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Abstract
Multiple sclerosis has rapidly changed over the last decade into a condition necessitating a multi-disciplinary approach to both its management and understanding. This book reflects all these advances including contributions from genetics, immunology and molecular biology. The many new drugs, both approved or in advanced stages of clinical trials, which give cause for optimism for the treatment of the disease, are described. This new comprehensive work has both editors and contributors that bring together basic science researchers and clinicians from Europe and the USA.
- A comprehensive reference on multiple sclerosis covering diagnosis, treatment and scientific background.
- Coverage of emergent drugs which are not in other books, eg Antegrin, as well as current frontline drugs.
- International group of contributors which includes leading researchers in the field from USA, Switzerland, France, UK and Germany.
- Based on cutting edge research but stresses the practical issues of diagnosis and treatment needed by neurologists.
- Comprehensive coverage of primary treatment of the disease process itself and symptomatic therapies, sexual and bladder dysfunction and rehabilitation.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front cover | Cover | ||
| Multiple Sclerosis: A Comprehensive Text | iii | ||
| Copyright page | iv | ||
| Preface | v | ||
| Contributors | vii | ||
| Table of contents | xi | ||
| SECTION 1: MULTIPLE SCLEROSIS: HISTORY AND CLINICAL MANIFESTATIONS | 1 | ||
| CHAPTER 1: History of multiple sclerosis | 1 | ||
| INTRODUCTION | 1 | ||
| EARLY CASE HISTORIES | 1 | ||
| FIRST DESCRIPTIONS OF MULTIPLE SCLEROSIS | 2 | ||
| ETIOLOGICAL THEORIES | 6 | ||
| REFERENCES | 9 | ||
| CHAPTER 2: Clinical features in multiple sclerosis | 10 | ||
| INTRODUCTION | 10 | ||
| CLINICAL COURSE OF MULTIPLE SCLEROSIS | 10 | ||
| SENSORY SYMPTOMS | 12 | ||
| MOTOR SYMPTOMS | 12 | ||
| SPASTICITY | 12 | ||
| BLADDER AND SEXUAL FUNCTION | 13 | ||
| FATIGUE | 14 | ||
| BOWEL SYMPTOMS | 14 | ||
| OPTIC NEURITIS | 14 | ||
| DYSARTHRIA | 15 | ||
| TREMORS AND OTHER MOVEMENT DISORDERS | 15 | ||
| PAIN | 15 | ||
| LHERMITTE’S PHENOMENON | 16 | ||
| VISUAL SIGNS AND SYMPTOMS | 16 | ||
| PSYCHIATRIC SYMPTOMS – DEPRESSION | 17 | ||
| SLEEP | 17 | ||
| PAROXYSMAL SYMPTOMS | 17 | ||
| DYSPHAGIA | 18 | ||
| VERTIGO | 18 | ||
| HEARING LOSS | 18 | ||
| EPILEPSY | 18 | ||
| RESPIRATORY SYMPTOMS | 18 | ||
| AUTONOMIC SYMPTOMS | 18 | ||
| SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE | 19 | ||
| CONCLUSION | 19 | ||
