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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competencies and with regard for appropriate balance.
Support for this project was provided by the National Multiple Sclerosis Society. The views presented in this report are those of the Institute of Medicine Committee on Multiple Sclerosis: Current Status and Strategies for the Future and are not necessarily those of the funding agencies.
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Library of Congress Cataloging-in-Publication Data
Multiple sclerosis : current status and strategies for the future / Janet E. Joy and Richard B. Johnston, Jr., editors.
p. ; cm.
Includes bibliographical references and index.
ISBN 0-309-07285-9 (hardcover)
1. Multiple sclerosis.
[DNLM: 1. Multiple Sclerosis—therapy. 2. Multiple Sclerosis—physiopathology. 3. Research. WL 360 M956378 2001] I. Joy, Janet E. (Janet Elizabeth), 1953- II. Johnston, Richard B., 1935-
RC377 .M8455 2001
Copyright 2001 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America.
The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.
“Knowing is not enough; we must apply. Willing is not enough; we must do.”
~ enlarge ~
INSTITUTE OF MEDICINE
Shaping the Future for Health
THE NATIONAL ACADEMIES
National Academy of Sciences
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Institute of Medicine
National Research Council
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COMMITTEE ON MULTIPLE SCLEROSIS: CURRENT STATUS AND STRATEGIES FOR THE FUTURE
RICHARD B. JOHNSTON, JR. (Chair), Professor of Pediatrics, National Jewish Medical and Research Center, University of Colorado School of Medicine
JACK P. ANTEL, Professor of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Quebec, Canada
SAMUEL BRODER, Executive Vice President for Medical Affairs, Celera Genomics, Rockville, Maryland
JESSE M. CEDARBAUM, Vice President of Clinical Affairs, Regeneron Pharmaceuticals, Tarrytown, New York
PATRICIA K. COYLE, Professor of Neurology, State University of New York, Stony Brook
STEPHEN L. HAUSER, Professor of Neurology, University of California, San Francisco School of Medicine
LISA I. IEZZONI, Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts
SUZANNE T. ILDSTAD, Director of Institute for Cellular Therapeutics, University of Louisville, Kentucky
SHARON L. JULIANO, Professor of Anatomy and Cell Biology and Neurosciences Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland
DONALD L. PRICE, Professor of Pathology, Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
RAYMOND P. ROOS, Professor of Neurology, University of Chicago, Illinois
ALAN J. THOMPSON, Professor of Neurology, University College, London, England
STEPHEN G. WAXMAN, Professor of Neurology, Yale Medical School, New Haven, Connecticut
HARTMUT WEKERLE, Director, Max-Planck-Institut fur Neurobiologie, Planegg-Martinsreid, Germany
JANET E. JOY, Study Director
JOHN A. ROCKWELL, Research Assistant
AMELIA B. MATHIS, Project Assistant
LINDA LEONARD, Administrative Assistant (until 9/2000)
LORA K. TAYLOR, Administrative Assistant (from 9/2000)
TERRY C. PELLMAR, Board Director
CARLOS GABRIEL, Financial Associate
BOARD ON NEUROSCIENCE AND BEHAVIORAL HEALTH
ANN M. GRAYBIEL (Chair), Massachusetts Institute of Technology, Cambridge
KENNETH B. WELLS (Vice-Chair), Neuropsychiatric Institute, University of California, Los Angeles
NANCY E. ADLER, University of California, San Francisco
RICHARD J. BONNIE, University of Virginia School of Law, Charlottesville
WILLIAM E. BUNNEY, University of California, Irvine
RICHARD G. FRANK, Harvard Medical School, Boston, Massachusetts
JEROME KAGAN, Harvard University, Cambridge, Massachusetts
HERBERT D. KLEBER, Columbia University and New York State Psychiatric Institute, New York, New York
BEVERLY B. LONG, World Federation for Mental Health, Atlanta, Georgia
KATHLEEN R. MERIKANGAS, Yale University, New Haven, Connecticut
STEVEN M. MIRIN, American Psychiatric Association, Washington, D.C.
STEVEN M. PAUL, Lilly Research Laboratories, Indianapolis, Indiana
DAVID REISS, George Washington University Medical Center, Washington, D.C.
RHONDA J. ROBINSON-BEALE, Blue Cross/Blue Shield of Michigan, Southfield
STANLEY J. WATSON, University of Michigan, Ann Arbor
STEPHEN G. WAXMAN, Yale Medical School, New Haven, Connecticut
NANCY S. WEXLER, Columbia University, New York, New York
ANNE B. YOUNG, Massachusetts General Hospital, Boston
Multiple sclerosis (MS) is not a new disease. Its effects on the brain were described in the 1830s, and it was identified as a distinct clinical entity in the 1860s. In fact, writings from the Middle Ages appear to describe individuals with this condition. MS is the most common neurological disorder of young adults; there are approximately 350,000 people with MS in the United States and an estimated 2 million patients worldwide.
