The Neurobiology of Multiple Sclerosis
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Table of contents
- Contentsv
- Contributorsxv
- Prefacexxi
- Acknowledgmentsxxiv
- Referencesxxiv
- Chapter 1: The Destructive Alliance: Interactions Of Leukocytes, Cerebral Endothelial Cells, and the1
- I. Introduction2
- II. Role of Activated Cerebral Endothelial Cells in Pathogenesis of MS3
- III. Potential Role of Endothelial Microparticles in Pathogenesis of MS4
- IV. Interactions Among Endothelial Cells and Activated Leukocytes in Pathogenesis of MS5
- V. MS and Endothelial Tight Junctions7
- VI. Conclusions7
- References8
- Chapter 2: Role of B Cells in Pathogenesis of Multiple Sclerosis13
- I. Introduction14
- II. Etiology of MS16
- A. Autoantigen Induced and Susceptible Genes16
- III. Generation and Development of B Cells17
- IV. The Role of B Cells in Immune Responses19
- V. The Role of B Cells in MS Pathogenesis19
- A. GC Formation21
- B. Somatic Hypermutation22
- C. B-Cell Clonal Expansion and Ab Secretion22
- D. Memory B-Cell and Plasma Cell Development23
- E. The Role of Antibody27
- F. Tissue-Specific Migration28
- G. Antigens in MS29
- VI. The Role of B Cells in Therapy31
- VII. Conclusions32
- Abbreviations33
- References34
- Chapter 3: The Role of CD4 T Cells in the Pathogenesis of Multiple Sclerosis43
- I. Overview of CD4+ T-Cell Immunology44
- A. The T-Cell Subset of Inflammatory Cells44
- B. Subsets of T Cells44
- C. Activation of T Cells44
- D. Memory T Cells45
- E. Migration of T Cells46
- F. T-Cell Cytokine Production46
- G. T-Cell-Signaling Pathways47
- H. Regulatory T Cells48
- II. T-Cell Immunologic Studies in MS49
- A. Animal Models of MS49
- B. Molecular Mimicry and the Initiation of an Immune Response in MS50
- C. CD4+ T Cells in the Peripheral Immune System of MS Patients50
- D. TCR Repertoires in MS51
- E. T Cells in MS Lesions52
- F. T-Cell Activation and Costimulation53
- G. T-Cell Cytokine Production in MS54
- H. Regulatory T Cells in MS56
- I. T-Cell Migration in MS56
- J. T-Cell Interaction with Axons and Neurons57
- III. T-Cell-Targeted Therapies in MS58
- IV. Conclusions61
- References62
- Chapter 4: The CD8 T Cell in Multiple Sclerosis: Suppressor Cell Or Mediator of Neuropathology?73
- I. Introduction74
- II. Genetic Association Between Class I Genes and Predisposition to MS75
- III. Pathological Studies Implicate a Role for CD8 T Cells in MS Lesions75
- IV. What Have We Learned About CD8 T Cells from Peripheral Blood of MS Patients?77
- V. CD8 T Cells as Suppressors of Neuropathology in MS80
- VI. CD8 T Cells as Mediators of Neuropathology and Motor Deficit in Animal Models of MS82
- VII. CD8 T Cells as Potential Regulators of the Blood-Brain Barrier85
- VIII. Future Directions: Define the CD8 T-Cell Epitopes and Exploit Them Therapeutically89
- IX. Conclusions91
- References92
- Chapter 5: Immunopathogenesis of Multiple Sclerosis99
- I. Introduction100
- II. MS as an Inflammatory Disease of the CNS100
- III. Genetic and Environmental Aspects of MS and Their Impact on Immune Functions103
- A. Genetic Influences in MS103
- B. Environmental Effects in MS104
- C. Infectious Agents as Triggers of MS104
- IV. Immune Components of MS105
- A. CD4+ T Cells105
- B. Th1 Verus Th2 CD4+ T Cells106
- C. CD8+ T cells107
- D. Bystander Immune Cells107
- V. Contribution of Components of Innate Immunity in MS108
- VI. CNS-Specific Cellular Contribution in MS109
- VII. Regulatory Mechanisms in MS110
- VIII. Chemokines in MS111
- IX. Role for Metalloproteinases in MS112
- X. MS Therapies and Their Effect on Immune Abnormalities in MS114
- A. Natalizumab115
- B. Interferon-beta115
- C. Glatiramer Acetate117
- D. Minocycline117
- XI. Conclusions118
- References118
- Chapter 6: Molecular Mimicry in Multiple Sclerosis127
- I. Introduction128
- II. Class I Molecules and Mimicry132
- III. Class II Molecules and Mimicry135
