Neurology REPORT. The. 66 th Annual Meeting of the American Academy of Neurology. Selected Reports from the. Guest Editor

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1 v o l u m e 7 n u m b e r 1 S u m m e r The Neurology REPORT Selected Reports from the 66 th Annual Meeting of the American Academy of Neurology Michael K. Racke, MD Guest Editor ConTInuING EDUCATIon For PHYSICIANS and nurses: 2.5 CreDITS AVAILAble This activity is supported by an educational grant from Biogen Idec.

2 Guest Editor: Michael K. Racke, MD The opinions or views expressed in this publication are those of the authors and do not necessarily reflect the opinions or recommendations of Biogen Idec, the University of Cincinnati, or the publisher, Direct One Communications, Inc. Please consult the full prescribing information before using any medication mentioned in this publication. This publication was made possible through an educational grant from Biogen Idec. Copyright 2014 by Direct One Communications, Inc. All rights reserved. Printed in the USA.

3 V O L U M E 7 N U M B E R 1 S U M M E R The Neurology REPORT Selected Reports from the 66 th Annual Meeting of the American Academy of Neurology Michael K. Racke, MD, Guest Editor 4 Introduction Michael K. Racke, MD The Ohio State University College of Medicine, Columbus, Ohio Advances in Basic and Translational Science Research in Multiple Sclerosis Salim Chahin, MD, MSCE University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania The Evolution in Diagnosis and Treatment of Multiple Sclerosis Tiffani Stroup, DO University of Chicago Medicine, Chicago, Illinois Current and Emerging Therapies for Multiple Sclerosis William Meador, MD University of Alabama at Birmingham School of Medicine, Birmingham, Alabama Dimethyl Fumarate and Peginterferon β-1a: New Insights Into the Pivotal Trials Pavan Bhargava, MD Johns Hopkins University School of Medicine, Baltimore, Maryland Symptomatic Management of Multiple Sclerosis Ariel Antezana, MD Multiple Sclerosis Comprehensive Care Center, NYU Langone Medical Center, New York, New York CME/CNE Post Test and Evaluation T H E N E U R O L O G Y R E P O R T S u m m e r

4 About This CME/CNE Activity RATIONALE AND PURPOSE The US Food and Drug Administration (FDA) first approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) over two decades ago. Currently, the available armamentarium can limit the frequency of relapses and improve patient quality of life but can do little to stop progression of the disease. However, clinical researchers and drug companies are striving to develop therapies that can halt the disease and provide a greater degree of normalcy to patients with MS, based on our growing understanding of what causes the disease on a molecular level. The articles in this edition of The Neurology Report turn the spotlight on the neuroimmunologic, environmental, and genetic roots of MS; approaches to achieving an accurate MS diagnosis; commonly reported symptoms of MS and their current management; the results of clinical trials evaluating the safety and efficacy of newer DMT regimens in patients with relapsing-remitting MS; and future research directions for improving the clinical management of MS. These reports, based upon presentations delivered during the 66 th Annual Meeting of the American Academy of Neurology, held April 26 to May 3, 2014, in Philadelphia, Pennsylvania, cover strategies that need to be considered by all members of multidisciplinary teams caring for MS patients, including neurologists, radiologists, immunologists, nurses, and physical and occupational therapists. The articles in this edition, written from the academic perspective of physicians-in-training at leading medical institutions, summarize the import of these new findings and place them into clinical context. This activity has been developed and approved by a planning committee of nationally recognized thought leaders to meet a perceived educational need to provide neurologists, other physicians, and nurses with diagnostic and therapeutic strategies to help them perform their clinical roles. LEARNING OBJECTIVES After studying this issue of The Neurology Report, participants in this educational activity should be able to: Explain current theories on the pathogenesis of MS, its physical symptoms, and potential strategies to slow or reverse nerve damage. Describe the results of pivotal clinical trials evaluating dimethyl fumarate, pegylated interferon β-1a, and other promising drugs in MS patients. Summarize common symptoms experienced by MS patients and best current practices for providing comfort and stability and preserving independence. Review current and future directions for MS research, considering treatment optimization, molecular targets, and neurologic reparation. TARGET AUDIENCE Neurologists, other physicians, and nurses significantly involved in the diagnosis and management of MS should find participating in this educational activity valuable. ACCREDITATION AND CREDIT DESIGNATION Physicians: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the University of Cincinnati and Direct One Communications, Inc. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians. The University of Cincinnati designates this Enduring Material Activity for a maximum of 2.5 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nurses: A total of 2.5 continuing education contact hours for nurses are approved by the Ohio Board of Nursing (OBN) through the OBN Approver Unit at the University of Cincinnati College of Nursing, Continuing Education Program (OBN ). Contact hours are valid in most states. Program # CREDIT AVAILABILITY Activity release date: August 5, 2014 Expiration date: August 6, 2015 METHOD OF PARTICIPATION This Enduring Material Activity is available in print and online at and consists of an introduction, five articles, a postactivity assessment, and an evaluation. Estimated time to complete the activity is 2.5 hours. To receive credit, participants must read the CME information on these two pages, including the learning objectives and disclosure statements, as well as the full content of this monograph, and then complete the post test and evaluation form online at Upon successful completion of the post test (80% correct) and evaluation form, a certificate of participation will be awarded automatically. The certificate 2 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

5 About This CME/CNE Activity may be printed directly from the Web site or ed and printed later. There are no fees for participating in or receiving credit for this activity. CME REVIEWER Rick Ricer, MD Adjunct Professor of Family Medicine University of Cincinnati Cincinnati, Ohio CME ACCREDITATION Susan P. Tyler, MEd, CMP, CCMEP Director, Continuing Medical Education University of Cincinnati Cincinnati, Ohio FACULTY DISCLOSURES All faculty members (or anyone else in a position to control content, such as activity planners) are required to complete a Disclosure of Commercial Interest and Resolution form and to cooperate with identified methods for resolving conflict of interest prior to participating in the activity. The University of Cincinnati requires disclosure to the learners of all relevant financial relationships and adheres strictly to the ACCME Standards for Commercial Support. Michael K. Racke, MD, is Professor of Neurology and Neuroscience at The Ohio State University College of Medicine, Columbus, Ohio. Dr. Racke is a consultant to Acorda Therapeutics, Biogen Idec, Novartis, Revalesio, and Teva Neuroscience and has received grant support from DioGenix, the National Institutes of Health, the National Multiple Sclerosis Society, and Novartis. Salim Chahin, MD, MSCE, a Multiple Sclerosis Fellow in the Department of Neurology at the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, has nothing to disclose. Tiffani Stroup, DO, a Multiple Sclerosis Fellow in the Department of Neurology, University of Chicago Medicine, Chicago, Illinois, has nothing to disclose. William Meador, MD, a National Multiple Sclerosis Society Clinical Care Fellow in Neuroimmunology at the University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, has nothing to disclose. Pavan Bhargava, MD, a Neuroimmunology Fellow in the Department of Neurology at Johns Hopkins University School of Medicine, Baltimore, Maryland, has nothing to disclose. Ariel Antezana, MD, a Multiple Sclerosis Fellow in the Multiple Sclerosis Comprehensive Care Center and Clinical Instructor of Neurology, NYU Langone Medical Center, New York, New York, has nothing to disclose. Rick Ricer, MD, has nothing to disclose. Susan P. Tyler, MEd, CMP, CCMEP, has nothing to disclose. Jacqueline Keenan and Edwin Geffner of Direct One Communications, Inc., have nothing to disclose. DISCLAIMER This activity is an independent educational activity under the direction of the University of Cincinnati. The activity was planned and implemented in accordance with the accreditation requirements and policies of the ACCME, the Ethical Opinions/Guidelines of the American Medical Association, the US Food and Drug Administration (FDA), the Office of Inspector General of the US Department of Health and Human Services, and the Pharmaceutical Research and Manufacturers of America Code on Interactions With Healthcare Professionals, thus assuring the highest degree of independence, fair balance, scientific rigor, and objectivity. However, the planning committee, faculty, University of Cincinnati, Biogen Idec, and Direct One Communications, Inc. shall in no way be liable for the currency of information or for any errors, omissions, or inaccuracies in this activity. The opinions and recommendations presented herein are those of the faculty and do not necessarily reflect the views of the provider, producer, or grantor. Participants in this activity are encouraged to refer to primary references or full prescribing information resources. DISCLOSURE OF UNAPPROVED/OFF-LABEL USE Discussions concerning drugs, dosages, devices, and procedures may reflect the clinical experience of the planning committee or faculty, may be derived from the professional literature or other sources, or may suggest uses that are investigational and not approved labeling or indications. A number of the drugs mentioned in this edition of The Neurology Report have not been approved by the FDA for use in the treatment of patients diagnosed with MS. They include ocrelizumab, riluzole, amiloride, ibudilast, alemtuzumab, peginterferon β-1a, daclizumab, and laquinimod, as well as several drugs used off-label to treat some of the symptoms of MS. These investigational or otherwise unapproved uses are clearly identified in the text. CONTACT INFORMATION We would like to hear your comments regarding this or other educational activities produced by Direct One Communications, Inc. In addition, suggestions for future activities are welcome. Contact us at: Direct One Communications, Inc Ridge Road Syosset, NY Phone: Fax: Website: T H E N E U R O L O G Y R E P O R T S u m m e r

6 Introduction Selected Reports from the 66 th Annual Meeting of the American Academy of Neurology Michael K. Racke, MD, Guest Editor The Ohio State University College of Medicine, Columbus, Ohio Dr. Racke is Professor of Neurology and Neuroscience at The Ohio State University College of Medicine, Columbus, Ohio. M ultiple sclerosis (MS) is a chronic, potentially devastating disease caused by a complex interaction of genetic, environmental, and immunopathologic factors. Over the past two decades, laboratory researchers and clinical investigators have discovered new clues that extend far beyond simple descriptions of MS as a demyelinating disease of the central nervous system. Strides in imaging and histologic techniques, characterization of the disease in younger and older patients, physiotherapy, and novel pharmacologic agents offer new hope for an eventual cure and even reversal of the ravages of MS. Over 11,000 researchers, physicians, nurses, pharmacists, and other allied health professionals met in Philadelphia, Pennsylvania, from April 26 to May 3, 2014, to attend the 66 th Annual Meeting of the American Academy of Neurology (AAN). As the largest international meeting of neurologists and neuroscience professionals, this conference offered numerous poster and abstract sessions, workshops and courses, symposia, and roundtable discussions to explain basic concepts, current best practices, and a glimpse into the future of patient-centered neurologic care. The authors of this edition of The Neurology Report, all fellows in neurology, neuroimmunology, or MS, attended a variety of scientific sessions and lectures to report on cutting-edge research, new pharmacologic discoveries for treating patients with MS, and targets for future study. n ADVANCES IN BASIC AND TRANSLATIONAL SCIENCE RESEARCH A complete characterization of MS clearly is not limited to inflammation and demyelination of the white matter. Salim Chahin, MD, from the University of Pennsylvania Perelman School of Medicine, summarizes our current knowledge of the neuropathology of MS and the evolution of the disease at both the molecular and anatomic levels. Dr. Chahin contrasts relapsing-remitting MS (RRMS) with secondary-progressive MS (SPMS); considers features of MS that result in disease progression and disability; and describes the phenomenon known as remyelination, which offers hope of MS remission. An epidemiologic discussion provides an overview of world populations most affected by MS, environmental factors and infectious agents that may be linked with the disease, and risk factors for its development. Finally, this article throws genetics into the mix, combining information about genetic susceptibility and environmental risk factors to enrich the discussion. n THE EVOLUTION IN DIAGNOSIS AND TREATMENT Tiffani Stroup, DO, from the University of Illinois at Chicago College of Medicine, covers the importance of imaging in diagnosis and monitoring of MS patients. Combining findings from magnetic resonance imaging (MRI) with patient and family histories and physical examination guides individualization of treatment strategies and selection of particular disease-modifying therapies (DMTs). Descriptions of diseases that mimic MS aid in the differential diagnosis of MS and lead to appropriate treatment, symptom management, and judicious use of medical resources. Dr. Stroup also touches upon the optimal treatment of MS relapse, methods for defining patient response to DMTs, and strategies for relieving common symptoms of MS. n CURRENT AND EMERGING THERAPIES Today s treatments for MS serve as a foundation for the pharmacologic breakthroughs to come. William Meador, MD, from the University of Alabama at Birmingham School of Medicine, presents an overview of current treatment strategies used in different populations of MS patients and considerations for drug selection. Dr. Meador discusses the goals of therapy in everyday practice and whether physicians should strive for no evidence of inflammatory disease activity in how they manage their MS patients. His paper also addresses the next decade of MS research, including new findings on remyelination, manipulation of genetic findings, and investigation of neuroprotective agents. Finally, Dr. Meador compares identification and treatment of pediatric and adult-onset 4 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

7 Michael K. Racke, MD Introduction MS and examines targets of ongoing therapeutic research. n DIMETHYL FUMARATE AND PEGINTERFERON β-1a Pavan Bhargava, MD, from the Johns Hopkins University School of Medicine, reviews post hoc analyses of pivotal clinical trials evaluating dimethyl fumarate, which was approved in March 2013 by the US Food and Drug Administration (FDA), and peginterferon β-1a, which is currently under FDA review, in specific patient subpopulations. Among the research trials discussed are the Determination of the Efficacy and Safety of Oral Fumarate In RRMS (DEFINE), the Efficacy and Safety Study of Oral BG00012 With Active Reference in RRMS (CON- FIRM), the Dose-Blind, Multicenter, Extension Study to Determine the Long- Term Safety and Efficacy of Two Doses of BG00012 Monotherapy in Subjects with RRMS (ENDORSE), and the Efficacy and Safety Study of BIIB017 (pegylated Interferon β-1a) in Participants With RRMS (ADVANCE). The outcomes of post hoc analyses of these studies expand our knowledge about racial differences in patient response, the effects of these new DMTs on patient quality of life and freedom from disease activity, their pharmacokinetics and pharmacodynamics, and their role in the therapeutic armamentarium we can bring to bear in treating RRMS. Notably, neither of these drugs nor any of the approved DMTs that preceded them have shown significant benefit in treating MS once it has transformed to the progressive form of the disease. n SYMPTOMATIC MANAGEMENT Symptomatic management of MS is often overlooked in the understandable desire to limit or halt the underlying immunopathology of the disease but is of undeniable importance in keeping MS patients strong and physically functional, relieving their discomfort, and preventing disability. Ariel Antezana, MD, from the Multiple Sclerosis Comprehensive Care Center at New York University s Langone Medical Center, summarizes current strategies for managing spasticity; locomotion difficulties; sleep disorders; fatigue; cognitive dysfunction; pain; mental depression; and gastrointestinal, genitourinary, and sexual dysfunction experienced by MS patients. Physical therapy and occupational therapy, as Dr. Antezana discusses, are tremendously important adjuncts to pharmacologic therapy to increase locomotion, lessen fatigue and other symptoms, and improve the quality of life of MS patients. We are grateful to these authors for bringing us these reports from the 2014 AAN meeting and for their incisive analysis of the importance of the findings presented and discussed there. In the coming weeks, look forward to more cutting-edge information on the etiology, diagnosis, and treatment of MS as The Neurology Report visits the joint annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) in Dallas. T H E N E U R O L O G Y R E P O R T S u m m e r

8 Advances in Basic and Translational Science Research in Multiple Sclerosis Salim Chahin, MD, MSCE University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania Abstract The revolution in our understanding and treatment of multiple sclerosis (MS) continues as we learn more about the genetics and pathways of this chronic, progressive disease. This paper reviews our current understanding of the immunobiology of MS and the influence of the environment and genetics on its pathogenesis and neuropathology. Speakers at the 66 th Annual Meeting of the American Academy of Neurology emphasized advances in basic science research and their translation to clinically useful applications. Their presentations included descriptions of the complex interplay of environmental and genetic contributions to disease susceptibility, recent findings in epidemiology and neuropathology, essential immunologic mechanisms involved in MS, and the immunologic effects of current disease-modifying treatments. M ultiple sclerosis (MS) is a chronic heterogeneous disease with a complex epidemiology and interacting environmental and genetic risk factors. Unraveling epidemiologic and immunologic factors that influence the course of the disease and understanding the pathologic substrates for neurodegeneration have produced great advances in MS therapeutics. During the 66 th Annual Meeting of the American Academy of Neurology, experts in the neuropathology, immunology, and epidemiology of MS presented the latest advances in basic and translational science research into this disease. n NEUROPATHOLOGY OF MS Based on a presentation by Josa M. Frischer, MD, PhD, Department of Neurology, Mayo Clinic, Rochester, Minnesota. Although MS has been considered an inflammatory, demyelinating disease of the white matter in the central nervous system (CNS), studies over the past decade have demonstrated that it possesses a much more complex pathology involving dynamic changes in MS plaques, heterogeneity in the immunopathogenesis of white-matter lesions, and several likely interacting etiologies for neuronal and axonal loss and disease progression. 1 Similar to clinical progression in MS, lesion pathology changes over time and evolves during the early versus chronic phases of the disease. Several processes drive the formation of plaques, including inflammation, myelin breakdown, oligodendrocyte injury, axonal loss, and remyelination. 1 MS Plaque Types and Stages of Demyelinating Activity Acute active plaques are characterized by relative axonal preservation and massive infiltration by macrophages containing myelin debris. 1 These myelin debris products disappear at different rates, allowing for more accurate pathologic timing of the demyelinating event. Early and late active and inactive demyelination differ in the presence or absence of certain myelin degradation products within macrophages, which stain differently in histologic specimens (Table 1). 1 The presence of minor myelin proteins, such as myelin oligodendrocyte glycoprotein (MOG) and myelin-associated glycoprotein (MAG), indicates early active demyelination, whereas the presence of larger, major myelin proteins (proteolipid protein and myelin basic protein) without the minor proteins indicates a late active lesion. In contrast to acute plaques, smoldering demyelinating lesions are characterized by an inactive center surrounded by a rim of activated macrophages and microglia, with few lesions containing myelin degradation products. Lastly, inactive plaques are completely demyelinated; there is substantial loss of axons and oligodendrocytes, and shadow plaques are sharply circumscribed regions that represent remyelinated areas. 1,2 Relationship of Plaque Type to Disease Duration and Clinical Course Acute active plaques are the pathologic substrate of clinical attacks and are seen most frequently in acute or fulminant MS (relapsing-remitting MS [RRMS]) and secondary progressive MS (SPMS) with relapses. Smoldering and inactive plaques, Dr. Chahin is a Multiple Sclerosis Fellow in the Department of Neurology at the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. 6 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

