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


Neurodegeneration and Neuroprotection in Multiple Sclerosis


GOAL
To examine the mechanisms of neurodegeneration in multiple sclerosis, evaluate the role of neurodegeneration in disease progression, and delineate strategies for neuroprotection.

TARGET AUDIENCE
This activity is designed for neurologists, neuropathologists, neuroradiologists, and other experts involved in the treatment of multiple sclerosis. No prerequisites required.

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

  • Understand the biologic mechanisms that are thought to play a role in
    neurodegeneration in multiple sclerosis.
  • Review the mechanisms that are believed to underlie axonal regeneration.
  • Discuss clinical as well as neuroradiologic methods for assessing and monitoring
    neurodegeneration in patients with multiple sclerosis.
  • Review current and future therapeutic strategies aimed at neuroprotection in
    multiple sclerosis.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education
for physicians.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for
a maximum of 3 category 1 credits toward the AMA Physician's Recognition Award.
Each physician should claim only those credits that he/she actually spent in the activity.

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

Release date: April 15, 2004. Expiration date: April 15, 2006.

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 Johns Hopkins University School of Medicine name 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 unrestricted educational grant from Biogen Idec.

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

PROGRAM DIRECTORS

    Jeffrey I. Greenstein, MD
    Director, Multiple Sclerosis Institute
    Chair, Department of Neurology
    Graduate Hospital
    Assistant Professor of Microbiology and Immunology
    Temple University School of Medicine
    Philadelphia, Pennsylvania
    Dr Greenstein reports receiving grants and/or research support from Biogen Idec, Neurocrine Biosciences, Inc, and Teva Pharmaceuticals; and receiving honoraria from Biogen Idec.

    Peter A. Calabresi, MD
    Associate Professor of Neurology
    Director, Multiple Sclerosis Center
    Johns Hopkins Hospital
    Baltimore, Maryland
    Dr Calabresi reports receiving grants and/or research support from Berlex Laboratories, Inc, and Biogen Idec; serving as a consultant to Genentech, Inc, and Vertex Pharmaceuticals Inc; and receiving honoraria from Berlex Laboratories, Inc, Biogen Idec, Serono, Inc, and Teva Pharmaceuticals.

PARTICIPATING FACULTY

    Raymond Dingledine, PhD
    Professor and Chairman
    Department of Pharmacology
    Emory University School of Medicine
    Atlanta, Georgia
    Dr Dingledine reports serving as a consultant to EmTech Bio, Research Advancing Cures in Epilepsy; holding stock in NeurOp, Inc; and receiving honoraria for various academic research seminars.

    Joseph A. Frank, MD, MS
    Chief, Experimental Neuroimaging Section
    Laboratory of Diagnostic Radiology Research
    National Institutes of Health
    Bethesda, Maryland
    Dr Frank reports having no financial or advisory relationships with corporate organizations related to this activity.

    Marion Murray, PhD
    Professor of Neurobiology and Anatomy
    Drexel University College of Medicine
    Philadelphia, Pennsylvania
    Dr Murray reports having no financial or advisory relationships with corporate organizations related to this activity.
    Dr Murray reports having no financial or advisory relationships with corporate organizations related to this activity.

    Cedric S. Raine, PhD, DSc
    Professor, Departments of Pathology, Neuroscience, and Neurology
    Albert Einstein College of Medicine
    Bronx, New York
    Dr Raine reports having no financial or advisory relationships with corporate organizations related to this activity.

    Richard A. Rudick, MD
    Director, Mellen Center for Multiple Sclerosis Treatment and Research
    Department of Neurology
    Chairman, Division of Clinical Research
    The Cleveland Clinic Foundation
    Cleveland, Ohio
    Dr Rudick reports receiving grants and/or research support from Biogen Idec, and Serono, Inc; serving as a consultant to Biogen Idec, Millenium Pharmaceuticals, Inc, and Vertex Pharmaceuticals Inc; and receiving honoraria from Biogen Idec, Serono, Inc, Teva Pharmaceuticals, and Vertex Pharmaceuticals Inc.

    Peter K. Stys, MD
    Professor, Department of Medicine
    Division of Neurology
    Senior Scientist
    Ottawa Health Research Institute
    University of Ottawa
    Ottawa, Ontario, Canada
    Dr Stys reports having no financial or advisory relationships with corporate organizations related to this activity.

    Bruce D. Trapp, PhD
    Chairman, Department of Neurosciences
    Lerner Research Institute
    The Cleveland Clinic Foundation
    Cleveland, Ohio
    Dr Trapp reports receiving grants and/or research support from Amgen Inc and Berlex Inc; serving as a consultant to Amgen Inc; and receiving honoraria from Amgen Inc, Aventis, Berlex Laboratories, Inc, Biogen Idec, Elan Pharmaceuticals, Inc, Serono, Inc, and Teva Pharmaceuticals.

