ISBN: 0-8247-0485-1 This book is printed on acid-free paper Headquarters Marcel Dekker, Inc 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http:/ /www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities For more information, write to Special Sales/Professional Marketing at the headquarters address above Copyright 2001 by Marcel Dekker, Inc All Rights Reserved Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher Current printing (last digit): 10 PRINTED IN THE UNITED STATES OF AMERICA Series Introduction Multiple sclerosis (MS) is a common disease of the central nervous system, affecting young women in particular This disease can devastate the professional and social life of those affected There has been a recent explosion in knowledge about how to diagnose MS and understand its pathophysiological mechanisms as well as provide efficacious treatment The third edition of the Handbook of Multiple Sclerosis has documented the impressive and dramatic advances that have occurred In particular, the immunopathology of the disease is now well established MS at one time was considered an untreatable disease; however, now there are many therapeutic approaches As Dr Cook states, these advances have led to a reduction in disability and a dramatic increase in the quality of life for patients suffering with this potentially disabling disease This edition of the Handbook of Multiple Sclerosis provides clinicians with informative and detailed information regarding almost every aspect of MS For health care professionals working with MS patients, this book provides an invaluable resource Treatment modalities are thoroughly discussed and comments are given about the ongoing research in MS, which will lead to better understanding and treatment in the future William C Koller iii Preface Only ten years have passed since publication of the first edition of the Handbook of Multiple Sclerosis, and impressive advances have been made in our understanding of multiple sclerosis (MS), particularly with regard to its natural history, immunopathology, lesion evolution based on imaging techniques, and therapy Physicians are now in a much better position to prescribe medications that can modify disease course, decrease lesion burden, and alleviate symptoms Many patients can look forward to fewer exacerbations, a slower rate of deterioration, and a better quality of life Although current treatments are only palliative, the exciting prospect of medications that can prevent further disability, and even promote recovery from fixed neurological deficits, no longer seems so remote Increased funding for MS research from a variety of sources, including federal funding agencies, the pharmaceutical industry, and national MS societies worldwide, has led to more scientists and clinicians partaking in basic and clinical studies directed toward finding the cause and cure of this enigmatic disorder Patients are much better informed about cutting-edge treatments and ongoing clinical trials through information available on the Internet Over the next few years, we can expect further advances in our knowledge about genetic susceptibility and environmental factors causing MS, and about the interaction between those factors and the immune response that results in lesion pathogenesis This should lead to better-focused research and more rapid development of effective therapies This edition of the Handbook of Multiple Sclerosis will provide the reader with the most up-to-date and detailed information currently available about all aspects of MS It should provide a valuable resource to anyone interested in this disease, be it patient, student, clinician, or scientist I am very grateful to the contributors, who are world leaders in MS research and treatment This book is dedicated to those individuals who bravely cope with MS on a daily basis, their devoted friends and family members, and their caring physicians Stuart D Cook v Contents Series Introduction William C Koller Preface Contributors iii v xi PART I ETIOPATHOGENESIS The History of Multiple Sclerosis W I McDonald The Epidemiology of Multiple Sclerosis William Pryse-Phillips and Fiona Costello 15 The Genetics of Multiple Sclerosis Jan Hillert and Thomas Masterman 33 Experimental Models of Virus-Induced Demyelination Mauro C Dal Canto 67 Evidence for a Viral Etiology of Multiple Sclerosis Stuart D Cook 115 Experimental Models of Autoimmune Demyelination Fred D