Multiple Sclerosis and the Spectrum of CNS Inflammatory Demyelinating Diseases

It is my great pleasure to introduce this issue of Seminars in Neurology on Multiple Sclerosis and the Spectrum of CNS Inflammatory Demyelinating Diseases. Inflammatory demyelinating diseases of the central nervous system (CNS) occur throughout the world and are the foremost cause of nontraumatic neurological disability in young adults. Multiple sclerosis (MS) is the most common of these disorders. The last decade has seen a resurgence of interest in MS, fueled by scientific advances in the epidemiology, genetics, immunology, pathology, neuroimaging, and treatment of the disease. However, MS represents only one member of a family of CNS idiopathic inflammatory demyelinating diseases, which include transverse myelitis, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO). Although these disorders are all similarly characterized by focal CNS demyelination, they vary in their clinical course, prognosis, regional distribution, pathology, and pathogenesis. In this issue of Seminars in Neurology, the authors provide a comprehensive, clinically-relevant update on MS and the heterogeneous spectrum of CNS inflammatory demyelinating disorders.

In the first article, Dr. Orhun Kantarci, Assistant Professor of Neurology, Mayo Clinic College of Medicine, and neurology consultant at Mayo Clinic, in Rochester, Minnesota, reviews our current understanding of the genetic epidemiology of MS susceptibility and outcomes, as well as the natural history of idiopathic demyelinating diseases of the CNS, including MS. There have been significant advances in genetic technologies that permit high-throughput studies; however, their future success will in part depend upon reliable and rigorous phenotyping of patients, which requires uniform and precise definitions of clinical and pathological disease phenotypes. Dr. Kantarci's clear and well-illustrated article reflects his ability to bridge his MS diagnostic and clinical skills with his expertise in MS genetics. His research interests focus on candidate gene association studies in MS, as well as exploring novel outcome measures for MS genetic epidemiological studies.

The next article by Dr. Alberto Ascherio, together with Kassandra Munger (M.Sc.), both from the Departments of Epidemiology and Nutrition at the Harvard School of Public Health in Boston, Massachusetts, describes the most recent epidemiological data regarding environmental risk factors for MS, and critically addresses both the potential causality of these associations, as well as possible interventions to reduce MS risk. Kassandra Munger is a research assistant in the Department of Nutrition. Dr. Ascherio is an Associate Professor of Medicine, and directs a large prospective seroepidemiological study based on the Department of Defense Serum Repository to identify pre-diagnostic markers of infection and nutritional status in relation to MS risk. Among his most significant contributions to the field are the identification of risk factors such as cigarette smoking and infection with the Epstein-Barr virus (EBV), as well as the prospective finding that high levels of vitamin D may reduce MS risk.

In the next article, Dr. Amit Bar-Or, Associate Professor of Neurology and Neurosurgery at the Montreal Neurological Institute (MNI) and McGill University/MUHC, provides a clear explanation of the principles of immune-CNS interactions that are relevant to MS immunopathogenesis, with a focus on studies of human immunology and MS patients. His review highlights the important insights gained from experimental animal models, as well as addresses some of the challenges of extrapolating these results to human disease. Dr. Bar-Or's laboratory studies principles of immune regulation and autoimmunity, as well as immune-neural interactions, and how these may relate to injury and repair in CNS inflammatory disease. Dr. Bar-Or serves as Scientific Director of the Clinical Research Unit at the MNI, where he also established and directs the Experimental Therapeutics Program.

In the article by Dr. Waqar Rashid and Dr. David Miller, both from the Department of Neuroinflammation at the Institute of Neurology at University College London at the National Hospital for Neurology and Neurosurgery, the authors discuss recent MS imaging studies based on conventional, quantitative, metabolic, and functional magnetic resonance imaging (MRI) techniques, as well as promising non-MRI methodologies, including retinal nerve fiber layer estimation. Advances in neuroimaging have substantially contributed to our understanding of the pathology and natural history of multiple sclerosis. Imaging tools are now available that provide a dynamic in vivo assessment of disease evolution, as well as a better appreciation for the extent of disease pathology. It is now clear that apart from the classic focal white matter demyelinated lesions, there is a more extensive global MS pathology involving both the normal appearing white matter and the cortical gray matter. Involvement of these regions may contribute to disease progression and severity. The authors also address the role of MRI in diagnosis and management of MS patients, as well as the correlations with pathology and use in treatment trials. Dr. Miller, Professor of Clinical Neurology, is Head of the Department of Neuroinflammation and is a joint leader of the Multiple Sclerosis/NMR Research Unit at the Institute of Neurology. Supported by the MS Society of Great Britain and Northern Ireland, this research group has been using MR imaging and spectroscopy to improve the accuracy of diagnosis of MS; identify MR measures to predict the future course; improve understanding of the mechanisms of disability and recovery; and monitor new treatments. He is Co-Chief Editor of the Journal of Neurology. Dr. Rashid is currently a Specialist Registrar in Neurology at King's College Hospital NHS Trust.

