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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


New Insights Into MS: Neurodegeneration And Neuroprotection


GOAL
To provide multiple sclerosis experts and neurologists with up-to-date information on the treatment and management of patients with multiple sclerosis.

TARGET AUDIENCE
This activity is designed for multiple sclerosis experts and neurologists. No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CE activity. At the conclusion of this activity, the participant should be able to:

  • Discuss the biology of demyelination, axonal degeneration, and neuronal cell death in multiple sclerosis.
  • Identify molecular and biologic strategies aimed at neuroprotection.
  • Analyze available and future clinical methods and technologies for the assessment and monitoring of neurodegeneration and neuroprotection.
  • Summarize the challenges of identifying neuroprotective agents and designing clinical trials to evaluate their efficacy.
  • Assess the potential efficacy of various neuroprotective agents currently under investigation.

ACCREDITATION STATEMENT
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

This 3 contact hour Educational Activity (Provider Directed/Learner Paced) is provided by The Institute for Johns Hopkins Nursing. Claim only those contact hours actually spent in the activity.

The estimated time to complete this educational activity: 3 hours.

Release date: August 15, 2007. Expiration date: August 15, 2009.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing names implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from Teva Neuroscience.

Full Disclosure Policy Affecting CE Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a provider has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director, Program Chairs, and Participating Faculty reported the following:


PROGRAM DIRECTOR

Benjamin Greenberg, MD, MHS
Assistant Professor
Johns Hopkins University School of Medicine
Department of Neurology
Co-Director, Johns Hopkins Transverse Myelitis Center
The Johns Hopkins Hospital
Baltimore, Maryland
Dr Greenberg reports receiving grants/research support from Genentech, Inc and Novartis; serving as a consultant for MedReviews; and receiving honoraria from Biogen IDEC and Teva.

PROGRAM CHAIRS
Douglas A. Kerr, MD, PhD
Associate Professor
Neurology and Molecular Microbiology and Immunology
Director, Johns Hopkins Transverse Myelitis Center
The Johns Hopkins Hospital
Baltimore, Maryland
Dr Kerr reports receiving speaker honoraria from Biogen IDEC, Serono, and Teva; and receiving scientific advisory board honoraria from Genentech, Inc NMO.

Michael K. Racke, MD
Professor and Chairman of Neurology
The Ohio State University Medical Center
Columbus, Ohio
Dr Racke reports receiving grants/research support from the National Institutes of Health and the National Multiple Sclerosis Society; serving as a consultant for Eisai Inc and Genentech; and receiving honoraria from Berlex Inc, Biogen IDEC, Serono, and Teva Neuroscience.

PARTICIPATING FACULTY
Laura J. Balcer, MD, MSCE
Associate Professor of Neurology
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania
Dr Balcer reports receiving grants/research support from the National Institutes of Health/National Eye Institute and the National Multiple Sclerosis Society; serving as a consultant for Biogen IDEC, Eisai Inc, and Salamandra LLC; and receiving honoraria from Biogen IDEC and Wayne State University.

Amit Bar-Or, MD, FRCPC
Neuroimmunology Unit
Montreal Neurological Institute
Montreal, Quebec, Canada
Dr Bar-Or reports receiving honoraria for speaking at meetings supported by or for consulting for Bayhill Therapeutics, Berlex Inc, Biogen IDEC, BioMS, Genentech, Inc, the Immune Tolerance Network/National Institutes of Health, Sanofi-Aventis, Serono, and Teva Neuroscience.

Suhayl Dhib-Jalbut, MD
Professor and Chairman
Department of Neurology
University of Medicine and Dentistry of New Jersey
Robert Wood Johnson Medical School
New Brunswick, New Jersey
Dr Dhib-Jalbut reports receiving grants/research support from Teva; serving as a consultant and on the speakersÕ bureau for and receiving honoraria from Berlex Inc, Serono, and Teva.