Research on the disorder has been energetic over recent decades. In 1996, the U.S. National Institutes of Health (NIH) spent almost $83 million on MS research. This sum exceeded the NIH expenditure that year on asthma, tuberculosis, or cervical cancer. MS has not been neglected by researchers in this country or worldwide.
As a result, important progress has been made in defining the pathologic changes of MS, in using new imaging techniques for evaluation, and in developing treatments that can modify its course. Yet, despite concerted effort on the part of many good researchers, the fundamental elements of MS are still not understood, and the path toward consistently preventing its progression or curing it remains obscure. For example, we do not know what causes MS to appear in one person and not another. We do not know what role genes play. We have known for decades that MS has a widely variable clinical expression and unpredictable course, but do the variations reflect different causative agents or different responses to the same basic cause? Most investigators consider MS to be an autoimmune disease, but what incites the autoimmune response—a change in the cells of the nervous system so that they appear foreign or a microbial agent that mimics a cell component? Why is it approximately twice as common in women
as in men? How can we most effectively relieve the various troubling symptoms of MS such as pain and fatigue? How can we help people with MS adapt to the disease and live their lives to the fullest level possible?
The National Multiple Sclerosis Society was founded in 1946 to address these and other questions about MS. Its mission is simple and forthright: “To end the devastating effects of multiple sclerosis.” Through the efforts of its 650,000 members and staff, it has made extraordinary contributions to understanding MS by a series of highly imaginative programs in research and patient services, including almost $300 million in research grants. The report that you see here is the result of a request from the Society to the Institute of Medicine (IOM) for guidance in developing a strategic plan to direct future investments in MS research.
The multidisciplinary committee convened by the IOM in response to this request was charged to review current knowledge of all aspects of MS from cells to symptoms; to identify techniques, resources, and innovations used outside the field that might be applied to the MS challenge; and to recommend strategies that might push MS research forward most effectively.
To address its charge, the committee, with the support of IOM staff, reviewed the scientific literature related to all aspects of MS and received input from 45 outside consultants: 9 of these wrote state-of-the-art commentaries on symptom management, some told us what they needed most as MS patients, and 17 described the newest science during three workshops. Most of the workshop participants were not primarily involved in MS research or with MS patients but agreed to brainstorm with us about how the best of their disciplines might be applied to MS. We clearly could not have accomplished our work without the help of these consultants, and their listing in the Acknowledgments badly understates our gratitude. Finally, the committee recognizes with the deepest appreciation the support given by the extraordinary staff assigned to us by the IOM—Janet Joy, John Rockwell, Amelia Mathis, and Terry Pellmar. In particular, Janet Joy, study director and neuroscientist by training, with intelligence, humor, and an exceptional intensity of commitment, inspired and guided us to the completion of our task.
Richard B. Johnston, Jr., M.D.
People live with multiple sclerosis (MS) for decades, making it a disease of selves as well as cells. The committee's assessment of the current status of progress against MS thus entailed a review from biomedical perspectives, as well as from psychological and social perspectives. This massive undertaking could not have been accomplished without the help of an array of experts as multifaceted as the disease itself. The committee is deeply indebted to these many people for their valuable contributions.
The following people wrote invaluable background papers for the committee: Dedra Buchwald (fatigue), Howard Fields (pain), Robert W. Hamill (bladder and bowel control), David E. Krebs (assistive technology), T. Jock Murray (cognitive impairment), Peggy Neufeld (assistive technology), Trevor Owens (genetic animal models), Robert G. Robinson (depression and brain injury), William Z. Rymer (spasticity and weakness), and Marca Sipski (sexual function).
Another group presented a series of excellent talks on new approaches to MS research at workshops for the committee. This group includes Mindy Aisen, Michael Conneally, Scott E. Fraser, Chien Ho, Ole Isacson, Elliott D. Kieff, Jeffery Kocsis, Henry McFarland, Deborah Miller, Rhona Mirsky, Marc Peschanski, John C. Roder, Jay Siegel, Joy Snider, Lawrence Steinman, Barbara Vickrey, and Michael Weinrich. (Topics are listed individually in Appendix C.)
The following people provided technical comments on draft sections of the report: Robert Burke, Mary Horwitz, Peggy Neufeld, John Roder, and Richard Rudick. Still others served as technical consultants either in meetings with the committee, sharing unpublished reports, or in consultations with Institute of Medi-
cine (IOM) staff. This group includes Elaine Collier, Gary Karp, Lorna Layward, Ian McDonald, Sarah Minden, Audrey Penn, and Albert van der Pol.
All of these people gave generously of their time and made a tremendous and much appreciated contribution to the breadth and depth of this report.
Stephen Reingold, Vice President of Scientific Programs, and Nicholas LaRocca, Director of Health Care Delivery and Policy Research, at the National Multiple Sclerosis Society were indispensable to the committee's efforts. They provided the committee with volumes of background material and fielded an endless stream of inquiries from IOM staff. They were unfailingly quick to reply to queries and provided stores of information.