In the article on MS therapies, Dr. Dean Wingerchuk, Associate Professor of Neurology, Mayo Clinic College of Medicine, and a neurology consultant at Mayo Clinic in Scottsdale, Arizona, provides a comprehensive and excellent critical review of current evidence supporting treatment decisions using currently approved and available agents for MS. The advent of medications that may alter MS course and prognosis has had a major impact on patients living with MS. With six approved therapies now available, the decision-making process is even more complex, and further complicated by the lack of head-to-head comparison trials. Dr. Wingerchuk's review discusses recent clinical trial results pertinent to clinical relapses, clinically isolated syndromes, relapsing-remitting, secondary progressive, and primary progressive MS, with a focus on the magnitude of individual drug benefits. His review emphasizes that clinical integration of this evidence must be individualized based upon a patient's clinical status and preferences. Dr. Wingerchuk also discusses what is on the horizon of MS therapeutics, including investigative oral and parenteral agents and combination drug therapies. Dr. Wingerchuk's clinical and research interests focus on MS, NMO, and related disorders. His research initiatives on the treatment of MS-related fatigue and its relation to cognitive and motor dysfunction are supported by the National Multiple Sclerosis Society. Dr. Wingerchuk also co-directs the Mayo Clinic's MERIT Center, a multidisciplinary evidence-based clinical practice educational and research program, and he serves as Vice-Chair for Clinical Research at Mayo Clinic Arizona.

The article by Dr. Terrence Thomas and Dr. Brenda Banwell, both from the Hospital for Sick Children, University of Toronto, Canada, highlights the importance and challenges of accurate MS diagnosis in the pediatric population, with an emphasis on clinical features and course of MS in children, as well as differential diagnosis and MRI features unique to pediatric patients. The authors integrate several excellent case vignettes into their summary and provide a detailed algorithmic approach to the assessment and care of children with acute demyelination. Because children with MS are closer in temporal proximity to potential environmental exposures, this population affords a unique opportunity to better define the events involved in MS pathogenesis. Recent pediatric MS research studies focusing on environmental triggers and immunological studies are also discussed. Dr. Banwell, Associate Professor of Neurology and Pediatrics, is Director of the Pediatric Multiple Sclerosis Clinic, a multidisciplinary clinic dedicated to children with MS and other acquired demyelinating diseases. She is lead investigator of a Canada-wide, 23 site, 5-year study of acute demyelination in Canadian children (funded by the Multiple Sclerosis Research Foundation), and was recently appointed as Research Chair of the International Pediatric Multiple Sclerosis Group. Dr. Banwell has described key clinical and MRI features of MS in children, and has provided the clinical interface for basic science studies of the immunological aspects of the disease. Dr. Terrence Thomas was a neurology fellow when he co-authored this article with Dr. Banwell, and is currently a pediatric neurologist at the Likas Women's and Children's Hospital in Sabah, Malaysia.

The next three articles highlight the broad spectrum of the CNS inflammatory demyelinating disorders and their relationship to MS, with an emphasis on ADEM, NMO, and transverse myelitis. In the article on Acute Disseminated Encephalomyelitis, Dr. Nathan Young, a recent graduate of the Mayo Neurology residency program, together with Dr. Brian Weinshenker, and myself, review current concepts about ADEM, and the importance of distinguishing ADEM from other CNS inflammatory demyelinating diseases, particularly first presentations of MS, and NMO. Early and accurate diagnosis is important since the prognosis and treatment of ADEM, MS, and NMO differs. Clinical definitions and criteria for ADEM are presented, including a summary of published clinically defined ADEM series. However, clinicopathological correlative data that might inform clinical distinction of ADEM from acute MS are lacking. The potential role of pathological diagnosis in distinguishing ADEM and MS is discussed. Dr. Young's interest in ADEM began in the context of his residency research project during which he tested the hypothesis that perivenous demyelination, the pathological hallmark of ADEM, distinguishes monophasic ADEM from patients with confluent demyelination, the hallmark of acute MS lesions. His series represents the first attempt to longitudinally follow a pathologically defined cohort of ADEM patients.

