Neuromuscular Junction Disorders: Handbook of Clinical Neurology Vol 91 (Series Editors: Aminoff, Boller and Swaab)

This volume provides concise and comprehensive information on neuromuscular disorders, including rapid advancements in the understanding of the neurobiology of neuromuscular transmission. In addition, clinicians will find timely discussions on the various forms of these disorders that have been discovered due to increased study within the field. New observations into the immunopathogenesis of myasthenia gravis, and the molecular mechanisms underlying the links between activity and patterns of gene expression, particularly in muscle, are also explored, along with novel information on the understanding of the pathophysiology of the heterogeneous group of peripheral nerve hyperexcitability syndromes. Each of these valuable insights, and their accompanying explanations, provides a framework on which new therapeutic strategies can be built to aid in the enhancement and restoration of normal function in neuromuscular junction disorders. \* New insights into the study of neuromuscular junction disorders, including rapid advancements in the field\* Comprehensive information on the neuromuscular junction, and a detailed examination of myasthenia gravis and other disorders\* A new framework upon which to build therapeutic strategies that will enhance the restoration of normal function in neuromuscular disorders Foreword......Page 1 Preface......Page 2 List of contributors......Page 4 History of human botulism......Page 30 Ham, 1897......Page 31 The motor unit......Page 32 Fish and seafood, 1936......Page 33 Wounds, 1951......Page 34 Infants, 1976......Page 35 Other forms of hyperexcitability......Page 202 Serologic tests......Page 36 Early symptomatic treatments for MG, 1900-1954......Page 37 Thymus involvement, from thymoma to thymectomy, 1901-1950......Page 39 Acetylcholine receptor antibodies......Page 262 But why is the MG patient weak? (1934-1972)......Page 42 Lambert-Eaton myasthenic syndrome, 1951-1989......Page 44 Thymectomy......Page 287 References......Page 48 An introduction to neuromuscular transmission......Page 55 Radioimmunoprecipitation of BuTx-AChR......Page 241 Inherited myokymia (potassium channel mutations)......Page 459 The motor neuron......Page 56 Immunopathology......Page 57 Diagnostic procedures......Page 59 Early evidence for quantal release......Page 60 Spatial aspects of quantal release......Page 61 The SNARE complex......Page 137 Frogs......Page 62 Slow channel congenital myasthenic syndrome......Page 65 Evidence for serum antibodies in SNMG......Page 208 Number of release sites and efficiency of release......Page 66 Statistical aspects of quantal release......Page 68 Diffusion of ACh in the cleft......Page 69 Properties of ACh-gated channels......Page 70 Introduction to the cable properties of the muscle fiber......Page 71 The threshold......Page 73 Folds and their electrical effects......Page 74 Safety factor of neuromuscular transmission: definition and measurement......Page 75 Origin of the concept of a safety factor in excitable cells......Page 76 Blocking action potential generation......Page 77 Estimating transmitter release using electrophysiology......Page 78 Estimating quantal content......Page 79 Comparison of reported values of safety factor at rat NMJs......Page 80 The effects of repetitive activity on release......Page 81 Decreases in quantal content......Page 82 Vesicle pools and their dynamics......Page 83 Mitochondria as modulators of quantal release......Page 84 Autocrine effects on release: purinergic......Page 86 NO as a modulator of release......Page 87 Modulation of quantal release by peptides and proteins......Page 88 Conclusions......Page 89 Release mechanism......Page 90 Postsynaptic specializations......Page 91 Matching NMJ size to muscle fiber size......Page 92 Matching of functional properties of NMJs to activity patterns......Page 93 Development of the motor neuron......Page 94 Synapse formation and elimination......Page 95 Molecular maturation of the developing NMJ......Page 97 Changes in the NMJ affecting safety factor during normal aging......Page 99 Structural reinnervation of the muscle......Page 101 Axon sprouting and muscle fiber type conversion......Page 102 Muscle damage......Page 103 Introduction to the toxins......Page 104 Presynaptic toxins that block release......Page 107 Presynaptic toxins that damage the nerve......Page 108 Overview......Page 109 Reduced quantal content of the EPP......Page 110 Conditions influencing transmitter action......Page 111 Inherited AChR deficiency......Page 112 Prolonged ACh action due to AChE deficiency......Page 113 Conditions influencing NMJ size......Page 114 Post-polio syndrome......Page 115 Many levels of organization contribute to the reliability of neuromuscular transmission......Page 117 Different factors may determine reliability in different species and different stages of development......Page 