9 Salim Chahin, MD, MSCE Advances in Basic and Translational Science Research in Multiple Sclerosis TABLE 1 Stages of Demyelination Stage Early active demyelination Late active demyelination Inactive demyelination Degradation products in macrophages CNPase positive MOG positive MAG positive PLP positive MBP positive MOG, MAG, and CNPase-negative Macrophages containing empty vacuoles or PASpositive products CNPase = 2 3 -cyclic nucleotide 3 -phosphodiesterase; MAG = myelin-associated glycoprotein; MBP = myelin basic protein; MOG = myelin oligodendrocyte glycoprotein; PAS = periodic acid-schiff; PLP = proteolipid protein Source: Popescu and Lucchinetti 1 in contrast, are more predominant in patients with primary progressive MS (PPMS) or SPMS without relapses. 1 The frequency of shadow plaques is similar in RRMS and progressive MS beyond 1 year of disease duration. 1,2 Remyelination The hallmark of remyelinated plaques is the presence of thinly myelinated axons with short intermodal distances. 1 As mentioned previously, shadow plaques are the result of complete remyelination. Interestingly, older remyelinated plaques show an almost normal myelin thickness and may be difficult to distinguish from normal white matter. 1,3 The extent of remyelination depends, at least partially, upon the availability of oligodendrocyte precursor cells (OPCs) and the pro- or anti-inflammatory balance within each plaque. 1,2,4 Several hypotheses for remyelination failure and variation among patients with MS have been explored, 2,4 including: n Areas of remyelination are preferential sites for new inflammation, and repeated demyelinating insults may exhaust the source of OPCs. n Axonal injury and loss may prevent appropriate interactions between axons and oligodendrocytes, thus inhibiting remyelination. n The dense glial scar that forms within lesions may act as a barrier that prevents OPC migration and remyelination. n Age-dependent loss of trophic support from microglia also may contribute to atrophy and prevent remyelination. Heterogeneity of Early Active MS Plaques The variation in clinical, genetic, and radiographic features and response to treatment among patients with MS partially may be due to underlying pathologic heterogeneity. 1 Work at the Mayo Clinic has shown that MS lesions can be classified into four immunopatterns based upon specific myelin protein loss, plaque extent and topography, oligodendrocyte destruction, remyelination, immunoglobulin deposition, and complement activation. 2,5 These four distinct immunopatterns may differ among patients but are similar within each patient in early active MS (Table 2). 1 Patterns I and II show close similarities to T-cell mediated and T- cell plus antibody-mediated experimental autoimmune encephalomyelitis (EAE). Patterns III and IV are highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination. 1,5 Other studies have challenged the TABLE 2 Heterogeneity of Early Active Multiple Sclerosis Lesions concept of pathologic heterogeneity, arguing that it is dependent on the age of the lesions (and the duration of disease) and not on the patient. Breij et al 6 showed that no lesion heterogeneity existed among different patients. They concluded that the initial heterogeneity of demyelinating lesions in the earliest phase of MS lesion formation might disappear over time, as different pathways converge in one general mechanism of demyelination. Recently, Metz et al 7 demonstrated that 95% of 22 pathologic cases showed persistence of all major immunopathologic patterns in tissue sampled at different times. This observation suggests that pathologic heterogeneity persists in early active MS lesions. Pathologic Substrate of Disease Progression Several overlapping factors contribute to neuronal and axonal loss and ultimate disease progression in MS. 1 How these factors interact needs further exploration, but studies, especially over the recent years, have expanded our knowledge about some of these factors and their contribution to disease progression. Pattern Frequency Pathology Gross examination I 15% of patients T-cell inflammation, active Sharply demarcated edges and demyelination, activated microglia, typical perivenous distribution and myelin-laden macrophages with no immunoglobulin or complement deposition A loss of oligodendrocytes at the active border with reappearance of numerous oligodendrocytes in the inactive center II 58% of patients In addition to T-cell inflammation Sharply demarcated edges and and myelin-laden macrophages, typical perivenous distribution immunoglobulin and complement activation on myelin and within macrophages Same pattern of oligodendrocyte distribution as pattern I III 26% of patients Oligodendrocyte apoptosis, T-cell Ill-defined edges, not centered inflammation, macrophages, and on veins or venules microglia activation Pronounced loss of oligodendrocytes at the active plaque border; inactive center devoid of oligodendrocytes IV 1% of patients Profound nonapoptotic death of oligodendrocytes Source: Popescu and Lucchinetti 1 T H E N E U R O L O G Y R E P O R T S u m m e r

10 Salim Chahin, MD, MSCE Advances in Basic and Translational Science Research in Multiple Sclerosis Axonal pathology. Axonal injury is now a well-recognized feature in MS that correlates with disability and disease progression. 8 Proposed mechanisms of axonal damage in MS include the influence of damaging inflammatory and immune processes, lack of trophic support from damaged myelin and oligodendrocytes, repeated demyelination within the lesion, and chronic mitochondrial failure. 1,8 Axonal degeneration is not a late phenomenon in MS. It begins early in the disease and seems to correlate with the degree of inflammation. 8 Axonal damage remains clinically silent until a threshold of axonal loss is reached and the compensatory capacity is surpassed, resulting in irreversible, progressive neurologic disability and heralding the secondary progressive phase of the disease. 8 Mitochondrial injury, oxidative stress, and iron accumulation. Mitochondrial injury may play an important role in neurodegeneration. 9 It likely is triggered by reactive oxygen and nitrogen species that mediate mitochondrial dysfunction 10 and result in a state of histotoxic hypoxia, leading to oligodendrocyte and neuronal damage 10 and, ultimately, neuronal and axonal loss This mechanism may be the etiology behind pattern III lesions 12 and may be involved in the neurodegeneration that results in chronic progression clinically. 9 Recently, iron deposition has been hypothesized to play a role in neurodegeneration in MS. 1,13 In liberated form, ferrous iron ions may generate reactive oxygen species, which are toxic to the mitochondria. 13 Hametner and others 13 showed an age-related increase in iron in the white matter of healthy individuals and MS patients with a short disease duration. However, in chronic MS, there was a significant, age-corrected decrease in iron concentration in the normal-appearing white matter that corresponded to disease duration. 13 Furthermore, extracellular accumulation of iron was seen in active MS lesions. Thus, iron may contribute directly or indirectly through mitochondrial damage to disease progression and degeneration. 13,14 Cortical pathology. Previously thought to be unaffected in MS, cortical involvement is now a recognized phenomenon that correlates with physical and cognitive impairment. 15 Cortical pathology can occur early in the MS disease process as a result of classically demyelinated lesions or neuronal loss following retrograde degeneration from white-matter lesions. 15,18 Furthermore, meningeal inflammatory infiltrates may contribute to the gray-matter pathology in MS. 18 In a cohort of patients with early-stage MS, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. 18 On the basis of their locations, three types of cortical lesions have been identified, 1,19 as follows: n subpial lesions extending from the pial surface into the deeper cortical layers, which are common in chronic MS; n intracortical lesions small perivascular lesions confined to the cortex; and n leukocortical lesions involving both the gray and white matter at the graywhite matter junction. Cortical lesion pathology is similar to that of white-matter lesions in that there are well-demarcated areas of demyelination with loss of oligodendrocytes and axons. 1,17 However, cortical lesions are less inflammatory, devoid of lymphocytes and macrophages, and, as mentioned previously, driven partly by meningeal infiltrates. 1,15,17,19,20 Interestingly, certain cortical areas in the brain are more affected than are others in MS, including the cingulate gyrus, insular cortex, temporobasal cortex, and hippocampus. 16 In fact, hippocampal demyelination may be frequent and extensive in MS. 21 Does neurodegeneration occur independently of inflammation? Neurodegeneration may occur independently of inflammation in patients with MS. 1 However, it is more likely that neurodegeneration occurs on an inflammatory background. 1,22 Recent magnetic resonance imaging (MRI) and pathology studies have shown that cortical lesions, despite being more common in SPMS, are already present in early disease, and these early cortical lesions can be highly inflammatory. 15,19 These findings suggest that cortical demyelination in early MS is inflammatory and argue against a neurodegenerative process at this early stage. 19 The process by which inflammation leads to degeneration is not completely understood, but the two are not likely to be independent. A lot has been learned this past decade about gray- and white-matter pathology in MS. 1 White-matter MS plaques are heterogeneous among patients, especially early in the disease course, and their appearance changes with disease progression. 1,7 Cortical and gray-matter involvement is now recognized, and often early, phenomenon 1,15,19 in MS that plays an integral role in disease progression. 1 Further exploration of the nature of cortical involvement in MS and the complex relationship between degeneration and inflammation and the role of the mitochondria and oxidative stress will lead to better treatments for MS patients. n EPIDEMIOLOGY AND GENETICS Based on a presentation by Emmanuelle Waubant, MD, PhD, Professor of Neurology, University of California at San Francisco School of Medicine, San Francisco, California. The epidemiology of MS may hold the key to complex mechanisms that contribute to the risk of MS and to disease progression. Epidemiologic studies have uncovered several genetic and environmental factors that place individuals at an increased risk of developing MS. Recent studies in pediatric MS have added a trove of information about development of the disease in young patients. Challenges persist, however, in understanding the contribution that genetic and environmental factors make to the underlying mechanisms, pathogenesis, and progression of MS. Epidemiology MS is a relatively common disease in Europe, the United States, Canada, New Zealand, and parts of Australia. 23 Among white, non-hispanic individuals, the lifetime risk of MS is about 1: The risk of MS tends to be lower among Hispanic, black, and Asian populations, 24 although 8 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

11 Salim Chahin, MD, MSCE Advances in Basic and Translational Science Research in Multiple Sclerosis it may be increasing in the non-hispanic black population. 25 Several large studies have evaluated the role of the environment in MS development. 24 The incidence of MS follows a latitude gradient, 24,26 in which the risk is low in the tropics and increases in frequency with increasing latitude in both hemispheres. 26 This latitude gradient was generally considered to be influenced by genetic factors, but an environmental role cannot be ignored. 24 People who migrate from high-risk regions to areas of low risk acquire a lower incidence of disease in a graded, age-related fashion: The younger the age at migration, the lower the risk. 27,28 Thus, an environmental exposure early in life (before age 15 years) could be important to determining MS risk. 27,28 A marked attenuation of the latitude gradient, however, has been observed in the United States and Europe The disappearance of the gradient in the United States is probably due to an increased incidence of MS in the southern portion of the country. In contrast, a strong latitude gradient persists in the southern hemisphere (Australia and New Zealand). 32,33 This difference between the northern and southern hemispheres is interesting, but no clear explanation has been set forth. 24 Furthermore, studies suggest a rising incidence of MS in certain populations, especially among women. 34,35 Orton et al 35 reported an increase in the ratio of females to males in the risk of developing MS in Canada. Their findings, along with other large cohort studies, suggest that the increase in affected females to males is independent of access to care and improvements in diagnosis and that the incidence of MS actually may be rising among women. 34,35 The authors further suggested that this increase among woman may have an environmental role, with environmentalgenetic interactions potentially contributing to the risk of developing MS. 34,35 Known environmental risk factors. Three environmental factors infection with the Epstein-Barr virus (EBV), low levels of vitamin D, and cigarette smoking likely are related to a greater risk of MS development. 24 Some of these risk factors follow a geographic distribution that TABLE 3 Risk of Developing Multiple Sclerosis in Children and Adults a Infectious findings Odds ratio 95% CI P value Children Anti-EBV VCA-positive DRB*1501/1503-positive Anti-EBNA-1-positive DRB*1501/1503-positive Anti-CMV-positive DRB*1501/1503-positive Anti-EBNA-1-positive Anti-HSV-1-positive/DRB*1501/1503-negative Anti-HSV-1-positive/ DRB*1501/1503-negative Adults Anti-CMV-positive CI = confidence interval; EBV = Epstein-Barr virus; VCA = viral capside antigen; EBNA = Epstein-Barr nuclear antigen; CMV = cytomegalovirus; HSV = herpes simplex virus a Risk in children was adjusted for age, gender, race, and ethnicity. Risk in adults was adjusted for age, gender, smoking, and sun exposure. Both analyses were adjusted for EBV virus exposure and HLA-DRB status. Source: Waubant et al (data on children) 39 and Sundqvist et al (data on adults) 42 resembles the latitude gradient observed in MS epidemiology 24 and help to explain the potential source of this gradient in MS incidence. Infection with EBV and other viruses. EBV is the most studied, possibly infectious agent linked to MS development; it consistently has shown an association with MS risk. 24 Infection with EBV in early life is common and usually asymptomatic. If the primary infection occurs later in life, an acute febrile illness known as infectious mononucleosis may result. 36 The geography and epidemiology of infectious mononucleosis are strikingly similar to those of MS, 37 and the risk of MS is two to three times higher in individuals with a history of infectious mononucleosis. 24,38 Older age at EBV infection (manifested as infectious mononucleosis) is a risk factor for MS. 24 Several pediatric MS studies also have shown an association between MS and EBV. 39 Some investigators have reported the presence of EBV in the meninges of MS patients, whereas others have not been able to reproduce these findings. 24 Some investigators have proposed that this association between EBV and the risk of MS can be explained by the hygiene hypothesis, 40 which suggests that good hygiene in childhood, and not EBV infection, is the common link between infectious mononucleosis and MS. Levin et al, 41 however, showed that in a large prospective study, only 10 cases of MS developed among EBV-negative individuals; in each case, symptoms developed months after serologic evidence of EBV infection was found. Waubant et al 39 have shown that remote cytomegalovirus (CMV) infection in children is associated with a lower risk of developing MS. This finding is supported by a study showing that CMV infection is negatively associated with adult-onset MS. 42 Remote infection with herpes simplex virus (HSV-1) has a more complex effect. Although remote infection with HSV-1 has not been shown to increase or decrease the risk of developing MS, a strong interaction between HSV-1 status and expression of HLA-DRB1 has been observed, further supporting a geneenvironment interaction related to MS. 39 Table 3 summarizes the risk of developing MS in children 39 and adults 42 depending upon infectious findings. 39,42 Vitamin D and sunlight exposure. The geography of MS also correlates with the degree and duration of sunlight exposure, which is the primary source of vitamin D in most populations. Although no clear causal relationship has been established, vitamin D is hypothesized to play an immunomodulatory role in several diseases, 24 and evidence is accumulating on the role of vitamin D in the pathogenesis of MS. 24,46,47 T H E N E U R O L O G Y R E P O R T S u m m e r

12 Salim Chahin, MD, MSCE Advances in Basic and Translational Science Research in Multiple Sclerosis Longitudinal research, such as the Nurses Health Study, has shown that the risk of MS is 40% lower among woman who reported taking vitamin D regularly. 46 Munger and others 47 reported a 62% lower risk of MS among non-hispanic white individuals who had high serum levels of vitamin D. These and other studies support the importance of vitamin D sufficiency in adolescence and young adulthood and possibly also in childhood and even in utero. 24 Further evidence of the possible effects of sun exposure (and vitamin D) on the risk of MS comes from a North American twin study, 48 which found that concordance rates among monozygotic twins born in the United States were twice as high as those for twins born elsewhere. Further, the average age at diagnosis for northern-latitude twins was independent of ancestry but earlier than for southernlatitude twins. Additionally, obesity, which is known to be associated with lower levels of vitamin D, was associated with a twofold increase in the risk of MS. 24 Exactly how vitamin D affects the risk of developing MS and disease progression remains under investigation. Interestingly, Ramagopalan et al 49 identified a vitamin D response element (VDRE) in the HLA-DRB1 promoter region, the main susceptibility locus for MS. This finding, although not yet reproduced, suggests a possible direct interaction between HLA- DRB1 and vitamin D. Vitamin D may also contribute to the disease course. 24 Mowry et al 50 showed that a 10 ng/ml increase in hydroxyvitamin D levels resulted in a 34% decrease in subsequent relapse rate among patients with pediatric-onset MS. Ascherio et al 51 showed that among patients with MS treated with interferon β-1b, a low vitamin D level early in the course of the disease was a strong risk factor for long-term relapse and disease progression. Several ongoing clinical trials are testing the association between vitamin D and disease progression and attempting to establish causality. The link between vitamin D and MS will be clearly established only in clinical trials. In fact, a recent systematic review of the literature on vitamin D suggests that the low vitamin D levels seen in inflammatory and autoimmune diseases may result from the inflammatory process rather than contributing to the inflammation. 52 Cigarette smoking. Cumulative evidence supports the association between cigarette smoking and the risk of MS. The risk of MS is 50% higher in people who always smoked than among those who never smoked In a longitudinal study, MS risk was about twofold higher among women who smoked 25 pack-years than among those who never smoked. 53 In patients with an established MS diagnosis, cigarette smoking also was associated with more rapid disease progression. 56 Other environmental factors. Among the large number of environmental exposures that have been investigated in the pathogenesis of MS, 24 few factors other than vitamin D level and cigarette smoking have shown a confirmed association. Recently, sodium and increased dietary salt intake have been implicated in the pathogenesis of the disease, since sodium chloride levels may play a role in modulation of the immune system and the development of autoimmune diseases such as MS via induction of pathogenic T helper 17 (Th 17 ) cells. 57,58 Heredity. The genetic contribution to the susceptibility of developing MS is suggested by several studies. 24,59 A high degree of heritability has been established in studies of twins, siblings, and adoptees. 24,60 The risk of MS in monozygotic twins is 25% and in dizygotic twins, 5%. 60 Furthermore, having a sibling with MS increases the risk 20- to 40-fold when compared with people who have no relatives affected by the disease. 60 The genetic association in MS likely results from multiple interacting polymorphic genes, with each exerting a small-to-moderate effect on the overall risk. 59 The strongest genetic risk of MS is conferred by the HLA-DRB1*1501 allele, 24 which has a 14% 30% frequency in populations of countries with a high risk of developing MS. This allele increases the risk of disease by an average of three times in heterozygous carriers and six times in homozygous individuals. 24,59 Other HLA-DRB1 alleles also are associated with a high MS risk. 59 However, the exact mechanism(s) by which the DRB1 gene influences susceptibility to MS remains unclear. 24 Genome-wide association studies (GWAS) have identified the contribution of over 110 non-hla genes, many of which code for proteins involved in the immune response. 59,61 Environmental/Genetic Interactions MS is likely caused by a complex interaction between multiple genes and environmental factors, the relative importance of which varies by person, time, and location. 24 Despite recent advances in the study of MS genetics, about 80% 90% of patients with MS have a negative family history, 24,62,63 suggesting a possibly dominant role of the environment and genetic-environment interactions. Examples of such an interaction include twin studies suggesting a role for geography and latitude in increased concordance of monozygotic twins, 48 the interaction between HSV-1 status and HLA-DRB1, 39 and vitamin D response element and HLA- DRB1. 49 Recently, Mechelli et al, 64 based upon aggregate analysis of GWAS data in MS, proposed a multifaceted approach to gene-environment interactions as triggers of MS. Their results support a causal role of the interaction between EBV infection and the products of MS-associated gene variants. The authors recommend future, more expansive research to study these interactions. 64 Epigenetics In the context of genetic susceptibility, the effect of environmental risk factors on MS pathogenesis could be explained by epigenetic modifications. 59,65,66 Several observations suggest a role for epigenetics in MS, including results from twin studies reporting a concordance rate of 30% (and not 100%) in monozygotic twins and an increase in MS risk if the mother (more so than the father) has MS. 24,66 These epigenetic changes influence gene expression without altering the DNA sequence and include processes such as DNA methylation, histone modification, microrna (mirna)-associated post-transcriptional gene silencing, and 10 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

13 Salim Chahin, MD, MSCE Advances in Basic and Translational Science Research in Multiple Sclerosis heterochromatin formation. 65,66 Evidence on the potential influence of mirna on disease immunology will be discussed in detail later in this article. 67 The Challenges Ahead Very few breakthroughs in mitigating the risk of MS onset or progression have been made despite our growing knowledge of several genetic and environmental risk factors for the disease. This failing is likely due to the heterogeneity of risk factors among individuals and the direct versus indirect effect of some of the environmental risk factors. However, Ascherio and colleagues 24 proposed that some risk factors may be addressed now: vitamin D supplementation and smoking cessation are immediately available interventions that may reduce the risk of MS and disease progression. 24 n NEUROIMMUNOLOGY OF MS Based on a presentation by Michael K. Racke, MD, Professor of Neurology and Neuroscience, The Ohio State University College of Medicine, Columbus, Ohio. Evidence from MS pathology and epidemiology studies helped establish MS as an autoimmune, inflammatory disorder that has the target antigen or antigens located in the CNS myelin. 68 Experts in neuroimmunology may have witnessed the greatest advances in uncovering disease pathophysiology; such research has been the driving force behind the development of therapeutic options in MS T-Cell Involvement Well-established animal models of MS, such as EAE, have demonstrated that autoreactive, myelin-specific T lymphocytes may work toward demyelination in the CNS The mechanisms of T-cell involvement in demyelination remain under investigation, but several discoveries have helped shape our understanding of T-cell involvement in MS. In human studies, the frequency of myelin-reactive T cells is very similar in MS patients and healthy individuals, but qualitative differences in the response mediated by these cells exist between patients and healthy individuals. 72,73 Notably, myelin-specific T cells have a memory or activated phenotype when compared with the naïve phenotype seen in healthy individuals. 72,73 Flow-cytometry techniques performed on neuroantigen-specific CD8 + T cells ex vivo have also demonstrated significant differences in cytokine production and chemokine receptor expression in patients with MS, suggesting that these cells have a greater pro-inflammatory phenotype in MS patients. 74,75 Both CD4 + and CD8 + T cells have been implicated in the pathogenesis of MS. Myelin-specific CD8 + T cells obtained from patients with RRMS exhibited a reduction in regulatory capacity during a relapse, 74 but this suppressed capacity seemed to return to normal as the patient recovered from the relapse. This Advances in uncovering the neuroimmunologic pathophysiology of MS have become the driving force behind development of therapeutic options for this disease. and other works highlight the importance of evaluating both CD4 + and CD8 + T-cell responses in MS. 74,75 Identifying the target antigen of the T-cell response has been the focus of many studies. In a clinical trial on altered peptide ligands in MS, Bielekova et al 76 reported a significant increase in T cells responding to a particular component of myelin basic protein (MBP 83-99) in those patients with increased clinical or radiologic activity. These observations support the hypothesis of a potential direct response of T cells against myelin antigens and their role in MS pathogenesis. 76 T-cell phenotypes in MS. Several teams of investigators have pioneered work exploring and clarifying the roles of different myelin-specific T cells phenotypes. Myelin-specific T cells from MS patients produce cytokines (interferon γ) consistent with a T helper 1 (Th 1 ) response, 77 whereas myelin-specific T cells from healthy individuals produce cytokines consistent with a T helper 2 (Th 2 ) response. 75 A different subset of T cells, Th 17 cells, may also contribute to inflammation in MS. 78 Interleukin (IL)-23 is an essential cytokine that results in survival of IL-17 producing T cells, 79 which are believed to be important in encephalitogenicity. 79 In fact, microarray studies on MS lesions have shown an increased expression of IL-17, suggesting that it may contribute to the development of inflammation and demyelination. 80 The differentiation of encephalitogenic Th 1 and Th 17 cells may differ among MS patients and is influenced by several transcription factors These differences may also explain why interferon therapy may not be effective in some patients. B-Cell and Humoral Involvement Several studies have demonstrated increased levels of B cells, plasma cells, and antibodies in the cerebrospinal fluid (CSF) of MS patients. 86 Cepok et al 86 showed that plasmablasts were present in high numbers in the CSF and correlated with radiologic disease activity. These plasmablasts were also responsible for the elevated immunoglobulin G (IgG) synthesis observed in the CSF of MS patients. The number of CSF plasmablasts strongly correlated with intrathecal IgG synthesis and inflammatory parenchymal disease activity on MRI. Thus, these plasmablasts are likely the main effector B-cell population involved in ongoing active inflammation in MS. Similar to the T-cell studies in MS, work is being done to identify target antigens for the antibody response in MS. Srivastava et al 87 identified an antibody specific for KIR4-1 that could bind to glial cells in a subgroup of MS patients. KIR4-1 is an inward-rectifying potassium channel located on astrocytes and oligodendrocytes. This antibody was present in 47% of patients with MS and fewer than 1% of patients with other neurologic disorders; however, neuromyelitis optica (NMO) was not included in this analysis. 87 The T H E N E U R O L O G Y R E P O R T S u m m e r

