NEUROLOGY IN PRACTICESeries editors Robert A. Gross & Jonathan W. Mink

Multiple Sclerosis and CNS Inflammatory Disorders

Edited byLawrence M. Samkoff and Andrew D. Goodman

Multiple Sclerosis and CNS Inflammatory Disorders(NEUROLOGY IN PRACTICE SERIES)

Multiple Sclerosis and CN

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www.wiley.com/wiley-blackwell

Lawrence M. Samkoff, MD, Associate Professor of Neurology at the School of Medicine and Dentistry,University of Rochester Medical Center, Rochester, NY, USA

Andrew D. Goodman, MD, Professor of Neurology, Chief of the Neuroimmunology Unit, and Director of the Multiple Sclerosis Center at the School of Medicine and Dentistry, University ofRochester Medical Center, Rochester, NY, USA

Multiple Sclerosis and CNS Inflammatory Disorders is a practical guide to effective care

of patients with multiple sclerosis and other neuroimmunologic and CNS inflammatory

disorders.

It provides the scientific basis of multiple sclerosis including etiology, epidemiology, and

pathogenesis. It covers the diagnostic process, the course of the disease and prognosis,

and the use of MRI in diagnosis and disease monitoring. Disease-modifying treatment

algorithms for relapsing-remitting multiple sclerosis, switching therapy, and progressive

multiple sclerosis treatment algorithms are all discussed in detail. It also addresses multiple

sclerosis in childhood and pregnancy and includes assessment of alternative therapies.

This new addition to the Neurology in Practice series contains practical guidance and

learning features:

Algorithms and guidelines

Tips and Tricks boxes on improving outcomes

Caution warning boxes to avoiding problems

Science Revisitedquick reminders of the basic science principles necessary for

understanding

Multiple Sclerosis and CNS Inflammatory Disorders is an ideal reference for neurologists

in practice and training.

201342File Attachment9780470673881.jpg

Multiple Sclerosis and CNS Inflammatory Disorders

NEUROLOGY IN PRACTICE:

SERIES EDITORS: ROBERT A. GROSS, DEPARTMENT OF NEUROLOGY, UNIVERSITY OF ROCHESTER MEDICAL CENTER, ROCHESTER, NY, USA

JONATHAN W. MINK, DEPARTMENT OF NEUROLOGY, UNIVERSITY OF ROCHESTER MEDICAL CENTER, ROCHESTER, NY, USA

Multiple Sclerosis and CNS Inflammatory DisordersEDITED BY

Lawrence M. Samkoff, MDAssociate Professor of NeurologyNeuroimmunology UnitDepartment of NeurologyUniversity of Rochester School of Medicine and DentistryRochester, NY, USA

Andrew D. Goodman, MDProfessor of NeurologyChief, Neuroimmunology UnitDepartment of NeurologyUniversity of Rochester School of Medicine and DentistryRochester, NY, USA

This edition first published 2014 2014 by John Wiley & Sons, Ltd

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Library of Congress Cataloging-in-Publication Data

Multiple sclerosis and CNS inflammatory disorders / edited by Lawrence M. Samkoff, Andrew D. Goodman. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-67388-1 (pbk.) I. Samkoff, Lawrence M., 1958 editor. II. Goodman, Andrew D., 1952 editor. [DNLM: 1. Multiple Sclerosis. 2. Central Nervous System Diseasesimmunology. 3. Neurogenic Inflammationphysiopathology. WL 360] RC377 616.834dc23

2014007073

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover image: iStockphoto.com/EraxionCover design by Sarah Dickinson Design

Set in 9.5/12.5pt Utopia by SPi Publisher Services, Pondicherry, India

1 2014

v

Contents

Contributors viiSeries Foreword xPreface xi

chapter 1 1

Etiology

Sonya U. Steele and Ellen M. Mowry

chapter 2 10

Immunopathogenesis of Multiple Sclerosis

Anne H. Cross and Laura Piccio

chapter 3 18

Diagnostic Process

Dalia Rotstein and Paul OConnor

chapter 4 29

MRI in Diagnosis and Disease Monitoring

Mara I. Gaitn and Daniel S. Reich

chapter 5 45

Relapsing MS: Disease Staging and Therapeutic Algorithms

Mohsen Khoshnam and Mark Freedman

chapter 6 57

Progressive MS Treatment Algorithms

Megan H. Hyland and Jeffrey A. Cohen

chapter 7 67

Sex-Determined Issues in Multiple Sclerosis

Callene Momtazee and Barbara Giesser

chapter 8 77

Pediatric Multiple Sclerosis

Robert Thompson Stone and Brenda Banwell

chapter 9 91

Complementary and Alternative Medicine: Risks and Benefits

Allen C. Bowling

chapter 10 102

Symptomatic Management of MS

Jessica Robb, Lawrence M. Samkoff, and Andrew D. Goodman

vi Contents

chapter 11 114

Invisible Symptoms of MS: Fatigue, Depression, and Cognition

Leigh E. Charvet, Benzi Kluzer, and Lauren B. Krupp

chapter 12 122

Rehabilitation

Nesanet S. Mitiku, Alexius E. G. Sandoval, and George H. Kraft

chapter 13 134

Psychosocial Adaptation to Multiple Sclerosis

David J. Rintell

chapter 14 144

Transverse Myelitis and Acute Disseminated Encephalomyelitis

Benjamin M. Greenberg

chapter 15 153

Neuromyelitis Optica

Marcelo Matiello and Brian G. Weinshenker

chapter 16 163

Neurosarcoidosis

Thomas F. Scott

chapter 17 169

Lyme Neuroborreliosis

Erica Patrick and Eric Logigian

chapter 18 178

Neuro-Behet Syndrome

Aksel Siva and Sabahattin Saip

Index 191

vii

Brenda Banwell MDDepartment of Pediatrics (Neurology)The Hospital for Sick ChildrenToronto, Ontario, Canada

