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This book is dedicated to the brave individuals and their families who cope with multiple sclerosis and its uncertainties on a daily basis.


Approximately 400,000 individuals in the United States and two million people worldwide have multiple sclerosis.

Up until 1993, no drugs were available to alter the course of this often debilitating disease. Much has changed since that time. Over the last decade, six drugs have been approved in the United States for the treatment of multiple sclerosis and, fortunately, more are on the horizon. Although not curative, these drugs decrease the frequency and, in some instances, the severity of acute attacks, slow the rate of neurological deterioration, at least for the short term, and diminish the number of new lesions seen on magnetic resonance imaging studies. For the first time, patients can look forward to at least partial control of their illness and the likelihood that newer and better drugs will be available in the near future. Despite this progress, many questions still remain to be answered. Fundamental issues such as determining the cause of multiple sclerosis, defining the precise mechanism of tissue injury, and understanding ways to promote regeneration of myelin and axons need to be resolved before multiple sclerosis can be controlled or cured and, hopefully, a patient's neurological disability can be reversed. Advances in molecular biology, genetics, chip technology, proteinomics, nanotechnology, informatics, neuroimag-ing, and the availability of patient databases have provided the necessary tools for resolving these issues in a timely fashion.

The fourth edition of the Handbook of Multiple Sclerosis updates the reader as to current knowledge about basic and clinical aspects of multiple sclerosis, therapeutic advances, and prospects for future research directives. As with previous editions, the fourth edition is meant to be a comprehensive reference book for practitioners, scientists, students, and patients and their families. I am very grateful to the contributors, who are world leaders in multiple sclerosis research and treatments.

Stuart D. Cook


The editor appreciates the work and effort provided by Ms. Mary Perez in making this edition of the Handbook of Multiple Sclerosis possible.


Preface . . . . v Acknowledgment . . . . vii Contributors xvii


1. Etiopathogenesis and Epidemiology: Clues to Etiology 1

William Pryse-Phillips and Scott Sloka Introduction 1

Familial Factors and Genetic Susceptibility 2 Prevalence and Incidence Studies 6 Intercurrent Factors with Possible Association 13 Natural History and Clinical Variability . . . . 22 Clues to Etiology 25 References 30

2. Genetics: Susceptibility and Expressivity 41

Thomas Masterman and Jan Hillert Susceptibility 41 Expressivity 49 Prospects . . . . 50 References . . . . 56

3. Evidence for an Infectious Etiology of Multiple Sclerosis 65

Stuart D. Cook

Evidence for an Infectious Etiology 67

Possible Mechanisms of Virus-Induced

Demyelination . . . . 70 Candidate Agents in MS . . . . 73 Conclusion 85 References 85

4. Multiple Sclerosis: An Autoimmune Disease of the

Central Nervous System? 95

John R. Rinker II, Robert T. Naismith, and Anne H. Cross Introduction 95 Epidemiology 96

Pathology Suggests an Autoimmune Etiology 96 Genetic Evidence Supporting Autoimmunity in MS ... . 97 Evidence for T-Cell Mediated Autoimmunity in MS ... . 98 Humoral Immunity as Indirect Evidence for

Autoimmunity in MS ... . 101 Response to Immunosuppressive Therapies Suggests an

Autoimmune Etiology 103 The Autoimmune Hypothesis Is Supported by

Animal Models . . . . 103 Summary 104 References . . . . 105


Claudia F. Lucchinetti and Joseph E. Parisi Introduction . . . . 113

How Does Stage of Demyelinating Activity Relate to Clinical

Phase of the Disease? 114 What Is the Pathogenic Role of Inflammation in MS? 119 What Is the Fate of the Oligodendrocyte and Extent of

Remyelination in MS Lesions? 121 Is There Evidence for Pathologic Heterogeneity in MS? 123 Does Pathologic Heterogeneity Reflect Pathogenic

Heterogeneity in MS? 128 What Is the Substrate of Irreversible Disability in MS? 130 The Inflammatory Demyelination/Neurodegeneration

Paradox 130 What Is the Spectrum of Idiopathic Inflammatory Demyelinating

Diseases? 136 What Do New Molecular Studies Tell Us About the

MS Lesion? 141 Conclusion 143 References 143

6. Clinical Features 153

Aaron E. Miller Introduction 153 Diagnosis 153 Age of Onset ... . 158 Clinical Manifestations 158 Course 166 Pregnancy 168 References 169

7. MRI Techniques in Multiple Sclerosis: Role in Diagnosis,

Pathophysiology, and Therapy 179

Massimo Filippi, Federica Agosta, Beatrice Benedetti, and Maria A. Rocca Introduction 179

A Brief Review of Basic Aspects of Nonconventional MRI

Techniques 182 The Role of MRI in the Diagnosis and Prognosis of MS ... . 185 The Role of MRI in Understanding MS

Pathophysiology 194 MRI in Monitoring Treatment Efficacy in

MS Trials 204 Conclusions 207 References 208

8. Multiple Sclerosis Biomarkers 223

Introduction 223 Potential Biomarkers 226 Neuroimaging . . . . 235 Conclusion . . . . 236 References . . . . 236

9. Evoked Potentials

Marc R. Nuwer Introduction 243 Visual Evoked Potentials 244 Brainstem Auditory Evoked Potentials Somatosensory Evoked Potentials . . . Motor EPs . . . . 252 Event-Related Potentials . . . . 253 Multimodality EP Testing . . . . 253 Use of EPs in MS Therapeutic Trials . References 260

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