14 Salim Chahin, MD, MSCE Advances in Basic and Translational Science Research in Multiple Sclerosis authors suggested that KIR4-1 might be a target of the antibody response in a subset of patients. 87,88 Recently, Kraus et al 89 also found serum antibodies to KIR4-1 in most children with acute demyelinating disorders but not in children with other diseases or healthy controls, confirming the potential role for KIR4-1 as an important target for autoantibodies in children as well as adults. Interestingly, the KIR4-1 channel colocalizes with the aquaporin 4 (AQP4) channel, 88 the antigen targeted in NMO, raising the possibility that KIR4-1 could be targeted in NMO patients who are NMO IgG-negative. 88 In fact, antibodies to KIR4-1 and AQP4 share a similar characteristic they are rarely detected in the CSF. 88 Additional work is needed to clarify the presence of the KIR4-1 antibodies in disorders such as NMO, to identify other potential targets in MS, and to incorporate this and other findings in developing more specific therapeutic interventions. Evidence of the role of B cells in MS pathogenesis also comes from successful therapeutic trials that have targeted B cells. Cross et al 90 showed that rituximab, an anti-cd20 monoclonal antibody that depletes CD20 + B cells, could benefit MS patients who do not respond to first-line treatment. CSF analysis showed that 90% of CD19 + cells in the CSF were depleted, and the population of T cells also was reduced. These findings suggest that one of the mechanisms through which B cells may play a role in MS is the subsequent recruitment of T cells into the CSF. Ocrelizumab, a humanized version of rituximab, is being evaluated in several ongoing clinical trials as a potential therapy for both RRMS and progressive MS. Epigenetics and the Role of mirna As mentioned previously, several epigenetic pathways may influence the effect of environment and genes in the pathogenesis of MS. 59,65,66 Recently, mirna has emerged as a leading epigenetic mechanism in MS via regulation of gene expression and T-cell activation. 65,66 These mirnas can be influenced by both genetic and environmental factors, making them attractive for study in MS. 91,92 The mirnas are small RNA molecules (19 24 nucleotides long) that bind to the 3ʹ UTR (untranslated region) target of mrnas and inhibit translation or induce mrna degradation, thus altering gene expression. 91,92 Studies of mononuclear cells obtained from the peripheral blood of MS patients have demonstrated mirna dysregulation. 93,94 Guerau-de-Arellano and colleagues 67 studied mirna expression in highly purified naïve CD4 + T cells from MS patients. Use of naïve CD4 + T cells is advantageous in such studies because these cells have not been activated, allowing the investigators to examine how mirna influences the differentiation of T cells into proinflammatory phenotypes in MS. Three mirnas (mir-128, mir-27a/b, and mir- 340) are increased in naïve T cells from MS patients. These mirnas suppressed Th 2 differentiation by targeting Bmi-1 (a molecule that promotes survival of the transcription factor GATA3 that drives Th 2 differentiation) and IL-4 expression and setting the stage for pro-inflammatory Th 1 autoimmune responses. Another mirna (mir-29b) that targets interferon γ and another transcription factor called T-bet are overexpressed in memory T cells of MS patients. T-bet levels are higher in MS patients than they are in healthy controls, 95 and they influence CD4 + differentiation and encephalitogenicity. The expected increase in mir-29b should result in reduced levels of T-bet and interferon γ, but the opposite happens Tbet levels actually were higher in MS patients, a discrepancy that can be explained if this mirna were dysregulated in MS. Smith and colleagues 95 activated memory CD4 + T cells from MS patients and healthy controls and found that levels of mir-29b increased in healthy controls but decreased in patients with MS. Thus, although resting memory CD4 + T cells appear to be primed to regulate a Th 1 response in MS patients by controlling T-bet and interferon γ levels (via mir-29b), this regulatory mechanism fails upon activation. This failure allows for the high T-bet expression observed in MS CD4 + T cells and promotes effector functions associated with the CNS pathology present in patients with MS. 67,95 These results add to our understanding of T-cell regulatory mechanisms and illustrate the biologic significance of mirnas in MS susceptibility. 67 Additional work is under way to identify other regulatory and epigenetic pathways in the immune system that might serve as potential therapeutic targets for patients with MS. n MECHANISMS OF ACTION: CURRENT AND FUTURE MS THERAPIES Based on a presentation by Lawrence Steinman, MD, Professor of Neurology and Neurological Sciences, Pediatrics, and Genetics, Stanford University School of Medicine, Stanford, California. Nine agents are currently approved by the US Food and Drug Administration (FDA) for the treatment of RRMS, including interferons, glatiramer acetate, natalizumab, fingolimod, teriflunomide, and dimethyl fumarate. Several other therapies for RRMS are in advanced stages of clinical development or nearing FDA approval. Little progress, however, has been made in the treatment of progressive MS. The mechanism of action of a therapeutic agent is sometimes well known and at other times may be complex and little understood. Knowing a drug s mechanism of action provides valuable insight into not only how a drug works but also its risk profile and side effects. Table 4 summarizes the mechanisms of action of FDA-approved drugs for treating RRMS. FDA-Approved Treatment Options Type 1 beta interferons. Interferons (specifically, interferon β-1a and β-1b) were among the first therapies approved for treating MS. Despite being available for two decades, the mechanism of action of these drugs in MS is still not well understood. 96 In vitro, interferons impact intracellular signaling, but the mechanism of action in vivo is much more complex and likely involves more than one pathway. 96 Several potential mechanisms have been proposed, some of which are on the genetic level. Attempts to identify molecular biomarkers of the therapeutic effect of interferons in MS 100 so far have been unsuccessful. 12 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

15 Salim Chahin, MD, MSCE Advances in Basic and Translational Science Research in Multiple Sclerosis TABLE 4 Mechanisms of Action of FDA-Approved Treatment Options for Multiple Sclerosis a Year Medication approved Mechanism of action Interferon β-1b SC 1993 Impact intracellular signaling; condition immune cell responses Interferon β-1a IM 1996 to other cytokines, shifting the immune response Interferon β-1a SC 2002 Glatiramer acetate 1996 Activation of the M2 anti-inflammatory monocyte increase in anti-inflammatory cytokines such as IL-10 shift from Th 1 to Th 2 response Natalizumab 2006 Monoclonal antibody to α4 integrin, impeding entry of T and B lymphocytes into the central nervous system Fingolimod 2010 S1P1 receptor agonist; traps lymphocytes and blocks their egress from the lymph nodes Teriflunomide 2012 Interferes with pyrimidine synthesis, decreases lymphocyte proliferation and activation toward myelin antigens Dimethyl fumarate 2013 Activation of the Nrf2 antioxidant pathway, resulting in cytoprotection from oxidative stress FDA = US Food and Drug Administration; SC = subcutaneous; IM = intramuscular; IL= Interleukin; Th = T helper cell; S1P1 = sphingosine phosphate, type 1; Nrf2 = nuclear factor (erythroid-derived 2)-like 2 a Certain agents, such as interferon β, glatiramer acetate, teriflunomide, and dimethyl fumarate, have complex mechanisms of actions that are not clearly understood ,106,107, We have gained insight into the mechanism of action of interferons from their effect in NMO. Once again, the two types of inflammatory pathways in MS are the Th 1 pathway (driven by interferon γ) and the Th 17 pathway (with its signature cytokine IL-17). 77,78 Both interferon γ and IL-17 are found in large amounts in MS lesions. 80 CSF levels of IL-17 are higher in NMO patients than in MS patients. IL-17 may recruit and activate granulocytes through several cytokines. 101 Treating NMO with interferon β not only is ineffective but may have devastating consequences, including an increased relapse rate, severity, and antibody levels This worsening of clinical status in the context of treatment with interferon β observed in NMO and in some patients with MS has occurred when the Th 17 immune response is prominent. 101,104 Glatiramer acetate. Several mechanisms of action have been proposed for how glatiramer acetate works in MS. In animal studies, an anti-inflammatory monocyte called M2 is elicited in response to glatiramer acetate exposure, 105 resulting in increased secretion of certain anti-inflammatory cytokines, such as IL- 10, and an overall shift from the Th 1 and interferon γ response to a Th 2 -modulated pathway. 105 Natalizumab is a humanized monoclonal antibody to α4 integrin, the main homing molecule on lymphocyte surfaces that binds to vascular adhesion molecule VCAM1 on endothelial cells and mediates lymphocyte transmigration across the blood-brain barrier. 106,107 Natalizumab interferes with this step and impedes both T- and B-cell entry into the CNS. The mechanism of action of natalizumab explains its efficacy but also highlights the risks associated with its use namely, infection with the JC virus resulting in progressive multifocal leukoencephalopathy (PML). It is unclear why PML is the only opportunistic infection associated with natalizumab use. 106,107 Studies to stratify the risk of PML in natalizumab-treated patients have identified three risk factors: exposure to the JC virus, duration of treatment, and prior exposure to immunosuppressive therapy or chemotherapy. 108 Fingolimod is a sphingosine phosphate (SP) receptor agonist. Several subtypes of SP receptors exist. The S1P1 subtype is present primarily on immune cells and neural cells. Through its agonist effect on S1P1 receptors, fingolimod causes the S1P1 receptor to be internalized, resulting in a pharmacologic antagonist effect. The drug effectively traps lymphocytes in the lymph nodes and impedes their egress. 109 This accounts not only for its anti-inflammatory activity but also the potential for opportunistic infections to occur in patients being treated with drug. Fingolimod has agonist activity toward other SP receptor subtypes, including S1P4, S1P5, and S1P3. The latter subtype is found on cardiac cells; modulation of these receptors is associated with bradycardia, a known complication of fingolimod use. 109 Teriflunomide is the active metabolite of leflunomide, an agent approved by the FDA to treat rheumatoid arthritis. Teriflunomide has a distinct profile and a complex mechanism of action. It interferes with pyrimidine synthesis through reversible inhibition of dihydroorotate dehydrogenase and decreases lymphocyte proliferation and activation toward key myelin antigens in MS. 110 Dimethyl fumarate and its primary metabolite, monomethyl fumarate, have shown efficacy in RRMS, 111,112 likely through cytoprotection from oxidative stress. A potential mechanism of neurodegeneration in MS is the effect of oxidative stress and reactive oxygen species. Dimethyl fumarate may protect against neuroinflammation, neurodegeneration, and oxidative stress through activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant pathway. 113 Other potential mechanisms of action that have been explored include induction of IL-4 producing CD4 + Th 2 cells, generation of type II dendritic cells that produce IL-10 instead of IL-12 and IL-23, suppression of pro-inflammatory cytokines, and direct inhibition of pro-inflammatory pathways. 111,112,114 Therapies in Advanced Stages of Development Alemtuzumab. This monoclonal antibody targets CD52 receptors and depletes T and B lymphocytes and monocytes mainly via antibody-dependent cytotoxicity and complement-mediated lysis. 115 This depletion can be long-lasting. Alemtuzumab may drive a sort of immune programming. When cells repopulate, they tend not to have the same autoimmune response; in 30% of cases, new autoimmune diseases, notably immune T H E N E U R O L O G Y R E P O R T S u m m e r

16 Salim Chahin, MD, MSCE Advances in Basic and Translational Science Research in Multiple Sclerosis thrombocytopenia, occur. The risk of this new autoimmunity is associated with increased levels of IL ,117 Ocrelizumab. Whereas rituximab is a chimeric monoclonal antibody against CD20 + cells, ocrelizumab is a recombinant humanized antibody designed to selectively target CD20 + B cells, resulting in antibody-dependent, cell-mediated cytotoxicity. In early clinical trials, it has shown efficacy in MS. 118 REFERENCES 1. Popescu BF, Lucchinetti CF. Pathology of demyelinating diseases. Annu Rev Pathol. 2012;7: Popescu BF, Pirko I, Lucchinetti CF. Pathology of multiple sclerosis: where do we stand? Continuum (Minneap Minn). 2013;19: Barkhof F, Bruck W, De Groot CJ, et al. Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance. Arch Neurol. 2003;60: Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: from biology to therapy. 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Disease mechanisms in MS: the potassium channel KIR4.1 a potential autoantigen in MS. Nat Rev Neurol. 2012;8: Kraus V, Srivastava R, Kalluri SR, et al. Potassium channel KIR4.1-specific antibodies in children with acquired demyelinating CNS disease. Neurology. 2014;82: Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol. 2006;180: Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116: Ambros V. The functions of animal micro- RNAs. Nature. 2004;431: Otaegui D, Baranzini SE, Armananzas R, et al. Differential micro RNA expression in PBMC from multiple sclerosis patients. PLoS One. 2009;4:e Keller A, Leidinger P, Lange J, et al. Multiple sclerosis: microrna expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls. PLoS One. 2009;4:e Smith KM, Guerau-de-Arellano M, Costinean S, et al. mir-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis. J Immunol. 2012;189: Borden EC, Sen GC, Uze G, et al. Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov. 2007;6: Calabresi PA, Tranquill LR, Dambrosia JM, et al. Increases in soluble VCAM-1 correlate with a decrease in MRI lesions in multiple sclerosis treated with interferon beta-1b. Ann Neurol. 1997;41: Shiow LR, Rosen DB, Brdickova N, et al. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature. 2006;440: Leppert D, Waubant E, Burk MR, Oksenberg JR, Hauser SL. Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann Neurol. 1996;40: Fernald GH, Knott S, Pachner A, et al. Genome-wide network analysis reveals the global properties of IFN-beta immediate transcriptional effects in humans. J Immunol. 2007;178: Axtell RC, Raman C, Steinman L. Interferon-beta exacerbates Th17-mediated inflammatory disease. Trends Immunol. 2011;32: Shimizu J, Hatanaka Y, Hasegawa M, et al. IFNbeta-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology. 2010;75: Uzawa A, Mori M, Hayakawa S, Masuda S, Kuwabara S. Different responses to interferon beta-1b treatment in patients with neuromyelitis optica and multiple sclerosis. Eur J Neurol. 2010;17: Shimizu Y, Yokoyama K, Misu T, et al. Development of extensive brain lesions following T H E N E U R O L O G Y R E P O R T S u m m e r

18 Salim Chahin, MD, MSCE Advances in Basic and Translational Science Research in Multiple Sclerosis interferon beta therapy in relapsing neuromyelitis optica and longitudinally extensive myelitis. J Neurol. 2008;255: Weber MS, Prod homme T, Youssef S, et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med. 2007;13: Rudick R, Polman C, Clifford D, Miller D, Steinman L. Natalizumab: bench to bedside and beyond. JAMA Neurol. 2013;70: Steinman L. The discovery of natalizumab, a potent therapeutic for multiple sclerosis. J Cell Biol. 2012;199: Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366: Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9: O Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365: Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367: Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367: Scannevin RH, Chollate S, Jung MY, et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012;341: Ghoreschi K, Brück J, Kellerer C, et al. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med. 2011;208: Hersh CM, Cohen JA. Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Immunotherapy. 2014;6: Wiendl H, Kieseier B. Multiple sclerosis: reprogramming the immune repertoire with alemtuzumab in MS. Nat Rev Neurol. 2013;9: Jones JL, Phuah CL, Cox AL, et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. 2009;119: Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378: T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

19 The Evolution in Diagnosis and Treatment of Multiple Sclerosis Tiffani Stroup, DO University of Chicago Medicine, Chicago, Illinois Abstract Management of multiple sclerosis (MS) has evolved significantly since the first disease-modifying therapy (DMT) was introduced. With increasing demand for magnetic resonance imaging (MRI), MS often is on the differential diagnosis of nonspecific white-matter lesions. Making an accurate diagnosis remains crucial to select appropriate therapies. Red flags in either the history or imaging should raise suspicion that an alternative diagnosis may be more likely. MRI is extremely useful to neurologists as they diagnose patients, monitor response to therapy, and, potentially, measure atrophy as a marker for disability. Treatment decisions should be individualized, but certain factors (eg, MRI evidence of clinically silent disease at diagnosis) can help physicians decide to use more aggressive therapies earlier. Transitioning to different DMTs can be guided by balancing the risks and benefits of such treatments. Treatment of symptoms due to MS can improve quality of life. Use of screening tools at follow-up visits can help in the identification of MS-specific symptoms. A multidisciplinary approach of incorporating ancillary services, addressing polypharmacy, and starting specific medications is most effective in combating common symptoms. M anagement of multiple sclerosis (MS) has changed significantly since magnetic resonance imaging (MRI) and the first disease-modifying therapies (DMTs) were introduced into clinical practice. Patients are being diagnosed earlier in the course of disease, and they may be maintained on DMT for decades. These developments have led to increased demand for making an accurate diagnosis and recognizing potential mimics of MS, because DMTs are expensive and may cause potentially serious side effects. n ESTABLISHING AN ACCURATE DIAGNOSIS Based on a presentation by Heather Jean MacLean, MD, Department of Neurology, University of Ottawa, and Director, MS Clinic, The Ottawa Hospital, Ottawa, Ontario, Canada. Since the 2010 McDonald criteria were introduced, there has been an urgency to diagnose MS early. 1 These criteria allowed for diagnosis based upon just one MRI scan. Because multiple relapses early in the course of the disease lead to more disability, the focus of MS therapy remains prevention of attacks. Unfortunately, misdiagnosis occurs in approximately 5% 10% of cases and is largely due to misinterpretation of MRI findings and failure to recognize disorders that mimic MS. Among the nearly 100 disorders that can mimic MS radiologically are microvascular disease, migraine headaches, and psychogenic phenomena. 2 Treatment and prognosis vary for these disorders, making appropriate diagnosis crucial. Certain red flags in the history such as progression of symptoms, childhood or elderly onset, a similar family history, or hearing loss should prompt evaluation for another disease process. Similarly, red flags related to imaging include lesions that are tumefactive, longitudinally extensive, or do not involve the corpus callosum. When red flags are detected, the physician should create a differential diagnosis and proceed with the appropriate workup, which may include contrast-enhanced imaging of the neuroaxis, lumbar puncture, and evoked potentials. 3 If appropriate, treatment can be started, but a working diagnosis should be maintained. The practitioner should keep a high index of suspicion that the case may evolve and that treatment eventually may need to be adjusted. Alternatively, it may be appropriate to delay treatment if the presentation is relatively benign and the diagnosis is still unclear. However, in typical cases, treatment should not be delayed, and ancillary tests can lead to false positives. 2 Specific Diseases and Disorders That Mimic MS Susac s syndrome is a rare condition that typically occurs in people years of age and more commonly in women than in men. This diagnosis is characterized by the classic triad of visual loss, hearing loss, and encephalopathy. Pathogenesis of Susac s syndrome is attributed to microangiopathic changes in the nervous system, with correlation of imaging findings in the corpus callosum and white matter. Notable findings along the corpus callosum include T2 hyperintensities or T1 black holes positioned around the midportion that project as radially oriented icicle- or snowball-shaped lesions. Characteristic white-matter lesions resemble a string of pearls in the internal capsule Dr. Stroup is a Multiple Sclerosis Fellow in the Department of Neurology, University of Chicago Medicine, Chicago, Illinois. T H E N E U R O L O G Y R E P O R T S u m m e r