Allen C. Bowling MDColorado Neurological InstituteEnglewood, CO, USA

Leigh E. Charvet PhDDepartment of NeurologyStony Brook MedicineStony Brook, NY, USA

Jeffrey A. Cohen MDMellen Center for Multiple Sclerosis Treatment and ResearchNeurological Institute, Cleveland ClinicCleveland, OH, USA

Anne H. Cross MDDepartment of NeurologyWashington University School of MedicineSt Louis, MO, USA

Mark Freedman MSc, MD, FAAN, FRCP(C)Multiple Sclerosis Research UnitUniversity of OttawaOttawa, Ontario, Canada

Mara I. Gaitn MDNational Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesda, MD, USAandDr. Ral Carrea Institute for Neurological ResearchFLENI, Buenos Aires, Argentina

Barbara Giesser MDDepartment of Neurology, MS DivisionUCLA School of MedicineLos Angeles, CA, USA

Andrew D. Goodman MDNeuroimmunology UnitDepartment of Neurology

University of Rochester School of Medicine and DentistryRochester, NY, USA

Benjamin M. Greenberg MD, MHSDepartment of Neurology and Neurotherapeutics andDepartment of PediatricsUniversity of Texas SouthwesternDallas, TX, USA

Megan H. Hyland MDNeuroimmunology UnitDepartment of NeurologyUniversity of Rochester School of Medicine and DentistryRochester, NY, USA

Mohsen Khoshnam MDMultiple Sclerosis Research UnitUniversity of OttawaOttawa, Ontario, Canada

Benzi Kluzer MDDepartment of NeurologyUniversity of ColoradoDenver, CO, USA

George H. Kraft MD, MSDepartment of Rehabilitation Medicineand NeurologyInstitute for Stem Cell and Regenerative MedicineUniversity of WashingtonSeattle, WA, USA

Lauren B. Krupp MDDepartment of NeurologyStony Brook MedicineStony Brook, NY, USA

Eric Logigian MDDepartment of NeurologyUniversity of Rochester Medical CenterRochester, NY, USA

Contributors

viii Contributors

Marcelo Matiello MD, MScDepartment of NeurologyMassachusetts General Hospital and Brigham and Womens HospitalHarvard Medical SchoolBoston, MA, USA

Nesanet S. Mitiku MD, PhDDepartments of Rehabilitation Medicine and NeurologyandCorinne Goldsmith Dickinson Center for Multiple SclerosisIcahn School of Medicine at Mount SinaiNew York, NY, USA

Callene Momtazee MDDepartment of Neurology, MS DivisionUCLA School of MedicineLos Angeles, CA, USA

Ellen M. Mowry MD, MCRDepartment of NeurologyJohns Hopkins UniversityBaltimore, MD, USA

Paul OConnor MDDivision of NeurologyInstitute of Medical ScienceandSt Michaels HospitalUniversity of TorontoToronto, Ontario, Canada

Erica Patrick MDDepartment of NeurologyUniversity of Rochester Medical CenterRochester, NY, USA

Laura Piccio MD, PhDDepartment of NeurologyWashington University School of MedicineSt Louis, MO, USA

Daniel S. Reich MD, PhDNational Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesda, MD, USA

David J. Rintell EdDPartners Multiple Sclerosis CenterBrigham and Womens HospitalandPartners Pediatric MS CenterMassachusetts General HospitalHarvard Medical SchoolBoston, MA, USA

Jessica Robb MDNeuroimmunology UnitDepartment of NeurologyUniversity of Rochester Schoolof Medicine and DentistryRochester, NY, USA

Dalia Rotstein MDDivision of Neurology Institute of Medical Scienceand St Michaels Hospital University of Toronto Toronto, Ontario, Canada

Sabahattin Saip MDDepartment of NeurologyCerrahpasa School of MedicineIstanbul UniversityCerrahpasa, Turkey

Lawrence M. Samkoff MDNeuroimmunology UnitDepartment of NeurologyUniversity of Rochester School of Medicine and DentistryRochester, NY, USA

Alexius E. G. Sandoval MDMaine Rehabilitation Outpatient CenterBangor, ME, USA

Thomas F. Scott MDDepartment of NeurologyDrexel University College of MedicineandAllegheny MS Treatment CenterPittsburgh, PA, USA

Contributors ix

Aksel Siva MDDepartment of NeurologyCerrahpasa School of MedicineIstanbul UniversityCerrahpasa, Turkey