Lublin 139 Evidence for Immunopathogenesis Ute Traugott 163 Autoantibodies in Demyelinating Disease Anne H Cross, Jeri-Anne Lyons, and John L Trotter 193 vii viii Contents PART II CLINICAL PATHOLOGIC FEATURES Clinical Features Aaron E Miller 213 10 Cognitive Impairment in Multiple Sclerosis Jill S Fischer 233 11 Loss and Restoration of Impulse Conduction in Disorders of Myelin Stephen G Waxman 257 12 Pathology of Multiple Sclerosis John W Prineas 289 13 Axonal Injury in Multiple Sclerosis Carl Bjartmar and Bruce D Trapp 325 14 Cerebrospinal Fluid John N Whitaker, Khurram Bashir, and Etty N Benveniste 347 15 Laboratory Tests: Evoked Potentials Marc R Nuwer 377 16 Neuroimaging and the Use of Magnetic Resonance in Multiple Sclerosis Lael A Stone, Nancy Richert, and Henry F McFarland 403 PART III THERAPEUTIC CONSIDERATIONS 17 The Natural History of Multiple Sclerosis Sandra Vukusic and Christian Confavreux 433 18 Prognostic Factors in Multiple Sclerosis Orhun H Kantarci and Brian G Weinshenker 449 19 Therapeutic Considerations: Rating Scales Richard Rudick, Brian G Weinshenker, and Gary Cutter 465 20 Therapeutic Considerations: Treatment of the Acute Exacerbation Raymond Troiano 493 21 Interferon--1b: Prophylactic Therapy in Multiple Sclerosis Kenneth P Johnson and Peter A Calabresi 503 22 Therapeutic Considerations: Prophylactic Therapy with Interferon--1a Lawrence Jacobs 519 Contents ix 23 Prophylactic Therapy—Glatiramer Acetate (Copaxone) Hillel Panitch 541 24 Treatment of Multiple Sclerosis with Intravenous Immunoglobulin Peter Rudge 561 25 Immunosuppressive Drugs Mariko Kita and Donald E Goodkin 579 26 Treatment of Multiple Sclerosis: Bone Marrow Reconstitution, Total Lymphoid Irradiation, and Plasma Exchange George P A Rice 593 27 Symptomatic Therapy Randall T Schapiro 601 28 Symptomatic Treatment and Rehabilitation in Multiple Sclerosis Charles R Smith and Labe Scheinberg 609 29 Experimental Therapies with T-Cell Vaccines, Oral Myelin, and Monoclonal Antibodies in Multiple Sclerosis Suprabha Bhat and Jerry S Wolinsky 635 30 Future Immunotherapies Christine Rohowsky-Kochan 653 Index 667 Index Demyelination, nonuniform conduction, 271–273 pathology, 333–336 Denmark, 17 Dental fillings, 23 Depression, 220 fatigue, 601–602 interferon-beta1b, 514 Design of Experiments, Detrusor-external sphincter dyssynergia, 220 Devic’s disease pathology, 303–304 prognosis, 454 Diagnosis, 3–4, 213–215 criteria, MRI, 410–414 Diazepam spasticity, 603, 616 tremor, 606 Diet, 22–23 Dietary fats, 22 Differential diagnosis MRI, 410–414 Diffuse multiple sclerosis, 292 Diffusion-weighted imaging (DWI), 422 Direct infection hypothesis, 120 Discrete scales, 467–468 Disease heterogeneity, 312–315 Divided attention, 237 Dogs exposure, 130 Donepezil memory deficit, 243 DQw6, 24–25 DTH, 144 TMEV, 89–90 DTH responses, 70 DWI, 422 Dysarthria, 217–218, 627–628 Dysesthesia, 605 Dysmetria, 219 Dysphagia, 628–630 Dystonic spasm scale, 471 EAE See Experimental allergic encephalomyelitis EBV, 26, 117, 118, 124–125 673 EC active chronic lesions, 179–180 cytokines, 171 immunocompetent properties, 150 immunopathology, 174 Echo time, 405 Ectopic action potential generation, 263 EDSS, 16, 222–223, 240–241, 479– 481, 611 E-2 envelope glycoprotein SFV, 95–96 Ejaculation, 221 Endothelial cells (EC) active chronic lesions, 179–180 cytokines, 171 immunocompetent properties, 150 immunopathology, 174 England, 18 Environmental Status Scale (ESS), 475– 476, 610 Ephaptic transmission, 263 Epidemiology, 5–6, 15–27, 117–118 birth month, 21 climate, 24 diet, 22–23 genetics, 24–25, 35–36 incidence rates, 16–20 infectious causes, 25–26 migration studies, 20–22 mortality studies, 15–16 pregnancy, 23–24 prevalence ratios, 16–20 socioeconomic factors, 23 toxins, 23 trauma, 21 Episodic memory, 235 Epitope spreading, 312, 642 EPs See Evoked potentials Epstein-Barr virus (EBV), 26, 117, 118, 124–125 Erectile dysfunction, 221 ESS, 475–476, 610 Estrogen, 659 Ethnic comparisons, 36 Etiology, Euphoria, 220 Europe, 17, 19, 20, 117 674 European-Canadian MRI study RR-MS glatiramer acetate, 548–550 Evoked potentials (EPs), 377–393 abnormalities, 264 abnormality rates, 379 antilymphocite globulin, 391 azathioprine, 390–392 brainstem, 380–383 chronic progressive MS, 388 diagnosis, hyperbaric oxygen, 393 interferon alpha, 393 motor, 386–387 multimodal testing, 387–389 somatosensory, 383–386 steroids, 391–392 therapeutic trials, 389–393 visual, 