20 Tiffani Stroup, DO The Evolution in Diagnosis and Treatment of Multiple Sclerosis on diffusion-weighted imaging. Treatment is anecdotal and usually involves immunosuppression with corticosteroids, cyclophosphamide, mycophenolate mofetil, azathioprine, or intravenous (IV) immunoglobulin. Prognosis varies greatly from minimal disability to significant cognitive and hearing deficits, but most cases are self-limited and can last from 6 months to 5 years. 3 Neurosarcoidosis. The pathogenesis of this rare disorder is related to inflammatory granulomas affecting multiple organ systems, such as the lungs, skin, eyes, joints, and nervous system. Neurologic involvement from sarcoidosis may include optic neuritis, cranial neuropathies, peripheral neuropathy, myopathy, chronic meningitis, or hypothalamic dysfunction. Most cases are monophasic, but one third of cases may be relapsing and remitting. In the United States, this disease predominantly affects African-Americans, whereas Caucasians are preferentially affected in Europe. Diagnosis includes MRI signs of parenchymal or leptomeningeal involvement, cerebrospinal fluid (CSF) findings of lymphocytic pleocytosis, imaging of other involved systems, and a gallium scan that may show a characteristic panda sign representing bilateral lacrimal and parotid gland uptake. 3 Acute disseminated encephalomyelitis may be difficult to distinguish from MS. Patients present with fulminant neurologic dysfunction hours to days after vaccination or infection and typically are encephalopathic. Relapses can occur, although rarely, and new neurologic symptoms occurring within 3 months of the initial diagnosis are still considered monophasic. The workup includes MRI showing large white-matter lesions that are similar in age with variable enhancement. Lumbar puncture findings typically are negative for oligoclonal bands. Nearly one half of patients with this disease recover completely. 3,4 Hereditary leukodystrophies. A history of family members dying young with significant neurologic disability should prompt investigation for hereditary leukodystrophies, which can also mimic MS. Most of these diseases present in childhood with progressive neurologic dysfunction and are due to an autosomalrecessive or X-linked recessive defect in myelin production or maintenance. An example of hereditary leukodystrophy that can present in adulthood is adultonset autosomal-dominant leukodystrophy, which radiologically presents with confluent frontoparietal white-matter lesions that spare the periventricular area and involve the corticospinal tracts and cerebellar peduncles. 3 Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy should be considered in the differential diagnosis of MS. Clinical features include subcortical infarcts at a young age, migraine headaches with or without an aura, vascular dementia, and depression. Diagnosis can be made with genetic testing for the NOTCH3 mutation on chromosome 19 or by skin biopsy showing deposits in vessel walls that test positive with periodic acid-schiff staining. Characteristic MRI findings include confluent white-matter T2 hyperintensities in the temporal poles and external capsules. 3 Neuromyelitis optica (NMO) is a demyelinating disorder that may be mistaken for MS, but its distinct clinical features include preferential involvement of the optic nerves and longitudinally extensive transverse myelitis extending over three or more spinal cord segments (Table 1). 5 Pathology of this disorder is necrotizing involvement of the parenchyma, and imaging can show swelling of the spinal cord. Other than MRI orbits and spinal imaging to demonstrate T2 lesions with TABLE 1 Diagnostic Criteria for Neuromyelitis Optica Optic neuritis + myelitis + two of the following: Longitudinally extensive transverse myelitis (three or more vertebral segments) noted on magnetic resonance imaging (MRI) MRI nondiagnostic for multiple sclerosis Positive for serum neuromyelitis optica immunoglobulin G (NMO-IgG) Source: Sellner et al 5 variable enhancement, the diagnostic workup also includes MRI of the brain, which may demonstrate some T2 hyperintensities around the third and fourth ventricles but is otherwise unremarkable; CSF that typically shows elevated protein and neutrophilic pleocytosis and that tests negative for oligoclonal bands; and serum positivity to NMO immunoglobulin G (IgG). Treatment is empirical, consisting of immunosuppression with rituximab or azathioprine; however, prognosis is poor, as most patients are left with residual disability. 5 Progressive multifocal leukoencephalopathy (PML) mimics MS and should be considered in immunosuppressed patients. Patients with PML present with subacute neurologic phenomena due to John Cunningham virus (JCV) infection of the brain. Classically, MRI shows large subcortical T2 hyperintensities with irregular borders, which can involve the gray matter, typically presenting in the temporal, parietal, and occipital regions and extending to the U fibers; these lesions do not enhance with contrast. Most affected patients undergo brain biopsy, which shows oligodendrocyte inclusions of JCV and enlarged astrocytes. 3 n THE USE AND MISUSE OF MRI IN DIAGNOSIS AND TREATMENT Based on a presentation by Nicola De Stefano, MD, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy. In neurologic practice, MRI is a useful tool to diagnose MS, monitor response to treatment, and evaluate possible side effects and tissue loss. Over the past 10 years, the number of MRI scans ordered has increased in both the United States and Europe. 6 Thus, neurologists have become increasingly familiar with typical MS brain lesions, which are ovoid, irregularly shaped, and distributed asymmetrically. These lesions evolve in varying patterns and occur in typical locations: periventricular, juxtacortical, infratentorial, and along the corpus callosum. 7 Clinically Isolated Syndrome (CIS) Since the 2010 McDonald criteria were introduced (Table 2), 1 patients with 18 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

21 Tiffani Stroup, DO The Evolution in Diagnosis and Treatment of Multiple Sclerosis TABLE Revised McDonald Criteria for Diagnosis of Multiple Sclerosis (MS) Clinical presentation Additional data needed for MS diagnosis Two or more attacks a ; None c objective clinical evidence of two or more lesions or one lesion with reasonable historic evidence of a prior attack b Two or more attacks a ; Dissemination in space, demonstrated by: objective clinical evidence One or more T2 lesions in at least two of four MS-typical central nervous system (CNS) regions (periventricular, of one lesion juxtacortical, infratentorial, or spinal cord) d or Await a further clinical attack a implicating a different CNS site One attack a ; objective Dissemination in time, demonstrated by: clinical evidence of two or The simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time or more lesions A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan or Await a second clinical attack a One attack a ; objective Dissemination in space and time, demonstrated by: clinical evidence of one For dissemination in space: lesion (clinically isolated One or more T2 lesions in at least two of four MS-typical CNS regions (periventricular, juxtacortical, infratentorial, or syndrome) spinal cord) d or Await a second clinical attack a implicating a different CNS site and For dissemination in time: The simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time or A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan or Await a second clinical attack a Insidious neurologic One year of disease progression (retrospectively or prospectively determined) plus two of the following three criteria d : progression suggestive Evidence of dissemination in space in the brain based on one or more T2 lesions in MS-characteristic regions of MS (PPMS) (periventricular, juxtacortical, or infratentorial) Evidence of dissemination in space in the spinal cord based on two or more T2 lesions in the cord Positive cerebrospinal fluid findings (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index) If the criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is MS ; if suspicious, but the criteria are not completely met, the diagnosis is possible MS ; if another diagnosis arises during the evaluation that better explains the clinical presentation, then the diagnosis is not MS. a An attack (relapse, exacerbation) is defined as patient-reported or objectively observed events typical of an acute inflammatory demyelinating event in the CNS, current or historic, with duration of at least 24 hours, in the absence of fever or infection. It should be documented by contemporaneous neurologic examination, but some historic events with symptoms and evolution characteristic for MS, but for which no objective neurologic findings are documented, can provide reasonable evidence of a prior demyelinating event. Reports of paroxysmal symptoms (historic or current) should, however, consist of multiple episodes occurring over not less than 24 hours. Before a definite diagnosis of MS can be made, at least one attack must be corroborated by findings on neurologic examination, visual evoked potential response in patients reporting prior visual disturbance, or MRI findings consistent with demyelination in the area of the CNS implicated in the historic report of neurologic symptoms. b Clinical diagnosis based on objective clinical findings for two attacks is most secure. Reasonable historic evidence for one past attack, in the absence of documented objective neurologic findings, can include historic events with symptoms and evolution characteristics of a prior inflammatory demyelinating event; at least one attack, however, must be supported by objective findings. c No additional tests are required. However, it is desirable that any diagnosis of MS be made with access to imaging based on these criteria. If imaging or other tests (for instance, CSF examination) are undertaken and the results are negative, extreme caution should be taken before making a diagnosis of MS, and alternative diagnoses must be considered. There must be no better explanation for the clinical presentation, and objective evidence must be present to support a diagnosis of MS. d Gadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in patients with brainstem or spinal cord syndromes. Source: Polman et al 1 CIS have been diagnosed with clinically definitive MS if the initial MRI findings fulfill the criteria for both dissemination in space and time. Dissemination in space is defined as the presence of at least one lesion in two or more characteristic areas (periventricular, juxtacortical, infratentorial, or spinal cord). In contrast, dissemination in time requires either the presence of asymptomatic gadoliniumenhancing and non-enhancing lesions on one scan or a new T2 lesion or gadolinium-enhancing lesion on a repeat MRI scan. 1 These criteria help to simplify the diagnostic process by requiring less imaging to diagnose MS. Radiologically Isolated Syndrome (RIS) RIS has been defined in recent years as incidental MRI findings that resemble MS lesions without any clinical correlate. Clinical criteria proposed to diagnose RIS (Table 3) 7 require that patients have no history of neurologic dysfunction and that other MS mimics have been ruled out. At 5 years after initial diagnosis, two thirds of patients with RIS will show progression TABLE 3 Characteristics of T2 Hyperintensities in Radiologically Isolated Syndrome Ovoid Well circumscribed Homogeneous May or may not involve the corpus callosum Size > 3 mm Fulfills three of four criteria for dissemination in space Not consistent with vascular distribution Source: Okuda et al 7 T H E N E U R O L O G Y R E P O R T S u m m e r

22 Tiffani Stroup, DO The Evolution in Diagnosis and Treatment of Multiple Sclerosis of MRI findings, and one third will have clinical manifestations. Certain risk factors that increase the odds of developing clinical progression include a cervical spinal cord or infratentorial location, numerous lesions, younger age, pregnancy, abnormal visual evoked potentials, the presence of oligoclonal bands in the CSF, or elevated IgG index plus the presence of at least 10 initial T2 lesions on MRI. 6 Use of MRI for Treatment Decisions For patients already on DMT, progression of MRI lesions over a prespecified period of time may help guide further treatment. Patients taking interferon β who experience more than one relapse or one relapse and at least four new T2 lesions within 1 year of initiating therapy are likely to be nonresponders. 8,9 The Italian Neurological and Neuroradiological Societies have proposed that patients with CIS undergo MRI at baseline and at 3 months and 1 year after diagnosis; for patients with relapsing-remitting MS, MRI should be performed at 6, 12, 24, and 36 months after treatment begins and, if patients are clinically stable, every 2 years thereafter. 10 MRIs may be useful for detecting PML, which can be a deleterious side effect of natalizumab therapy. In patients who are anti-jcv antibody positive, MRI should be repeated annually after natalizumab therapy begins, and discontinuation of natalizumab should be considered. 11 Certain characteristics, such as lack of mass effect for large lesions and subcortical location, can help distinguish PML from a new MS lesion. 3 Assessment of Brain Tissue Loss Brain atrophy can be seen at any stage of MS, but it tends to be more severe in secondary progressive MS and correlates with clinical disability. Unfortunately, a lack of standardization limits the widespread use of brain atrophy measures in MS patients. To further complicate this issue, pseudoatrophy related to resolution of inflammation can be seen after initiation of DMT. 12 MRI findings may be useful in guiding diagnosis, prognosis, and safety of MS treatment. For comparison purposes, patients should have repeat imaging done on the same MRI scanner with standardized MS protocols. 12 n TREATMENT OPTIMIZATION FOR RELAPSING MS Based on a presentation by Mark S. Freedman, MD, MSc, Professor of Neurology and Director, Multiple Sclerosis Research Unit, University of Ottawa, Ottawa, Ontario, Canada. Treatment of MS should be individualized for each patient. However, certain factors, such as estimated risk of disease progression and medication safety profile, may help guide such decisions. Relapses early in the course of MS decrease the functional reserve of the brain and contribute to axonal loss. With the diagnostic criteria for CIS, physicians may intervene at the first neurologic presentation of MS. The type of treatment initially provided may vary if the patient is presenting early, with a relatively mild disease burden on MRI, or later, with a high radiologic burden of previously silent disease. 13 TABLE 4 Tiers of Treatment in Multiple Sclerosis First-line Injectable: interferon β-1a, interferon β-1b, glatiramer acetate Oral: teriflunomide, dimethyl fumarate, fingolimod Second-line Intravenous: natalizumab, alemtuzumab (not approved in the US) Oral: fingolimod Third-line Intravenous: mitoxantrone, cladribine, cyclophosphamide Source: Freedman et al 13 What Factors Should Be Considered Before Initiating Treatment? During the first 5 years after diagnosis, factors related to a poor prognosis with risk for faster disease progression include non-caucasian descent; initial presentation with multiple neurologic deficits; increased numbers of attacks; shortened time between attacks; evidence of disability; high lesion load on MRI; and early involvement of disease affecting motor, cerebellar, or bowel and bladder function. High disease burden on MRI is defined by two or more gadolinium-enhancing lesions with at least nine T2 hyperintensities. 13 Individualization of MS treatment should account for the current severity of the disease, the patient s experience with other therapies, medical comorbidities, and desired onset of therapeutic effect. Determination of estimated disease progression soon after diagnosis can be challenging, but this can be a key factor in deciding whether first-line or more aggressive therapies should be started. Patients with a low risk of imminent disease progression should be placed on first-line agents with proven long-term safety. Alternatively, patients with the previously mentioned risk factors for poor prognosis at disease onset can be considered at high risk for imminent disease progression and may be candidates for more aggressive immunosuppressant medications that have a narrow safety profile. 13 Clinical trials of DMT have shown variable relapse rates for MS. However, a clear definition of treatment tiers is complicated by a lack of comparison trials. Moreover, the use of older agents in newer studies has been associated with lower relapse rates than previously noted, perhaps as a result of trial patients entering trials early in the course of disease or after they have received DMT. 13 Lastly, treatment should be individualized, as trial data are not necessarily applicable to all patients. In the low-risk patient, initiation of first-line therapy with interferons, glatiramer acetate, or any of the oral agents is reasonable (Table 4). 13 Key factors to further individualize therapy include safety based on medical comorbidities and tolerability, since this medication is intended to be used for a long period. In the high-risk patient, escalation of therapy to second-tier agents and above may be considered with the trade-off of more serious safety concerns. Escalation of therapy can be temporary; for example, in induction, a second-line or above agent is used to achieve a desired response goal, and then therapy is switched to a safer first-line agent when the disease is relatively quiescent. An alternative approach involves the use of permanent escalation, 20 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

23 Tiffani Stroup, DO The Evolution in Diagnosis and Treatment of Multiple Sclerosis TABLE 5 Level of Concern Based on the Number and Timing of Relapses, Disability Progression, and Number of Lesions Detected on Magnetic Resonance Imaging Relapses and Level of Concern Level of concern a Criterion Low Medium High Rate One relapse in the second year of One relapse in the first year of More than one relapse in the first treatment treatment year of treatment Severity Mild Moderate Severe Steroids not required Steroids not required Steroids and/or hospitalization Minimal effect on activities of daily Moderate effect on activities of daily required living living Severe effect on activities of daily One functional domain affected More than one functional domain living No or mild motor and/or cerebellar affected More than one functional domain involvement Moderate motor and/or cerebellar affected involvement Severe motor and/or cerebellar involvement Recovery (duration) Prompt recovery Incomplete recovery at 3 months Incomplete recovery at 6 months No functional deficit Some functional impairment Functional impairment a Level of concern determined by meeting at least one criterion Disability Progression and Level of Concern Level of concern Criterion Low Medium High EDSS score a point 2 points at 6 months > 2 points at 6 months or 2 points at 12 months < 1 point 1 point at 6 months > 1 point at 6 months or 1 point at 12 months point at 6 months > 0.5 point at 6 months Clinically No motor involvement Some motor, cerebellar, or cognitive Pronounced motor, cerebellar, or documented Minor sensory involvement involvement cognitive involvement progression Multiple EDSS domains affected Multiple EDSS domains affected Change in Timed 20% increase confirmed at > 20% and < 100% increase confirmed 100% increase confirmed at 25-Foot Walk Test b 6 months at 6 months 6 months EDSS = Expanded Disability Status Scale a If EDSS progression alone is used to assess response to treatment, any change requires subsequent confirmation at 3 6 months. b From baseline (established with walking aid, if needed) Annual MRI Findings and Level of Concern Level of concern Criterion Low Medium High Number of new gadolinium-enhancing lesions per year or annual accumulation of new T2 lesions a 1 lesion 2 lesions 3 lesions MRI = magnetic resonance imaging a Routine follow-up MRI with gadolinium is recommended 6 12 months after initiating therapy for relapsing-remitting multiple sclerosis (or in clinically isolated syndrome if therapy is not initiated). New T2 lesions that are also enhancing on the same scan are counted only once as unique active lesions. The presence of gadolinium-enhancing lesions is more reliable than new T2 lesion counts. New T2 lesion counts require high-quality comparable MRI scans and interpretation by highly qualified individuals. Source: Freedman et al 13 during which a second-line agent is initiated and maintained for the best efficacy. 13 Defining Response to Treatment Nonresponse to treatment can be defined as continued disease activity despite the use of DMT. Within the first year of diagnosis, patients should be followed every 3 or 4 months, encouraged to contact the office with medication side effects or relapses, have neuroimaging at baseline and surveillance at 1 year, and have laboratory parameters monitored based on the therapy used. 13 Baseline neuroimaging should be accomplished when the drug is effective, which means at least 3 months after starting a drug that affects lymphocytes; these cells must undergo one life cycle before the full effect of the drug is seen. Markers for disease progression include the number of clinical relapses, disability progression, and MRI findings. The Canadian Treatment Optimization Model has been proposed as a guide to switching therapy based on low, medium, or high risk of disease progression (Table 5). 13 Patients at low risk of disease progression have up to one attack by 2 years of treatment, less than a 20% change noted in the Timed 25-Foot Walk Test (T25FWT) at 6 months, and fewer than two new T2 lesions on MRI. Conversely, high-risk patients have more than one attack in the first year of treatment, a greater than 100% change in the T25FWT at 6 months, and three or more new T2 lesions on MRI. 13 T H E N E U R O L O G Y R E P O R T S u m m e r