Sonya U. Steele MScDepartment of NeurologyJohns Hopkins UniversityBaltimore, MD, USA

Robert Thompson Stone MDDepartment of NeurologyUniversity of Rochester Medical CenterRochester, NY, USA

Brian G. Weinshenker MD, FRCP(C)Department of NeurologyMayo ClinicRochester, MN, USA

x

Series Foreword

The genesis for this book series started with the proposition that, increasingly, physicians want direct, useful information to help them in clinical care. Textbooks, while comprehensive, are useful primarily as detailed reference works but pose challenges for uses at the point of care. By contrast, more outline-type references often leave out the hows and whyspathophysiology, pharmacologythat form the basis of management decisions. Our goal for this series is to present books, covering most areas of neurology, that provide enough background information to allow the reader to feel comfort-able, but not so much as to be overwhelming, and to associate that with practical advice from experts about care, combining the growing evi-dence base with best practices.

Our series will encompass various aspects of neurology, with topics and the specific content chosen to be accessible and useful.

Chapters cover critical information that will inform the reader of the disease processes and mechanisms as a prelude to treatment planning. Algorithms and guidelines are presented, when appropriate. Tips and Tricks boxes provide expert suggestions, while other boxes present cautions and warnings to avoid pitfalls. Finally, we provide Science Revisited sections that review the most important and relevant sci-ence background material, and references and

further reading sections that guide the reader to additional material.

We welcome feedback. As additional volumes are added to the series, we hope to refine the content and format so that our readers will be best served.

Our thanks, appreciation, and respect go out to our editors and their contributors, who conceived and refined the content for each volume, assuring a high-quality, practical approach to neurological conditions and their treatment.

Our thanks also go to our mentors and students (past, present, and future), who have challenged and delighted us; to our book editors and their contributors, who were willing to take on additional work for an educational goal; and to our publisher, Martin Sugden, for his ideas and support, for wonderful discussions and commiseration over baseball and soccer teams that might not quite have lived up to expectations. We would like to dedicate the series to Marsha, Jake, and Dan, and to Janet, Laura, and David. And also to Steven R. Schwid, MD, our friend and colleague, whose ideas helped to shape this project and whose humor brightened our lives; but he could not complete this goal with us.

Robert A. GrossJonathan W. Mink

Rochester, NY, USA

xi

Preface

The treatment of multiple sclerosis (MS) has been revolutionized by the expanding arma-mentarium of disease-modifying agents that have been developed over the past two decades. These advances have resulted from the rapidly increasing understanding of the pathogenesis of MS. It is in this context that we have under-taken to compose a text to assist the practicing neurologists in training in the day-to-day care of patients with MS and MS-like inflammatory disorders of the central nervous system (CNS), with a review of the essential basic science and clinical principles needed to provide that care.

Chapters 1 and 2 provide an excellent overview of the basic science, epidemiology, and patho-physiology of MS, focusing on immunologic, genetic, and environmental factors. Chapters 3 and 4 present the diagnostic approach to MS, with emphasis on current criteria that incorporate clinical, laboratory, and MRI data to fulfill the classic definition of MS as a disorder dissemi-nated in time and space. Chapter 5 reviews the rapidly changing therapeutic landscape for relapsing MS, which includes not only the original first-line injectable drugs (interferon beta and glatiramer acetate) but also monoclonal antibody infusions and oral agents. Chapter 6 then dis-cusses treatment strategies for patients with progressive forms of MS, a population that is arguably underserved by available medications. MS can also be differentiated on the basis of sex and age of presentation, with disease-specific features in women, men, and children that are expertly reviewed in Chapters 7 and 8.

Despite the great advances in MS disease modifying therapy, they generally do not relieve already established symptoms. In fact, most

people with MS are burdened with permanent and often fluctuating or worsening symptoms. Chapters 913 detail the management of the wide array of physical and neuropsychiatric MS-associated symptomatology, focusing on pharmacologic, alternative medicine, cognitivebehavioral, and rehabilitative approaches to patient care.

The diagnosis of MS implies that other diseases that mimic MS have been reliably excluded. The last section of the book, covered in Chapters 1418, addresses other primary and secondary CNS inflammatory disorders that can be confused with MS, highlighting their differentiating features and treatment options.

Throughout the book, we have strived to include easy-to-read Tips and Tricks and Science Revisited boxes, and algo-rithms to emphasize important and practical information that can be useful in the clinic. We thank our chapter authors for their superb contributions to this effort. We are grateful for the assistance of the staff at Wiley Publishing, and for the valuable comments of series editors, Dr. Robert Gross and Dr. Jonathan Mink, in the production of this textbook. We deeply appreciate the enduring support of Sharon and Jordan, and of Terry, Adam, and Sarah, and we dedicate this book to them. It is our hope that this text will be a valuable addition to the bookshelves of clini-cians caring for patients with MS and related illnesses.