118 References......Page 119 Patterns of motor innervation......Page 130 Current classification and use of OPs......Page 425 The acetylcholine receptor......Page 280 Acetylcholinesterase......Page 131 Mental status......Page 132 The nerve terminal......Page 133 Coated vesicles......Page 134 Dense-core vesicles......Page 135 Diagnosis......Page 282 Movement of synaptic vesicles......Page 136 Priming of the docked synaptic vesicles......Page 138 Previous reports......Page 139 Systemic distribution of BoNT......Page 140 Histopathology......Page 264 References......Page 193 Intracellular mechanisms of BoNT-LCs......Page 142 Morphologic correlates of quantal transmitter release......Page 143 Endocytotic events and the formation of new synaptic vesicles......Page 144 Noncholinesterase mechanisms of neurotoxicity......Page 145 Synaptic laminins......Page 146 Functional significance of the junctional folds......Page 147 The acetylcholine receptor......Page 149 Structure-function correlations......Page 150 Postsynaptic cytoskeletal components......Page 151 AChR synthesis and degradation......Page 153 The structural development of the NMJ......Page 154 Agrin, MuSK, Rapsyn, and Dok-7......Page 156 References......Page 294 Regulation of synapse specific transcription......Page 158 The metabolic stability of NMJ AChR......Page 159 AChE expression at the NMJ......Page 160 Nerve sprouting......Page 161 References......Page 162 Introduction......Page 176 Endplate potentials and the safety margin of NMT......Page 178 Standard motor NCS......Page 179 Foodborne botulism......Page 312 Repetitive stimulation technique......Page 180 Differential diagnosis......Page 182 Concentric and single fiber EMG......Page 183 Autoimmune myasthenia gravis......Page 184 Seronegative autoimmune myasthenia gravis......Page 185 Prognosis......Page 186 Congenital myasthenic syndromes......Page 187 Original description......Page 188 Endplate acetylcholine esterase deficiency......Page 189 Congenital AChR deficiency......Page 192 AChR-specific T-cell lines......Page 211 Clinical findings of OPIDP in man......Page 444 Immunological principles......Page 196 General overview......Page 240 Pattern recognition receptors of the innate immune system......Page 197 Cholinesterase inhibitors as warfare agents......Page 242 The adaptive immune system: T-cell receptor and antigen presentation......Page 198 T-cell-B-cell cooperation......Page 200 Peripheral tolerance, immunoregulatory mechanisms and autoimmunity......Page 204 Experimental evidence for antibodies in SNMG......Page 205 Functional effects of AChR antibodies......Page 206 Properties of AChR antibodies......Page 207 Antibodies in the Lambert-Eaton myasthenic syndrome......Page 210 Regulation of the T-cell response......Page 212 Morphologic features......Page 213 Cellular responses of the innate immune system in MG......Page 214 Immunogenetics of myasthenia gravis......Page 215 Early notions of the role of the thymus in MG......Page 216 AChR structure......Page 324 Severe combined immunodeficiency mice as a model of MG pathogenesis......Page 218 Pathogenesis of MG with thymic lymphofollicular hyperplasia......Page 219 Pathogenesis of thymoma-associated MG......Page 220 Generalized tetanus......Page 406 Acute EAMG......Page 222 Risk factors for myasthenia gravis and association with other immunological diseases......Page 223 References......Page 224 Pathogenicity and characteristics of AChR antibodies......Page 243 Epidemiological studies based on serological studies......Page 244 Antibodies in seronegative MG......Page 246 Characteristics and mechanisms of action of MuSK antibodies......Page 247 Antibodies to AChRs in SNMG......Page 249 References......Page 466 Clinical presentation......Page 255 Physical findings......Page 256 Oropharyngeal and facial muscle examination......Page 257 Course......Page 258 Infant botulism......Page 363 Pathophysiology of MG......Page 259 Quinine and quinidine......Page 398 Diagnosis......Page 260 Iatrogenic botulism......Page 365 Edrophonium (Tensilon) test......Page 261 Azathioprine......Page 263 Recreational drugs......Page 401 Trafficking and internalization of BoNT-LCs into the neuronal cytosol......Page 376 Genetics of MG......Page 265 Thymoma......Page 266 Hypertension......Page 267 Childhood myasthenia gravis......Page 268 Differential diagnosis of childhood myasthenia......Page 269 ``Seronegative ́ ́ MG......Page 270 New immunosuppressive agents......Page 271 Pregnancy in MG......Page 272 Therapeutic strategies......Page 293 Interferon-induced MG......Page 273 References......Page 307 The neuromuscular junction in MG......Page 279 Background......Page 457 Anesthetics, local......Page 281 Bretylium......Page 397 Search for associated conditions......Page 283 Medications that exacerbate LEMS......Page 284 Hormones......Page 285 Adrenal corticosteroids......Page 286 Refractory MG: ``rebooting ́ ́ the immune system with high dose cyclophosphamide......Page 289 