24 Tiffani Stroup, DO The Evolution in Diagnosis and Treatment of Multiple Sclerosis Approaching Disease Breakthrough A suboptimal response to treatment may result from poor tolerance to the DMT prescribed, financial issues, or disease breakthrough. A change to a new agent may be accomplished by a lateral switch to a similarly effective DMT, induction therapy, or escalation maintenance. Patients considered at low risk of imminent disease progression can be switched via a lateral move, and high-risk patients typically require either temporary or permanent escalation. The lateral approach can be used with first-line medications patients are monitored in a manner similar to that used during the first year of treatment, with therapy escalated if further disease activity is noted. For patients with more aggressive disease, an induction strategy using a second-line agent (eg, natalizumab) may be given for 1 2 years; use of the first-line agent then may be resumed with a more acceptable safety profile. In even more aggressive cases, escalation maintenance may be used, such that a second-line or higher-tier medication is used indefinitely, since first-line agents may no longer be effective in this population. The long-term safety profile of these agents is not well defined. Treatment with natalizumab for more than 2 years in patients who are positive for anti-jcv antibody increases the risk of PML, and use of mitoxantrone is limited by lifetime maximum exposure. As with any treatment decision, switching should be based on a risk-benefit profile, although newer agents do not have a clearly defined longterm safety profile outside of clinical trials. Individualization of a treatment plan should be based on the perceived risk of disease progression, with use of more aggressive treatments reserved for patients with a large burden of silent lesions at initial presentation or early disease progression. 13 Early on, a plan should be in place for switching medication if the patient has early disease progression or cannot tolerate therapy with a particular agent. n SYMPTOMATIC MANAGEMENT Based on a presentation by Stephen Krieger, MD, Assistant Professor of Neurology, Mount Sinai Medical Center, New York, New York. Managing MS patients entails a comprehensive evaluation of symptoms that may affect them as a result of the disease. At each visit, addressing these components can help improve patient functioning and quality of life. Often, addressing the symptoms of disease involves a multidisciplinary approach and, in some cases, is achieved by reducing polypharmacy. Common symptoms affecting MS patients include fatigue, spasticity, weakness, balance, mobility, tremor, paroxysmal symptoms, bladder issues, pain, and depression. Fatigue Fatigue may be the most common MS symptom. Assessment of fatigue involves screening for depression, common medical problems (eg, hypothyroidism), polypharmacy, and sleeping difficulty. The pathophysiology of fatigue in MS is multifactorial and likely includes a combination of cytokines and neurochemicals secreted throughout the nervous system. Underlying disability may require extra energy expenditure, and fatigue may be most prominent in excessively warm weather or at the end of the day. 14 Factors that can contribute to poor sleep in patients with MS include poorly treated pain or spasticity, restless legs syndrome, and anxiety. The Epworth Sleepiness Scale is a simple questionnaire that can be completed by patients to clarify whether poor sleeping habits are contributing to fatigue. Affected patients may be referred to a sleep disorders clinic, since management of sleeping problems can significantly improve fatigue. 15 After sleeping problems and polypharmacy have been addressed, patients with continued fatigue can try pharmacologic therapies. Various medications such as amantadine, modafinil, and methylphenidate have been used to combat fatigue in patients with MS with limited success and should be selected on a case-by-case basis. 14 Spasticity On physical exam, signs suggesting that a patient is starting to develop spasticity may include weakness, pain, and hyperreflexia. Identifying the type of spasticity as phasic or tonic may help guide further treatment decisions. Phasic spasticity is defined as painful muscle spasms that occur intermittently. Conversely, tonic spasticity is long-lasting and is associated with stiffness and restricted mobility. 16 The Modified Ashworth Spasticity Scale can help quantify tonic spasticity and may allow comparison across visits. 17 Effective management of spasticity can aid in pain control, hygiene, prevention of contractures, mobility, and functional independence. The most critical portion of spasticity treatment is to remove any contributing noxious stimuli. Spasticity initially should be addressed by physical therapists. Beyond physical therapy and stretching, medications can be useful. First-line oral medications (eg, baclofen, tizanidine, and benzodiazepines) can be helpful, but their use often is limited by sedation. Certain antiepileptics (eg, gabapentin, carbamazepine, and levetiracetam) are useful for managing phasic spasticity, particularly to break the cycle of pain and spasticity. Injection with botulinum toxin may improve focal spasticity, particularly in distal muscles, but it causes weakness of the injected muscle. For patients with generalized spasticity that requires high doses of oral medications, an intrathecal baclofen pump is another treatment option. 18 Limited Mobility Mobility can be limited due to weakness, dorsal column sensory loss, visual impairment, edema, or ataxia in MS. 19,20 External factors such as social attitudes, accessibility of businesses, and climate also contribute to limited mobility. Incorporation of physical therapy for gait assessment and evaluation for assistive devices can be important in improving mobility in these patients. Specific interventions such as ankle-foot orthosis, electrical stimulation, and compression stockings also may be beneficial. The T25FWT is a useful screening tool for walking impairment and may be used as a comparison tool across visits to assess changes. Treatment with dalfampridine can improve performance on the T25FWT but may cause dizziness, 22 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

25 Tiffani Stroup, DO The Evolution in Diagnosis and Treatment of Multiple Sclerosis gastrointestinal upset, and insomnia. At higher doses, there is a risk of seizures. Balance and coordination often is affected in MS patients. Once again, physical therapy has a significant role in teaching balance-training exercises to patients. 20 Bladder Difficulties Bladder difficulties can occur in MS patients due to either a spastic (storage) or hypotonic (emptying) dysfunction. Differentiating between the types of dysfunction is crucial to guide treatment. Patients with spastic bladder typically complain of urinary frequency and urge incontinence, which are best treated with medications such as oxybutynin. However, patients with hypotonic bladders typically complain of urinary hesitancy, which is treated with α-adrenergic 1 antagonists or intermittent catheterization. Initial evaluation of bladder disorders should include screening for urinary tract infection, post-void residuals, and occasional referral to a urologist for urodynamic testing or cystometry. 21 Episodic Symptoms Episodic symptoms in MS can also be disturbing. Paroxysmal symptoms include pain, tonic spasms causing intermittent dysarthria, myokymia, sensory phenomena (eg, trigeminal neuralgia, Lhermitte s phenomenon, and numbness), or Uhthoff s phenomenon, which causes transient visual impairment. Treatment should be directed at the type of complaint, but pain and sensory symptoms have improved with use of either antidepressants or anticonvulsants (eg, carbamazepine or gabapentin). Patients with trigeminal neuralgia who do not respond to pharmacologic intervention may be referred to a neurosurgeon for surgical intervention. A course of IV corticosteroids is a reasonable option if the sensory or visual complaints are new and signify a relapse. 18,22 Mood Impairment Mood impairment can be a disabling symptom of MS. Depression is common; its exact cause is not known, but it may be a reaction to the diagnosis, a sign of the unpredictability of the disease, or a side effect of interferon therapy. Unfortunately, patients with untreated depression can experience worsening of other MS symptoms. Screening for depression includes administering a simple two-question test recommended by the US Preventive Services Task Force, which screens for depressed feelings or anhedonia over the previous 2 weeks. Common side effects of antidepressant therapy include anticholinergic effects, sexual dysfunction, and weight gain. 23,24 Pseudobulbar affect characterized by outbursts of inappropriate laughing or crying also may occur in MS patients. A US Food and Drug Administration approved medication that combines dextromethorphan and quinidine may significantly reduce the frequency and severity of outbursts due to pseudobulbar affect. 24 Summary Incorporating ancillary services, referrals to other specialists, and appropriate pharmacologic interventions may improve the quality of life of MS patients significantly. Too often, patients may express hopelessness due to the diagnosis of a chronic, potentially disabling disease. Management of secondary symptoms is as valuable as prevention of further relapses. REFERENCES 1. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69: Rolak LA, Fleming JO. The differential diagnosis of multiple sclerosis. Neurologist. 2007;13: Charil A, Yousry TA, Rovaris M, et al. MRI and the diagnosis of multiple sclerosis: expanding the concept of no better explanation. Lancet Neurol. 2006;5: Miller DH, Weinshenker BG, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler. 2008;14: Sellner J, Boggild M, Clanet M, et al. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol. 2010;17: Granberg T, Martola J, Kristoffersen-Wiberg M, Aspelin P, Fredrikson S. Radiologically isolated syndrome-incidental magnetic resonance imaging findings suggestive of multiple sclerosis: a systematic review. Mult Scler. 2013;19: Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009;72: Rio J, Castillo J, Rovira A, et al. Measures in the first year of therapy predict the response to interferon beta in MS. Mult Scler. 2009;15: Sormani MP, De Stefano N. Defining and scoring response to IFN-β in multiple sclerosis. Nat Rev Neurol. 2013;9: Filippi M, Rocca MA, Bastianello S, et al. Guidelines from the Italian Neurological and Neuroradiological Societies for the use of magnetic resonance imaging in daily life clinical practice of multiple sclerosis patients. Neurol Sci. 2013;34: SØrenson PS, Bertolotto A, Edan G, et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler. 2012;18: Simon JH, Li D, Traboulsee A, et al. Standardized MR imaging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. AJNR Am J Neuroradiol. 2006;27: Freedman MS, Selchen D, Arnold DL, et al. Treatment optimization in MS: Canadian MS working group updated recommendations. Can J Neurol Sci. 2013;40: Lapierre Y, Hum S. Treating fatigue. Int MS J. 2007;14: Brass SD, Duquette P, Proulx-Therrien J, Auerbach S. Sleep disorders in patients with multiple sclerosis. Sleep Med Rev. 2010;14: Hawker K, Frohman E, Racke M. Levetiracetam for phasic spasticity in multiple sclerosis. Arch Neurol. 2003;60: Ghotbi N, Nakhostin AN, Naghdi S, et al. Measurement of lower-limb muscle spasticity: intrarater reliability of Modified Ashworth Scale. J Rehabil Res Dev. 2011;48: Pollmann W, Feneberg W. Current management of pain associated with multiple sclerosis. CNS Drugs. 2008;22: Olggiati R, Burgunder JM, Mumenthaler M. Increased energy cost of walking in multiple sclerosis: effect of spasticity, ataxia, and weakness. Arch Phys Med Rehabil. 1988;69; Bethoux F. Gait disorders in multiple sclerosis. Continuum. 2013;19: DasGupta R, Fowler CJ. Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies. Drugs. 2003;63: O Connor AB, Schwid SR, Herrmann DN, et al. Pain associated with multiple sclerosis: systematic review and proposed classification. Pain. 2008;137: Fragoso YD, Adoni T, Anacleto A, et al. Recommendations on diagnosis and treatment of depression in patients with multiple sclerosis. Pract Neurol. 2014;14: Minden SL, Feinstein A, Kalb RC, et al. Evidence-based guideline: assessment and management of psychiatric disorders in individuals with MS: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;8: T H E N E U R O L O G Y R E P O R T S u m m e r

26 Current and Emerging Therapies for Multiple Sclerosis William Meador, MD University of Alabama at Birmingham School of Medicine, Birmingham, Alabama Abstract Over the past 21 years, nine treatments for multiple sclerosis (MS) have been approved by the US Food and Drug Administration (FDA), with three drugs given marketing clearance between 2010 and These additions to our armamentarium have made our choice of disease-modifying therapy for MS patients increasingly complex. Established agents are safe and reasonably effective, whereas newer agents carry more risk but may offer more benefit. A B-cell therapy probably will be approved by the FDA in the next few years, and ongoing neuroprotective or neuroreparative trials may produce a treatment option for progressive disease. R isk stratification of multiple sclerosis (MS) patients for treatment with an appropriate disease-modifying therapy (DMT) includes early assessment of disease severity, consideration of an individual s risk tolerance, and recognition of potential risks that may result from the use of a particular medication. The type of MS involved greatly influences therapeutic options, and relapsing -remitting MS (RRMS) presents its own unique challenges. Many neurologists use a firstand second-line approach a DMT with a low-risk safety profile is started, and if treatment failure occurs, a second-line therapy with potentially more risk is considered. Many potential therapeutic options that are currently being evaluated target B cells, hone in on neuroprotective targets, and feature neuroreparative goals. At a symposium held during the 66 th Dr. Meador is a National Multiple Sclerosis Society Clinical Care Fellow in Neuroimmunology at the University of Alabama at Birmingham School of Medicine, Birmingham, Alabama. Annual Meeting of the American Academy of Neurology, experts on the many dimensions of MS discussed treatment of relapsing disease, diagnostic and prognostic issues, different directions and targets for therapy, and the treatment of MS in younger patients. The symposium was co-chaired by Robert Fox, MD, FAAN, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, Cleveland, Ohio, and Eric Klawiter, MD, of the Department of Neurology at Massachusetts General Hospital, Boston. n TREATING RRMS: CHOOSING AMONG THE OPTIONS Based on a presentation by Myla D. Goldman, MD, MSc, Assistant Professor of Neurology and Director of the James Q. Miller Multiple Sclerosis Clinic, University of Virginia, Charlottesville, Virginia. Before 1993, the US Food and Drug Administration (FDA) had not approved any therapies for MS. Currently, nine drugs have been approved (Table 1), making our treatment decisions increasingly more complex. Many agents have been proven beneficial in studies with endpoints assessing the inflammatory components of MS, but no drug has been FDA approved for progressive disease. Therefore, determination of individual treatment goals should be based on the goal of no evidence of inflammatory disease activity (NEIDA), which better incorporates trial results into our clinical decision-making. This goal considers clinical relapses, enhancing lesions on magnetic resonance imaging (MRI), and detection of new T2 lesions as a possible indicator of therapeutic failure. The Process of Decision-Making When deciding on a DMT, 86% of neurologists report that efficacy is most important. 1 Clinical trials in MS patients that have been conducted over the past 19 years have shown increasingly reduced annualized relapse rates (ARRs) in both treatment and placebo arms. Thus, it is difficult many feel impossible to compare different DMTs based solely on relapse reduction rates reported during large clinical trials. The only effective method of comparing these agents would TABLE 1 History of Disease-Modifying Therapy for Multiple Sclerosis 1990s Glatiramer acetate Interferon β-1a (intramuscular) Interferon β-1b 2000s Interferon β-1a (subcutaneous) Mitoxantrone Natalizumab Early 2010s Dimethyl fumarate Fingolimod Teriflunomide Future therapies B-cell therapies? Neuroprotective agents? Neuroreparative agents? 24 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

27 William Meador, MD Current and Emerging Therapies for Multiple Sclerosis be to design and perform head-to-head efficacy trials. Of 28 possible combinations, only 7 head-to-head trials have been performed, and these studies generally have not demonstrated significant differences among different DMTs. An extension of the TRANSFORMS study 2 showed that patients who switched from intramuscular interferon β-1a to fingolimod experienced a reduction in ARR from 0.33 to Although efficacy most influences a physician s choice of DMT, safety tends to be the second most common consideration. 1 Heesen et al 3 showed that patients are generally less risk-averse than are their physicians during the DMT selection process. Actually, 80% of patients were willing to accept a risk of serious adverse event 1:100 when choosing a DMT, whereas most physicians surveyed placed their acceptable risk between 2:10,000 and 1:100. These results suggest that the risk tolerance of individual patients should be explored and considered when a DMT is being chosen. Other factors that may drive our treatment decision include disease severity at the time of decision, pregnancy and family planning, tolerability, compliance, monitoring, cost, and comorbidities. Our ability to assess disease severity in the early stages of MS is flawed, yet factors such as initial frequency of relapses, impairment of activities of daily living (ADL), degree of recovery from relapses, and motor versus sensory involvement should be considered when patients are stratified to low-, medium-, and high-risk groups. The risk tolerance of both treating physicians and patients may differ when disease severity is included in this assessment. In addition, the likelihood of pregnancy should be assessed in each patient. Further, the development of so many treatments for relapsing forms of MS over the past 21 years has been exciting and has contributed to a much more complex DMT decision. n TREATING RRMS: RISK STRATIFICATION AND MITIGATION Based on a presentation by Bruce A.C. Cree, MD, PhD, Associate Professor of Neurology, University of California at San Francisco School of Medicine, San Francisco, California. TABLE 2 Risk of Developing Progressive Multifocal Leukoencephalopathy in Patients Treated with Natalizumab Anti-JCV Anti-JCV antibody positive antibody No prior use of Prior use of negative Natalizumab exposure immunosuppressants immunosuppressants 1 24 months < 1/1,000 1/1,000 < 1/1, months 3/1,000 13/1,000 JCV = John Cunningham virus Source: Tysabri (natalizumab) package insert months 7/1,000 9/1,000 Currently, physicians have practical and commonly used methods for selecting DMTs to treat MS. An easily implemented two-tiered approach involving first- and second-line agents takes advantage of use of DMTs with better risk profiles initially; if these treatments are ineffective, escalation to an agent that may offer more benefit but that poses a greater risk of serious adverse effects may be tried. In typical practice, first-line agents might be the interferons or glatiramer acetate; these medications have been used in MS patients for two decades and have been associated with minimal serious adverse events. If use of these agents does not control a patient s disease, then that individual might try a DMT that may be more effective but more risky, such as natalizumab, fingolimod, or teriflunomide. This two-tiered approach probably is used commonly in the United States, but it has some major disadvantages. Patients with more aggressive disease upfront may have unnecessary exposure to disease activity if a less effective DMT with a better side-effect profile is used. In addition, this approach does not account for the patient s individual risk tolerance it would more directly reflect the risk tolerance of the treating physician who is determining which drug to use first. Choices for DMT Interferons tend to cause side effects that include flu-like symptoms, injectionsite reactions, depression, and transaminitis. Over the 20 years since their introduction, interferons have only rarely caused serious adverse events. Likewise, glatiramer acetate has been widely used for MS for almost 20 years; it features a relatively benign side-effect profile that includes injection-site reactions, lipoatrophy, and a less-common post-injection systemic reaction resembling a panic attack. Due to their prolonged and widespread use, effectiveness, and minimal serious adverse events, these agents are ideal first-line choices for DMT. Natalizumab, a monoclonal antibody, exerts its therapeutic benefit by blocking lymphocytes from entering the central nervous system (CNS). When compared with placebo, natalizumab therapy resulted in a significant reduction in relapse rates (68%) and disability (hazard ratio = 42%). 4 Natalizumab is infused every 28 days. The drug held great promise for managing MS until a risk of progressive multifocal leukoencephalopathy (PML) was discovered. Natalizumab was withdrawn from the market, but it was then reapproved with a black-box warning concerning the risk of PML. Over the years, patients have been risk-stratified for PML according to John Cunningham virus (JCV) antibody status, history of immune suppression, and duration of treatment (Table 2). 5 However, JCV antibody seronegativity is not completely protective from PML there have been two known cases of PML in patients who were JCV antibody negative. Villar 6 evaluated 367 patients given natalizumab; among 23 who developed PML, lipid-specific immunoglobulin-m bands in the cerebrospinal fluid (CSF) were thought to correlate with a reduced risk of PML. Patients with CSF containing these bands seemed to have a PML risk similar to that of patients who are JCV antibody negative, even though some of this cohort were JCV antibody positive. T H E N E U R O L O G Y R E P O R T S u m m e r