Lawrence M. Samkoff, MDAndrew D. Goodman, MD

Multiple Sclerosis and CNS Inflammatory Disorders, First Edition. Edited by Lawrence M. Samkoff and Andrew D. Goodman. 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

1

EtiologySonya U. Steele and Ellen M. Mowry

Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

1

Background

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by the breakdown of the insu-lating myelin sheath that covers the nerve axons in the CNS and subsequent degeneration of axons. The process leads most commonly to intermittent neurological symptoms followed, over time, by progressive neurological symp-toms in many patients. MS affects approxi-mately 400,000 people in the USA and more than 2.1 million people worldwide, but the incidence has increased in the last five decades, particularly in women (3.6/100,000 person-years) compared to men (2.0/100,000 person-years) (Alonso & Hernan 2008; National Multiple Sclerosis Society 2012). While the eti-ology of MS is not understood in detail, it is unlikely to be the result of a single causative event. Instead, converging evidence suggests that MS is caused by an abnormal autoimmune response in genetically susceptible individuals after specific environmental exposures. Thus, it is not a heritable disease in the classic sense, but a complex disease that emerges from genes interacting with other genes and genes interact-ing with the environment. The factors thought to mediate the risk of MS are subject to intense ongoing research and include genetic, immu-nologic, infectious, and environmental contrib-utors. The aim of this chapter is to review the current data on MS risk factors, with particular

emphasis on those that may be modifiable on a personal or population level.

Genes

Familial aggregation is a well-recognized phenomenon in MS, and family and twin studies have long shown evidence for a strong genetic component underlying MS. This is illus-trated by the 2530% concordance among monozygotic twins, the 5% concordance among same-sex dizygotic twins, and the 3.5% concor-dance among nontwin siblings (Gourraud et al. 2012). However, the inheritance of MS cannot be explained by a simple genetic model, and

caution!

Over the years, many different causes for MS have been suggested, several of which have led to unfounded angst in those living with or at risk for developing MS. Here are some of the most popular theories that have not been proven to date (National Multiple Sclerosis Society 2012): Owning a dog or other small pet (canine

distemper) Allergies Exposure to heavy metals (e.g., mercury,

lead, or manganese) Physical trauma Aspartame

2 Etiology

neither the familial recurrence rate nor twin con-cordance supports the presence of a Mendelian trait. Rather, susceptibility is polygenic, with each gene contributing a relatively small amount of the overall risk. More than likely, genetic hetero-geneity (different susceptibilities among indi-viduals) also exists. Additionally, epidemiological data strongly hint at a parent-of-origin effect in MS: maternal half-siblings having double the risk for MS compared to paternal half-siblings (2.35% vs. 1.31%), while the risk for MS in maternal half-siblings compared to their full siblings does not differ significantly (Gourraud et al. 2012). The mechanism of the increased risk conferred maternally remains to be eluci-dated, but epigenetic mechanisms such as DNA methylation or histone modification may play a role (Handel et al. 2010).

The first direct evidence for a relationship between genes and MS susceptibility came in 1972, when MS was shown to be associated with the human leukocyte antigen (HLA) on chromosome 6p21 (encoding proteins involved in presenting peptide antigens to T cells) (Gourraud et al. 2012). This association was later fine-mapped to a specific locus, HLA-DRB1 of the class II gene HLA-DRB1 (Gourraud et al. 2012). Although the HLA-DRB*1501 haplotype exerts the strongest genetic effect in MS (heterozy-gosity conferring an odds ratio (OR) of 2.7 and homozygosity of 6.7), the association is not straightforward. In fact, a number of HLA-DRB1 haplotypes are both positively and negatively associated with the disease, differ in magnitude of effect, and either act on their own or greatly alter risk in combination with another haplotype (Kallaur et al. 2011). For example, HLA-DRB1*08 only modestly increases MS risk, but in combination with HLA-DRB1*15, it more than doubles the risk associated with a single copy of the latter (Kallaur et al. 2011). On the other hand, HLA-DRB1*14 carries such a protective effect that it completely abrogates the increased risk of HLA-DRB1*15 (Kallaur et al. 2011). And whereas association of MS with HLA-DRB1*15 has long been known in Northern Europe, in other regions, such as Sardinia, HLA-DRB1*0301, HLA-DRB1*0405, and HLA-DRB1*1303 are more commonly associated with MS (Kallaur et al. 2011). In fact, the relative frequencies of suscep-tibility and protective HLA haplotypes, which vary between countries, may play important roles in determining the risk of the disease.

It has been estimated that the HLA locus accounts for 2060% of the genetic susceptibility in MS, leaving a large portion of the genetic component of MS (still) to be explained. In 2007, the International Multiple Sclerosis Genetics Consortium (IMSGC) completed the first MS genome-wide association study (GWAS) using trios (an affected individual and both their parents) from the UK and the USA (Gourraud etal. 2012). In addition to the HLA-DRB1 region, two new risk loci were identified: the genes for interleukin-7 receptor alpha (IL-7RA) and interleukin-2 receptor alpha (IL-2RA), which have since been replicated. These genes code for the

science revisited

Maternal parent-of-origin effectMendelian traits are controlled by a single

locus and involve the transmission of one allele from both mother and father to a diploid offspring. This simple rule may not be followed in MS and other complex disorders, in which not only do multiple genes appear to contribute to susceptibility, but genomic imprinting may play an important role. Imprinting is an epigenetic process through which the expression of a gene is dependent on the sex of the parent from whom it was inherited. In other words, imprinted alleles are silenced such that the genes are either expressed only from the nonimprinted allele inherited from the mother or the father. Epidemiological data hint at a maternal parent-of-origin effect in MS. The mechanism of the increased risk conferred maternally remains to be elucidated, but epigenetic mechanisms that regulate genomic function (such as DNA methylation, RNA-associated silencing, and histone modifications) have been strongly implicated. Examples of other imprinted genetic disorders include PraderWilli/Angelman syndrome and RussellSilver syndrome.