Stuart A. Lipton, MD, PhD
Director, Burnham Center for Neurosciences, Stem Cells, and Aging Research
Professor of Neurology and Neurosciences
The Salk Institute, The Scripps Research Institute, and the University of California at San Diego
La Jolla, California
Dr Lipton reports receiving grants/research support from and holding stock in NeuroMolecular Pharmaceuticals, Inc; and serving as a consultant for Forrest Laboratories, Inc and NeuroMolecular Pharmaceuticals, Inc.

Nancy Richert, MD, PhD
Staff Clinician, Neuroimmunology Branch
National Institutes of Health
Bethesda, Maryland
Dr Richert reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Notice: The audience is advised that articles in this CE activity contain reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Bar-Or—several drugs currently in clinical trials for multiple sclerosis.
Dr Lipton—memantine and nitro-memantine.

All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.
New Insights Into MS: Neurodegeneration And Neuroprotection

Benjamin Greenberg, MD, MHS,* Douglas A. Kerr, MD, PhD, and Michael K. Racke, MD

Multiple sclerosis (MS) is a frequent cause of neurologic disability in young adults. Despite advances in our understanding of fundamental processes underlying immunology and neurobiology, the mechanisms underlying MS are not completely understood. The cognitive and neurologic features of MS were first described by Jean-Martin Charcot 130 years ago and subsequently quantified by psychometric testing methods developed in the mid 20th century.1 Slowed information processing appears to be a common characteristic linking the cognitive effects of MS.2

The pathology of MS involves the presence of widely disseminated sclerotic plaques or lesions found predominantly in the cerebral white matter, the optic nerve, tracts of the periventricular region, brain stem, and spinal cord. These lesions have significantly diminished myelin content as well as many axonal transections.3 Perivascular infiltrates of inflammatory cells are numerous within these lesions and include primarily oligoclonal T-cell populations and monocytes, and to a lesser extent, B cells.4

Multiple sclerosis often begins as a relapsing-remitting disease (85%–90% of patients). Other potential forms of MS are clinically defined as secondary progressive, progressive relapsing, and primary progressive. Relapses or attacks begin subacutely, build in intensity over hours or days, remain for days to weeks, and then slowly dissipate. These attacks are thought to be caused by the infiltration of myelin-reactive T cells into the central nervous system (CNS), causing acute inflammation, edema, and tissue injury. Untreated, 50% of patients with MS require a walking aid within 10 years.5 Current treatments have focused on blocking the inflammatory/immune component of the disease.

Our understanding of MS has evolved significantly over the past few years. We now realize that in addition to the inflammatory/immune component of MS, there exists an underlying neurodegenerative component. This has profound implications in terms of the strategies for developing future treatments. This issue of Johns Hopkins Advanced Studies in Medicine provides complete coverage of the 4th Annual Johns Hopkins MS Symposium held in New York City, on March 17, 2007, which included educational presentations followed by lively discussions. The goal of this symposium was to provide the latest information concerning advances in the understanding of the cellular mechanisms underlying MS, new imaging technologies capable of providing diagnostic information, and new molecular research that is providing insight into potential targets for next-generation therapies.

Amit Bar-Or, MD, FRCPC, from the Montreal Neurological Institute, opened with an overview of MS, in which he discussed both immune pathogenesis and neurodegenerative aspects of the disease. He provided data from several areas of research illustrating how the neurodegenerative aspects of MS interact with the inflammatory/autoimmune aspects of the disease. Perhaps the most dramatic example of this was the description of a clinical trial involving syngeneic bone marrow transplant to remove the activated components of the immune system. Remarkably, the reconstituted immune system refrained from continuing the attack on the CNS despite the presence of a similar T- cell repertoire; however, atrophy continued despite the amelioration of inflammation. Our understanding of how this process is regulated remains incomplete and serves as an important goal for future research.

Michael K. Racke, MD, from The Ohio State University Medical Center in Columbus, then presented on the use of the murine experimental autoimmune encephalomyelitis (EAE) model for studying MS. Although EAE is only an approximation of MS, Dr Racke showed how several potential therapies have been tested using this model. He described the experiments demonstrating the identification of cell adhesion proteins responsible for allowing T cells to access the CNS. Dr Racke went on to show conflicting data on insulin-like growth factor in the EAE model, which underscored how details of the disease model can affect the outcome in the clinic. Finally, he presented exciting data on Nogo-A, a potential target to stimulate neuroregeneration.

