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


Current Issues and Ongoing Challenges in MS: Neurodegeneration and Neuroprotection


GOAL
To provide neurologists, neuropathologists, neuroradiologists, multiple sclerosis (MS) nurses, and other professionals of the multidisciplinary team involved in the treatment of MS with up-to-date information on the current issues and ongoing challenges in MS.

TARGET AUDIENCE
This activity is designed for neurologists, neuropathologists, neuroradiologists, multiple sclerosis (MS) nurses, and other professionals of the multidisciplinary team involved in the treatment of MS. No prerequisites required.

LEARNING OBJECTIVES
At the conclusion of this activity, the participant should be able to:

  • Describe the pathophysiology and the biology of demyelination, axonal degeneration, and neuronal cell death in multiple sclerosis (MS).
  • Recognize the inflammatory and neurodegenerative nature of MS and its ramifications on disease progression.
  • Summarize diagnostic measures for assessing neurodegeneration and neuroprotection.
  • Evaluate the effects of molecular and biologic strategies involved in neuroprotection and neuroregeneration.
  • Explain the potential role of immunomodulatory therapy on neuroprotection.
  • Analyze available and emerging clinical technologies for the assessment and monitoring of neurodegeneration and neuroprotection.
  • Apply the latest clinical information of immunomodulatory therapy into clinical case studies.

The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing take responsibility for the content, quality, and scientific integrity of this CE activity.

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 2 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

This 1.6 contact hour Educational Activity 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: 2 hours. After reading this monograph, participants may receive credit by completing the CE test, evaluation, and receiving a score of 70% or higher.

Release date: September 15, 2008. Expiration date: September 15, 2010.

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 activity 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, 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 Course Directors and Participating Faculty reported the following:

COURSE DIRECTORS

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

Michael K. Racke, MD
Professor and Chairman of Neurology
The Helen C. Kurtz Chair in Neurology
The Ohio State University Medical Center
Columbus, Ohio
Dr Racke reports receiving grants/research support from the National Institutes of Health and National Multiple Sclerosis Society; serving as a consultant for Bristol-Myers Squibb Company, Peptimmune, and Teva Neuroscience; and serving on the speakers’ bureau for Bayer, Serono, and Teva Neuroscience.

PARTICIPATING FACULTY

Clyde E. Markowitz, MD
Associate Professor of Neurology
University of Pennsylvania
Director, Multiple Sclerosis Center
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
Dr Markowitz reports receiving grants/research support from and serving as a consultant for Bayer Healthcare, Biogen Idec, BioMS Medical, EMD Serono, Inc, Genentech, Inc, Novartis Pharmaceuticals Corporation, and Teva Neuroscience.

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

Olaf Stüve, MD, PhD
Assistant Professor of Neurology
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas
Dr Stüve reports having no financial or advisory relationships with corporate organizations related to this activity.

Timothy K. Vartanian, MD, PhD
Associate Professor of Neurology
Harvard Medical School
Department of Neurology
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Dr Vartanian reports receiving grants/research support from Biogen Idec and Serono; serving as a consultant for Biogen Idec; and serving on the speakers’ bureau for Serono.

This monograph was reviewed by Faith H. Howarth, MSN, EdM, CRNP, CS, LNC, for the American Nurses Credentialing Center’s accreditation purposes.

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

Dr Greenberg—cyclophosphamide, cytoxan, high-dose chemotherapy, intravenous immunoglobulin, mitoxatrone, mycophenolate mofetil, and rituximab.
Dr Markowitz—alemtuzumab, autologous T-cell vaccination in patients with clinically isolated syndrome or relapsing-remitting multiple sclerosis, BG-12, cladribine, daclizumab, FTY720, MBP8298, rituximab, and teriflunomide.

All other faculty have indicated that they have not referenced unlabeled or 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.

Current Issues and Ongoing Challenges in MS: Neurodegeneration and Neuroprotection
Benjamin Greenberg, MD, MHS,* and Michael K. Racke, MD

Multiple sclerosis (MS) is a chronic inflammatory disease that is characterized by demyelinating lesions, axonal loss, and gliosis within the central nervous system (CNS).1 Despite several significant advances in the diagnosis and treatment of MS during the last 2 to 3 decades, MS remains the most common disabling neurologic condition in young adults, with most people experiencing their first signs or symptoms between ages 20 and 40.2 Although there is no cure for MS, several disease-modifying drugs have been shown to alter the course of the disease, prevent exacerbations, and improve function.3,4 However, their limited effectiveness—especially in progressive forms of MS—in addition to the inconvenience and toxicity associated with their use, emphasize the need for new treatment strategies.5

Models of the pathophysiology of MS have traditionally emphasized the importance of CNS inflammation and demyelination following the infiltration of self-reactive T lymphocytes (especially CD4+ T cells) from the periphery to the CNS.6 More recently, research has increasingly focused on the importance of axonal damage and neurodegeneration in the pathogenesis of MS.7 It is now clear that axonal damage, including axonal transection and degeneration, begins early in the course of MS and occurs even in normal-appearing white matter.8,9 Several mechanisms have been proposed to account for axonal loss in MS, including the release of inflammatory mediators and other toxic products by infiltrating immune cells, the loss of myelin-derived growth factors, and excitotoxic injury following the excessive activation of CNS glutamate receptors.10,11 Recent observations supporting the role of axonal loss and neurodegeneration in MS have suggested that neuroprotective strategies may provide a critical approach to MS management.12 However, all of the currently available disease-modifying treatments for MS are believed to act by suppressing CNS inflammation. Although some of these agents may produce secondary neuroprotective effects by decreasing the release of tissue-injuring inflammatory mediators, none of the current therapies are believed to act primarily by targeting neurodegeneration or axonal loss.