378–380 vs MRI, 388–389 Exacerbations, 222, 434–435 acute See Acute exacerbation stress, 223 Exanthem subitum, 126 Executive functions, 236–238, 242 Exercise, 223–224, 617 spasticity, 602 Experimental allergic encephalomyelitis (EAE), 48, 77, 139– 152 attack site, 148–150 axonal loss, 336 B cells, 200–202 cellular components, 143–145 chemokines, 146–148, 657–658 clinical signs, 141 complement, 202 course, 141 cytokines, 146–148 environmental influences, 151 glatiramer acetate, 552 histopathology, 141–143 immunogenetics, 150–151 immunopathogenesis, 143–148 induction protocols, 140–141 MBP, 139–140, 148–149 neurological disability, 336 oral myelin, 639 Index [Experimental allergic encephalomyelitis] pathology, 305 PLP, 139–140 relevance to MS, 139–140 T-cell receptors (TCR), 144–145 treatment, 151–152 Experimental demyelination intravenous immunoglobulin, 572 Explicit memory, 234–235 methylprednisolone, 244 Facial paresis, 218 Facial perception, 238 Family studies, 24–25, 35–36 Faroe Islands, 25 Fast spin-echo (FSE) imaging, 406 Fatigue, 220, 627 cognitive dysfunction, 241 depression, 601–602 therapy, 601–602 Fatigues Scales (FSS), 476 FcR antibodies, 199 Fc receptors (FcR) antibodies, 199 Fecal incontinence, 626 Fever-induced conduction block, 25 Fiber-fiber excitation, 263 Finland genomic screens, 51–52 FLAIR imaging, 406–407 Fluid-attenuated inversion recovery (FLAIR) imaging, 406–407 Flu-like symptoms interferon-beta1b, 513 Fluoxetine fatigue, 627 lassitude, 602 FMRI, 422–423 France, 21 Frenkel’s exercises, 619–621 Frequency monitoring, 238 Friedreich’s ataxia VEP latencies, 379 Fruit, 22 FSE imaging, 406 FSS, 476, 479–481 Functional MRI (fMRI), 422–423 Index Functional System Scales (FSS), 479– 481 Fundoscopy, 218 Gabapentin spasticity, 603 Gadolinium-DPTA, Gait, 614–623 Gait ataxia, 219 Gait training, 622 GBS, 117, 267 Gelatinase B (MMP-9) CSF, 168–169 serum levels, 167 Gene therapy, 660 Genetic background axonal injuries, 336–337 Genetic geography, 24–25 Genetic markers prognosis, 458 Genetic models criticisms, 36 Genetics, 5–6, 33–55 epidemiology, 35–36 genome screens, 51–54 history, 34 methodological aspects, 36–38 non-HLA candidate genes, 47–51 prospects, 54–55 Genetic studies, 24–25 Genome screens, 37–38, 51–54 SNPs, 54–55 Genomic typing HLA-Dw2 haplotype, 42 Genu recurvatum, 618 Germany, 19 GGF2 EAE, 152 Glatiramer acetate, 7, 541–556 clinical studies, 542–552 chronic progressive MS phase II pilot study, 542–543 in progress, 550–552 RRMS European-Canadian MRI study, 548–550 RRMS phase III pivotal trial, 543– 548 RRMS phase II pilot study, 542 675 [Glatiramer acetate] composition, 545 CSF IgG, 362 immunological activity, 552–555 EAE, 552 mechanisms of action, 552–555 oral myelin, 640–641 Glia hyperplasia, Glial growth factor (GGF2) EAE, 152 Gliotic lesion center active chronic lesions, 180 GM allotypes, 48 GM1 gangliosides, 195 GNDS, 477–478 Gradient-recalled echo (GRE) pulse sequences, 405 GRE pulse sequences, 405 Gross pathology, 290–292 Guillain-Barre syndrome (GBS), 117, 267 Gustation, 219 Guys Neurologic Disability Scale (GNDS), 477–478 Gypsies, 24–25 Headache, 217 Hearing loss, 218 Heat VEP, 380 Heat-sensitivity, 443 Heat shock proteins (HSP) reactivity, 170 Heel-knee-shin test, 219 Hemiageusia, 219 Hemifacial spasm, 221 Heminodes, 276 Hepatitis b, 27 Hereditary motor and sensory neuropathy (HMSN), 387 Herpes simplex virus (HSV) 1, 81–83 Herpes simplex virus (HSV) 2, 83–84 Herpes simplex virus (HSV) infection, 81–84, 120 Herpes zoster, 120 Herpetoviridae, 81 HHV-6, 26, 120, 126–127 676 High-performance liquid chromatography (HPLC) NA, 332 Hill, Bradford, Histology, 292–302 Historical aspects, 1–8 early, twentieth century, 2–8 HIV, 120 HLA-A2, 46 HLA-A3, 46 HLA class I genes, 45–46 HLA class II, 38–47 disease, 40–41 inheritance modes, 43 MS heterogeneity, 45 nomenclature, 41–42 typing techniques, 41–42 HLA class II genes importance, 46 HLA class III region, 40 HLA class II molecule, 39–40 HLA class II region, 33–34 HLA class I molecule, 39–40 HLA-DM genes, 46 HLA-DP alleles, 45 HLA-DR3, 43–44 HLA-DR3, DQ2 phenotypic frequencies, 44 HLA-DR4, 44 HLA-DR15, DQ6, Dw2, 36 HLA-Dw2 haplotype, 42–43 DR or DQ, 42–43 genomic typing, 42 phenotypic frequencies, 43 HLA genes, 37 chromosome 6, 39 mechanisms, 46–47 HMSN, 387 Hormones future, 658–659 Host immune response CDV, 69 Hot-bath test, 224 HPLC NA, 332 HSP reactivity, 170 Index HSV 1, 81–83 HSV 2, 83–84 HSV infection, 