| REFERENCES | 19 | ||
| CHAPTER 3: Unusual presentations and variants of idiopathic central nervous system demyelinating diseases | 24 | ||
| OVERVIEW AND NOSOLOGY | 24 | ||
| MONOPHASIC FOCAL CEREBRAL EVENTS: ‘TUMEFACTIVE’ DEMYELINATING LESIONS | 24 | ||
| MONOPHASIC MULTIFOCAL/DISSEMINATED DISORDERS | 25 | ||
| TOPOGRAPHICALLY-RESTRICTED IDIOPATHIC INFLAMMATORY DEMYELINATING DISEASES: THE NEUROMYELITIS OPTICA SPECTRUM | 32 | ||
| CONCLUSION | 37 | ||
| REFERENCES | 38 | ||
| CHAPTER 4: Pediatric multiple sclerosis | 43 | ||
| INTRODUCTION | 43 | ||
| CLINICAL FEATURES OF ACUTE DEMYELINATION | 43 | ||
| DIAGNOSIS OF MULTIPLE SCLEROSIS IN CHILDREN | 44 | ||
| CHARACTERISTICS OF MULTIPLE SCLEROSIS IN CHILDREN | 46 | ||
| DIFFERENTIAL DIAGNOSES | 48 | ||
| MANAGEMENT | 49 | ||
| STUDIES OF MULTIPLE SCLEROSIS PATHOBIOLOGY IN CHILDREN | 51 | ||
| FUTURE DIRECTIONS | 51 | ||
| ACKNOWLEDGMENT | 51 | ||
| REFERENCES | 52 | ||
| CHAPTER 5: Diagnosis of multiple sclerosis | 55 | ||
| INTRODUCTION | 55 | ||
| BACKGROUND | 55 | ||
| POSITIONING OF THE McDONALD CRITERIA | 56 | ||
| DISSEMINATION IN SPACE | 57 | ||
| DISSEMINATION IN TIME | 57 | ||
| CEREBROSPINAL FLUID | 58 | ||
| IMPLEMENTATION | 58 | ||
| THE 2005 REVISION OF THE McDONALD CRITERIA | 59 | ||
| ELIMINATION OF ALTERNATIVE CONDITIONS | 60 | ||
| CONCLUSION | 66 | ||
| REFERENCES | 67 | ||
| CHAPTER 6: Neuroimaging in multiple sclerosis | 69 | ||
| INTRODUCTION | 69 | ||
| NEUROIMAGING TECHNIQUES | 69 | ||
| DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS | 72 | ||
| MAGNETIC RESONANCE IMAGING AND LONG-TERM PROGNOSIS | 74 | ||
| MAGNETIC RESONANCE IMAGING, PATHOLOGY AND CLINICAL EFFECTS | 75 | ||
| MONITORING TREATMENT | 79 | ||
| MAGNETIC RESONANCE IMAGING IN MANAGEMENT OF INDIVIDUAL PATIENTS | 82 | ||
| REFERENCES | 82 | ||
| CHAPTER 7: Cerebrospinal fluid analysis in multiple sclerosis | 88 | ||
| INTRODUCTION | 88 | ||
| BRIEF HISTORY OF CEREBROSPINAL FLUID ANALYSIS IN RELATION TO MULTIPLE SCLEROSIS | 89 | ||
| DIAGNOSTIC TESTING | 90 | ||
| PATHOGENETIC STUDIES AND MONITORING DISEASE PROCESSES | 94 | ||
| DEFINING PROGNOSIS | 94 | ||
| MONITORING EFFECTS OF THERAPEUTIC INTERVENTIONS | 96 | ||
| CONCLUSIONS | 97 | ||
| REFERENCES | 97 | ||
| CHAPTER 8: Natural history of multiple sclerosis | 100 | ||
| INTRODUCTION | 100 | ||
| FORESHADOWING SYMPTOMS AND SUBCLINICAL DYSFUNCTION BEFORE THE FIRST EPISODE OF UNEQUIVOCAL SYMPTOMS | 100 | ||
| PREMONITORY SYMPTOMS AS PART OF THE GENERAL MULTIPLE SCLEROSIS SYMPTOMATOLOGY | 101 | ||
| THE FIRST UNAMBIGUOUS MULTIPLE SCLEROSIS SYMPTOMS: THE ‘CLINICALLY ISOLATED SYNDROME’ OR INSIDIOUS PROGRESSION | 101 | ||