28 William Meador, MD Current and Emerging Therapies for Multiple Sclerosis Fingolimod, the first FDA-approved oral agent to treat MS, was approved in 2010 for relapsing forms of the disease. In the pivotal FREEDOMS trial, 7 fingolimod therapy reduced the ARR by 54% and accumulated disability by 30% when compared with placebo. Fingolimod inhibits sphingosine 1-phosphate receptors, which prevents egress of lymphocytes from lymphoid tissue. However, because these receptors are present in other parts of the body, fingolimod therapy can cause bradycardia, de novo hypertension, and macular edema. With the initial dose, patients may experience significant bradycardia; after receiving that first dose, patients should undergo electrocardiographic examination before and after a 6-hour monitoring period. Varicella zoster virus reactivation also is possible with fingolimod therapy. Patients who do not have adequate titers of varicella zoster virus immunoglobulin G on serum testing should receive immunization 30 days prior to starting therapy. Monitoring for side effects is recommended, but no exact parameters regarding the frequency of monitoring are available. Teriflunomide was approved by the FDA in 2011 for the treatment of relapsing forms of MS. This oral drug may exert its beneficial action as an antimetabolite that inhibits DNA synthesis. In clinical trials, its use resulted in a 32% reduction in ARR and a 30% reduction in disability when compared with placebo. 8 The medication can cause reactivation of latent tuberculosis, alopecia, and transaminitis. Teriflunomide has a Pregnancy Category X status; rapid elimination protocols are available if a patient on teriflunomide becomes pregnant. Henson et al 9 reported on 70 pregnancies occurring while on teriflunomide and 22 men who fathered children on treatment; as of early 2014, the offspring have shown no structural or functional deficits. However, spontaneous abortions occurred at a rate of about 19%, which is similar to the rate observed among pregnant women who do not have MS. Dimethyl fumarate, the most recently approved oral medication, was approved by the FDA in 2013 based on the results of two large trials showing significant benefit versus placebo in MS patients. Treatment with dimethyl fumarate resulted in a 47% relative reduction in ARR and a 59% reduction in disability progression when compared with placebo. 10 Common side effects include a diffuse flushing reaction and gastrointestinal (GI) distress; rare side effects include lymphopenia and a theoretical risk of PML and renal cell carcinoma, which have occurred when a similar medication was used to treat psoriasis. Taking aspirin before each dose can reduce flushing, and drug administration with a meal can reduce GI distress. B-cell therapy in MS has gained significant traction over the past few years, with several trials showing promising results. Ofatumumab is an anti-cd20 monoclonal antibody that profoundly reduces circulating B lymphocytes. In the MIRROR study, 11 ofatumumab was compared with placebo in 232 RRMS patients. From week 0 to week 12 of treatment, a 65% reduction in the number of gadolinium-enhancing lesions was observed among the five groups treated with ofatumumab when compared with the group receiving placebo. Analysis of MRI scans taken during weeks 4 12 showed that ofatumumab-treated patients experienced an astonishing 90% reduction in gadolinium-enhancing lesions when compared with the placebo group. Of note, however, 52% of patients treated with ofatumumab had injection-related reactions, and five serious adverse events occurred. Physicians should use caution when considering using the most effective medicine initially, despite its risk profile. Starting with the most effective DMT makes it difficult to find an alternative if the treatment fails. In addition, our ability to accurately predict patient response to these drugs is limited. Some physicians believe that brief, aggressive induction therapy followed by an ongoing DMT with a more tolerable side-effect profile may reduce risk while maximizing benefit. This approach warrants further investigation. Currently, it is acceptable to choose an initial DMT with a reasonable benefit and side-effect profile and to continue ongoing treatment until clinical or radiographic disease progression prompts consideration of a different therapy. n IS NO EVIDENCE OF MS DISEASE ACTIVITY AN ACHIEVABLE GOAL? Based on a presentation by Robert Bermel, MD, Medical Director of the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, Ohio. Appropriate goals to guide treatment of patients with MS are controversial. Using the treatment of rheumatoid arthritis as an example, results of the TICORA trial 12 showed that earlier, more intensive therapy in a population of patients with an autoimmune disease may result in significant long-term benefit in multiple outcome measures. Therefore, early and aggressive treatment in MS patients based on NEIDA may be the most appropriate approach to take. The first published discussion of NEIDA involved disease-free status used in the AFFIRM trial of natalizumab versus placebo. 13 Disease-free status was defined as the absence of relapses, progression of disability, enhancing lesions, and new T2 lesions on MRI. At the end of the 2-year trial, 7% of the placebo group and 37% of natalizumab-treated patients maintained a disease-free status. However, disease-free status may be an inaccurate term, since histopathologic disease activity cannot be ruled out completely, and surrogate markers for disease activity (eg, MRI) are being used. NEIDA, on the other hand, implies that the treating physician is monitoring the patient for evidence of disease activity and cannot find any such evidence. Should NEIDA Be Considered Clinically Meaningful? Data from the 2-year AFFIRM trial showed that NEIDA correlated well with brain atrophy, cognition, ambulation scores, visual function, disability scores, and patient-reported outcomes. Likewise, NEIDA patients had more improvement in paced auditory serial addition test (PASAT) scores. Bermel et al 14 found improved Expanded Disability Status Scale (EDSS) scores in patients achieving NEIDA in the AFFIRM trial to persist for up to T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

29 William Meador, MD Current and Emerging Therapies for Multiple Sclerosis weeks; MRI activity seems to play a key function in NEIDA and may be a strong predictor of poor outcome. In patients on interferon therapy, early MRI activity carried an odds ratio (OR) of 8.96 for poor long-term outcome, whereas new T2 lesions and clinical relapses only held ORs of 2.89 and 4.44, respectively. Similarly, using a Modified Rio Score, Sormani et al 15 reported that early disease activity on MRI predicted the probability of disability over time. Prosperini et al 16 found that detection of three or more new MRI lesions in the first year of interferon treatment predicted EDSS worsening, with a hazard ratio of 30. These findings seem to show that short-term NEIDA may result in sustained benefit, and MRI is an instrumental tool in defining NEIDA. We can incorporate the concept of NEIDA into our assessment of clinical trial results by comparing NEIDA rates in treated and placebo groups (Table 3). n TREATING MS IN 2020: REMYELINATION, PROGRESSIVE MS, AND BEYOND Based on a presentation by Catherine Lubetzki, MD, PhD, Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France. We have been unable to offer any MS treatment that can effectively stop progressive disease or promote repair of the CNS. Aside from one subgroup of rituximab-treated patients and one European trial that evaluated interferon β-1b, no DMT has shown any benefit in patients with progressive forms of MS. A great deal of progressive damage occurs via chronic demyelination and subsequent axonal loss; some experts believe that remyelination may reduce these degenerative changes. Basic science research principles currently are being used to better delineate how myelin repair occurs and to discover therapeutic targets and meaningful medications to help repair previously injured nervous system tissue. Both neuroprotection and remyelination therapies hold great promise for all patients suffering from MS, especially for those with progressive forms of MS. Since the mid-1960s, remyelination has been known to occur in MS patients. Remyelination can reduce axonal loss during injury, but it does not seem to be completely protective. Oligodendrocytes myelinate axons within the CNS and can serve to remyelinate if they are activated. Oligodendrocyte progenitor cells (OPCs) reside in young and adult brains and can differentiate to form activated oligodendrocytes. After an injury, such as an area of demyelination, the OPCs initially activate and then migrate to the area of injury; they mature into oligodendrocytes and finally begin to remyelinate the local axons. Potential therapeutic targets could modulate any of these steps to improve activation, recruitment, maturation, or remyelination as they relate to OPCs and oligodendrocytes. Manipulating Genetic Roots of MS Dr. Lubetzki s work has focused on two primary areas: activation and migration. CCL2 and IL1B receptors seem to be active during OPC activation. Investigators in her laboratory induced myelin injury with cuprizone and showed that CCL2 and IL1B were upregulated. They also showed that activation of NETRIN1 and SEMA3A receptors repels OPCs, whereas TABLE 3 Rates of No Evidence of Inflammatory Disease Activity (NEIDA) in Multiple Sclerosis Clinical Trials Rate of NEIDA in Rate of NEIDA in Clinical trial treatment arm placebo arm Increase ( ) AFFIRM (natalizumab) 37% 7% 5.3 CARE-MS 2 (alemtuzumab) 32% 13% 2.5 CLARITY (cladribine) 44% 16% 2.8 DEFINE (dimethyl fumarate) 28% 15% 1.9 FREEDOMS (fingolimod) 33% 13% 2.5 Peginterferon 34% 15% 2.2 activation of SEMA3F receptors attracts OPCs. In human MS lesions and in experimental models, OPCs express these receptors. Through the use of a lentivirus, these investigators upregulated the genes that control these receptors, resulting in increased migration of OPCs into a demyelinated area of injury. Multiple laboratories have shown that an increased density of OPCs in areas of injury correlate with an increase in the number of axons undergoing remyelination. Cell Maturation and Gene Activity An area of particular excitement relates to the process of maturation of OPCs into oligodendrocytes. When activated, the LINGO1 receptor blocks the OPC from maturing into an oligodendrocyte. Reducing LINGO1 receptor activity may increase the number of mature oligodendrocytes present in the area of injury and, in turn, increase the amount of remyelination. An anti-lingo1 monoclonal antibody has been produced; two phase 2 trials of this potential DMT in patients with MS and optic neuritis are ongoing. Investigators affiliated with the Relapsing- Remitting Multiple Sclerosis Synergy trial plan to enroll 400 patients who will be followed for 18 months. The optic neuritis trial plans to enroll 80 patients and follow them for 6 months. The active metabolite of fingolimod may increase OPC maturation into oligodendrocytes via the ERK1/2 and p28mapk pathways and may increase the number of mature oligodendrocytes. 17 Thus, fingolimod may have direct modulatory activity on the OPC maturation process. Neuroprotection also may impart possible benefit in patients with all forms of MS, but especially those with progressive disease. Two ongoing trials are evaluating possible neuroprotective agents in patients with progressive forms of MS. SPRINT-MS is a phase 2 trial that is comparing ibudilast with placebo in patients with progressive forms of MS. This trial will enroll 250 patients and have 2 years of follow-up. Similarly, MS-SMART is a phase 2 trial being conducted in the United Kingdom that will evaluate three drugs versus placebo in patients with primary T H E N E U R O L O G Y R E P O R T S u m m e r

30 William Meador, MD Current and Emerging Therapies for Multiple Sclerosis progressive MS. In all, 440 patients will be enrolled; those in the active arms will receive riluzole, amiloride, or ibudilast. n TREATING PEDIATRIC MS: IS IT DIFFERENT FROM TREATING ADULTS? Based on a presentation by Tanuja Chitnis, MD, Director of the Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, Massachusetts. Over the past decade, patients who had been diagnosed with acute disseminated encephalomyelitis during the 1990s increasingly have been considered to have pediatric-onset MS (POMS). In many respects, POMS is similar to adult-onset disease, although a few key differences are apparent. Adult-onset MS and POMS share defining characteristics, such as relapses, disease progression, risk factors, and response to medications. However, POMS seems to have more of an inflammatory component, more frequent relapses, and more MRI activity. Also, POMS is related to a more robust response of interleukin (IL)-17 producing effector T helper cells, more cognitive effects, different pharmacokinetics, and a higher prevalence of myelin oligodendrocyte glycoprotein (MOG) antibodies. Benson et al 18 have shown that relapses are more frequent in POMS. Children tend to have slower accumulation of disability when measured with the EDSS. At any given age, however, POMS patients have higher rates of disability than do their adult counterparts. Approximately 35% of pediatric MS patients have significant cognitive impairment, which increases with time. 19 POMS patients have a greater T-cell response to myelin peptides than do their adult MS counterparts or children and adults without MS. 20 The disease progression in children is compounded by the fact that CNS myelination is not complete until the third decade of life. Pediatric MS patients require different management of their disease. They need reinforcement of medication adherence, involvement of the entire family, and more frequent visits, since they tend to underreport new symptoms. Allowing children with MS and their families to socialize and interact with other families who are living with the same disease helps them to cope with their illness. Interferons and glatiramer acetate generally are first-line agents titrated to adult doses in children, as tolerated, but only limited data support these treatments in children, and none of these therapies is FDA-approved. The clinical effectiveness of these medications in children appears to be similar to that in adults in smaller cohorts. 21 One of the largest studies in POMS was the REPLAY study, which evaluated subcutaneous administration of interferon β-1a in 307 pediatric patients. 22 Retrospective analysis showed few serious adverse events, on the order of < 1%, but the ARR on treatment was still A collaborative study of pediatric MS centers followed 210 patients for an average of 4 years; 56% received one treatment over this period, 25% received two, and 19% received at least three. 23 Natalizumab was used in 55 patients; it significantly reduced clinical disease activity and resulted in a less robust decrease in MRI measures. 24 Few prospective trials, and virtually no randomized clinical trials, support the use of DMT in pediatric-onset disease, but new legislation may change protocols. In 2007, the US Congress passed the Pediatric Research Equity Act, which mandated that any investigational new drug (IND) study should evaluate the effectiveness in children. The sponsoring pharmaceutical company can apply for a waiver to extend its exclusive patent rights for 6 months beyond the expected time frame if they test the drug in pediatric patients. However, there are only an estimated 2,000 4,000 cases of pediatric MS worldwide, which makes prospective randomized clinical trials difficult to complete. After 2000, the International Pediatric Multiple Sclerosis Study Group (IPMSSG) was established. This group focuses on the evaluation of new and existing therapeutics for pediatric MS, according to its consensus statement. 25 The plan is to carefully design randomized clinical trials using therapies that have shown promise in adult phase 3 studies, to better establish useful treatments in pediatric patients, and to use the growing number of centers participating in POMS management and research. n NEW RESEARCH AND FUTURE DIRECTIONS Ehler et al 26 evaluated a retrospective cohort of 90 glucocorticoid-unresponsive patients with MS relapses. Gadoliniumenhancing lesions were the only significant predictor of response to therapeutic plasma exchange in this cohort; there were no significant differences in terms of other potential predictors such as time from relapse onset, diagnosis, and age. This cohort included 21 patients with clinically isolated syndrome, 46 with RRMS, 18 with secondary-progressive MS, and 5 with primary -progressive MS. Adverse events associated with plasma exchange occurred in 18% of patients. Vitamin D has been an area of particular interest in the MS community, since it modulates the immune system. A deficiency in vitamin D correlates with disease severity and is a risk factor for developing MS. 27 Vitamin D status was evaluated in patients treated with either glatiramer acetate or interferon β in the CLIMB study 28 cohort. Vitamin D levels obtained within 18 months of starting therapy were assessed in 151 patients on glatiramer acetate and 96 patients on interferon β. Higher levels of vitamin D correlated with a longer time to first event for the interferon β group, but it did not correlate with time to first event for glatiramer acetate. This suggests that the relevance of vitamin D status in MS patients may be modified by ongoing DMT. Ongoing research continues to attempt to modulate the immune system to reduce disease activity in MS and MS models. Mayo et al 29 showed that use of a nasal spray with anti-cd3 could alter the disease course in a mouse model of progressive MS. The response occurred in an IL-10 dependent manner; the benefit was abolished if IL-10 was blocked. This research needs further validation and study, but it may offer a unique mechanism of action for a future MS therapeutic approach. Despite our best care efforts, many patients develop significant disability and 28 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

31 William Meador, MD Current and Emerging Therapies for Multiple Sclerosis progressive disease. Rehabilitation often is instrumental in allowing patients to maintain their independence. Constraintinduced (CI) therapy has been beneficial in stroke and cerebral palsy patients. Mark et al 30 evaluated its usefulness in patients with progressive MS by randomizing 20 adults to undergo either 35 hours of CI therapy or 35 hours of complementary and alternative medicine (CAM). They evaluated outcomes with the motor activity log and with cortical gray-matter volume using voxel-based imaging scores. Use of CI resulted in significantly more benefit in both outcomes than did CAM, and it appeared to counteract some of the progressive functional loss and CNS degeneration that occur in progressive MS. Sanders et al 31 evaluated the compound IRX4204 in experimental autoimmune encephalitis (EAE), a mouse model for MS. The compound is an optically purified isomer of a synthetic molecule that has high affinity for the homodimerized RXR receptor. This compound has been well studied in over 70 humans with cancer, but it has only undergone study in neurologic disease (ie, Parkinson s and Alzheimer s diseases) more recently. It significantly reduced disease activity in EAE mice; its use may promote T-regulatory cells and inhibit T-helper 17 cells, a theoretically favorable action in reducing MS pathogenesis. This compound may impart immunomodulatory effects and increase remyelination after injury. Vosckuhl and others 32 presented data from a study of estriol used to modify MS disease activity. Relapses in pregnant MS patients are reduced by more than 70% during the third trimester; during this time, females are exposed to high levels of estriol. The hormone may mediate its effects in an anti-inflammatory manner to prevent fetal rejection. The design was a double-blind, placebo-controlled, 2-year study comparing patients taking glatiramer acetate plus placebo with those taking glatiramer acetate plus oral estriol; patients in the latter group also received periodic progesterone to protect the uterus. No significant safety issues were noted during the study. Relapse rates in the estriol plus glatiramer acetate group were 47% lower than were those in the group using only glatiramer acetate during the first 12 months. However, the difference between the two groups seemed to wane over the months of treatment. The investigators attributed this finding to a maximum effect of glatiramer acetate occurring during the second year, but it also may have represented a wearing off of the estriol effect. Cognitive outcomes were more robust and persisted into the second year. Patients given glatiramer acetate plus estriol who had PASAT scores below 55 at baseline had a significant increase in PASAT scores that persisted throughout the trial. Viglietta et al 33 presented results from the EXPLORE study that assessed the Despite our best efforts, many patients develop significant disability and progressive disease. Rehabilitation often is instrumental in allowing them to maintain independence. safety and tolerability of combining dimethyl fumarate with either glatiramer acetate or interferon β. This study enrolled patients who had been on the same treatment for over a year; they remained on monotherapy for 2 months, after which dimethyl fumarate was added, and they were followed for 6 months. Side effects were similar to those of dimethyl fumarate monotherapy, with three serious adverse events of worsening diabetes, clostridial infection, and significant GI distress resulting in discontinuation. Mean leukocyte counts were within normal limits, and transaminitis was mild. Treatment effect, which was not a primary outcome, seemed similar to that of dimethyl fumarate monotherapy. Schippling and others 34 evaluated the use of transcranial magnetic stimulation (TMS) in patients with MS. This therapeutic modality currently is used to treat depression and other neuropsychiatric disorders, and it has been tested in various neurologic diseases. Of 28 participants, 10 were given sham therapy, 9 were given TMS to the prefrontal cortex, and 9 were given TMS to the motor cortex. Statistically significant improvement in fatigue and depression occurred within 2 weeks of the start of TMS when the motor cortex was stimulated but not when the prefrontal cortex was stimulated. There were no significant adverse events, and the most common side effect of active treatment was lower extremity paresthesias, which may have been related to underlying MS lesions. Birnbaum et al 35 presented results from a prospective trial evaluating the cessation of DMT in patients with progressive MS. This study investigated whether or not patients with SPMS benefit from DMT that tends to reduce relapse rates; in addition, it sought to identify patients who could stop DMT without adverse events. The first group was comprised of patients who with stable disease for 8 10 years; their treating physician proposed that they stop therapy, and those who agreed were enrolled. The second group was made up of patients who initiated the discussion about stopping therapy without prompting from their physician. Of 62 patients in group 1, symptoms in 4 worsened after DMT was stopped; the median age in these patients was 54 years, whereas those whose symptoms did not worsen had a median age of 62 years. All had been stable on treatment for a similar length of time. In the second group, 4 of 10 patients worsened; however, the age difference was not similar to that in group 1. Thus, younger patients and those who voluntarily wish to stop therapy may be at higher risk of disease progression after DMT ends than are older patients who are asked to stop by their treating physicians. n CONCLUSION Physicians must find an appropriate risk tolerance for choosing new thera- T H E N E U R O L O G Y R E P O R T S u m m e r