In the next article, Dr. Sean Pittock, Assistant Professor of Neurology, Mayo Clinic College of Medicine, and neurology consultant at Mayo Clinic Rochester, summarizes the evolving clinical and pathogenic concepts related to NMO. Neuromyelitis optica (NMO; Devic's disease) is an inflammatory demyelinating syndrome characterized by severe attacks of optic neuritis and myelitis that, unlike classical MS, tends to spare the brain in early stages. NMO represents the first instance in which a relatively homogeneous disorder can be identified from within the heterogeneous group of idiopathic inflammatory demyelinating diseases of the central nervous system using a combination of clinical, neuroimaging, serological, and pathological characteristics. Whereas MS has no specific biomarker, the recent identification of a circulating autoantibody, NMO-IgG, targeting the water channel protein aquaporin-4, represents the first antibody marker for any of the CNS inflammatory demyelinating disorders. Dr. Pittock describes the epidemiological, clinical, genetic, imaging, and pathologic spectrum of NMO and related disorders, as well as the diagnostic and pathogenic relevance of NMO-IgG. Dr. Pittock's clinical and laboratory expertise lies in modifying antibody assays for clinical application developed by the Mayo Clinic Neuroimmunology Laboratory. Dr. Pittock is Director of the Autoimmune Neurology Clinic, which interacts closely with the Mayo Clinic Neuroimmunology Laboratory and has facilitated the development of a unique translational practice extending the laboratory's serological findings directly to the bedside. Dr. Pittock's clinical, imaging, and serological correlative studies are providing the foundation for future investigations on the basic immunopathological mechanisms that cause NMO.

The article by Dr. Anu Jacob and Dr. Brian Weinshenker discusses the differential diagnosis of acute transevse myelitis (ATM) and reviews the clinical, immunological, and radiological features of noncompressive myelopathies, as well as provides a systematic algorithm for the diagnosis and management of acute myelopathies. The characteristics of ATM in association with MS, NMO, and ADEM are reviewed, as are predictors associated with ATM recurrence in patients with these demyelinating disorders. Dr. Jacob was a recent graduate of the Mayo Clinic Rochester MS Fellowship training program, during which time he was actively involved in clinical research related to MS and NMO. Currently, Dr. Jacob is a Consultant Neurologist at the Walton Center in Liverpool, United Kingdom. Dr. Weinshenker is Professor of Neurology at Mayo Clinic College of Medicine and Consultant in Neurology at the Mayo Clinic in Rochester, Minnesota. Dr. Weinshenker's major research interests are directed at the understanding of inflammatory demyelinating diseases of the CNS, including MS. His specific areas of interest include MS natural history studies, genetics of MS, and classification, diagnosis, and treatment of severe inflammatory demyelinating syndromes of the CNS, including NMO. He is considered a world authority on NMO and its spectrum of disorders. Dr. Weinshenker was also the principal investigator of a randomized trial of plasma exchange in steroid-refractory severe CNS inflammatory demyelinating diseases, which showed that plasma exchange was highly effective in ~40% of cases. Prior to this observation, there was no rescue treatment available for such patients.

The issue concludes with a well-organized comprehensive review of future research directions in MS by Dr. Benjamin Greenberg and Dr. Peter Calabresi, both from Johns Hopkins School of Medicine. The authors discuss current MS experimental therapies with positive phase-II clinical data, as well as summarize the status of novel immunotherapies that may be better tolerated and more specifically target the effector mechanisms of tissue injury in MS. Apart from targeting the immune processes, there is increasing attention focused on the neurodegenerative aspects that contribute to disease progression and disability in MS. The authors describe strategies for both neuroprotection and neurorepair. Dr. Greenberg is currently Clinical Instructor of Neurology and attending physician at Johns Hopkins School of Medicine. Dr. Peter Calabresi, Associate Professor of Neurology, is Director of the Johns Hopkins MS Center, where he is the principal investigator of several clinical trials as well as oversees translational laboratory research projects. Dr. Calabresi's basic science research investigates the mechanisms of T-lymphocyte migration into the brain and spinal cord. He is the recipient of a 5-year collaborative MS center grant from the National MS Society to study mechanisms of neurodegeneration and strategies for neuroprotection in MS.

I would like to thank the authors of this Seminars in Neurology issue for all their time and effort in preparing their articles. Each author has combined their wealth of clinical experience together with their basic and clinical scientific research expertise to create an outstanding, comprehensive, and up-to-date collection of articles on MS and the heterogeneous spectrum of CNS inflammatory demyelinating disorders. It has truly been an honor and privilege to work with this group of respected clinicians and scientists, each committed to finding the cause and improving the care for patients suffering from these disabling disorders.