Etiology 3

alpha chain of the IL-7 or IL-2 receptors, which promote lymphocyte growth and differentiation. MS-associated variants in the IL-2RA gene contribute to the production of soluble IL-2RA, a biomarker of peripheral inflammation. The IL-7/IL-7RA interaction is important for memory T-cell maintenance and development and proliferation and survival of Band T cells; the protective haplo-type is associated with less soluble IL-7RA; the risk allele thus likely produces a change in function (Gregory et al. 2007).

The most recent GWAS data from the IMSGC demonstrate at least 102 SNPs exerting a modest effect (OR, 1.061.22) (Gourraud et al. 2012). Most of the loci harbor genes with pertinent immunological roles, including several genes associated with other autoimmune disorders, consistent with the autoimmune hypothesis of MS etiology. Most notably, the results of the GWAS implicate genes coding for cytokine path-ways (CXCR5, IL-2RA, IL-7R, IL-7, IL-12RB1, IL-22RA2, IL-12A, IL-12B, IRF8, TNFRSF1A, TNFRSF14, TNFSF14) and for costimulatory (CD37, CD40, CD58, CD80, CD86, CLECL1) and signal transduction (CBLB, GPR65, MALT1, RGS1, STAT3, TAGAP, TYK2) molecules of immu-nological relevance (Gourraud et al. 2012). Of interest, at least two genes (KIF1B, GPC5) not involved in the immune system but instead with neuronal growth and repair mechanisms may also be associated with MS. These genes may influence the potential of remyelination of lesions, and their discovery gives a hint to a dis-turbance of repair mechanisms in addition to autoimmune processes in MS.

Still relatively little is known about how the identified MS risk variants exert their effects at the molecular and cellular levels. Their incom-plete penetrance and moderate individual effects probably reflect interactions with other genes, posttranscriptional regulatory mech-anisms, or significant environmental and epigenetic influences. Further genetic and functional studies are required to pinpoint the functionally relevant genes and pathways, to understand how these influence risk, and to determine if the genes themselves, or the downstream effects thereof, can be modified to alter MS risk.

Gender effects: Genetic or biologic?

MS is more prevalent in females than males, and this female predominance appears to have increased markedly over the past 100 years. Interestingly, the preponderance of females among MS patients is even seen in the pediatric MS population, especially after about the age of 10 years. The mechanisms underlying these observations are still incom-pletely understood, and most investigations have focused on the role of gonadal hormones. However, several other factors may be of key relevance, such as intrinsic biological differ-ences in the male and female immune system and CNS, genetic and epigenetic factors, maternal microchimerism, and differences in environmental exposures for males and females (e.g., higher numbers and changing roles of women in the workforce, outdoor activity, die-tary habits, and alterations in menarche and in the age of childbearing).

The role of the environment

Genetic factors account only partially for MSsus-ceptibility, as illustrated by the twin concordance data. Moreover, even among families, MS risk is known to be strongly influenced by location, season of birth, and the childhood environment. The environment thus appears to play an impor-tant role in setting thresholds for genetic pene-trance. Further, recent increases inMS incidence are too rapid to be the result of genetic alterations and must, therefore, reflect differential exposure to environmental factors (Alonso & Hernan 2008). In particular, the rising worldwide inci-dence and increasing female to male preponder-ance have focused interest on environmental factors that may influence MS risk.

Environmental MS risk factors: The major players

All of the environmental factors involved in MS are not yet known, but accumulating evidence lends strong support to several candidates, most notably sunlight and/or vitamin D exposure, EpsteinBarr virus (EBV), and cigarette smoking (Ascherio & Munger 2007a, b), with unconfirmed

4 Etiology

or hypothetical support for obesity, diet, and altered gut microbiota as risk factors. These factors could conceivably act to alter suscepti-bility to MS at any point in life from conception (or even before) to the onset of disease.

GeographyThe uneven geographical distribution of MS iscentral to understanding the role of environ-ment. The prevalence of MS increases with distance from the equator (Ascherio & Munger 2007b) and is greater in areas with temperate rather than tropical climates. Within regions oftemperate climate, MS incidence and prev-alence increase with latitude. Some of these observations may be explained by the non-random geographic distribution of racial/ethnic groups within these risk areas, such that what appears to be a latitudinal effect may be confounded by the genetic backgrounds of those who live in the various regions (i.e., racial/ethnic groups with a higher burden of risk alleles may be those who happen to live in regions of higher prevalence). However, migration studies demonstrate that moving from a region of high to low risk, or vice versa, leads to the adoption of the risk of the new region, especially if the migration occurred at a young age (Ascherio & Munger 2007b) such that at least part of the latitudinal gradient must be due to environmental differences.