This issue of Johns Hopkins Advanced Studies in Medicine includes proceedings from the 5th Annual Johns Hopkins MS Symposium, which was held in Washington, DC, on April 26, 2008. Speakers explored the role of neurodegeneration in the pathogenesis of MS, in addition to the potential neuroprotective effects of current and emerging MS therapies. The importance of neurodegeneration in MS was further examined in question-and-answer sessions with the presenters and a series of in-depth case discussions. In the first article, Timothy K. Vartanian, MD, PhD, of Harvard Medical School, reviews recent research that has examined the role of neurodegeneration and axonal loss in the pathogenesis of MS. Next, Nancy Richert, MD, PhD, of the National Institute of Neurological Disorders and Stroke, discusses the use of new magnetic resonance imaging (MRI) techniques to assess neurodegeneration and neuroprotection in MS. Although MRI is a sensitive technique for detecting MS and for assessing the response to therapy, the techniques that are currently used in clinical practice lack sensitivity and specificity for the evaluation of axonal loss and neurodegeneration. Dr Richert reviewed the advantages and limitations of advanced MRI methodologies, such as diffusion tensor imaging and magnetization transfer, to provide further insight into tissue integrity and its disruption in MS. The next 2 articles discuss the impact of current and emerging therapies on CNS inflammation and neurodegeneration. Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas, discusses the diverse mechanisms of action of the currently available MS therapies. Dr Stüve describes the complex effects that disease-modifying therapies produce on immune function and also reviews the secondary neuroprotective effects of current therapies. In the final presentation, Clyde E. Markowitz, MD, of the University of Pennsylvania, reviews several potential new MS medications that are currently in development. T-cell vaccines, humanized monoclonal antibodies against cell-surface proteins, and inhibitors of T-cell proliferation all have the potential to suppress the immune-mediated processes that are believed to trigger MS. Other potentially neuroprotective compounds include glutamate antagonists or sodium ion channel blockers. It may be possible to repair neuronal injury through the use of nerve growth factors or by replacing neurons or oligodendrocytes with hematopoietic stem cells.13 These clinical reviews are followed by a discussion of MS case studies, in which the presenters were joined by Benjamin Greenberg, MD, MHS, of The Johns Hopkins University School of Medicine, and Michael K. Racke, MD, of The Ohio State University Medical Center.

Together, the articles and case discussions presented in this monograph provide a comprehensive update on current concepts of neurodegeneration and neuroprotection in the pathogenesis and treatment of MS. At the conclusion of this activity, readers should be able to describe the pathology of MS, discuss the biologic mechanisms that are thought to underlie neurodegeneration and axonal regeneration, summarize the role of MRI in monitoring and assessing neurodegeneration, and describe the potential neuroprotective effects of current MS therapies and those that are in development.

REFERENCES

1.    Stadelmann C, Albert M, Wegner C, Brück W. Cortical pathology in multiple sclerosis. Curr Opin Neurol. 2008;21:229-234.
2.    Mayo Clinic. Multiple Sclerosis. Available at: http://www.mayoclinic.com/health/multiple-sclerosis/DS00188. Accessed June 24, 2008.
3.    Coyle PK. Evidence-based medicine and clinical trials. Neurology. 2007;68:S3-S7.
4.    Buttmann M, Rieckmann P. Interferon-b1b in multiple sclerosis. Expert Rev Neurother. 2007;7:227-239.
5.    Killestein J, Polman CH. Current trials in multiple sclerosis: established evidence and future hopes. Curr Opin Neurol. 2005;18:253-260.
6.    Johnson AJ, Suidan GL, McDole J, Pirko I. The CD8 T cell in multiple sclerosis: suppressor cell or mediator of neuropathology? Int Rev Neurobiol. 2007;79:73-97.
7.    Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology. 2007;68:S22-S31.
8.    Neumann H. Molecular mechanisms of axonal damage in inflammatory central nervous system diseases. Curr Opin Neurol. 2003;16:267-273.
9.    Stadelmann C, Brück W. Interplay between mechanisms of damage and repair in multiple sclerosis. J Neurol. 2008;255(suppl 1):12-18.
10.    Compston A. The pathogenesis and basis for treatment in multiple sclerosis. Clin Neurol Neurosurg. 2004;106:246-248.
11.    Gonsette RE. Oxidative stress and excitotoxicity: a therapeutic issue in multiple sclerosis? Mult Scler. 2008;14:22-34.
12.    Rieckmann P. Neurodegeneration and clinical relevance for early treatment in multiple sclerosis. Int MS J. 2005;12:42-51.
13.    Silani V, Cova L. Stem cell transplantation in multiple sclerosis: safety and ethics. J Neurol Sci. 2008;265:116-121.

*Assistant Professor, The Johns Hopkins University School of Medicine, Department of Neurology, Co-Director, The Johns Hopkins Transverse Myelitis Center, Director, The Johns Hopkins Encephalitis Center, Baltimore, Maryland.

Professor and Chairman of Neurology, The Helen C. Kurtz Chair in Neurology, The Ohio State University Medical Center, Columbus, Ohio.

Address correspondence to: Benjamin Greenberg, MD, MHS, Assistant Professor, The Johns Hopkins University School of Medicine, Department of Neurology, 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.