| THE SECOND ATTACK IN RELAPSING–REMITTING MULTIPLE SCLEROSIS | 102 | ||
| THE PHASE OF RELAPSING–REMITTING MULTIPLE SCLEROSIS | 104 | ||
| PSEUDORELAPSES | 104 | ||
| EVOLUTION OF COGNITIVE SYMPTOMS AND FATIGUE | 105 | ||
| PAIN AND PAROXYSMAL SYMPTOMS AND THE COURSE OF MULTIPLE SCLEROSIS | 105 | ||
| STATE AT THE ONSET OF SECONDARY PROGRESSION | 105 | ||
| TIME TO THE ONSET OF PROGRESSION | 105 | ||
| THE COURSE OF SECONDARY PROGRESSION | 106 | ||
| SUPERIMPOSED RELAPSES | 106 | ||
| PRIMARY PROGRESSIVE AND PROGRESSIVE–RELAPSING COURSE | 107 | ||
| MEDIAN TIME TO A DEFINED DISABILITY SCORE IN PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS | 107 | ||
| MEDIAN TIME FROM ONSET TO A DEFINED DISABILITY SCORE IN ATTACK ONSET AND SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS | 107 | ||
| THE CLUSTER OF PREDICTORS IN THE RELAPSING–REMITTING COURSE | 108 | ||
| HOW WELL DOES THE CURRENT IMPAIRMENT LEVEL PREDICT SUBSEQUENT IMPAIRMENT LEVELS? | 110 | ||
| LIMITATION OF PREDICTORS TO THE CURRENT PHASE | 111 | ||
| ONE EXTREME OF THE COURSE: THE ISSUE OF ‘BENIGN’ CASES | 112 | ||
| THE SKEWED SPECTRUM OF RISK | 112 | ||
| THE ISSUE OF ‘MARBURG MULTIPLE SCLEROSIS’ | 112 | ||
| DISABILITY AS A FUNCTION OF AGE: THE HAZARD FUNCTION FOR TRANSITION TO PROGRESSION | 113 | ||
| RELATIVE CONTRIBUTION FROM RELAPSES VERSUS PROGRESSION TO THE ULTIMATE DEFICIT | 113 | ||
| MORTALITY | 114 | ||
| PREGNANCY AND THE COURSE OF MULTIPLE SCLEROSIS | 114 | ||
| INFECTIONS AND THE COURSE OF MULTIPLE SCLEROSIS | 114 | ||
| GENETIC INFLUENCE ON THE COURSE OF MULTIPLE SCLEROSIS | 115 | ||
| THE DESIGN OF NATURAL COURSE STUDIES: LIMITING VARIABILITY IN THE FLOW OF PATIENTS | 115 | ||
| NATURAL HISTORY STUDIES AND FUTURE TRIALS | 116 | ||
| BIOLOGY OF NATURAL HISTORY KEY FEATURES | 117 | ||
| REFERENCES | 117 | ||
| CHAPTER 9: Epidemiology of multiple sclerosis | 121 | ||
| EPIDEMIOLOGY AND MEASURES OF OCCURRENCE | 121 | ||
| THE DEFINITION OF A CASE AND DIAGNOSTIC CRITERIA | 121 | ||
| METHODS OF ASCERTAINMENT | 122 | ||
| REGISTRIES | 122 | ||
| THE GEOGRAPHY OF MULTIPLE SCLEROSIS | 123 | ||
| AGE | 130 | ||
| GENDER | 130 | ||
| RACE | 131 | ||
| SURVIVAL | 131 | ||
| THE MULTIPLE SCLEROSIS LATENCY PERIOD | 132 | ||
| MIGRATION STUDIES | 132 | ||
| CLUSTER STUDIES | 133 | ||
| EPIDEMICS | 133 | ||
| GENETIC EPIDEMIOLOGY | 133 | ||
| ENVIRONMENTAL RISK FACTORS | 135 | ||
| CONCLUSIONS | 136 | ||
| REFERENCES | 136 | ||
| CHAPTER 10: Neurophysiological studies in multiple sclerosis | 141 | ||
| INTRODUCTION | 141 | ||