- IV. Antibody and Mimicry138
- V. Discussion140
- Acknowledgments141
- References142
- Chapter 7: Molecular "Negativity" May Underlie Multiple Sclerosis: Role of the Myelin Basic Protein149
- I. Multiple Sclerosis149
- II. MBP: A Membrane Velcro in CNS Myelin151
- III. MBP: A Conformationally Adaptable and Multifunctional Protein152
- IV. MBP Deimination and MS154
- V. MBP Deimination and Autoimmunity in MS156
- VI. Does Deimination of MBP Precipitate the Autoimmune Response in MS?159
- VII. PAD and Protein Deimination162
- VIII. Conclusions163
- Abbreviations164
- Acknowledgments164
- References165
- Chapter 8: Microchimerism and Stem Cell Transplantation in Multiple Sclerosis173
- I. Introduction174
- II. Microchimerism175
- A. Portal of Entry175
- B. Origin of the Hypothesis176
- C. A New View176
- D. Dual-Role Performance178
- E. An Interesting Observation178
- F. Lessons Learned178
- G. Our Experience180
- H. MC and MSCs: Unforeseen Potentials181
- III. Therapy182
- IV. Stem Cells182
- V. Hematopoietic Stem Cells183
- A. Their Characterization183
- B. HSC Transplantation184
- VI. Mesenchymal Stem Cells185
- A. Their Characterization185
- B. MSCs and the Immune System186
- C. MSC and GVHD189
- D. Regenerative Potential of MSCs190
- E. Aging and MSC194
- VII. Concluding Remarks195
- References195
- Chapter 9: The Insulin-like Growth Factor System in Multiple Sclerosis203
- I. Introduction204
- II. Growth Factors Guide Oligodendrocyte Behavior205
- III. Overview of the IGF System206
- A. The IGFs206
- B. IGF-Binding Proteins208
- IV. Role of IGF-1 in the CNS208
- A. IGFs as Neurotrophic Factors209
- B. IGF Actions on Glial Cells210
- V. Clinical Uses of IGF-1 in Models of Neurodegenerative Demyelinating Disease212
- A. Animal Models of Demyelination212
- VI. IGF System in MS214
- A. Serum and Cerebrospinal Fluid214
- B. Central Nervous System214
- C. Role of IGFBPs in MS215
- VII. Is IGF-1 a Good Candidate for MS Treatment?217
- VIII. Summary218
- References219
- Chapter 10: Cell-Derived Microparticles and Exosomes in Neuroinflammatory Disorders227
- I. General Considerations228
- A. Aims, Scope, and Terminology228
- B. Historical Development229
- C. Assay Methodologies230
- D. Assay of MP Versus Soluble Markers in Clinical Studies233
- E. Multiple Phenotypes of MP236
- II. MP Studies Relevant to Neuropathologies237
- A. Introduction237
- B. EMP in MS237
- C. Platelet Activation in Alzheimer's Disease238
- D. PMP/Platelets in Vascular Dementia239
- E. MP in Cognitive Impairment by Coronary Procedures239
- F. Concluding Remarks240
- III. Inflammatory MP-Borne Agents Relevant to Neuropathologies240
- A. Introduction240
- B. Interleukin-1 beta242
- C. Chemokines, Their Receptors, and Their Transfer via MP242
- D. Caspase-3, Fas, FasL, and Apoptosis243
- E. beta2-GPI, APS, and MS243
- F. CD40/CD40L245
- G. Inflammation, MP, and the C System246
- H. Summary246
- IV. Exosomes247
- A. Background247
- B. Overlap with MP of Plasma Membrane?247
- C. Overlap of Physiological Functions249
- V. Summary and Conclusions249
- Abbreviations250
- Glossary251
- References252
- Chapter 11: Multiple Sclerosis in Children: Clinical, Diagnostic, and Therapeutic Aspects269
- I. Introduction269
- II. Clinical Aspects of Children with Early-Onset MS270
- III. Differential Diagnostic Aspects272
- IV. Treatment of Children with MS274
- V. Conclusions276
- Abbreviations276
- References277
- Chapter 12: Migraine in Multiple Sclerosis281
- I. Epidemiology282
- II. Problems in Diagnosing MS and Migraine283
- A. Case Reports283
- B. Misdiagnosis of MS284
- C. Clinical Symptoms of Demyelination285
- D. Transient Focal Neurological Deficits in Migraine285
- III. MRI Findings in MS and Migraine287
- A. Multiple Sclerosis287
- B. Migraine288
- C. Migraine and MS Occurring Concurrently289
- IV. Headache and IFN-beta290
- V. Pathophysiology292
- A. Neuronal Pathways292