One of the strongest correlates of latitude is the duration and intensity of sunlight. Thus, it is not surprising that an inverse correlation between MS prevalence and sunlight was already noted in early ecological studies; among US veterans, the average annual hours of sunshine and the average December daily solar radiation at place of birth were strongly inversely correlated with MS (Ascherio & Munger 2007b). Furthermore, several retrospective studies have demonstrated that sun exposure during childhood and adoles-cence as well as outdoor activity as an occupa-tional exposure is inversely related to MS susceptibility (Ascherio & Munger 2007b). The protective effects of sunlight are thought to be mediated by ultraviolet radiation (UVR), possibly via vitamin D (see section Vitamin D).

Migration studies and timing of environmental effectWhile early migration studies suggested that migration prior to age 15 is critical to altering the risk of MS (Ascherio & Munger 2007b), more recent data suggest that the critical age period might even extend into the third decade. These intriguing findings suggest that MS risk factors may operate in childhood and beyond puberty, suggesting a more prolonged period of vulnerability (but notably also for potential intervention). There may also be transgenera-tional epigenetic modifications that influence MS risk, which could potentially be influenced by factors such as diet or sex hormones (Ascherio & Munger 2007b). Studies in UK migrants followed from gestation to the third decade of life suggest risk increases in the subsequent generation (Elian et al. 1990). Gestational or early life timing as a vulnerable period is also suggested by a marginally significant excess risk in dizygotic twins compared with nontwin siblings, coupled with evidence for maternal effects. More direct evidence comes from studies of month of birth in several northern countries, which have latitude-correlated increased risks for spring births and decreased risks for late fall births (Willer et al. 2005). The polarity of this distribu-tion reverses in the southern hemisphere. Moreover, unaffected sibling controls differ in birth-month distribution from the general population as much as their affected brothers and sisters did but in the opposite direction (Willer et al. 2005). Since serum concentrations of vitamin D fluctuate in parallel with seasonal changes in exposure to ultraviolet B (UVB) light, this month of birth effect might reflect maternal end-of-winter deficiencies in vitamin D or in UVB itself. Taken together, these striking findings suggest that risk might be influenced in each of the periods of gestation, childhood, adolescence, and early adulthood. In addition to uncertainties regarding the exact timing of an exposure, it is unclear if exposure needs be discrete or prolonged. Since MS incidence peaks in early adulthood and then declines, risk cannot be determined by age-related

Etiology 5

mutations. Nevertheless, these data do not rule out a type of environmental imprinting, or that susceptibility (and resistance) could be entrained by cumulative exposures of (more than one) factors in the environment.

Vitamin D

It has become increasingly clear that vitamin D has a wide role in physiology and, importantly, also in disease. Evidence is mounting in support of vitamin D deficiency underlying risk for several autoimmune diseases. The pleiotropic actions of vitamin D, including immunomodulatory functions, lend strong support to the hypothesis that this hormone is important in the etiology of MS.

For most people, skin exposure to sunlight is the major source of vitamin D and the most important predictor of vitamin D status. Several observations support that vitamin D insuffi-ciency is a risk factor for MS: (1) MS prevalence increases as distance from the equator increases (corresponding with a decrease in sunlight exposure) (Ascherio & Munger 2007b); (2) those who migrate adopt the risk of the new area (Kurtzke et al. 1985); (3) UVB radiation (the main source of vitamin D) and skin cancer are inversely correlated with MS risk (Ascherio & Munger 2007b); (4) vitamin D intake signifi-cantly decreases the risk of MS (Munger et al. 2004); and (5) vitamin D levels inversely correlate with risk of MS later in life (Munger et al. 2006).

The strongest evidence for a role for vitamin D comes from a, nested case-control study among US military personnel showing that higher vitamin D levels conferred a lower subsequent risk of MS (Munger et al. 2006). Further evidence to support a protective effect of vitamin D on MS risk comes from the longitudinal Nurses Health Study: those with intake of vitamin D of at least 400 international units (IU)/day had a relative risk (RR) for MS of 0.59 compared with those who did not take supplemental vitamin D (Munger et al. 2004). Although confounding by unknown factors cannot be excluded, these cohort data strongly support a protective effect of vitamin D on MS risk. Ecological studies in coastal fishing areas in Norway have shown that inhabitants of these areas have lower MS prevalence than their neighbors dwelling in inland agricultural communities, which may be explained by their greater consumption of fatty seafood and cod liver oil, both rich in vitamin D (Kampman et al. 2007).

science revisited

Vitamin DThe main source of vitamin D in humans

is skin exposure to sunlight (hence its nickname, the sunshine vitamin), although it can also be obtained through the diet (e.g., through oily fish such as salmon, tuna, and mackerel, as well as cod liver oil) and from supplements. Previtamin D3 is formed in the skin upon exposure of 7-dehydrocholesterol to UVB radiation and is then converted to vitamin D3. Vitamin D from sun exposure and diet is hydroxylated (predominantly) in the liver to produce calcidiol (25(OH)D), the major circulating form of vitamin D. Since calcidiol is biologically inert, it requires further hydroxylation (predominantly) in the kidney to form the physiologically active form of vitamin D, calcitriol (1,25(OH)2D), alipid-soluble secosteroid. Calcitriol is generally not used as an indicator of vitamin D status because it has a short half-life (15 h), and serum concentrations are closely regulated for purposes of calcium homeostasis. Calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells and acts

as a transcription factor that modulates gene expression. Vitamin D also affects the immune system, and VDRs are expressed in several cells involved in innate and adaptive immune responses, including monocytes, dendritic cells, and activated T and B cells.