| SENSORY EVOKED POTENTIALS: TECHNICAL AND STATISTICAL ASPECTS OF TESTING AND INTERPRETATION | 141 | ||
| VISUAL EVOKED POTENTIALS | 142 | ||
| OTHER NEUROPHYSIOLOGICAL MEASUREMENTS OF VISUAL PATHWAY: ELECTRORETINOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY | 143 | ||
| BRAINSTEM AUDITORY EVOKED POTENTIALS | 143 | ||
| OTHER MEASUREMENTS OF BRAINSTEM\rFUNCTION: ELECTRONYSTAGMOGRAPHY\rAND BLINK REFLEX | 144 | ||
| SOMATOSENSORY EVOKED POTENTIALS | 144 | ||
| MOTOR EVOKED POTENTIALS | 145 | ||
| PRACTICAL CONSIDERATIONS | 146 | ||
| REFERENCES | 147 | ||
| SECTION 2: MULTIPLE SCLEROSIS: PATHOPHYSIOLOGY AND BIOLOGY | 151 | ||
| CHAPTER 11: The neuropathology of multiple sclerosis | 151 | ||
| INTRODUCTION | 151 | ||
| HISTORY OF MULTIPLE SCLEROSIS PATHOLOGY | 152 | ||
| DEMYELINATING DISEASE | 152 | ||
| ANIMAL MODELS AND/OR OTHER HUMAN CONDITIONS IN UNDERSTANDING THE DEVELOPMENT OF MULTIPLE SCLEROSIS | 152 | ||
| STAGING AND DEFINITION OF LESION PATHOLOGY | 153 | ||
| THE MORPHOLOGY OF THE MULTIPLE SCLEROSIS LESION | 153 | ||
| THE INFLAMMATORY RESPONSE IN MEDIATING DISEASE AND REGENERATION | 163 | ||
| THE PATHOGENESIS OF DEMYELINATION IN MULTIPLE SCLEROSIS | 164 | ||
| AXONAL DAMAGE IN MULTIPLE SCLEROSIS | 166 | ||
| PATHOLOGY OF CORTEX AND GRAY MATTER | 167 | ||
| PATHOLOGY OF NORMAL APPEARING WHITE MATTER | 167 | ||
| REMYELINATION AND SHADOW PLAQUES | 168 | ||
| BALO’S CONCENTRIC SCLEROSIS | 169 | ||
| NEUROMYELITIS OPTICA | 171 | ||
| DIFFUSE MULTIPLE SCLEROSIS OR SCHILDER’S DISEASE | 171 | ||
| ACUTE DISSEMINATED ENCEPHALOMYELITIS | 172 | ||
| GLIOSIS | 172 | ||
| PATHOLOGY–IMAGING CORRELATES | 173 | ||
| CONCLUSIONS | 173 | ||
| ACKNOWLEDGMENTS | 173 | ||
| REFERENCES | 173 | ||
| CHAPTER 12: Neurophysiology of demyelination | 178 | ||
| INTRODUCTION | 178 | ||
| THE MYELINATED AXON | 178 | ||
| IONIC CHANNEL ORGANIZATION OF NORMAL MYELINATED AXONS: HETEROGENEOUS DISTRIBUTION OF SODIUM AND POTASSIUM CHANNELS | 179 | ||
| ELECTRICAL BASIS FOR CONDUCTION SLOWING AND BLOCK IN DEMYELINATED AXONS | 180 | ||
| CONDUCTION ABNORMALITIES IN DEMYELINATED AXONS | 181 | ||
| EXPERIMENTAL STRATEGIES TO IMPROVE CONDUCTION IN DEMYELINATED AXONS | 181 | ||
| MOLECULAR REORGANIZATION OF ION\rCHANNELS ON SPINAL AXONS\rREMYELINATED BY TRANSPLANTED\rCELLS | 186 | ||
| CONCLUSIONS | 187 | ||
| REFERENCES | 189 | ||
| CHAPTER 13: Immunology of multiple sclerosis | 192 | ||
| INTRODUCTION | 192 | ||
| STEP 1: ACTIVATION OF AUTOREACTIVE CD4+ T CELLS IN THE PERIPHERY | 192 | ||
| STEP 2: MIGRATION THROUGH THE BLOOD–BRAIN BARRIER AND FORMATION OF THE INFLAMMATORY LESION | 197 | ||