Diabetes......Page 290 Pregnancy and neonatal MG......Page 291 Leflunomide......Page 292 Symptoms......Page 299 Pathophysiology......Page 300 Electrodiagnostic tests......Page 302 Voltage-gated calcium channel antibodies......Page 303 Treatment of LEMS......Page 304 MG/LEMS overlap syndrome......Page 306 Events after release of a single ACh quantum......Page 310 Antibiotics......Page 395 Transmitter release by repetitive nerve stimulation......Page 311 Cramp-fasciculation syndrome......Page 314 Clinical features......Page 315 Molecular studies......Page 316 Therapy......Page 317 Severe CMS with reduced quantal release......Page 318 Electrophysiologic features......Page 319 Central effects of botulinum neurotoxins......Page 380 Molecular pathogenesis......Page 321 Diagnosis......Page 322 Mechanisms of receptor activation by ACh......Page 325 Electrophysiologic features......Page 326 Pathogenetic mechanisms......Page 327 Molecular pathogenesis......Page 329 Therapy......Page 330 Fast-channel syndromes......Page 331 Arthropods......Page 332 Fast-channel syndromes due to unstable (mode-switching) kinetics......Page 333 Clinical features......Page 334 Endplate studies......Page 335 Molecular pathogenesis......Page 336 Rapsyn function and structure......Page 337 Clinical features......Page 339 Molecular pathogenesis......Page 340 Clinical features......Page 341 Morphologic features......Page 342 Molecular pathogenesis......Page 343 Diagnosis......Page 344 Clinical features......Page 345 Molecular pathogenesis......Page 346 Relation to other sodium channel disorders......Page 347 Therapy......Page 348 References......Page 349 Introduction......Page 357 Clinical and electromyographic features......Page 358 Carbamates......Page 360 General properties of botulinum neurotoxin......Page 361 Types of botulism......Page 362 Intestinal botulism in adolescents and adults......Page 364 Trimethaphan......Page 366 Diagnosis of botulism......Page 368 Differential diagnosis......Page 370 Pathophysiology of botulism and cellular mechanisms of botulinum neurotoxins......Page 371 Adsorption of botulinum toxin into the lymphatic system......Page 372 Receptors for BoNTs in neuronal cells......Page 374 Synaptic and postsynaptic effects......Page 378 References......Page 381 Pharmacological blockade of neuromuscular transmission......Page 393 Analgesics......Page 394 Anticonvulsants......Page 396 Magnesium......Page 399 Neuromuscular blocking drugs......Page 400 Miscellaneous......Page 402 Botulism......Page 403 Differential diagnosis......Page 404 Pathogenesis......Page 405 Management......Page 407 Spider bites......Page 408 Tick paralysis......Page 409 Snake bites......Page 410 Marine toxins......Page 411 Heavy metals......Page 412 References......Page 413 Use of AChE inhibitors in human medicine......Page 427 Inhibition of cholinesterases by OPs and CMs......Page 428 Reactivation of inhibited cholinesterases by oximes......Page 430 Electrophysiological aspects in peripheral neurotoxicity......Page 431 Electromyography in patients with OP and CM intoxication......Page 432 Clinical presentation......Page 433 Measurement of cholinesterase activity in acutely poisoned patients......Page 435 The necrotizing myopathy......Page 436 Introduction......Page 437 Observations in patients......Page 439 Comparison with other human diseases with impaired neuromuscular transmission......Page 441 Therapeutic considerations......Page 443 Role of OPs and CMs in the Gulf War Syndrome......Page 446 Atropine......Page 447 References......Page 448 PNH secondary to toxins......Page 460 Neuromyotonia (Isaacs syndrome)......Page 461 Morvan syndrome......Page 462 Voltage-gated potassium channel antibodies......Page 463 Hyperexcitability of the motor nerve terminal......Page 464 Summary......Page 465 Index......Page 468 The Most Vulnerable Synapse: Historic Aspects Of Neuromuscular Junction Disorders / John Keesey -- Reliability Of Neuromuscular Transmission And How It Is Maintained / Clarke R. Slater -- The Neuromuscular Junction / Andrew G. Engel -- Electromyographic Aspects Of Neuromuscular Junction Disorders / C. Michel Harper -- The Immunopathogenesis Of Myasthenia Gravis / Norbert Sommer, Bjö̈rn Tackenberg And Reinhard Hohlfeld -- Autoantibodies In Different Forms Of Myasthenia Gravis And In The Lambert-eaton Syndrome / Angela Vincent -- Clinical Features Of Myasthenia Gravis / Donald B. Sanders And Janice M. Massey -- Therapy Of Myasthenia Gravis / Donald B. Drachman -- The Lambert-eaton Myasthenic Syndrome / Donald B. Sanders And Vern C. Juel -- Congenital Myasthenic Syndromes / Andrew G. Engel -- Botulism / Eric A. Johnson And Cesare Montecucco -- Neurotoxicology Of Neuromuscular Transmission / James F. Howard, Jr. And Donald B. Sanders -- Organophosphate And Carbamate Poisoning / Jan L. De Bleecker -- Peripheral Nerve Hyperexcitability And The Neuromuscular Junction / Steven Vermino. Volume Editor, Andrew G. Engel. Includes Bibliographical References And Index.