32 William Meador, MD Current and Emerging Therapies for Multiple Sclerosis pies that incorporate a patient s disease severity and individualized risk tolerance. The DMT should be initiated with a goal of NEIDA. If treatment failure occurs, reassessment of risk tolerance is prudent before a second therapy is chosen. Ongoing work aims to further elucidate targets for treatments that focus on myelin repair or neuroprotection to benefit all patients with MS but especially those with progressive disease. With these approaches, a growing supply of many DMT options hopefully will continue to improve management of MS patients and may even lead to reversal of the disease in the future. REFERENCES 1. Hanson KA, Agashivala N, Wyrwich KW, Raimundo K, Kim E, Brandes DW. Treatment selection and experience in multiple sclerosis: survey of neurologists. Patient Prefer Adherence. 2014;8: Khatri B, Barkhof F, Comi G, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. TRANSFORMS Study Group. Lancet Neurol. 2011;10: Heesen C, Kleiter J, Gyuyen F, et al. Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists. Mult Scler. 2010;16: Polman CH, O Connnor MW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. AFFIRM Investigators. N Engl J Med. 2006;354: Tysabri (natalizumab) injection, for intravenous use [package insert]. Cambridge, MA: Biogen Idec Inc; December Villar L. Lipid-specific IgM bands contribute to stratify PML risk in MS patients treated with natalizumab. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Abstract Kappos L, Radue E-W, O Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. FREEDOMS Study Group. N Engl J Med. 2010;362: O Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. TEMSO Trial Group. N Engl J Med. 2011;365: Henson LJ, Benamor M, Truffinet P, Kieseier B. Updated pregnancy outcomes in patients and partners of patients in the Teriflunomide Cynical Trial Program. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster P Gold R, Kappos L, Arnold DL, et al. Placebocontrolled phase 3 study of oral BG 12 for relapsing multiple sclerosis. DEFINE Study Investigators. N Engl J Med. 2012;367: Bar-Or A, Grove R, Austin D, et al. The MIRROR study: a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study to investigate the safety and MRI efficacy of subcutaneous ofatumumab in subjects with relapsing-remitting multiple sclerosis. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster I Grigo C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;36: Havrdova E, Galetta S, Utchinson M, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009;8: Bermel RA, You X, Foulds P, et al. Predictors of long-term outcome in multiple sclerosis patients treated with interferon beta. Ann Neurol. 2013;73: Sormani M, Signon A, Stromillo M, De Stefano N. Refining response to treatment as defined by the Modified Rio Score. Mult Scler. 2013;19: Prosperini L, Gallo V, Petsas N, Borriello G, Pozzilli C. One-year MRI scan predicts clinical response to interferon beta in multiple sclerosis. Eur J Neurol. 2009;16: Cui Q, Kennedy T, Almazan G, Antel J. S1P receptor modulation by fingolimod promotes human oligodendrocyte progenitor cell differentiation through cell-autonomous and non-cell autonomous mechanisms via ERK1/2 and p28mapk activation. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster I Benson LA, Healy BC, Gorman MB, et al. Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years. Mult Scler Relat Disord. 2014;3: Ghezzi A, Goretti B, Portaccio E, Roscio M, Amato MP. Cognitive impairment in pediatric multiple sclerosis. Neurol Sci. 2010;31(suppl 2):S215 S Vargas-Lowy D, Kivisäkk P, Gandhi R, et al. Increased Th17 response to myelin peptides in pediatric MS. Clin Immunol. 2013;146: Ghezzi A. Immunomodulatory treatment of early onset multiple sclerosis: results of an Italian Co-operative Study. Immunomodulatory Treatment of Early Onset MS (ITEMS) Group. Neurol Sci. 2005;26(suppl 4):S183 S Tenembaum SN, Banwell B, Pohl D, et al. Subcutaneous interferon beta-1a in pediatric multiple sclerosis: a retrospective study. REPLAY Study Group. J Child Neurol. 2013;28: Yeh EA, Waubant E, Krupp LB, et al. Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis. National Network of Pediatric MS Centers of Excellence. Arch Neurol. 2011;68: Ghezzi A, Pozzilli C, Grimaldi LM, et al. Natalizumab in pediatric multiple sclerosis: results of a cohort of 55 cases. Italian MS Study Group. Mult Scler. 2013;19: Krupp LB, Tardieu M, Amato MP, et al. International pediatric multiple sclerosis study group criteria for pediatric multiple sclerosis and immunemediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19: Ehler J, Sauer M, Koball S, et al. Therapeutic plasma exchange in 90 glucocorticosteroid-unresponsive patients with multiple sclerosis prediction of response. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster I Simon KC, Munger KL, Ascherio A. Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics. Curr Opin Neurol. 2012;25: Rotstein D, Healy B, Malik MT, et al. Differential effects of vitamin D in GA- versus IFN-treated MS patients. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster I Mayo L, Pires da Cuhna A, Sobel R, et al. A nasal anti-cd3 vaccine treats a model of secondary progressive MS by inducing IL-10 dependent T regulatory cells and regulating CNS innate immunity. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster I Mark V, Taub E, Uswatte G, et al. Randomized controlled trial of CI therapy for progressive MS: increased real-world function and neuroplasticity on MRI. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster I Sanders M, Medicetty S, Chandraratna R. IRX4204: a clinical stage, potent, and highly selective RXR agonist compound is brain penetrant and promotes differentiation of oligodendrocyte precursor cells in vitro. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster PI Voskuhl R, Wang, J, Wu TCJ, et al. A combination trial of estriol plus glatimer acetate in relapsing-remitting multiple sclerosis. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster I Viglietta V, Vollmer T, Zhang R, et al. Safety and tolerability of delayed-release dimethyl fumarate administered as add-on therapy to beta interferons or glatiramer acetate in relapsing remitting multiple sclerosis patients. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster I Schippling S, Tiede M, Lorenz I, et al. Deep transcranial magnetic stimulation can improve depression and fatigue in multiple sclerosis a clinical phase I/IIa study. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster I Birnbaum G. Stopping disease-modifying therapy in progressive multiple sclerosis a prospective study. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster I T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

33 Dimethyl Fumarate and Peginterferon β-1a: New Insights Into the Pivotal Trials Pavan Bhargava, MD Johns Hopkins University School of Medicine, Baltimore, Maryland Abstract Treatment options for multiple sclerosis (MS) continue to expand. Balancing efficacy with the adverse effects of a given treatment is paramount in choosing disease-modifying therapies. Beyond the cut-and-dry clinical and radiologic findings that generally become the primary and secondary outcomes of clinical trials, other less-tangible outcomes, such as quality of life and the tolerability of medications, also play a role in treatment decisions. Long-term follow-up of participants in clinical trials provides further data to help with these decisions. During the 2014 Annual Meeting of the American Academy of Neurology, post hoc analyses of the DEFINE and CONFIRM trials, which evaluated dimethyl fumarate in patients with relapsing-remitting MS, and data from the pivotal ADVANCE trial of peginterferon β-1a were presented. The outcomes of these clinical trials provide us with a better perspective of the usefulness of these agents in patients with MS. T he armamentarium of medications approved by the US Food and Drug Administration (FDA) to treat multiple sclerosis (MS) continues to grow, 1 presenting a plethora of additional considerations. Treatment decisions must balance the efficacy of a disease-modifying therapy (DMT) with its adverse effects. 2 Other factors, such as its impact on patient quality of life (QOL), may play a role in determining the real-world effectiveness of a medication as compared with its efficacy in a trial setting. Long-term follow-up data are needed to establish the continued efficacy and safety of medications. This article describes post hoc analyses of the Determination of the Efficacy and Safety of Oral Fumarate in Relapsing- Remitting Multiple Sclerosis (DEFINE) and the Efficacy and Safety Study of Oral BG00012 with Active Reference in RRMS (CONFIRM), interim data from the extension Dose-Blind, Multicenter, Extension Study to Determine the Long- Term Safety and Efficacy of Two Doses of BG00012 Monotherapy in Subjects with RRMS (ENDORSE), and findings from the Efficacy and Safety Study of BIIB017 (PEGylated Interferon β-1a) in Participants with RRMS (ADVANCE). In this fast-changing therapeutic landscape, these additional data may aid clinicians in choosing the right DMT for their patients. n DIMETHYL FUMARATE Dimethyl fumarate is an oral, secondgeneration fumarate ester that was approved by the FDA in 2013 to treat RRMS. 3 Dimethyl fumarate apparently exerts its effects primarily through activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, a protective cellular defense mechanism against oxidative stress and immune homeostasis. 4 Other postulated mechanisms of action include induction of interleukin (IL)-4 producing CD4 + T cells, induction of type II dendritic cells that produce IL-10 rather than IL-12 and IL-23, suppression of other pro-inflammatory cytokines, and direct inhibition of proinflammatory pathways. 5 The efficacy of dimethyl fumarate was demonstrated in two pivotal phase 3 clinical trials DEFINE and CONFIRM. In the DEFINE study, patients with RRMS were randomized to receive placebo or 240 mg of dimethyl fumarate given two or three times a day for 2 years. 6 Analysis of the trial data showed a significant reduction in annualized relapse rate (ARR), magnetic resonance imaging (MRI) outcomes (number of new or enlarging T2 lesions and gadolinium-enhancing lesions), and confirmed 3-month disability progression in both groups of patients receiving dimethyl fumarate as compared with the group given placebo. The CONFIRM trial was a four-arm study that included an active comparator group that received 20 mg/d of glatiramer acetate in addition to the two groups receiving dimethyl fumarate and the single placebo group studied in the DEFINE trial. 7 The duration of CONFIRM, 2 years, was the same as DEFINE s. The major inclusion and exclusion criteria of DEFINE and CONFIRM are summarized in Table 1. All active treatment groups demonstrated significant reductions in Dr. Bhargava is a Neuroimmunology Fellow in the Department of Neurology at Johns Hopkins University School of Medicine, Baltimore, Maryland. T H E N E U R O L O G Y R E P O R T S u m m e r

34 Pavan Bhargava, MD Dimethyl Fumarate and Peginterferon β-1a: New Insights Into the Pivotal Trials TABLE 1 Major Inclusion and Exclusion Criteria in the DEFINE and CONFIRM Studies Inclusion criteria Age years Diagnosis of RRMS by 2005 McDonald criteria Expanded Disability Status Scale score of > 1 relapse in the 12 months prior to randomization or > 1 gadoliniumenhancing lesion on brain magnetic resonance imaging within 6 weeks of randomization Exclusion criteria Progressive forms of MS Abnormalities in prespecified laboratory parameters or other significant comorbid illnesses Relapse or steroid use within 50 days prior to randomization Prior treatment with glatiramer acetate (within 3 months for the DEFINE study and any time in the past for the CONFIRM study) RRMS = Relapsing-remitting multiple sclerosis; MS = multiple sclerosis; DEFINE = Determination of the Efficacy and Safety of Oral Fumarate in RRMS; CONFIRM = Efficacy and Safety Study of Oral BG00012 with Active Reference in RRMS ARR and MRI outcomes when compared with the placebo group. A significant benefit of dimethyl fumarate over glatiramer acetate was not demonstrated. Efficacy in Patients with Highly Active Disease Hutchinson et al 8 described the clinical efficacy of dimethyl fumarate in RRMS patients with highly active disease who participated in DEFINE and CONFIRM. Highly active disease was defined by at least two relapses in the year prior to study entry and the presence of at least one gadolinium-enhancing MRI lesion at baseline. Of 2,301 patients treated with dimethyl fumarate given two or three times daily or placebo, 136 met the criteria for highly active disease. Twice-daily dosing of dimethyl fumarate reduced the ARR by 60.3% (P = ) as compared with placebo (Figure 1). 8 The proportion of relapsing patients in each group was estimated using the Kaplan-Meier product limit method; it revealed a significantly reduced risk of Adjusted annualized relapse rate (95% CI) Placebo (n = 48) P = P = Dimethyl fumarate bid (n = 45) Dimethyl fumarate tid (n = 43) FIGURE 1 Annualized relapse rate (ARR) at 2 years in patients with highly active multiple sclerosis who participated in the DEFINE and CONFIRM studies. When compared with placebo, delayed-release dimethyl fumarate given twice daily (bid) significantly reduced the ARR. In patients given dimethyl fumarate three times a day (tid), the reduction in the ARR was not statistically significant. Adapted, with permission, from Hutchinson et al. 8 relapse for patients treated with dimethyl fumarate twice daily as compared with those given placebo (hazard ratio [HR] = 0.368; P = 0.003). Effects on clinical efficacy measures in the group given dimethyl fumarate three times daily were not significant. This post hoc analysis suggested that twice-daily dimethyl fumarate showed efficacy in patients with highly active disease. The authors recommended caution, however, in interpreting the results of this study due to the small number of patients involved who had highly active disease. Efficacy in Minority Populations There is some evidence that MS severity may be greater among African-Americans than among other racial or ethnic groups. 9 Hutchinson et al 10 studied the efficacy of dimethyl fumarate in minority populations in DEFINE and CONFIRM. Of 2,651 patients enrolled in the two phase 3 trials, those given either placebo or dimethyl fumarate two or three times daily were identified by race and ethnicity. In all, 29 were African-American, 54 were Hispanic, and 136 were Asian. Similar to the intent-to treat populations in the original trial, patients given twice-daily dimethyl fumarate from all three subgroups showed a reduction in ARR and in the proportion of patients who relapsed at 2 years, with the greatest effect noted among African- Americans and the smallest effect seen among Asian patients. Due to the small sample sizes in each group, the confidence intervals of all estimates were wide and did not reach statistical significance. A similar trend was also noted in 12-week confirmed disability progression at 2 years. These results, though preliminary, suggested the need for larger prospective studies to determine the effects of dimethyl fumarate in various minorities. Health-Related Quality of Life (HRQOL) MS has a significant impact on HRQOL, and assessing the effects of DMTs on measures of HRQOL may have an important impact on treatment decisions. Since MS leads to detriments in both the physical and mental domains, HRQOL test instruments must capture both. The HRQOL measures used in DEFINE and CONFIRM included the Short Form-36 Health Survey (SF-36) and the European Quality of Life Five Dimensions Health Survey (EQ-5D). 11,12 Table 2 provides an overview of these two measurement scales. Kita et al 13 presented an integrated analysis of the effect of dimethyl fumarate treatment on HRQOL in US patients who participated in DEFINE and CONFIRM. A total of 464 patients were included in the analysis; 136 were given placebo, 128 were given dimethyl fumarate twice daily, 135 were given dimethyl fumarate three times daily, and 65 were given glatiramer acetate. Effects on HRQOL were assessed using the mean change in SF-36 and EQ- 5D scores between baseline and the end of the study 2 years later, adjusting for study region and baseline values. There was a significant increase in the SF-36 physical component summary (PCS) scores among patients given dimethyl fumarate twice daily (0.70; P = 0.003) or three times daily (0.96; P = 0.014), but no significant change was observed among patients receiving glat- 32 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

35 Pavan Bhargava, MD Dimethyl Fumarate and Peginterferon β-1a: New Insights Into the Pivotal Trials TABLE 2 Description of Patient Reported Outcome Measures Used in the DEFINE, CONFIRM, and ADVANCE Studies Patient-reported outcome measure Short Form Health Survey (SF-36) European Quality of Life Five Dimensions Health Survey (EQ-5D) Multiple Sclerosis Impact Scale 29 Components of the outcome measure Eight multi-item domains scored on a five-level scale and transformed to a score ranging from 0 to 100, with higher scores suggesting better health-related quality of life Physical component summary (PCS): physical functioning, role-physical, bodily pain, general health Mental component summary (MCS): vitality, social functioning, role-emotional, mental health A health utility index using five dimensions mobility, self-care, usual activities, pain/discomfort, and anxiety/ depression each scored on a three-level scale Combined scores produce a summary EQ-5D index score. Also includes global rating of current health using a visual analog scale ranging from 0 to 100 A 29-item, disease-specific, validated patient-reported outcomes measure examining physical and psychologic impact of multiple sclerosis Consists of 20 items assessing physical impact and 9 items assessing psychologic impact Scores range from 0 to 100, with 0 being the best and 100 being the worst DEFINE = Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS); CONFIRM = Efficacy and Safety Study of Oral BG00012 with Active Reference in RRMS; ADVANCE = Efficacy and Safety Study of BIIB017 (PEGylated Interferon β-1a) in Participants with RRMS iramer acetate compared with those given placebo. There was a significant increase in the SF-36 mental component summary (MCS) score among those taking dimethyl fumarate twice daily (1.17; P = 0.017) group, but this was not noted among the other treatment groups. The increase in SF-36 scores in the group taking twicedaily dimethyl fumarate was seen across all subscales. A significantly greater number of patients receiving dimethyl fumarate showed a clinically significant increase of 5 points in the SF-36 PCS score (P < 0.001). Patients taking dimethyl fumarate two or three times daily also demonstrated increased EQ-5D scores at 24, 48, and 96 weeks when compared with those taking placebo, whereas a similar change was not observed in the glatiramer acetate group. However, fewer patients were using glatiramer acetate, and a lack of effect could have resulted from insufficient statistical power to demonstrate such an effect in those who took the drug. Kappos et al 14 performed a post hoc analysis of the effect of dimethyl fumarate on HRQOL in the DEFINE and CON- FIRM trials based on previous therapy. They used the SF-36 and a global wellbeing visual analog scale (VAS) as their outcome measures. Patients were divided into those who were treatment naïve at trial entry, those who had received interferon β or glatiramer acetate (ABCRE) previously, and those who had been on any other treatment. In the treatment-naïve subgroup, SF-36 PCS scores increased over the 96-week study period in patients taking dimethyl fumarate two or three times daily and in the glatiramer acetate group, whereas there was a decline in scores in the placebo group. In the ABCRE group, however, a significant difference in PCS scores was seen in the dimethyl fumarate groups but not in the glatiramer acetate group. A similar trend was observed in the other treatment group, but it did not reach statistical significance. MCS scores remained stable in the treatment-naïve subgroup for all treatments, but only dimethyl fumarate given twice daily produced a significant increase in MCS scores in the ABCRE group. MCS scores increased significantly in the other treatment subgroup in patients taking dimethyl fumarate two or three times daily. The authors also evaluated stability or improvement of HRQOL using a 5-point increase in the PCS or MCS as a minimal clinically significant difference. In the treatment-naïve subgroup, a significantly greater proportion of patients taking dimethyl fumarate two or three times daily showed improvements or no change in their PCS scores, but not in their MCS scores, as compared with the placebo group. In the ABCRE group, a significant proportion of patients using dimethyl fumarate two or three times daily showed an increase in both their PCS and MCS scores or had no change in their scores. In the glatiramer acetate subgroup, no significant differences in these scores were noted compared with patients given placebo. These results continue to demonstrate the benefit of dimethyl fumarate on HRQOL, irrespective of previous therapy. Freedom from Disease Activity As treatment options for MS expand, more experts are advocating freedom from clinical and radiologic disease activity as the goal of DMTs. 15 Havrdova et al 16 performed a pooled analysis of data from DEFINE and CONFIRM to assess the effect of dimethyl fumarate treatment on freedom from clinical and neuroradiologic disease activity. Absence of measured clinical disease activity was defined as no evidence of relapse or 12-week sustained progression on the Expanded Disability Status Scale (EDSS). No measured neuroradiologic activity was defined as no evidence of new and/or enlarging T2 lesions or gadolinium-enhancing lesions. Patients with no measured overall disease activity had no evidence of clinical or neuroradiologic activity. A total of 2,301 patients were included in the analysis for clinical disease activity, and 1,046 patients were included in the MRI cohort to assess neuroradiologic disease activity. A significantly larger proportion of patients taking dimethyl fumarate two (69%) or three (71%) times daily had no measurable clinical disease activity at 2 years, as compared with those who received placebo (53%; P = ). In the MRI cohort, a significantly larger proportion of patients taking dimethyl fumarate two (34%) or T H E N E U R O L O G Y R E P O R T S u m m e r

36 Pavan Bhargava, MD Dimethyl Fumarate and Peginterferon β-1a: New Insights Into the Pivotal Trials Adjusted annualized relapse rate (95% CI) year (first year of DEFINE and CONFIRM) 1 2 years (second year of DEFINE and CONFIRM) 2 3 years (first year of ENDORSE) 3 4 years (second year of ENDORSE) DMF bid to DMF bid DMF tid to DMF tid PBO bid to DMF bid three (35%) times daily had no measured neuroradiologic disease activity at 2 years when compared with those who received placebo (20%; P = ). In the same cohort, a significantly larger proportion of patients taking dimethyl fumarate two (23%) or three (23%) times daily had no measured overall disease activity at 2 years, when compared with the placebo group (11%; P = ). These findings were similar to those reported in the individual trials and supported the use of dimethyl fumarate as an effective DMT for MS. Long-Term Follow Up Data from the ENDORSE Extension Study ENDORSE is a 5-year extension study of the DEFINE and CONFIRM trials that evaluated the long-term safety and efficacy of dimethyl fumarate. This study enrolled patients who completed either DEFINE or CONFIRM. Patients on dimethyl fumarate given two or three times daily were continued on the same medication, whereas those on placebo or glatiramer acetate were randomized 1:1 to PBO tid to DMF tid GA qd to DMF bid GA qd to DMF tid FIGURE 2 Annualized relapse rate (ARR) by yearly intervals in the DEFINE, CONFIRM, and integrated ENDORSE studies. This graph depicts the yearly ARR in different subgroups of the ENDORSE study. Transition of treatment from placebo (PBO) or glatiramer acetate (GA) to dimethyl fumarate (DMF) twice daily (bid) or three times daily (tid) led to reductions in ARR similar to those seen in these groups in the original DEFINE and CONFIRM studies. The adjusted ARR and 95% confidence interval were based on negative binomial regression adjusted for baseline Expanded Disability Status Scale score ( 2.0 vs > 2.0), baseline age (< 40 years vs 40 years), region, and number of relapses in the 1 year before entry into DEFINE or CONFIRM. Data after patients switched to alternative medications for multiple sclerosis during this period were excluded. Adapted, with permission, from Gold et al. 17 treatment with dimethyl fumarate given two or three times daily. All patients continued to have MRI scans yearly at their original trial site. Gold et al 17 reported integrated clinical efficacy data from DEFINE, CONFIRM, and ENDORSE (interim 2-year data). Of the 2,651 patients originally enrolled in DEFINE and CONFIRM, 1,736 were enrolled in ENDORSE. In this study, 501 patients continued taking dimethyl fumarate twice daily, and 502 continued taking the drug three times a day. A total of 248 patients who had taken placebo started taking dimethyl fumarate three times daily, 118 patients who had taken glatiramer acetate started taking dimethyl fumarate twice daily, and an additional 118 patients who had taken glatiramer acetate started taking dimethyl fumarate three times daily. Among the patients who continued taking dimethyl fumarate twice daily, the ARR was (95% confidence interval [CI] = 0.108, 0.187) after 2 years. At 4 years, the ARR rose to (95% CI = 0.155, 0.252), suggesting continued efficacy of dimethyl fumarate. Similar results were noted in the proportions of patients who relapsed while taking dimethyl fumarate: 15.4% of those taking the drug twice daily and 16.8% of those taking it three times a day showed disability progression. Among patients switching from placebo or glatiramer acetate to dimethyl fumarate two or three times a day, the ARR was similar to that observed at the end of 2 years in DEFINE and CONFIRM (Figure 2), 17 suggesting the sustained clinical efficacy of dimethyl fumarate at 4 years of treatment. Arnold et al 18 reported on the integrated MRI outcomes from DEFINE, CONFIRM, and ENDORSE (interim 2-year data). The MRI endpoints included new and/or enlarging T2 lesions, new nonenhancing T1 hypointense lesions, gadolinium-enhancing lesions, and the adjusted mean number of T2 and T1 hypointense lesions. The MRI cohort in DEFINE and CONFIRM consisted of 1,221 patients; 718 went on to participate in the ENDORSE study. Among patients who continued dimethyl fumarate twice daily, 68% were free of new/enlarging T2 lesions, 76% were free of new T1 hypointense lesions, and 88% were free of gadolinium-enhancing lesions at 2 years in the ENDORSE trial. Similar results were seen among patients switching from placebo or glatiramer acetate to twice-daily dimethyl fumarate (Figure 3). 17 Thus, at year 2 of ENDORSE, the MRI activity in patients switched from placebo or glatiramer acetate to dimethyl fumarate seemed to be about the same as that noted in the parent studies. The two groups that remained on dimethyl fumarate seemed to continue showing a low frequency of new MRI lesions similar to that seen in DEFINE and CONFIRM, suggesting that dimethyl fumarate is effective at reducing disease activity over 4 years. n PEGINTERFERON β-1a Peginterferon β-1a is a modified form of interferon β-1a that has a polyethylene glycol (PEG) group attached to the α-amino group of the N-terminus of interferon β-1a. Alterations in pharmaco- 34 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