81–84, 120 HTLV-1, 26, 120, 125–126 Human herpes virus (HHV-6), 26, 120, 126–127 Human leukocyte antigen (HLA) class II region, 33–34 Human T-cell lymphotrophic virus (HTLV-1), 26, 120, 125–126 Hungarian Gypsies, 17, 36 Hyperbaric oxygen, EPs, 393 ICAM-I, 144 IDDM, 41 Idiopathic inflammatory demyelinating diseases (IIDDs), 449–450 prognosis, 452–455 Idiotypes CSF immunoglobulin, 355–356 IFN-beta-1a memory, 244 IFN-beta-1b visual memory, 244 IFN-gamma, 657 IFN-gamma-inducing factor, 654–655 IGF-1 EAE, 152 IgG, 351 preparation, 573–574 IIDDs, 449–450 prognosis, 452–455 IL-2 CSF, 168 IL-4 EAE, 147 serum levels, 167 IL-6 CSF, 360 EAE, 147 IL-10 EAE, 147 serum levels, 167 IL-12, 654 EAE, 147 serum levels, 167 IL-18, 654–655 Index IL-1ra, 50–51 IL1RN*2, 50 Images jumping, 217 Immune complexes, 198 Immune globulins intrathecal synthesis, 194 Immune-mediated myelin injury TMEV, 88 VV infection, 79 Immune modulation, Immune response coronavirus infection, 74–75 Immune response genes, 40, 41 Immune system intravenous immunoglobulin, 570– 572 Immune tolerance, 638–639 Immunodysregulation qualitative immunologic changes, 169–170 Immunoglobulin cerebrospinal fluid, 350–356 Immunoglobulin deposits silent chronic lesions, 184 Immunoglobulin genes, 48 Immunoglobulin G (IgG), 351 preparation, 573–574 Immunoglobulin-positive cells active chronic lesions, 178–179 Immunopathogenesis, 163–185 Immunoregulatory cytokines quantitative immunologic changes, 167 Immunosuppression, Immunotherapies future, 653–661 Impedance matching demyelinated axons, 274–277 Implicit memory, 236 Impulse reflection, 263 Impulse transmission demyelinated axons recovery, 269–271 Incapacity Status Scale (ISS), 475–476, 610 Incidence rates stability, 19 677 Incidence studies, 17–19 Indians American, 17, 25 Infection oligodendrocytes, 68–69 Infectious agents, 118–119 Infectious antigens, 116 Infectious causes, 25–26 Infectious genomes, 116 Inflammation conavirus infection, 76 Inflammatory cells active chronic lesions, 174 Inflammatory demyelination axonal injuries animal models, 336–337 axonal transection, 333 INH tremor, 606 Inheritance pattern, 35 Injection-site reaction interferon-beta1b, 513–514 Insulin-dependent diabetes mellitus (IDDM), 41 Insulinlike growth factor-1 (IGF-1) EAE, 152 Intention tremor, 219 Interferon EAE, 147 Interferon alpha CSF IgG, 362 EPs, 393 Interferon beta CSF IgG, 362 Interferon beta1b, 503–516 clinical studies, 506–515 adverse effects, 513–515 pilot study, 506 RRMS phase trial, 506–508 secondary-progressive MS European Trial, 508–513 mechanisms, 504–506 Interferon-gamma EAE, 146 oligodendrocytes, 172 oligodendroglia, 75–76 Interferons, Interindividual fixedness, 442 678 Interindividual variability, 441–442 Internodal conduction time, 260–261 Internodes, 259 Internuclear ophthalmoplegia, 217 Interval scales, 467–468 Intravenous immunoglobulin, 561– 575 clinical trials, 562–570 early trials, 562–563 MRI, 568–570 since 1990, 563–568 IgG preparation, 573–574 mechanisms of action, 570–573 experimental demyelination, 572 immune system, 570–572 remyelination, 572–573 safety, 574 Inuit, 17 Inversion recovery (IR) pulse sequences, 405 Iodide, 6–7 Ion channel organization myelinated fiber, 259 IR pulse sequences, 405 Ischemic theory, 6–7 Isoniazid (INH) tremor, 606 ISS, 475–476, 610 Italy genomic screens, 52 Japan, 17 Japanese, 17, 20 JHM virus, 72, 77 KAFO, 618 Kappa/Lambda ratios CSF immunoglobulin, 356 Kinesigenic dystonia, 221 Knee-ankle-foot orthosis (KAFO), 618 Knee joint hyperextension, 618 Kurtzke Expanded Disability Status Scale (EDSS), 16, 222–223, 240–241, 479–481, 611 Kurtzke functional systems, 612–613 Kuwaitis, 17 Index Language, 238–239 Lapps, 17, 36 Lassitude, 602 Latitude, 24 Laughing pathological, 606–607 Lawry, Sylvia, Leber’s hereditary optic neuropathy (LHON), 48–49 Lesions immunopathology, 174–175 light microscopy, 173 macroscopic level, 173 pathology, 173–174 Leukodystrophy white matter hyperintensities, 413 Lhermitte’s sign, 216 LHON, 48–49 Libido, 221 Life expectancy, 16 Light microscopy lesions, 173 Limb ataxia, 219 Linkage analysis, 37 Linkage disequilibrium analysis, 54 Lofstrand crutch, 621 Low back pain, 216–221 Lower extremity orthotics, 617–618 Lumbar puncture, Lymphocytes CSF, 168 Lymphocytic infiltrates acute lesions, 184 Lymphotoxin alpha, 46 MAbs, 642 TMEV, 91–92 Macrophages, 309, 311 active chronic lesions, 174, 175–176 acute lesions, 184 CDV, 69–70 silent chronic