Miriam Davis and Jane Durch provided substantive editing for sections of the report, Amy Fluet wrote material for several of the explanatory boxes in the report, and Florence Poillon edited the uncorrected proofs. Each of them greatly enhanced the readability of the report and we are grateful for their excellent work.
This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their participation in the review of this report:
Fred Barkhof, Diagnostic Radiology, Vrije Universiteit Hospital, Amsterdam, Netherlands
George Ebers, Professor, Department of Clinical Neurology, Oxford University
Jill S. Fischer, Director, Psychology Program (1985-2000), Mellen Center for MS Treatment and Research Cleveland Clinic
Zach W. Hall, Vice Chancellor, Office of Research, University of California, San Francisco
Charles A. Janeway, Jr., Department of Immunobiology, Yale School of Medicine
Alan M. Jette, Dean, Sargent College of Health and Rehabilitation Services, Boston University
Jurg Kesselring, Professor and Head, Department of Rehabilitation Centre, Valens, Switzerland
Samuel K. Ludwin, Professor, Pathology Department, Queens University, Ontario, Canada
Robert H. Miller, Associate Professor, Case Western Reserve University School of Medicine
Mary Beth Moncrief, Manager, Associate National Scientific Program Juvenile Diabetes Foundation International
John Newsom-Davis, Professor, Clinical Neurology, University of Oxford
Michael B.A. Oldstone, Professor, Department of Neuropharmacology, Division of Virology, The Scripps Research Institute
Jerry Wolinsky, Professor, Department of Neurology, University of Texas, Houston Medical Center Health Science Center
Although the individuals listed above have provided constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by Joseph B. Martin, Dean, Harvard Medical School and Floyd R. Bloom, Chair, Department of Neuropharmacology, the Scripps Research Institute, who were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the Committee on Multiple Sclerosis: Current Status and Strategies for the Future and the Institute of Medicine.
|Ataxia and Tremor,||138|
|Bladder and Bowel Dysfunction,||140|
|4||DISEASE MANAGEMENT AND MEASUREMENT||177|
|Living with MS,||178|
|Measuring Functional Status and Quality of Life,||193|
|Information and Communication,||216|
|5||STRATEGIES FOR FUTURE RESEARCH ON DISEASE MECHANISMS||241|
|Technologies and Research Strategies,||267|
|6||FUTURE STRATEGIES FOR THERAPIES||277|
|Strategies for Disease Modification,||278|
|Challenges in MS Clinical Trials,||298|
|7||BUILDING AND SUPPORTING THE RESEARCH ENTERPRISE||325|
|Biotechnology and Pharmaceutical Firms,||341|
|Health Care Research,||343|
|Role of Voluntary Health Organizations,||344|
|Etiology and Pathogenesis,||348|
|Tools for Research and Diagnosis,||355|
|Health Status and Quality of Life,||361|
|A||Committee and Staff Biographies,||371|
|B||List of Expert Consultants,||377|
|D||Kurtzke's Expanded Disability Status Scale,||385|
|E||Drugs Used in the Treatment of MS,||387|
|F||U.S. Social Security Administration's Criteria for Qualifying as Disabled from MS,||401|
|G||Treatments That Have Been Claimed to Be of Benefit in MS,||405|
List of Tables and Figures
|3.5||Medications Used to Treat Bladder and Bowel Dysfunction,||144|
|3.6||Medications Used to Treat Optic Neuritis and Abnormal Eye Movements,||150|
|3.7||Medications Used to Treat Fatigue,||154|
|3.8||Neurological Pathways That Control Sexual Response in Men and Women,||157|
|3.9||Medications Used to Treat Erectile Dysfunction,||159|
|5.1||Hypothetical Results of a Clinical Trial,||262|
|6.1||MRI Outcomes for Clinical Trials,||310|
|7.1||Research Budgets of Selected Health Organizations in 1998,||329|
|1.1||MS distribution map,||18|
|1.2||The nerve fiber in multiple sclerosis,||19|
|2.1||Spectrum of disease course,||31|
|2.2||Areas of the CNS affected by MS,||32|
|2.3||MRI scans of the brain,||37|
|2.4||Oligodendrocyte making myelin,||55|
|2.6||Axonal transection and degeneration,||59|
|2.7||Possible mechanisms of demyelination,||61|
|2.8||The blood-brain barrier,||63|
|2.9||Interactions between major cell components of the immune system,||68|
|2.10||Possible mechanism of viral etiology,||70|
|3.1||Functions controlled by nerves at different levels of the spine,||129|
|5.1||Demyelination and axonal degeneration in multiple sclerosis,||242|
|5.2||Possible role of AMPA/kainate receptors on neurons and glia,||244|
|6.2||Lineage of neural stem cells,||294|
|7.1||Relationship between NIH disease-specific research funding,||327|
|7.2a||Summary of publications in general medical journals,||328|
|7.2b||Summary of publications in neurology journals,||330|
|7.3||Ph.D and postdoctoral fellowship trends,||335|
|7.4||Trends in postdoctoral fellowship applications,||337|