Notice:
In accordance with the ACCME Standards for Commercial Support, the audience is advised that one or more articles in this continuing medical education activity may contain reference(s) to unlabeled or unapproved uses of drugs or devices.

Faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

 

Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. 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.

Neurodegeneration and Neuroprotection in Multiple Sclerosis
Jeffrey I. Greenstein, MD,* and Peter A. Calabresi, MD †

One of the most significant problems in the treatment of multiple sclerosis (MS) is that many patients undergo a transition from an initial relapsing and remitting course of the disease to a later stage characterized by progressive irreversible deterioration with or without superimposed exacerbations. Researchers have long debated whether this transition in the course of MS represents a change in the underlying pathogenesis of the disease. During the past decade it has become increasingly clear that the progressive phase of MS is the result of neurodegenerative processes that are triggered by injury to the central nervous system (CNS) during the early inflammatory stages of the disease. Although demyelination has traditionally been regarded as the primary cause of neurologic injury in MS, recent research has identified axonal degeneration and brain atrophy as significant causes of irreversible neurologic injury in these patients.

Many pathologic processes within the CNS probably contribute to the neurodegeneration that occurs in the late stages of MS. Considerable recent research has focused on the mechanisms of axonal injury, which may occur directly or secondarily to damage to oligodendrocytes. There is also a significant proliferative astrocytic response that may be important to axonal injury. Damage to the extracellular matrix as a result of the release of proteolytic enzymes from macrophages is probably also important in axonal injury in MS, although this has received relatively little attention.

For many years the generally accepted view has been that MS is a T-cell–mediated disorder. It may be the case that T-cells determine the specificity of the response, although it now appears that macrophages, through their interactions with specific chemical mediators (eg, heat-shock proteins) are also important as early triggers of an autoimmune response. There is also clear evidence that macrophages are important in initiating the neurodegenerative processes of MS, and perhaps CD8+ T-lymphocytes. Thus, one way to view the pathophysiology of MS is that the disorder begins with the activation of T-lymphocytes, followed by entry of these cells and macrophages into the CNS. A process of demyelination, concurrent axonal injury, and long-term changes in CNS structure are accompanied by increasing physical and cognitive disability.

Axonal injury has long been recognized in MS, although recent years have seen a significant change in our understanding of this injury. Recent pathology studies have shown that large numbers of axons are transected as a result of inflammatory processes that occur within active MS lesions. Other axonal pathologic processes have been identified, including axon degeneration and failed remyelination. Axonal degeneration in MS may be caused by any of a number of different processes, including classic Wallerian degeneration, calcium-mediated cell injury, the initiation of intracellular signaling cascades that trigger programmed cell death pathways, and alterations of the axonal membrane. Several chemical mediators that influence neuron function, axonal integrity, and cell survival have been identified. These include cytokines, oxygen free radicals, proteases, and other substances. Astrocytes are also significant in the development of axonal pathology, because of the chemical mediators that they modulate and because of direct physical effects, such as scar formation, which prevents axon regrowth.

This issue of Advanced Studies in Medicine is intended to provide neurologists with an overview of recent clinical and scientific research investigating the pathophysiology of MS, with specific emphasis on molecular mechanisms and the roles of neurotransmitters and inflammatory cytokines. In addition to basic biology, this issue addresses the clinical and neuroradiologic implications of neurodegeneration in MS and explores current and emerging therapeutic strategies to reduce neurologic injury. Although the articles primarily cover recent developments in MS, research from other neurologic disorders also provides valuable clues about the processes of neurodegeneration. Studies of hypoxia, CNS trauma, seizure disorders, and other myelin disorders of the central and the peripheral nervous systems have identified many different mechanisms of neuronal injury that may be common to a large number of neurodegenerative conditions, including MS.

The articles presented here encompass a broad range of issues that are important in MS research and treatment, including the development and validation of MS clinical rating scales (Dr Rudick), cellular and molecular changes that occur in and around MS lesions (Dr Raine; Dr Trapp), the role of T-lymphocytes in chronic neurodegeneration (Dr Calabresi), and the use of new magnetic resonance imaging techniques to visualize the effects of MS and its treatment within the CNS (Dr Frank). Some of the articles review research in other neurodegenerative conditions that may contribute to a better understanding of the pathophysiology of MS, such as  anoxia/ischemia (Dr Stys) or in seizure disorders (Dr Dingledine). As described by Dr Murray, animal model systems are being used to identify treatment strategies that may help to restore function to nerve tracts that are injured or even completely transected. Finally, the results of recent clinical trials in MS described in several of the papers are summarized by Dr Greenstein. Together, these studies suggest that it is possible to slow the progression of neurodegeneration in patients with MS and raise the possibility of restoring lost function in patients with MS and other neurodegenerative conditions.

*Director, Multiple Sclerosis Institute, Chair, Department of Neurology, Graduate Hospital, Assistant Professor of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania.
†Associate Professor of Neurology, and Director, Multiple Sclerosis Center, Johns Hopkins Hospital, Baltimore, Maryland.





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