lesions, 183 TMEV, 89 MAG, 88 CSF, 356 MAG-deficient mice axonal degeneration, 334–335 Index Magnetically evoked motor potentials (MEPs), 386–387 Magnetic resonance imaging (MRI), 4, 19, 214, 242, 403–423 atrophy, 421–422 corticosteroids, 495 future directions, 422–423 histopathological correlation, 414– 415 intravenous immunoglobulin, 568– 570 magnetization transfer imaging, 410 MS vs ADEM, 414 NP, 242 optic nerve, 410–423 principles, 404–405 prognosis, 457–458 pulse sequences, 405–409 quantitative techniques, 419–421 spinal cord, 410–423 surrogate outcome measure, 417– 419 technical advances, 405 vs EPs, 388–389 Magnetic resonance spectroscopy (MRS), 4–5, 214, 420–421 NA, 331–332 NAA, 420 Magnetization transfer imaging (MTI), 242–243, 410, 419–420 Major histocompatibility complex (MHC), 39 Major histocompatibility complex (MHC) class II antigens astrocytes, 149 Major histocompatibility complex (MHC) class II restricted T-helper cells, 144 Major histocompatibility complex (MHC) genes, 40 Malarial treatment, Maoris, 17, 36 Marburg’s variant prognosis, 454–455 Marcus Gunn pupil, 218 Marie, Pierre, 115–116 Mast cells active chronic lesions, 178–179 679 Matrix metalloproteases (MMP) active chronic lesions, 176–177 CSF, 357 quantitative immunologic changes, 167 MBP See Myelin basic protein MBP 83-99, 169 MCP-1 CSF, 168–169 Measles antibody titer, 119 Measles virus, 120, 123 Mechanosensitivity, 263 Median nerve SEPs, 385 Mediterranean, 117 Membrane reorganization demyelinated axons, 273–274 Memory, 234–235 IFN-beta-1a, 244 Memory deficit donepezil, 243 Memory impairment, 239 MEPs, 386–387 Mercury, 6, 23 Methotrexate, 244, 580–581 EAE, 151 Methylprednisolone (MP) acute exacerbation, 494–495 CSF IgG, 361 cyclical pulses, 581–582 explicit memory, 244 MHC, 39 MHC class II antigens astrocytes, 149 MHC class II restricted T-helper cells, 144 MHC genes, 40 MHV, 71 Microglia active chronic lesions, 175–176 acute lesions, 184 autoimmunity, 149 cytokines, 172 immunopathology, 174 silent chronic lesions, 183 Micrographia, 221 Micturition, 220 Migration, 20–22, 117 680 Minimal Record of Disability (MRD), 475–476, 610 Mini-Mental State Examination (MMSE), 245–246 Minnesota, 19 MIP-1 alpha, 658 active chronic lesions, 177 CSF, 168–169 MIP-1 beta active chronic lesions, 177 Misoprostol pain, 605 Mitochondrial DNA, 48–49 Mitoxantrone, 7, 583–584 EAE, 151 MMP active chronic lesions, 176–177 CSF, 357 quantitative immunologic changes, 167 MMP-9 CSF, 168–169 serum levels, 167 MMSE, 245–246 Modafinil fatigue, 627 MOG, 195 Molecular mimicry, 41, 94–95 Monoclonal antibodies (mAbs), 642 TMEV, 91–92 Monocytes CSF, 168 quantitative immunologic changes, 165–166 Morbillivirus, 67, 129 Mortality studies, 15–16 Motor evoked potentials, 386–387 Motor symptoms, 215–216 Movement disorders, 221 MP acute exacerbation, 494–495 CSF IgG, 361 cyclical pulses, 581–582 explicit memory, 244 MRD, 475–476, 610 MRI See Magnetic resonance imaging MRS, 4–5, 214, 420–421 NA, 331–332 NAA, 420 Index MSFC, 485–487, 613 MSIS, 482–483 MSQLI, 476–477 MTI, 242–243, 410, 419–420 Multiple sclerosis-associated retrovirus, 26 Multiple sclerosis bladder, 603–605 Multiple Sclerosis Functional Composite (MSFC), 485–487, 613 Multiple Sclerosis Impairment Scale (MSIS), 482–483 Multiple Sclerosis Quality of Life Inventory (MSQLI), 476–477 Multivariable composite outcome, 471– 472 Multivariate clinical outcome measures, 470–472 attributes, 472 Multivariate composite outcome, 471– 472 Murine hepatitis virus (MHV), 71 Myasthenia gravis, 41 Mycoplasma pneumoniae, 26, 118 Myelin breakdown, 307 Myelin antigens reactivity, 169 Myelin-associated glycoprotein (MAG), 88 CSF, 356 Myelin-associated glycoprotein (MAG)deficient mice axonal degeneration, 334–335 Myelinated axons membrane architecture, 259–260 Myelinated fibers functional organization, 258–259 ion channel organization, 259 potassium channels, 260 sodium channels, 260 Myelin basic protein (MBP), 70 autoantibodies, 194–195 CSF, 356–358 EAE, 139–140, 148–149 gene, 37, 48 SFV, 95 TMEV, 89–90 Myelin-forming cells transplantation, 278 Index Myelin lipids antibodies, 201–202 Myelin-oligodendrocyte glycoprotein (MOG), 195 Myelin opsonization antibodies, 199 Myelin-related genes axonal pathology, 335–336 Myelin sheaths, 258–259 oligodendrocytes, 258 NA axonal injuries, 331 HPLC, 332 MRS, 331–332 NAA MRS, 420 N-acetylaspartate (NAA) MRS, 420 N-acetyl aspartic acid (NA) axonal injuries, 331 HPLC, 