- B. Brainstem Demyelination293
- C. Serotonin293
- D. Genetic Factors294
- E. Neuroimmunologic Mechanisms295
- VI. Conclusions296
- References296
- Chapter 13: Multiple Sclerosis As A Painful Disease303
- I. Introduction304
- II. Measuring Pain305
- III. Epidemiology305
- IV. Pain and Disability307
- V. Pain Syndromes in MS307
- A. Headache308
- B. Dysesthetic Pain308
- C. Painful Tonic Spasms308
- D. Lhermitte's Sign309
- E. Trigeminal Neuralgia309
- VI. Pain Management in MS Patients309
- A. Treatment of TN309
- B. Treatment of Other Types of Pain in MS310
- VII. Pathophysiology of MS-Related Pain311
- A. Plaque Location and Pain311
- B. Remote Effects of MS on Sensory Function312
- C. Channelopathy as a Cause of Pain313
- D. Hyperalgesia in Animal Models of MS313
- E. The Immune System and Pain314
- VIII. Glia as Pain Inducers316
- IX. Conclusions317
- References317
- Chapter 14: Multiple Sclerosis and Behavior323
- I. Introduction324
- II. Cognitive Functioning324
- A. Executive Functioning325
- B. Processing Speed325
- C. Attention326
- D. Learning and Memory326
- E. Language and Visual Spatial Functioning327
- F. Differential Diagnosis327
- G. Treatment328
- III. Psychiatric Manifestations329
- A. Depression329
- B. Bipolar Disorder330
- C. Euphoria and Pathological Laughing and Crying331
- D. Psychosis and Maladaptive Personality Traits331
- IV. Quality of Life in MS331
- A. Fatigue332
- B. Pain333
- C. Sexual Dysfunction333
- D. Disease Progression and Quality of Life334
- E. Employment335
- F. Cognitive Impairment335
- References336
- Chapter 15: Cerebrospinal Fluid Analysis in Multiple Sclerosis341
- I. Introduction342
- II. Basic CSF Analysis343
- III. CSF Analysis for Immunoglobulins344
- IV. CSF Analysis for Prognostic and Therapeutic Response Biomarkers348
- References352
- Chapter 16: Multiple Sclerosis in Isfahan, Iran357
- I. Introduction358
- II. Materials and Methods360
- A. Study Area360
- B. Data Source360
- C. Diagnostic Criteria361
- D. Statistical Analysis362
- III. Results362
- A. Clinical and Demographical Features362
- B. Prevalence and Incidence362
- C. Laboratory Findings363
- D. Early-Onset MS365
- E. Late-Onset MS365
- F. Familial MS366
- G. Conjugal MS366
- IV. Discussion366
- A. Prevalence and Incidence366
- B. Laboratory Findings368
- C. Early Onset369
- D. Late-Onset MS369
- E. Familial MS370
- F. Conjugal MS370
- V. Conclusions371
- References371
- Chapter 17: Gender Issues in Multiple Sclerosis377
- I. Introduction378
- II. Sex Hormones380
- III. Sex Hormones in Animal Models381
- IV. MS and the Menstrual Cycle382
- V. MS and Pregnancy383
- VI. Effects of Pregnancy on MS Prognosis385
- VII. MS and Menopause386
- VIII. MS Symptoms in Females and Males387
- IX. Sex Hormones in Treatment of MS387
- X. Preventative Healthcare in MS388
- XI. Conclusion389
- References389
- Chapter 18: Differential Diagnosis of Multiple Sclerosis393
- I. Introduction394
- II. Differential Diagnosis of Inflammatory/Autoimmune Diseases395
- A. Systemic Lupus Erythematosus395
- B. Antiphospholipid (Hughes) Syndrome397
- C. Primary Sjogren's Syndrome398
- D. Neurosarcoidosis400
- E. Neuro-Behcet's Disease401
- F. Primary Angiitis of the CNS402
- G. Polyarteritis Nodosa403
- H. Wegener's Granulomatosis404
- I. Susac Syndrome404
- III. Differential Diagnosis of Infectious Etiologies405
- A. Lyme Disease (Neuroborreliosis)405
- B. Neurosyphilis406
- C. Progressive Multifocal Leucoencephalopathy406
- D. Tropical Spastic Paraparesis406
- E. HIV-Related Disorders of the CNS407
- IV. Differential Diagnosis of Genetic/Heriditary Disorders408
- A. Migraine408
- B. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy409
- C. Leber's Hereditary Optic Neuropathy410
- D. Mitochondrial Encephalomyopathy with Lactic Acidosis and Strokelike Episodes411
- V. Differential Diagnosis of CNS Neoplasms411
- VI. Differential Diagnosis of Dysmyelinating Disorders412