| STEP 3: DAMAGE WITHIN THE CENTRAL NERVOUS SYSTEM | 202 | ||
| CONCLUSIONS | 206 | ||
| REFERENCES | 206 | ||
| CHAPTER 14: Genetics of multiple sclerosis | 214 | ||
| MULTIPLE SCLEROSIS AS A GENETIC DISEASE | 214 | ||
| MULTIPLE SCLEROSIS GENOMICS | 214 | ||
| GENETIC HETEROGENEITY IN MULTIPLE SCLEROSIS | 217 | ||
| SUSCEPTIBILITY GENES VERSUS MODIFIERS | 219 | ||
| GENES AND ENVIRONMENTAL FACTORS | 219 | ||
| GENETICS IN ANIMAL MODELS OF MULTIPLE SCLEROSIS | 219 | ||
| GENETIC VARIATION AND THE CLINICAL RESPONSE TO THERAPY IN MULTIPLE SCLEROSIS | 221 | ||
| CONCLUSIONS | 222 | ||
| ACKNOWLEDGMENTS | 222 | ||
| REFERENCES | 222 | ||
| CHAPTER 15: Infectious agents and multiple sclerosis | 226 | ||
| INTRODUCTION | 226 | ||
| PATHOLOGY OF MULTIPLE SCLEROSIS | 226 | ||
| THE CAUSE OF MULTIPLE SCLEROSIS IS UNKNOWN | 226 | ||
| INFECTION AS A CAUSE OF CHRONIC NEUROLOGICAL DISEASE | 226 | ||
| RATIONALE FOR AN INFECTIOUS ETIOLOGY OF MULTIPLE SCLEROSIS | 227 | ||
| ASSOCIATION OF DEMYELINATING DISEASE IN HUMANS AND ANIMALS WITH VIRUS INFECTION | 228 | ||
| IMMUNIZATION AND MULTIPLE SCLEROSIS | 230 | ||
| THE SEARCH FOR AN INFECTIOUS AGENT IN MULTIPLE SCLEROSIS BRAIN CELLS | 230 | ||
| ASSOCIATION OF VARIOUS MICROORGANISMS WITH MULTIPLE SCLEROSIS | 230 | ||
| ANTIGEN IDENTIFICATION IN MULTIPLE SCLEROSIS | 232 | ||
| CONCLUSION | 233 | ||
| ACKNOWLEDGMENTS | 233 | ||
| REFERENCES | 233 | ||
| CHAPTER 16: Models of chronic relapsing experimental autoimmune encephalomyelitis | 237 | ||
| INTRODUCTION | 237 | ||
| THE NEED FOR AN IMMUNOLOGICAL MODEL FOR MULTIPLE SCLEROSIS | 237 | ||
| EARLY CHRONIC MODELS | 238 | ||
| MOUSE MODELS | 238 | ||
| LATER CHRONIC MODELS IN MOUSE | 239 | ||
| LESION TOPOGRAPHY IN COMPARISON TO MULTIPLE SCLEROSIS | 239 | ||
| THE AXON IN THE ESTABLISHED LESION OF CHRONIC EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS | 240 | ||
| THE ACTIVE PLAQUE IN CHRONIC EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS | 240 | ||
| THE PATTERN OF MYELIN BREAKDOWN | 242 | ||
| MECHANISMS RELATED TO RECURRENCE OF DISEASE | 243 | ||
| MARMOSET MODEL OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS | 246 | ||
| PRIMARY DEMYELINATING FORMS OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN CALLITHRIX JACCHUS | 246 | ||
| THE DIFFERENT EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS PHENOTYPES IN CALLITHRIX JACCHUS | 247 | ||
| EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS INDUCED WITH OTHER MYELIN AUTOANTIGENS | 249 | ||
| IMMUNE REPERTOIRES AGAINST MYELIN PROTEINS IN CALLITHRIX JACCHUS | 251 | ||
| REMYELINATION IN CHRONIC EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS | 251 | ||