332 MRS, 331–332 Nasal speech, 218 National Multiple Sclerosis Society, 7–8 National Multiple Sclerosis Society Clinical Outcome Assessment Initiative, 466–467 Natural history, 433–445 classification, 434–435 course, 438–441 daily life, 443–444 onset, 435–437 prognosis, 441–442 Neopterin CSF, 168 Nerve conduction, 2–3 Neural growth factors EAE, 152 Neurobiology, Neurological disability EAE, 336 Neurologic examinations clinical outcome measures, 478–487 Neuromyelitis optica pathology, 303–304 prognosis, 454 681 Neuronal loss ALS, 337 Neuronal pathology cortical lesions, 328–329 Neuropsychological evaluation (NP), 244–245 Neuropsychological Screening Battery, 246 Neurosarcoidosis MRI, 412 Neurosyphillis VEP latencies, 379 Newfoundland, 19, 20 New lesions histology, 297–300 New Zealand, 117 Nine-hole peg test (9PHT), 484–485 Nodes of Ranvier, 259 Nominal scales, 467–468 Non-HLA candidate genes, 47–51 Nonuniform conduction demyelination, 271–273 North America, 21 Norway, 19 genomic screens, 52 NP, 244–245 Nystagmus, 217 Occupational exposure, 23 Old lesions histology, 292–295 Olfaction, 219 Oligoclonal bands CSF, 169 Oligoclonal immunoglobulin bands CSF, 353–354 Oligoclonal immunoglobulins, 196–197 Oligodendrocytes cytokines, 172 degenerating, 314 destruction, 306–307 epitope, 315 immunocompetent properties, 150 infection, 68–69 myelin sheaths, 258 regeneration, 300–302 remyelination, 277, 300–302 TMEV, 91–92 682 Oligodendrocyte-specific protein (OSP), 195 Oligodendroglia interferon-gamma, 75–76 ON, 218 prognosis, 452–453 VEPs, 3–4 One-and-a-half syndrome, 217 Onset, 435–437 age at, 435 clinical variables, 437 symptoms at, 436–437 types, 435–436 Onset-adjusted prevalence rate, 18 Optic nerve lesion, 294 MRI, 410–423 Optic neuritis (ON), 218 prognosis, 452–453 VEPs, 3–4 Opticospinal multiple sclerosis, 45 Oral myelin, 638–641 EAE, 639 glatiramer acetate, 640–641 Ordinal scales, 467–468 Orgasm, 221 Orkney Islands, 19 Orthotics lower extremity, 617–618 Oscillopsia, 217 OSP, 195 Osteoporosis, 217 Ouabain, 260 Outcomes, 441 Outcomes assessment complexities, 466 Outcomes measures clinical See Clinical outcome measures Paced auditory serial addition test (PASAT 3), 613 PAFO, 618 Pain therapy, 605 Palestinians, 17 Pandy test, 350–351 Papovavirus, 120 Index Paraclinical lesions, 214 Paramyxoviruses, 25–26 Paroxysmal dysarthria, 221 Paroxysmal kinesigenic choreoathetosis, 221 Paroxysmal spasms therapy, 606 Paroxysmal symptoms, 221 PASAT 3, 613 Pathogenesis, 4–5, 304–315 Pathological crying, 606–607 Pathological laughing, 606–607 Pathology, 2, 289–315 gross, 290–292 histology, 292–302 Pathophysiology, 2–3 PBL, 164 Pemoline fatigue, 627 Peptide-bearing HLA class II molecule, 47 Peripheral blood leukocytes (PBL), 164 Periventricular plaque, 293 PET, 422–423 Phenotypic frequencies HLA-DR3, DQ2, 44 HLA-Dw2 haplotype, 43 Phi nodes, 271–273 Phonemic fluency, 235 Phonological loop, 237 9PHT, 484–485 Physical disability cognitive impairment, 240–241 Physical impact measurement, Physostigmine verbal learning, 243 Planning/sequencing, 238 Plaque, 310 PLP, 170 EAE, 139–140 TMEV, 89–90 PLP-deficient mice axonal degeneration, 334–335 PMSA, 25 Point source outbreaks, 20 Polygenic models criticisms, 36 Index Polymorphic markers, 37–38 Population-based twin studies, 35–36 Poser, Charles, 214 Poser criteria, 214 Positron emission tomography (PET), 422–423 Posterior ankle-foot orthosis (PAFO), 618 Posterior tibial nerve SEPs, 385 Postinfectious encephalomyelitis, 123 Potassium channels myelinated fiber, 260 PPMS, 16–17, 222 pathology, 304 prognosis, 455 Precession, 404 Prednisone acute exacerbation, 494–495 CSF IgG, 361 Pregnancy, 23–24, 224, 443–444 Pressure sores, 630–631 Prevalence, 17–19 Primary chronic progressive multiple sclerosis, 45 Primary memory, 237 Primary multiple sclerosis affection (PMSA), 25 Primary progressive multiple sclerosis (PPMS), 16–17, 222 pathology, 304 prognosis, 455 Primidone tremor, 605–606 Principle of randomization, Procedural memory, 236 Progesterone, 659 Prognosis, 50–51, 441–442, 449–459 categories, 450–451 interindividual fixedness, 442 interindividual variability, 441–442 outcome, 441 Progression, 434–435 Progressive-relapsing multiple sclerosis, 222 Proinflammatory cytokines quantitative immunologic changes, 166–167 683 PROMiSe trial, 550–551 Prophylaxis glatiramer acetate, 541–556 interferon beta1b, 503–516 Propranolol tremor, 605 Prostaglandins sexual dysfunction, 