- A. Overview412
- B. Metachromatic Leukodystrophy413
- C. Krabbe's Leukodystrophy413
- D. Multiple Sulfatase Deficiency413
- E. Alexander Disease413
- F. Adrenoleukodystropy414
- G. Pelizaeus-Merzbacher Disease414
- VII. Differential Diagnosis Other Demyelinating Disorders415
- A. Neuromyelitis Optica (Devic's Disease)415
- B. Acute Disseminated Encephalomyelitis416
- C. Concentric Sclerosis (Balo's Disease)417
- D. Schilder's Disease418
- E. Optic Neuritis418
- VIII. Conclusions419
- References420
- Chapter 19: Prognostic Factors in Multiple Sclerosis423
- I. Introduction424
- II. Prognostic Factors at the Disease's Onset424
- A. Demographic Factors424
- B. Clinical Features427
- C. Neuroradiological Findings428
- D. Biological Markers433
- E. Neurophysiological Examinations433
- III. Prognostic Factors During the Early Phase/Course of the Disease434
- A. Clinical Features434
- B. Neuroradiological Findings436
- C. Biological Markers438
- IV. Conclusions439
- References441
- Chapter 20: Neuroimaging In Multiple Sclerosis449
- I. Introduction450
- II. Role of Conventional MRI in Detecting Inflammation and Neurodegeneration451
- A. Gd Enhancement451
- B. New Cell-Specific Contrast Agents453
- C. T2-Weighted MRI Scans454
- D. Cortical Demyelination458
- III. Role of Nonconventional MRI in Detecting Chronic Inflammation and Neurodegeneration460
- A. Hypointense Lesions on T1-WI460
- B. CNS Atrophy461
- C. Magnetization Transfer Imaging463
- D. Magnetic Resonance Spectroscopy464
- E. Diffusion Imaging465
- IV. Conclusions466
- Acknowledgments466
- References466
- Chapter 21: Detection of Cortical Lesions is Dependent on Choice of Slice Thickness in Patients with475
- I. Introduction476
- II. Methods478
- A. MRI Acquisition and Analysis479
- B. Statistical Analysis481
- III. Results481
- A. Cortical, Juxtacortical, and Cortical-Juxtacortical Lesion Volumes According to the Different Sli481
- B. Gray Matter Atrophy and Lesion Volumes482
- C. Relationship of Cortical, Juxtacortical, and Cortical-Juxtacortical Lesion Volumes to Disability483
- IV. Discussion483
- Acknowledgments486
- References486
- Chapter 22: The Role of Quantitative Neuroimaging Indices in the Differentiation of Ischemia From De491
- I. Introduction492
- A. Apparent Diffusion Coefficients493
- B. T2 Relaxometry493
- C. Edema and Neuroimaging Indices494
- D. Magnetic Resonance Spectroscopy495
- II. ADC and T2R in Acute Ischemia and Acute Demyelination495
- A. Introduction495
- B. Methods495
- C. Results496
- D. Discussion499
- III. ADC, T2R, and MRS in a Case of Posttraumatic Bilateral Intranuclear Ophthalmoplegia500
- A. Introduction500
- B. Case Report501
- C. Method502
- D. Results509
- E. Discussion513
- IV. Conclusions516
- References516
- Chapter 23: HLA-DRB 1ast1501, -DQB1ast0301, -DQB1ast0302, -DQB1ast0602, and -DQB1 ast0603 Alleles ar521
- I. Introduction522
- II. Methods524
- A. MRI Outcome Measures524
- B. HLA Typing525
- C. Statistical Analysis525
- III. Results526
- A. Demographic, MRI, and HLA Characteristics526
- B. Comparison of MRI Measures According to HLA Status526
- C. Relationship Between HLA Status and MRI Measures528
- IV. Discussion529
- Acknowledgments532
- References532
- Chapter 24: Glatiramer Acetate: Mechanisms Of Action In Multiple Sclerosis537
- I. Introduction538
- II. Pathology and Immunology538
- III. MS as Neurodegenerative Disease540
- IV. The Janus Face of CNS-Directed Autoimmune Inflammation542
- V. Neurotrophic Factors Are Released by Different Immune Cells544
- VI. Glatiramer Acetate: Historical Remarks546
- VII. GA: Overview of Clinical Studies547
- VIII. GA: Imaging Studies548
- IX. GA: Animal Models549
- X. GA in MS: Mechanisms of Action552
- A. Effects of GA by Binding to MHC Class II Molecules553
- B. Effects of GA on the APC Level553
- XI. Effects of GA on the B-Cell Level556
- XII. Effects of GA on the T-Cell Level557