| THERAPEUTIC APPLICATIONS OF THE MODELS TO MULTIPLE SCLEROSIS | 252 | ||
| CONCLUSIONS AND FUTURE PERSPECTIVES | 254 | ||
| ACKNOWLEDGMENTS | 256 | ||
| REFERENCES | 256 | ||
| CHAPTER 17: Genetic manipulations of experimental autoimmune encephalomyelitis in the mouse | 261 | ||
| INTRODUCTION | 261 | ||
| EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IS A T-HELPER-1 DISEASE REGULATED BY COMPLEX CYTOKINE NETWORKS | 261 | ||
| EPITOPE SPREADING IS DRIVEN BY ANTIGEN PRESENTATION WITHIN THE CENTRAL NERVOUS SYSTEM | 263 | ||
| COSTIMULATOR LIGANDS ON ANTIGEN-PRESENTING CELLS CONTROL INFLAMMATION IN THE CENTRAL NERVOUS SYSTEM | 264 | ||
| INTERFERON-g IS A KEY REGULATORY T-HELPER-1 CYTOKINE | 264 | ||
| INNATE CENTRAL NERVOUS SYSTEM IMMUNITY IS CRITICAL FOR EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS | 266 | ||
| T-CELL APOPTOSIS IS A NATURAL REGULATOR OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS | 268 | ||
| CHEMOKINES AND ADHESION MOLECULES DRIVE IMMUNE CELL ENTRY TO THE CENTRAL NERVOUS SYSTEM | 268 | ||
| SUMMARY AND CONCLUSIONS | 269 | ||
| REFERENCES | 270 | ||
| CHAPTER 18: Biology of myelin | 274 | ||
| INTRODUCTION | 274 | ||
| THE BIOCHEMICAL COMPOSITION OF MYELIN | 275 | ||
| ORIGIN OF OLIGODENDROCYTES | 276 | ||
| MULTIPLE ORIGINS OF OLIGODENDROCYTES | 277 | ||
| FACTORS CONTROLLING OLIGODENDROCYTE DEVELOPMENT | 277 | ||
| MIGRATION OF OLIGODENDROCYTES | 277 | ||
| PROGRESSION IN THE OLIGODENDROCYTE LINEAGE | 278 | ||
| SIGNALS AND MECHANISMS OF MYELINATION | 279 | ||
| CONCLUDING REMARKS | 282 | ||
| ACKNOWLEDGMENTS | 282 | ||
| REFERENCES | 282 | ||
| CHAPTER 19: New tools for investigating the immunopathogenesis of multiple sclerosis: principles and applications | 286 | ||
| INTRODUCTION | 286 | ||
| CHARACTERIZATION OF AUTOREACTIVE T AND B CELLS IN CENTRAL NERVOUS SYSTEM TISSUES | 286 | ||
| ‘UNBIASED’ APPROACHES FOR TRANSCRIPTIONAL PROFILING: APPLICATION TO MULTIPLE SCLEROSIS | 292 | ||
| PROTEOMICS TECHNIQUES AS NEW TOOLS FOR MULTIPLE SCLEROSIS RESEARCH | 296 | ||
| CONCLUDING REMARKS | 298 | ||
| ACKNOWLEDGMENTS | 298 | ||
| REFERENCES | 298 | ||
| SECTION 3: MULTIPLE SCLEROSIS: TREATMENT AND PROSPECTS | 303 | ||
| CHAPTER 20: Immunomodulatory therapy: critical appraisal of trial results and marketing claims | 303 | ||
| INTRODUCTION AND BACKGROUND | 303 | ||
| PUBLISHED LARGE-SCALE TRIALS | 303 | ||
| CLINICALLY ISOLATED SYNDROMES | 305 | ||
| RELAPSING–REMITTING MULTIPLE SCLEROSIS | 306 | ||
| SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS | 308 | ||
| PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS | 310 | ||
| ADVERSE EFFECTS OF IMMUNOMODULATORY AGENTS | 310 | ||
| PERCEPTIONS OF EFFICACY | 311 | ||
| FUTURE STRATEGIES | 311 | ||
| REFERENCES | 312 | ||
| CHAPTER 21: Treatment of multiple sclerosis with disease-modifying therapies | 315 | ||
| INTRODUCTION | 315 | ||
| DISEASE-MODIFYING THERAPY IN MULTIPLE SCLEROSIS (APPROVED AGENTS) | 316 | ||
| DISEASE-MODIFYING THERAPY IN MULTIPLE SCLEROSIS (NONAPPROVED AGENTS) | 322 | ||
| DISEASE-MODIFYING THERAPY IN MULTIPLE SCLEROSIS (CURRENTLY UNDER INVESTIGATION IN PHASE II OR III TRIALS) | 326 | ||
| CONCLUSION | 328 | ||
| REFERENCES | 329 | ||
| CHAPTER 22: Escape therapies and management of multiple sclerosis | 333 | ||
| INTRODUCTION | 333 | ||
| TREATMENT FAILURE | 333 | ||
| MITOXANTRONE | 335 | ||
| AZATHIOPRINE | 337 | ||
| CYCLOPHOSPHAMIDE | 337 | ||
| MYCOPHENOLATE MOFETIL | 339 | ||
| METHOTREXATE | 340 | ||
| CLADRIBINE | 341 | ||
| STEROIDS | 341 | ||
| INTRAVENOUS IMMUNOGLOBULIN | 342 | ||
| PLASMA EXCHANGE | 343 | ||
| TACROLIMUS | 343 | ||
| CICLOSPORIN | 343 | ||
| SULFASALAZINE | 344 | ||
| ALEMTUZUMAB | 344 | ||
| RITUXIMAB | 345 | ||
| DACLIZUMAB | 345 | ||
| BONE MARROW TRANSPLANTATION | 346 | ||
| WHAT TO DO IF THE PATIENT DOES NOT RESPOND TO STANDARD THERAPY: A SYSTEMATIC APPROACH | 346 | ||
| REFERENCES | 347 | ||
| CHAPTER 23: Novel and promising therapeutic strategies in multiple sclerosis | 353 | ||
| INTRODUCTION | 353 | ||
| CURRENT THERAPY | 353 | ||
| IMMUNOSUPPRESSIVE/ANTIPROLIFERATIVE AGENTS | 354 | ||
| IMMUNOBIOLOGICALS/MISCELLANEOUS | 355 | ||
| ANTI-B-CELL THERAPIES | 356 | ||
| BONE MARROW/HEMATOPOIETIC STEM CELL TRANSPLANTATION | 356 | ||
| SELECTED INNOVATIVE THERAPIES | 357 | ||
| A VIEW TO THE FUTURE | 362 | ||
| REFERENCES | 362 | ||
| CHAPTER 24: Moving towards remyelinating and neuroprotective therapies in multiple sclerosis | 366 | ||
| INTRODUCTION | 366 | ||
| RATIONAL AND SCIENTIFIC BACKGROUND TO REMYELINATION AND NEUROPROTECTION IN MULTIPLE SCLEROSIS | 366 | ||
| NEUROPROTECTION | 367 | ||
| PROMOTING AXON REGROWTH | 370 | ||
| REMYELINATION | 370 | ||
| GENE THERAPY AND MULTIPLE SCLEROSIS | 375 | ||
| REMAINING HURDLES | 375 | ||
| HOW CLOSE ARE THESE THERAPIES AND HOW SHOULD THEY BE USED? | 376 | ||
| REFERENCES | 377 | ||
| CHAPTER 25: Symptomatic therapies for multiple sclerosis | 383 | ||
| INTRODUCTION | 383 | ||
| FATIGUE | 383 | ||
| SPASTICITY | 385 | ||
| PAROXYSMAL SPASMS (SYMPTOMS) | 386 | ||
| TREMOR/ATAXIA/DIZZINESS/VERTIGO | 386 | ||
| BLADDER | 387 | ||
| BOWEL | 387 | ||
| SEXUALITY | 387 | ||
| DEPRESSION | 387 | ||