604 Proteolipid protein (PLP), 170 EAE, 139–140 TMEV, 89–90 Proteolipid protein (PLP)-deficient mice axonal degeneration, 334–335 Proton-density images, 406 Prototypical multiple sclerosis prognosis, 455–458 clinical and demographic factors, 456–457 genetic markers, 458 MRI, 457–458 Pseudoexacerbation, 478 Psychiatric disturbances, 219–220 Pulse sequences, 405 QENF, 483–484 QMSE, 246 Quantitative Evaluation of Neurological Function (QENF), 483–484 Quantitative Mental Status Examination (QMSE), 246 Quantitative Motor Power Testing, 484 Rabies, 117 Racial factors, 17 Radiofrequency (RF) pulse, 404 RANTES (regulated upon activation, normal T cells expressed and secreted), 167 CSF, 168–169 Rating scales, 465–488 clinical outcome measures, 473–487 measurement characteristics, 467–470 measurement responsiveness, 469– 470 measurement type, 467–468 multivariate clinical outcome measures, 470–472 684 [Rating scales] National MS Society Clinical Outcome Assessment Initiative, 466–467 neurologic function quantification, 473 practical considerations, 470 reliability, 468–469 sensitivity, 469–470 validity, 470 Ratio scales, 467–468 Recent memory, 234 Recurrence rates, 35–36 Regeneration oligodendrocytes, 300–302 Regulated upon activation, normal T cells expressed and secreted, 167 CSF, 168–169 Relapse frequency, 440, 478–479 treatment CSF, 361–363 Relapsing-remitting multiple sclerosis (RR-MS), 45, 222, 326, 330, 338–339, 360 glatiramer acetate European-Canadian MRI study, 548–550 phase III pivotal trial, 543–548 phase II pilot study, 542 interferon-beta1b phase trial, 506–508 Remission, 222–223 Remote memory, 234 Remyelination, 3, 277 autoantibodies, 199–200 intravenous immunoglobulin, 572– 573 oligodendrocytes, 300–302 Repetition time, 405 Respiratory failure, 222 Retrieval hypothesis, 235 Retroviruses, 125–126 RF pulse, 404 Rheumatoid arthritis, 41 Roseola, 126 Index RR-MS See Relapsing-remitting multiple sclerosis Rubella virus encephalopathy, 120 Safety factor conduction, 261 Sardinia, 19 Scandinavian gene, 37 Scanning speech, 217–218 Schumacher criteria, 214 Schwann cells remyelination, 277 Scotland, 17, 18 Screening cognitive impairment, 245, 247 Screening Examination for Cognitive Impairment in Multiple Sclerosis (SECIMS), 246 Screening Examination for Cognitive Impairment (SEFCI), 245–246 Scripps Neurologic Rating Scale (SNRS), 481–482 SEB, 151 SECIMS, 246 Secondary progressive multiple sclerosis, 222 European Trial interferon-beta1b, 508–513 SEFCI, 245–246 Segmental demyelination, Segmental myoclonus, 221 Selective breeding, 55 Self-reports, 244–245, 475–478 Semantic fluency, 235 Semantic memory, 235 Semliki Forest virus (SFV) infection, 94–96 axoplasmic viral transport, 95 E-2 envelope glycoprotein, 95–96 MBP, 95 mechanisms, 94–95 pathogenesis, 94 Sensations, 216 SEPs, 383–386 sensitivity, 384 SE pulse sequences, 405 Serological studies, 119 Index Serum antibody titer, 120 Serum demyelinating antibodies, 197– 198 Sexual dysfunction therapy, 604–605 Sexual symptoms, 221, 626 SFV infection, 94–96 axoplasmic viral transport, 95 E-2 envelope glycoprotein, 95–96 MBP, 95 mechanisms, 94–95 pathogenesis, 94 S glycoprotein, 73 Shadow plaques, 300–302 Shetlands Islands, 19 Short-term memory, 234 S1 hypervariable region mutations, 73 Sickle cell disease, 117 Sildenafil, 626 sexual dysfunction, 604–605 Silent chronic lesions, 174, 183–184 Single nucleotide polymorphisms (SNPs) genomewide screen, 54–55 Skill learning, 236 SLE, 41 Sleep, 220 SNPs genomewide screen, 54–55 SNRS, 481–482 Socioeconomic factors, 23 Sodium channel-blocking, 267 Sodium channels, 273–274 myelinated fiber, 260 Soluble adhesion molecules CSF, 360–361 Soluble TNF-R (sTNF-R) CSF, 360 Somatosensory evoked potentials (SEPs), 383–386 sensitivity, 384 Somatosensory symptoms, 216–217 South America, 117 Spasticity, 215–216, 615–616 interferon-beta1b, 515 therapy, 602–603 Spastic paraparetic gait, 216 685 Speech, 627–628 Spherula insularis, Spike (S) glycoprotein, 73 Spinal cord atrophy, 421 lesions, 296 axonal loss, 327–328 MRI, 410–423 Spin-echo (SE) pulse sequences, 405 Spirochetal theory, 5, SSPE, 120 Staphylococcal enterotoxin B (SEB), 151 Stem cell transplantation, 659–660 Sterile milk, Steroids EPs, 391–392 Stimulus modality monitoring, 238 STNF-R CSF, 360 Streptococcus-induced rheumatic heart disease, 121 Stress exacerbations, 223 Subclinical multiple sclerosis pathology, 303 Subcortical dementia, 239 Subcortical