6 Etiology

There is also functional evidence associating vitamin D and MS. There is a vitamin D response element (VDRE) close to the pro-moter region of HLA-DRB1, and calcitriol (the active form of vitamin D) modulates the expression of the particular allele most consis-tently associated with increased risk of MS, HLA-DRB1*1501 (Ramagopalan et al. 2009). While the in vivo functional consequence of this finding is yet to be determined, it does form a conceptual basis for an environmentgene interaction in the determination of MS risk. The HLA-DRB1*15 risk allele also inter-acts with the season of birth such that the reported relationship with risk of MS appears to be predominately driven by those carrying at least one copy of the DRB1*15 risk allele (Ramagopalan et al. 2009). In addition, a recent GWAS found association with genetic regions containing vitamin D metabolism genesCYP24A1 and CYP27B1 (Gourraud etal. 2012)providing more evidence for the potential role for vitamin D in MS. However, some data suggest that UV light may exert effects on MS risk independent of vitamin D status, such that some or all of the geographic distribution of MS thought to be due to UV-determined vitamin D levels could in fact be due to another UV-mediated mechanism.

Infection

That MS might be triggered by infection is supported by presence of high concentrations of a number of IgGs in the cerebrospinal fluid (CSF) of more than 90% of MS patients that are not present in the blood (oligoclonal bands), indicative of immune activation. Indirect support for a role of infection in MS is that viruses have been associated with other human and experimental demyelinating dis-eases. Although dozens of pathogens have been investigated as MS risk factors, it is still not clear which, if any, are definitively etiologic. That being said, there is strong support for EBV infection as important to disease risk in many MS patients.

EpsteinBarr virusA link between EBV and MS was first proposed to explain the striking similarity between the epidemiology of IM and that of MS in terms of age, geographical distribution, socioeconomic status, and ethnicity (Ascherio & Munger 2007a). IM, like MS, is rare in developing countries and, more generally, in conditions of poor hygiene, in which virtually all children are infected with EBV in the first years of life (prior to the age at which symptomatic infection with EBV, or IM, occurs). In contrast, IM is common in Western countries, in which about 50% of individuals escape early EBV infection and acquire it during

science revisited

EpsteinBarr virusEBV, also known as human herpesvirus-4

(HHV-4), belongs to the gamma-herpesvirus family, which includes herpes simplex virus and cytomegalovirus. EBV is present in all populations and infects over 90% of individuals at some point in their life. Its discovery dates to the early 1960s, where it was isolated in lymphoma cells cultivated from tumor biopsies obtained from African children with jaw tumors. Primary infection usually occurs through contact with infected saliva and is asymptomatic in young children, but in up to 40% of adolescents and adults, it results in the symptomatic illness infectious mononucleosis (IM), an acute and usually self-limited lymphoproliferative disease. Since EBV preferentially infects B lymphocytes and persists lifelong in a transcriptionally quiescent state in circulating memory B cells, it goes largelyundetected by the immune system.By immortalizing autoreactive Bcells, which act as professional antigen-presenting cells, it is thought that EBV may drive persistent autoimmunity, possibly through antigen mimicry, immortalization of B-cell clones, and cytotoxic T-cell dysfunction against viral-infected B cells.

Etiology 7

adolescence and young adulthood. In these countries, MS risk is two- to threefold higher among individuals with history of IM (Ascherio & Munger 2007a).

Although more than 90% of the general population appears to encounter EBV at some point in life, several lines of evidence highlight its possible role in the pathogenesis of MS. Large, independent studies have shown that nearly all (>99%) adults with MS are seropositive for antibodies directed against EBV, while the seropositivity rate is slightly lower in unaffected adults. The strongest evidence for the association with MS, however, comes from a nested case-control study of healthy individuals infected with EBV, whose subsequent MS risk increases by severalfold with increasing serum titers of anti-EpsteinBarr nuclear antigen (EBNA) com-plex and anti-EBNA-1 antibodies (Ascherio & Munger 2007a). These data show that EBV seroconversion predates MS onset. A history of EBV-induced IM increases the risk of devel-oping MS, particularly in individuals who develop IM after the age of 15 years. Given the observation that EBV-negative individuals (likely to be exposed to the highest levels of hygiene) have the lowest risk of MS makes the hypothesis that good hygiene during childhood may predis-pose both to MS and to a later contact with EBV and therefore IM unlikely (Ascherio & Munger 2007a). However, whether the link between MS and EBV infection is actu-ally causal or merely represents an association continues to be debated. In adults who are sero-negative for EBV, there seems to be virtually no risk of developing MS (Ascherio & Munger 2007a). However, while a recent investigation of pediatric MS patients showed that EBNA-1 sero-positivity is associated with an increased risk of developing MS,not all individuals with MS were positive forEBV, suggesting that infection with EBV is not necessary for all cases of MS (Waubant etal. 2011).