Moving to human studies, Nancy Richert, MD, PhD, from the National Institutes of Health, examined the role of magnetic resonance imaging (MRI) in MS. She presented studies showing the presence of neurodegeneration using magnetic resonance spectroscopy and magnetization transfer. These new MRI techniques allow for the monitoring of discrete brain regions before and after lesion formation, as well as the establishment of a series of useful measures that correlate well with disease. These tools will become invaluable in the monitoring of patients in neuroprotection trials with new therapeutic agents.

Next, Laura J. Balcer, MD, MSCE, from the University of Pennsylvania School of Medicine, demonstrated how the retina and optic nerve can serve as an excellent model for the entire CNS in the diagnosis and monitoring of neuroprotection in MS. She demonstrated how the use of low-contrast letter acuity tests could detect MS-mediated damage at very early time points and how this correlated with measures of retinal nerve fiber layer thickness using optical coherence tomography.

Stuart A. Lipton, MD, PhD, from Burnham Center for Neurosciences, Stem Cells, and Aging Research in La Jolla, California, then spoke about new therapeutic strategies. He discussed glutamate receptor signaling as one of the premier mediators of neural and oligodendrocyte damage. Dr Lipton presented a novel strategy, termed noncompetitive inhibition, which targets pathologically active glutamate receptors while leaving normally functioning glutamate receptors unaffected. He showed how the antiviral drug, memantine, serendipitously exhibited these properties. Numerous clinical trials using memantine and related compounds are now under way.

The symposium ended with a discussion of protective aspects of the immune system, by Suhayl Dhib-Jalbut, MD, from the University of Medicine and Dentistry of New Jersey in New Brunswick. He provided data from numerous experimental systems showing firstly, that immune-derived cells, such as T cells, can secrete neuroprotective molecules, and secondly, that T cells specific for the copolymer glatiramer acetate were strongly neuroprotective. Finally, data were presented demonstrating microglia are also capable of supplying neuroprotection. These data strongly suggest that current therapies that target the immune system globally are blocking pathogenic and protective functions. It will be critical in the future to find ways to selectively inhibit the immune system, thus these important neuroprotective functions can be spared.


REFERENCES

1.    Rao SM. Neuropsychology of multiple sclerosis: a critical review. J Clin Exp Neuropsychol. 1986;8:503-542.
2.    Demaree HA, DeLuca J, Gaudino EA, Diamond BJ. Speed of information processing as a key deficit in multiple sclerosis: implications for rehabilitation. J Neurol Neurosurg Psychiatry. 1999;67:661-663.
3.    Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338:278-285.
4.    Prineas JW, Wright RG. Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest. 1978;38:409-421.
5.    Weinshenker BG. The natural history of multiple sclerosis. Neurol Clin. 1995;13:119-146.

*Assistant Professor, Johns Hopkins University School of Medicine, Department of Neurology, Co-Director, Johns Hopkins Transverse Myelitis Center, The Johns Hopkins Hospital, Baltimore, Maryland.
Associate Professor, Neurology and Molecular Microbiology and Immunology, Director, Johns Hopkins Transverse Myelitis Center, The Johns Hopkins Hospital, Baltimore, Maryland.
Professor and Chairman of Neurology, The Ohio State University Medical Center, Columbus, Ohio.
Address correspondence to: Benjamin Greenberg, MD, MHS, Assistant Professor, Johns Hopkins University School of Medicine, Department of Neurology, Co-Director, Johns Hopkins Transverse Myelitis Center, The Johns Hopkins Hospital, 600 North Wolfe Street, Pathology 627C, Baltimore, MD 21287. E-mail: bgreenb7@jhmi.edu.

The content in this monograph was developed with the assistance of a staff medical writer. Each author had final approval of his or her article and all its contents.



Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.