromes | p. 173 |
A Brief History of the Congenital Myasthenic Syndromes | p. 173 |
Mechanisms Compromising the Safety Margin of Neuromuscular Transmission | p. 174 |
The Classification of Congenital Myasthenic Syndromes | p. 174 |
The Investigation of Congenital Myasthenic Syndromes | p. 174 |
Clinical Observations | |
Morphology 125I-¿-bgt Binding Sites per Endplate | |
In Vitro Electrophysiology Studies | |
Molecular Genetic Studies | |
Presynaptic CMS | p. 181 |
CMS Caused by Defects in Choline Acetyltransferase (ChAT) | |
Paucity of Synaptic Vesicles and Reduced Quantal Release | |
Congenital Myasdienic Syndrome Resembling the Lambert-Eaton Syndrome | |
Synaptic Basal-Lamina-Associated CMS | p. 186 |
Endplate Acetylcholinesterase Deficiency | |
Defects in ß2-Laminin | |
Postsynaptic CMS Caused by Mutations in Achr | p. 194 |
Slow-Channel Syndromes | |
Fast-Channel Syndromes | |
AChR Deficiency Caused by Recessive | |
Mutations in AChR Subunits | |
Escobar Syndrome | |
CMS Caused by Defects in Rapsyn | p. 206 |
Defects in Mechanisms Governing Endplate Development and Maintenance | p. 210 |
CMS Caused by Defects in Agrin | |
CMS Caused by Defects in MuSK | |
CMS Caused by Defects in Dok-7 | |
CMS Caused by Defects in die Hexosamine Biosynthetic Pathway | |
Miscellaneous Rare Congenital Myasthenic Syndromes | p. 214 |
Sodium-Channel Myasdienia | |
CMS Caused by Plectin Deficiency | |
CMS Associated widi Centronuclear Myopatliy (CNM) | |
Endplate Acetylcholine Receptor, A Target for Myasthenic Disorders: Structural and Mechanistic Essentials | p. 231 |
Introduction | p. 231 |
AChR Structure | p. 231 |
AChR Structure at die Atomic Scale | |
Pore Domain | |
Ligand-binding Domain | |
Interface Between Ligand-binding and Pore Domains | |
Mechanism of AChR Activation | p. 238 |
Intermediate State Between Closed and Open States | |
Links Between Agonist Binding and Channel Opening | |
AChR Disease Mechanisms | p. 243 |
Slow-channel CMS | |
Fast-channel CMS | |
Perspective | p. 248 |
10. Peripheral Nerve Hyperexcitability Syndromes | p. 252 |
Background | p. 252 |
Clinical and Electrodiagnostic Features of Hyperexcitability Syndromes | p. 253 |
Pathophysiology | p. 255 |
Hyperexcitability of die Motor Nerve Terminal | |
Hyperexcitability of Neuromuscular Junction | |
Inherited Myokymia (Potassium-Channel Mutations) | p. 257 |
Autoimmune PNH | p. 257 |
Neuromyotonia (Isaacs Syndrome) | |
Morvan Syndrome | |
Cramp-fasciculation | |
Syndrome | |
Antibodies against Voltage-gated Potassium Channel Complex Proteins | |
Other Antibodies | |
PNH Secondary to Toxins | p. 260 |
Hyperexcitability due to Peripheral Nerve Disorders | p. 261 |
Other Peripheral Hyperexcitability Syndromes | p. 261 |
Treatment Options for Hyperexcitability Syndromes | p. 262 |
Summary | p. 262 |
Effects of Anti-Ganglioside Antibodies at the Neuromuscular Junction | p. 265 |
Neuronal Gangliosides | p. 265 |
Structure and Synthesis | |
Localization | |
Physiological Functions | |
Peripehral Nerve Disorders Associated With Anti-Ganglioside Antibodies | p. 267 |
Experimental Evidence for Anti-Ganglioside Antibody-Mediated Attack of NMJs | p. 269 |
Clinical Evidence for Nmj Synaptopathy in Anti-Ganglioside Antibody-Mediated Human Neuropathy | p. 271 |
Comparing Clinical and Experimental Electrophysiological Findings | p. 272 |
Therapeutic Considerations | p. 273 |
Index | p. 279 |
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