It is important to note that IM is also not sufficient to cause MS; since the large majority of individuals are infected with EBV, but only a relatively small percentage will ever get MS, other genetic and environmental factors must

be critical for MS development. Indeed, the HLA-DRB1*1501 allele has been shown to interact with high levels of EBV antibodies in its association with greater risk of MS (De Jager et al. 2008). Evidence suggests that there may be a synergistic effect of vitamin D and IM on MS risk, possibly by an alteration of the initial education of the immune system or of the subsequent immune response to EBV infection in vitamin D deficient states or by EBV itself potentiating the effects of vitamin D deficiency, leading to autoimmunity.

Other virusesWhile several studies of adult MS have attempted to link other viruses to MS risk, the results have been inconclusive. On the other hand, the pediatric MS study described earlier found that, independent of EBV status, remote infection with CMV was associated with a lower risk of developing MS and that HSV-1 status interacted with HLA-DRB1 in predicting MS, such that HSV-1 positivity was associated with a greater MS risk in those without a DRB1*15 allele and a reduced risk in those who were DRB1*15 positive (Waubant et al. 2011). These results need confirmation, but the totality of data suggests that there might be a complex interplay between various viral infections acquired during childhood and MS risk.

Smoking

Cigarette smoking has been shown to sizably increase susceptibility to MS in multiple studies (Ascherio & Munger 2007b). The most recent meta-analysis examining the effect of past or current smoking on MS susceptibility reported an RR between 1.3 and 1.8 associated with smoking (Ascherio & Munger 2007b). The smoking effect appears to be independent of gender (Hedstrom et al. 2009)) as well as of latitude and ancestry (Ascherio & Munger 2007b). The risk of MS increases with cumulative doses of cigarettes. Even children ever exposed to parental smoking have been found to have a higher risk of developing MS (Mikaeloff et al. 2007).

8 Etiology

The mechanism relating cigarette smoking to MS risk is unclear. Smokeless tobacco (snuff ) use has not been found to increase the risk of MS (Hedstrom et al. 2009), suggesting that the effect does not appear to be mediated solely by nicotine, but perhaps by components of the actual cigarette smoke, such as nitric oxide, which has putative roles in demyelin-ation and axonal loss. Animal models have also indicated that smoke exposure affects several facets of the immune system, including innate immunity, B and T lymphocytes, and natural killer cells, so a direct impact of smoking on immune function is possible. Recent studies are just beginning to shed light on how smoking interacts with other factors in influencing MS risk.

Combining risk factors

While genetic and environmental risk factors clearly act together to influence MS risk, they have rarely been studied concomitantly, and much remains to be discovered about their respective contributions to or possible interplay in disease susceptibility. To date, the most comprehensive attempt at mathematically modeling risk factors to improve the prediction of MS was that by De Jager and colleagues, who attempted to combine 16 genetic risk loci, sex, smoking, and anti-EBNA-1 titers into a prediction model (DeJager et al. 2009). Overall, their data suggest that information obtained from MS susceptibility loci might provide useful if incorporated into clinical algorithms that contain other information, such as detailed immunological characteriza-tions and environmental risk factors. More studies in large cohorts are needed to better understand the combined predictive power of risk factors.

Conclusion

Understanding the etiology of MS requires solv-ing the complex genetics underlying the disease as well as advancing the understanding of the environmental components of its etiology. More information is needed on how the growing set of genetic susceptibility factors is affected by envi-ronmental risk factors such as EBV infection, smoking, and vitamin D status. Advances in genetics, immunology, and cell biology are greatly adding to the understanding of MS, and large national and international collaborations are underway to characterize the precise nature and extent of the multifaceted interactions bet-ween these known risk factors, as well as uncov-ering yet unknown ones. In recent years, the emphasis has increasingly been on identifying modifiable risk factors and translating these findings to the clinic. Thus, low circulating levels of vitamin D and cigarette smoking, clearly modifiable, are promising targets for the prevention and treatment of MS.

Acknowledgment

Dr. Mowry is funded by NIH K23NS067055.

science revisited

Cigarette smokingCigarette smoking is the most important

preventable cause of premature disability and death in much of the world. Smokers have a higher prevalence of common diseases such as chronic obstructive pulmonary disease (COPD) and atherosclerosis, as well as some autoimmune diseases. How smoking may be related to the increased incidence of MS is unclear. The link may depend on the immunomodulatory effects of smoking, a direct effect of cigarette smoke components on the bloodbrain barrier, or directly toxic effects on the CNS. A low-grade systemic inflammatory response is evident in smokers: elevated levels of C-reactive protein (CRP), interleukin-6, fibrinogen, as well as increased counts of WBC have been reported. Furthermore, coagulation and endothelial function markers like fibrin d-dimer, hematocrit, blood and plasma viscosity, circulating adhesion molecules, tissue plasminogen activator antigen, and plasminogen activator inhibitor type I are altered in chronic cigarette smokers.