lesions predictive value, 242 Sunlight, 24 Surrogate outcome measure MRI, 417–419 Sweating abnormal, 221–222 Sweden, 20 Swedish knee cage, 618 Swinging flashlight test, 218 Symptomatic therapy, 601–607 Symptoms remission, 222–223 Systemic lupus erythematosus (SLE), 41 T whippelli, 116 TAP genes, 46 Tat protein, 78, 80 Tay-Sachs disease, 117 686 T-cell receptor (TCR), 47, 636–637 EAE, 144–145 genes, 47–48 T-cells active chronic lesions, 174, 177– 178 APC, 144 quantitative immunologic changes, 164–165 T-cell vaccine, 635–638 TCR, 47, 636–637 EAE, 144–145 Temperature axonal impulse conduction, 265 demyelinated axons, 266 Temporal dispersion, 263 Temporal ordering, 238 Testosterone, 659 TGF-beta EAE, 147 serum levels, 167 Theiler’s murine encephalomyelitis virus infection (TMEV), 84–93 astrocytes, 91 cell-mediated immunity, 89 DTH, 89–90 immune-mediated myelin injury, 88 macrophages, 89 MBP, 89–90 monoclonal antibodies, 91–92 oligodendrocytes, 91–92 PLP, 89–90 Theiler’s murine encephalomyelitis virus infection (TMEV)-demyelinating disease host susceptibility, 88 Theiler’s original, 85 Therapeutic plasma exchange (TPE), 597–598 Thermal sensitivity demyelinated axons, 266 Thrombocytopenia, 222 Timed Ambulation and Maximal Distance Walk, 485 TIMP active chronic lesions, 176–177 serum levels, 167 Tissue culture studies, 170–172 Index Tissue inhibitor of metalloprotease (TIMP) active chronic lesions, 176–177 serum levels, 167 Tizanidine spasticity, 615 T lymphocytes, 305–306 TMEV See Theiler’s murine encephalomyelitis virus infection TNF EAE, 146 TNF-alpha, 46 CSF, 168, 359–360 oligodendrocytes, 172 TNF-beta, 46 Tolerance induction, Tonic seizures, 221 Total lymphoid irradiation, 596–597 Toxins, 23 TPE, 597–598 Transaldolase, 195 Transforming growth factor beta (TGF-beta) EAE, 147 serum levels, 167 Trauma, 21 Treatment, 6–7 Tremor therapy, 605–606 Trigeminal neuralgia, 221 Troiano Scale, 483 Ts8 virus, 73 Tumor necrosis factor (TNF) EAE, 146 Tumor necrosis factor (TNF)-alpha, 46 CSF, 168, 359–360 oligodendrocytes, 172 Tumor necrosis factor (TNF)-beta, 46 T1W hypointensities, 417 T1W images, 407–409 information gained, 416–417 T2W images, 405–407 hyperintensities conditions producing, 412 information gained, 415–416 Twin studies, 24, 118 Typhoid vaccine, Index Uhthoff’s phenomenon, 25, 223–224 United Kingdom, 18, 19, 24 genomic screens, 52 University of Pennsylvania Smell Identification Test (UPSIT), 219 Upper extremities symptoms, 626–627 UPSIT, 219 Urinary dysfunction therapy, 603–605 URTIs, 25 Vaccines, 444 Variants pathology, 302–304 Vasopressin bladder dysfunction, 624 VCAM-1, 144 Vegetable fats, 22 Vegetables, 22 VEPs, 378–380 heat, 380 optic neuritis, 3–4 sensitivity, 380 Verbal learning physostigmine, 243 Vertical gaze paresis, 217 Viral antibody titers, 119 Viral upper respiratory infections (URTIs), 25 Virus-induced demyelination, 115–131 candidate agents, 122–131 evidence, 117–119 historical perspective, 115–117 mechanisms, 120–122 persistent infection, 120–121 transient infection, 121–122 Virus-induced demyelination models, 67–96 acute, 93–96 chronic, 67–93 687 Vision blurring, 223–224 Visna, 129 Visna virus (VV) infection, 77–81 genome, 77–78 immune-mediated, 79 Visual dysfunction therapy, 606 Visual evoked potentials (VEPs), 378– 380 heat, 380 optic neuritis, 3–4 sensitivity, 380 Visual-evoked responses, 218 Visual field defects, 218 Visual memory IFN-beta-1b, 244 Visual pathway symptoms, 218 Visual perception, 238 Visuospatial perception, 238 Visuospatial sketchpad, 237 Vitamin B12, 22 deficiency VEP latencies, 379 VLA-4, 144 VV infection, 77–81 genome, 77–78 immune-mediated, 79 Walkers, 621 Weakness, 616–617 therapy, 603 Western-type multiple sclerosis, 45 West Indies, 20–21 Wheelchairs, 622–623 Whipple’s disease, 116 Working memory, 237, 240, 241 WT-JHM virus, 72 Zinc, 23 ... have passed since publication of the first edition of the Handbook of Multiple Sclerosis, and impressive advances have been made in our understanding of multiple sclerosis (MS), particularly with... ETIOPATHOGENESIS The History of Multiple Sclerosis W I McDonald The Epidemiology of Multiple Sclerosis William Pryse-Phillips and Fiona Costello 15 The Genetics of Multiple Sclerosis Jan Hillert and... Complex role of gamma-herpesviruses in multiple sclerosis and infectious mononucleosis Neurol Res 1993; 156:391–394 Epidemiology of Multiple Sclerosis 31 96 Haahr S Cluster of multiple sclerosis