37 Pavan Bhargava, MD Dimethyl Fumarate and Peginterferon β-1a: New Insights Into the Pivotal Trials kinetics and pharmacodynamics allow for a reduced dosing frequency of interferon β-1a. 19 ADVANCE was a phase 3 randomized clinical trial that compared placebo with 125 μg of peginterferon β-1a given subcutaneously every 2 or 4 weeks for 1 year. 20 The design of this trial is shown in Figure Reductions in ARR, disability progression, and MRI measures were noted in both peginterferon β-1a groups as compared with the placebo group at 48 weeks. At 2 years, the group treated with peginterferon β-1a every 2 weeks had significantly greater reductions in ARR, the proportion of patients with relapses, and MRI outcomes than did patients who were treated with the drug every 4 weeks. Less than 1% of patients receiving peginterferon β-1a in the ADVANCE trial developed neutralizing antibodies to interferon over 2 years. Adverse events were similar to those noted for other interferon β preparations and included injection-site erythema, influenza-like reactions, pyrexia, and headache. Peginterferon β-1a is currently under review by the FDA for use in the treatment of relapsing forms of MS. Pharmacokinetics and Pharmacodynamics of Peginterferon β-1a Results of phase 1 studies suggested that peginterferon β-1a had greater biologic activity with less frequent dosing due to a prolonged terminal half-life, a higher area under the curve, and consistent elevation in pharmacodynamic markers of interferon receptor activation. Hu and colleagues 21 reported on the pharmacokinetics and pharmacodynamics of peginterferon β-1a among patients enrolled in the ADVANCE study. All patients in the trial had blood samples drawn for pharmacodynamic and/or pharmacokinetic assessment. A subset of patients gave consent for an intensive pharmacokinetic study, with blood draws at 6, 24, 28, 36, 72, 120, 168, and 240 hours post dose during weeks 4 and 24. The remaining patients had one sample taken after each dose at weeks 4, 12, 24, 56, and 84. Sufficient intensive samples were obtained from 25 patients. Adjusted mean number of new/enlarging T2 lesions (95% CI) year (first year of DEFINE and CONFIRM) 1 2 years (second year of DEFINE and CONFIRM) 2 3 years (first year of ENDORSE) 3 4 years (second year of ENDORSE) DMF bid to DMF bid DMF tid to DMF tid PBO bid to DMF bid The maximum serum concentration of peginterferon β-1a was reached at days after injection, and the terminal half-life was 2 5 days for every-2-week PBO tid to DMF tid GA qd to DMF bid GA qd to DMF tid FIGURE 3 Number of new and/or enlarging T2 lesions by yearly intervals in the DEFINE, CONFIRM, and integrated ENDORSE studies. The number of new and/or enlarging T2 lesions at yearly intervals in various subgroups of the ENDORSE study are depicted. There was a sustained reduction in new and/or enlarging T2 lesions in subjects who continued dimethyl fumarate (DMF) twice daily (bid) or three times daily (tid) and a reduction in new and/or enlarging T2 lesions in the placebo (PBO) and glatiramer acetate (GA) groups to a level comparable to those of the dimethyl fumarate groups. The adjusted mean and 95% confidence intervals (CI) were based on negative binomial regression, adjusted for region and baseline volume of T2 lesions at the start and end of the DEFINE and CONFIRM trials. Data after patients switched to alternative medications for multiple sclerosis were excluded. Adapted, with permission, from Gold et al. 17 1,516 patients with relapsing forms of multiple sclerosis randomized 1:1:1 (roughly 500 patients per treatment arm) Placebo Dose escalation 63 µg 94 µg 125 µg over 4 weeks Dose escalation for placebo patients Peginterferon β-1a, 125 µg q4w subcutaneously Peginterferon β-1a, 125 µg q2w subcutaneously Peginterferon β-1a, 125 µg q4w subcutaneously Peginterferon β-1a, 125 µg q2w subcutaneously YEAR 1 YEAR 2 FOLLOW-UP Superiority versus placebo at 1 year Safety/immunogenicity at 2 years FIGURE 4 Design of the ADVANCE study of peginterferon β-1a (PEG-IFN). During year 1, patients were randomized 1:1:1 to receive treatment with PEG-IFN given every 2 weeks (q2w) or every 4 weeks (q4w) or placebo. During year 2, patients in the placebo arm were randomized to receive PEG-IFN given either q2w or q4w. Adapted, with permission, from Calabresi et al. 20 and every-4-week regimens (Figure 5a). 21 By doubling the frequency of dosing, the every-2-week regimen provided twice the area under the curve as did the every-4- T H E N E U R O L O G Y R E P O R T S u m m e r

38 Pavan Bhargava, MD Dimethyl Fumarate and Peginterferon β-1a: New Insights Into the Pivotal Trials a Serum peginterferon β-1a concentration (pg/ml) 400 b Serum neopterin concentration (ng/ml) Dosing every 2 weeks Dosing every 4 weeks 15 Dosing every 2 weeks Dosing every 4 weeks Days after last dose Days after last dose FIGURE 5 Pharmacokinetics and pharmacodynamics of peginterferon β-1a given every 2 weeks. These figures depict pharmacokinetic (PK) and pharmacodynamic (PD) data obtained from subjects in the intensive PK/PD sampling arm of the ADVANCE study after a single injection of peginterferon β-1a. (a) Change in serum peginterferon β-1a concentration over time with complete clearance of the drug 10 days post injection. (b) Change in serum neopterin concentration (a marker of interferon receptor activation) over time. Adapted, with permission, from Hu et al week regimen. There were weak negative correlations between interferon exposure and body size and creatinine clearance. Interestingly, anti-peg antibodies had no effect on the pharmacokinetics of peginterferon β-1a. The number of patients with interferon-neutralizing or interferon-binding antibodies was low; the effect of these antibodies on the pharmacokinetics or pharmacodynamics of peginterferon β-1a could not be determined. In the intensive pharmacodynamic group, neopterin levels reached a peak elevation at 3 days post peginterferon β-1a injection and remained elevated for days (Figure 5b). 21 These findings help to explain the additional efficacy of the every-2-week regimen of peginterferon β-1a over the every-4-week regimen. Effect on Relapse-Associated Costs O Day et al 22 studied the impact of peginterferon β-1a given every 2 or 4 weeks on potential cost savings associated with reductions in relapse rate, MS-related hospitalizations, and intravenous (IV) corticosteroid usage. This is an important consideration, since the annual cost of MS management per patient in the United States is estimated to range from $44,000 to $88,000 in 2006 dollars. 23 The costs are proportional to the level of disability. Expenses related to treating relapses are related to the severity of the relapses. 24 The researchers created an economic model in which the mean cost of hospitalization, treatment with IV corticosteroids, and management of MS relapses in the placebo group were calculated by multiplying the estimated cost by the annualized rate of the occurrence of such an event over 1 year. For groups given peginterferon β-1a every 2 or 4 weeks, these estimates were multiplied by the HR to yield mean estimates. HRs were derived from the 1-year interim analysis of the ADVANCE trial. The costs of hospitalization and MS relapse were derived from the Bureau of Labor Statistics Medical Care Component of the Consumer Price Index. 25 The cost of IV corticosteroid treatment was based on a 5-day course. Treatment with peginterferon β-1a every 2 weeks reduced the cost of hospitalization by $1,297 (95% CI = $288, $2,173), the cost of IV corticosteroids by $62 (95% CI = $20, $99), and the cost of MS relapse by $1,941 (95% CI = $877, $2,931) when compared with placebo over 1 year. Administration of peginterferon β-1a every 2 weeks had a high probability of reducing costs when compared with therapy given every 4 weeks. Limitations of this study include the inability to generalize results consistently from the clinical trial setting to routine clinical practice, lack of comparison with the costs of other active DMTs, and the fact that the costs associated with treating adverse effects of the drug and the costs of the medication itself were not considered. Future studies also may incorporate indirect costs in their analyses. Reducing the Impact of Relapses on HRQOL Kinter et al 26 reported on the impact of peginterferon β-1a treatment on HRQOL in the first year of the ADVANCE trial. The patient-reported outcomes (PRO) included the MS Impact Scale-29 (MSIS- 29), SF-12 Health Survey, and EQ-5D. 27 All patients with such information were included in the analysis. The authors used mixed-effects regression models with treatment, time, sustained disability progression, relapses, and adverse events as predictors of MSIS-29 physical and mental scores. Baseline characteristics were similar between the treatment groups. Over the course of the first year, the MSIS-29 physical score worsened in the placebo group, but it did not change significantly in the groups given peginterferon β-1a 36 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

39 Pavan Bhargava, MD Dimethyl Fumarate and Peginterferon β-1a: New Insights Into the Pivotal Trials every 2 or 4 weeks. All treatment groups showed a significant improvement in the MSIS-29 psychological scale. There were no significant differences in PRO scores between the treatment groups over the course of the first year. In the multivariate regression model, relapses and disability progression, but not adverse events, were linked with worse HRQOL. As compared with the placebo group (rise of 6.04), disability progression was associated with a lower rise in MSIS-29 physical scores among patients using peginterferon β-1a every 2 weeks (reduced by 4.16; P < 0.05). Similarly, the rise of MSIS-29 psychological scores associated with a relapse in the placebo group (rise of 9.95) was greatly attenuated in these patients (reduced by 6.41; P < 0.05). A similar effect was also noted on other PRO measures, such as the SF-12 and EQ-5D. These results suggested that peginterferon β-1a given every 2 weeks not only reduces relapse rates and disability progression but also reduces the impact of these events on patient s HRQOL. n CONCLUSION The data presented in these studies help clarify the efficacy and safety of dimethyl fumarate, an important oral DMT for MS. Post hoc analyses of the DEFINE and CONFIRM trials and interim data from the ENDORSE extension study suggest continued evidence of clinical and radiologic efficacy in addition to HRQOL benefits. Further data from the ENDORSE study will help elucidate the long-term efficacy and safety of this medication. Results from the pivotal ADVANCE study help establish the efficacy and safety of peginterferon β-1a given every 2 weeks. Pegylated interferon β-1a will be an important addition to the MS therapeutic armamentarium, since it preserves the efficacy of previous interferon β-1a formulations with markedly fewer injections. This could potentially translate into better patient adherence with peginterferon β-1a therapy. In addition, these findings demonstrated possible cost savings related to MS-related healthcare costs and a reduction in the impact of relapses and disability progression on HRQOL. REFERENCES 1. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc. 2014;89: Sørensen PS. Balancing the benefits and risks of disease-modifying therapy in patients with multiple sclerosis. J Neurol Sci. 2011;311(suppl 1):S29 S Fox RJ, Kita M, Cohan SL, et al. BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety. Curr Med Res Opin. 2014:30: Chen X-L, Dodd G, Thomas S, et al. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol. 2006;290:H1862 H Ghoreschi K, Brück J, Kellerer C, et al. 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Clinical efficacy of delayed-release dimethyl fumarate in minority patients with relapsing-remitting multiple sclerosis: an integrated analysis of the phase 3 DEFINE and CONFIRM studies. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster P Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 2001;33: Fischer JS, LaRocca NG, Miller DM, Ritvo PG, Andrews H, Paty D. Recent developments in the assessment of quality of life in multiple sclerosis. Mult Scler. 1999;5: Kita M, Fox R, Gold R, et al. Health-related quality of life in US patients with relapsing-remitting multiple sclerosis treated with delayed-release dimethyl fumarate: an integrated analysis of the phase 3 DEFINE and CONFIRM studies. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster P Kappos L, Fox R, Gold R, et al. Effect of delayed-release dimethyl fumarate on health-related quality of life in relapsing-remitting multiple sclerosis patients according to prior therapy: an integrated analysis of the phase 3 DEFINE and CONFIRM studies. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster P Havrdova E, Galetta S, Stefoski D, Comi G. Freedom from disease activity in multiple sclerosis. Neurology. 2010;74(suppl 3):S3 S Havrdova E, Gold R, Fox R, et al. Effect of delayed-release dimethyl fumarate on freedom from measured clinical and neuroradiological disease activity in relapsing-remitting multiple sclerosis patients: an integrated analysis of DEFINE and CONFIRM. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster P Gold R, Phillips T, Bar-Or A, et al. 4-Year follow-up of delayed-release dimethyl fumarate treatment in relapsing-remitting multiple sclerosis: integrated clinical efficacy data from DEFINE, CONFIRM, and the ENDORSE extension study. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster P Arnold D, Fox R, Gold R, et al. 4-Year follow-up of delayed-release dimethyl fumarate treatment in relapsing-remitting multiple sclerosis: integrated magnetic resonance imaging outcomes from DEFINE, CONFIRM, and the ENDORSE extension study. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster P Kieseier BC, Calabresi PA. PEGylation of interferon-β-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26: Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon beta-1a for relapsingremitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014;13: Hu X, Cui Y, White J, et al. Pharmacokinetics and pharmacodynamics of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis: data from the pivotal phase 3 ADVANCE study. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster P O Day K, Meyer K, Mitchell M, Agarwal S, Kinter E. Peginterferon beta-1a reduces relapseassociated costs in patients with relapsing-remitting multiple sclerosis. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster P Kobelt G, Berg J, Atherly D, Hadjimichael O. Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States. Neurology. 2006;66: Parisé H, Laliberté F, Lefebvre P, et al. 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40 Pavan Bhargava, MD Dimethyl Fumarate and Peginterferon β-1a: New Insights Into the Pivotal Trials multiple sclerosis relapses: excess costs of persons with MS and their spouse caregivers. J Neurol Sci. 2013;330: US Department of Labor. Consumer Price Index. Bureau of Labor Statistics Web site. Accessed May 13, Kinter E, Guo S, Altincatal A, Proskorovsky I, Phillips G, Sperling B. Peginterferon beta-1a treatment reduces the impact of multiple sclerosis relapse and disability progression on health-related quality of life: results from the ADVANCE trial. Presented at the 66 th Annual Meeting of the American Academy of Neurology; April 26 May 3, 2014; Philadelphia, PA. Poster P Hobart J, Lamping D, Fitzpatrick R, Riazi A, Thompson A. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure. Brain. 2001;124: T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 1

41 Symptomatic Management of Multiple Sclerosis Ariel Antezana, MD Multiple Sclerosis Comprehensive Care Center, NYU Langone Medical Center, New York, New York Abstract A majority of patients with multiple sclerosis (MS) experience a variety of symptoms related directly or indirectly to the disease. For many patients, carefully chosen medications can control these symptoms successfully, especially when used with physical and/or occupational therapy and, when indicated, surgery. At a course given during the 66 th Annual Meeting of the American Academy of Neurology, experts discussed the current management of spasticity; locomotion difficulties; sleep disorders; fatigue; cognitive dysfunction; pain; mental depression; and gastrointestinal, genitourinary, and sexual dysfunction in patients with MS. The strategies they use and recommend form the basis of this review. S ince the introduction of diseasemodifying therapies (DMTs) for multiple sclerosis (MS), researchers have focused on developing stronger, more tolerable treatments for the disease. However, relatively less attention has been paid to improving the symptoms experienced by most patients with MS, including fatigue, muscle spasms, pain, gait and sleep disturbances, and others. Inattention to these symptoms can lead to a vicious cycle of worsening and perpetuation. Their correction improves the quality of life (QOL) of MS patients, their social interrelationships, and their work performance and functionality. During the 66 th Annual Meeting of the American Academy of Neurology (AAN), an innovative course on managing the most common MS symptoms highlighted common manifestations of the disease and current strategies for managing them. n GAIT DISTURBANCES Based on a presentation by Andrew Goodman, MD, FAAN, Professor of Neurology, Chief of the Neuroimmunology Unit, and Director of the Multiple Sclerosis Center, University of Rochester. Rochester, New York. One of the most frequent problems reported by MS patients is gait disturbances. Leg weakness, spasticity, cerebellar or sensory ataxia, foot drop, knee instability with buckling, spastic paresis, or steppage gait are manifestations of walking disturbances. These abnormalities can be detected by asking patients to walk several feet quickly or repeating the 25-foot walking test (T25FW) two or three times. About 50% of MS patients require some assistance with walking within 15 years of disease onset. 1 In an online interview of 1,011 MS patients and caregivers, 2 41% reported walking difficulty; 70% confirmed that walking was the most challenging aspect of their disease. Gait impairment affects QOL by causing loss of independence, physical disability, unemployment, and depression. 3 Physical and Occupational Therapy A multidisciplinary approach involving physical and occupational therapists and physiatrists plays a crucial role in the treatment of gait disturbances. Regular, tailored physical therapy that addresses specific patient needs is essential in managing gait problems. To prevent injuries, healthcare professionals must evaluate patients for any need of assistive devices; these devices may include ankle or foot orthotics for individuals with food drop and devices to assist with walking, such as a single-point or quad cane, forearm crutches, or a rollator (wheeled walker). 4 Ideally, occupational therapists should assess the patient s home for safety and recommend any alterations in the home environment. These changes may include installation of grab bars in showers and bathrooms, limitation of obstacles, and clearance of pathways within the home. Pharmacologic Management The only pharmacologic therapy currently approved by the US Food and Drug Administration (FDA) to treat gait abnormalities is 10 mg of dalfampridine given twice daily. This drug represents the extended-released form of fampridine (4-aminopyridine), a potassium channel blocker that may improve electrical transmission across the demyelinating axons and facilitate synaptic transmission. 5 Dalfampridine has class I level of evidence based on two phase 3 studies. In one by Goodman et al, 6 10 mg of dalfampridine or placebo was given twice daily to 301 MS patients with gait disturbances for 14 weeks; 35% of the active treatment group and 8% of the placebo group were considered to be timed-walk responders. This improvement was maintained during the 14-week treatment period. The most common side effects reported have been Dr. Antezana is a Multiple Sclerosis Fellow in the Multiple Sclerosis Comprehensive Care Center and Clinical Instructor of Neurology, NYU Langone Medical Center, New York, New York. T H E N E U R O L O G Y R E P O R T S u m m e r