- A. Th1-Th2 Shift558
- B. GA as Altered Peptide Ligand559
- C. Secretion of Neurotrophic Factors559
- D. Induction of GA-Specific CD8+ Suppressor T Cells561
- E. Induction of Regulatory CD4+CD25+ T Cells561
- XIII. Conclusions562
- References563
- Chapter 25: Evolving Therapies For Multiple Sclerosis571
- I. Introduction572
- II. Monoclonal Antibodies573
- A. Rituximab573
- B. Natalizumab573
- C. Daclizumab576
- D. Alemtuzumab577
- III. Statins579
- IV. Minocycline and Doxycycline580
- V. Vitamin D582
- VI. Fingolimod582
- VII. T-Cell Vaccination583
- VIII. Stem Cell Therapy584
- IX. Conclusions584
- References584
- Chapter 26: Remyelination In Multiple Sclerosis589
- I. What is Remyelination?590
- A. Remyelination in MS592
- B. Why is Remyelination Important?593
- II. Experimental Remyelination594
- A. Autoimmune Models594
- B. Viral Demyelination595
- C. Toxin-Mediated Demyelination595
- D. Genetic Models of Demyelination596
- III. The Biology of Remyelination is Complex597
- A. Remyelination Occurs in Distinct Phases597
- B. Factors Regulating OPC Activation and Proliferation598
- C. Factors Regulating OPC Differentiation600
- D. Inflammation: A Double-Edged Sword?601
- IV. What Causes Remyelination Failure in MS603
- V. MS Therapy: Strategies to Enhance Remyelination607
- A. Strategies to Stimulate or Enhance Endogenous Remyelination607
- B. Transplantation of Myelinogenic Cells609
- Acknowledgments612
- References612
- Chapter 27: Trigeminal Neuralgia: A Modern-Day Review621
- I. Introduction621
- II. Methods622
- III. Results and Discussion622
- A. Clinical Diagnosis622
- B. Imaging Diagnosis623
- C. Pathophysiology and Classification of TN623
- D. Differential Diagnosis624
- E. Treatment and Prognosis626
- IV. Conclusions629
- References629
- Chapter 28: Optic Neuritis And The Neuro-Ophthalmology Of Multiple Sclerosis633
- I. Disorders of the Afferent Visual System634
- A. Optic Neuritis634
- B. Chronic ON642
- C. Ocular Inflammation642
- D. Demyelination of the Optic Chiasm, Optic Tracts, and Optic Radiations645
- E. Higher Cortical Visual Dysfunction645
- II. Disorders of the Ocular Motor System646
- A. Diplopia647
- B. Nystagmus652
- C. Treatment of Nystagmus653
- D. Disorders of Saccades654
- III. Summary655
- Acknowledgments656
- References656
- Chapter 29: Neuromyelitis Optica: New Findings on Pathogenesis665
- I. Introduction666
- II. NMO: Evolution of Disease Definition and Spectrum666
- A. Historical Background666
- B. NMO-IgG Discovery and Revised NMO Diagnostic Criteria667
- C. The NMO Spectrum of Disorders670
- III. Evidence for Humoral Autoimmunity in NMO670
- A. Coexisting Systemic Autoimmune Disease and Serological Data671
- B. Human Immunopathologic Findings in NMO672
- C. Immunologic Studies in NMO673
- D. Animal Models with NMO-Like Pathological Patterns674
- E. The NMO-IgG Autoantibody Marker675
- F. Observations from Treatment Responses in NMO681
- IV. Conclusions684
- References685
- Index689
Multiple sclerosis (MS) is an immune-mediated neurodegenerative disorder of the human central nervous system (CNS) which usually affects young adults with certain genetic backgrounds who are then exposed to certain precipitating environmental antigen(s). Despite major advances of the past two decades in understanding the pathophysiology of MS, and in spite of the introduction of new immunomodulatory and immuno-suppressive agents which may slow down disease progression and delay the onset of disability, the “cause and the “cure for MS remain elusive. This volume of International Review of Neurobiology focuses on MS and related disorders. The volume can be divided into various sections with the main emphasis on MS pathogenesis, clinical features and epidemiology, neuroimaging, and treatment. The ultimate goal of this book is to encourage further research into the pathogenesis of this elusive disease.