| PAIN | 388 | ||
| COGNITION | 388 | ||
| WEAKNESS | 388 | ||
| SWALLOWING | 388 | ||
| SIDE EFFECTS OF INJECTABLES | 388 | ||
| REFERENCES | 389 | ||
| CHAPTER 26: Bladder and sexual dysfunction in multiple sclerosis | 391 | ||
| INTRODUCTION | 391 | ||
| NEURAL CONTROL OF THE BLADDER | 391 | ||
| MANAGEMENT OF BLADDER SYMPTOMS IN MULTIPLE SCLEROSIS | 391 | ||
| SEXUAL DYSFUNCTION IN MULTIPLE SCLEROSIS | 396 | ||
| REFERENCES | 399 | ||
| CHAPTER 27: Neuropsychological aspects of multiple sclerosis | 401 | ||
| INTRODUCTION | 401 | ||
| COGNITION IN MULTIPLE SCLEROSIS | 401 | ||
| INDIVIDUAL DIFFERENCES IN COGNITION IN MULTIPLE SCLEROSIS: RELATIONS WITH DEMOGRAPHICS, DISEASE-RELATED VARIABLES AND NEUROIMAGING | 404 | ||
| ASSESSMENT OF COGNITION IN MULTIPLE SCLEROSIS | 406 | ||
| FUTURE DIRECTIONS | 409 | ||
| REFERENCES | 409 | ||
| CHAPTER 28: Rehabilitation of multiple sclerosis | 413 | ||
| INTRODUCTION | 413 | ||
| PHILOSOPHY AND PRINCIPLES | 413 | ||
| CHALLENGES OF MULTIPLE SCLEROSIS | 416 | ||
| SPECIFIC APPLICATIONS | 417 | ||
| DEVELOPING AND EVALUATING MODELS OF CARE | 421 | ||
| CONCLUSION | 422 | ||
| REFERENCES | 422 | ||
| CHAPTER 29: Design and analysis of clinical trials in multiple sclerosis | 425 | ||
| INTRODUCTION | 425 | ||
| CLINICAL TRIAL NOMENCLATURE | 426 | ||
| ETHICAL CONSIDERATIONS IN CLINICAL RESEARCH | 427 | ||
| FUNDAMENTAL ISSUES RELATING TO THE DESIGN AND CONDUCT OF A CLINICAL TRIAL | 429 | ||
| TRIAL DESIGN | 432 | ||
| ALTERNATIVE TRIAL DESIGNS | 433 | ||
| TRIAL DESIGN FOR STUDIES OF NEUROPROTECTION AND NEUROREPAIR | 436 | ||
| SUMMARY | 436 | ||
| REFERENCES | 436 | ||
| CHAPTER 30: The role of data monitoring committees in multiple sclerosis clinical trials | 438 | ||
| INTRODUCTION | 438 | ||
| WHAT IS THE PURPOSE OF A DATA MONITORING COMMITTEE? | 438 | ||
| THE HISTORY OF DATA MONITORING COMMITTEES | 439 | ||
| COMPOSITION OF A DATA MONITORING COMMITTEE | 439 | ||
| RELATIONS WITH THE SPONSOR AND OTHER TRIAL COMMITTEES | 440 | ||
| DEFINING THE ROLE OF THE DATA MONITORING COMMITTEE IN A CLINICAL TRIAL | 442 | ||
| SETTING THE RESPONSIBILITIES AND OPERATIONS OF THE DATA MONITORING COMMITTEE: CHARTER DEVELOPMENT | 444 | ||
| CONCLUSIONS | 448 | ||
| ACKNOWLEDGMENTS | 448 | ||
| REFERENCES | 448 | ||
| CHAPTER 31: Outcome measures in multiple sclerosis | 449 | ||
| INTRODUCTION | 449 | ||
| WHAT DEFINES OUTCOME MEASURES | 450 | ||
| OUTCOMES FOR MULTIPLE SCLEROSIS | 452 | ||
| OTHER MEASURES OF IMPAIRMENT AND DISABILITY | 455 | ||
| PROMISING NEW OUTCOME MEASURES | 456 | ||
| SUMMARY | 457 | ||
| REFERENCES | 457 | ||
| Index | 459 |