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


Multiple Sclerosis: 2006 Update


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

TARGET AUDIENCE
This activity is designed for neurologists and nurses. No prerequisites required.

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

  • Describe the latest criteria for the diagnosis of multiple sclerosis (MS).
  • Evaluate and manage patients with the clinically isolated syndrome.
  • Demonstrate strategies for selecting, monitoring, and adjusting MS therapies.
  • Organize treatment of MS-related symptoms, complications, and comorbidities.
  • Discuss emerging MS therapies and diagnostic methods.

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. The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses' Credentialing CenterÕs 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)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The 2.4 contact hour Educational Activity (Learner Directed) 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.
Release date: August 15, 2006. Expiration date: August 15, 2008.

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 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 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 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

Benjamin M. Greenberg, MD, MHS 
Instructor
Department of Neurology
Johns Hopkins Hospital
Baltimore, Maryland
Dr Greenberg reports receiving grants/research support from Biogen and Genentech.

Douglas Kerr, MD, PhD 
Associate Professor
Neurology and Molecular Microbiology and Immunology
Director, Johns Hopkins Transverse Myelopathy Center
Johns Hopkins Hospital
Baltimore, Maryland
Dr Kerr reports having no financial or advisory relationships with corporate organizations related to this activity.

PARTICIPATING FACULTY

Douglas L. Arnold, MD
Montreal Neurological Institute
Department of Neurology and Neurosurgery
McGill University
Montreal, Quebec, Canada
Dr Arnold reports receiving grants/research support from Biogen and Teva Neuroscience; serving as a consultant for Berlex, Biogen, and Teva Neuroscience; receiving honoraria from Biogen and Teva Neuroscience; and receiving other financial or material support from Serono.

Amit Bar-Or, MD, FRCP(C), MSc
Assistant Professor
Department of Microbiology and Immunology
McGill University
Montreal, Quebec, Canada
Dr Bar-Or reports having no financial or advisory relationships with corporate organizations related to this activity.

Patricia K. Coyle, MD
Professor and Acting Chair
Department of Neurology
Director, Stony Brook Multiple Sclerosis Comprehensive Care Center
SUNY at Stony Brook
Stony Brook, New York
Dr Coyle reports receiving grants/research support from Berlex, Serono, and Teva Neuroscience; serving as a consultant for Berlex, Pfizer Inc, Serono, and Teva Neuroscience; and receiving honoraria from Berlex, Pfizer Inc, Serono, and Teva Neuroscience.

Karen E. DeBusk, BSN, RN
Clinical Research Program Manager
Johns Hopkins Multiple Sclerosis Center
Baltimore, Maryland
Ms DeBusk reports receiving honoraria from Biogen-IDEC.

Steven L. Galetta, MD
Van Meter Professor of Neurology
Director, Neuro-Ophthalmology Services
Residency Director
Department of Neurology
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
Dr Galetta reports receiving grants/research support from Biogen; serving as a consultant for Biogen; and receiving honoraria from Biogen.

Clyde E. Markowitz, MD
Assistant Professor of Neurology
Director, Multiple Sclerosis Center at PENN
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
Dr Markowitz reports receiving grants/research support from Berlex, Biogen, Genentech, PDL, Pfizer Inc, Serono, and Teva Neuroscience; serving as a consultant for Bristol-Myers Squibb Company and Wyeth; and receiving honoraria from Berlex, Biogen, Pfizer Inc, and Teva Neuroscience. 

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—multiple (future directions of therapy).
Dr Greenberg—natalizumab.

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.

Multiple Sclerosis: 2006 Update
Benjamin M. Greenberg, MD, MHS, and Douglas Kerr, MD, PhD 

Multiple sclerosis (MS) is a condition for which new discoveries are made nearly on a daily basis, yet it still remains an enigma well over a century after it was first described in the medical literature. The first recorded case of possible MS is thought to date back to the year 1400, when Ludwina of Scheiden, the Dutch Patron Saint of ice skating, developed symptoms that in retrospect appear to be consistent with the diagnosis. Centuries later, in 1868, Jean-Martin Charcot described clinical MS in detail and related it to white matter lesions of the central nervous system (CNS). A decade later, Dr Ranvier discovered myelin. Since that time, the proposed etiologies of MS have included "lack of sweat," various toxins, poor circulation, and, later, allergic or autoimmune reactions. Likewise, treatments have varied from bed rest to purgatives, vasodilators, vitamins, antihistamines, and, today, immunomodulatory therapies.

Multiple sclerosis is a neurologic disease most often afflicting young or middle-aged (20-50 years) Caucasian females of northern European ancestry, although it can affect all racial, gender, ethnic, and age groups. There are various forms of the disease with variable courses and severity, and although mortality is low (generally secondary to severe disability resulting in pneumonia, infection, or suicide), MS is associated with significant morbidity. Worldwide, there are approximately 2.5 million individuals with MS, and 400 000 cases in the United States.1 Most patients (55%) have relapsing-remitting MS followed by secondary progressive MS (31%). The remainder of patients (9%) have the primary progressive and progressive relapsing (5%) types, respectively.2 Disease progression is most accurately monitored via magnetic resonance imaging (MRI) studies, and clinical disability is frequently assessed via the Kurtzke Expanded Disability Status Scale. In this monograph, we will discuss the natural history of MS as reflected by these criteria, including new MRI evidence of burden of disease preceding the appearance of clinically definite multiple sclerosis (CDMS), in addition to decreasing brain volume over time. The diagnostic criteria for MS continue to evolve, reflecting ongoing advancements in neuroimaging and neuroimmunology, and will be reviewed.

Although many etiologies have been proposed over the years, scientists still do not have a clear understanding of the cause(s) of this condition. It is currently hypothesized to be multifactorial, including a possible viral/immune-modulated etiology. Various viruses and childhood exposures have been implicated, although no single infectious agent has been identified. Evidence for an infectious cause includes previous epidemiological studies suggesting "outbreaks" of disease and the fact that systemic infections can provoke relapses, perhaps triggering an immune attack on the CNS.

In light of the potential role of the immune system in the pathogenesis of MS, disease-modifying therapies have focused on immunomodulatory and immunosuppressant treatments, including interferon beta-1a, interferon beta-1b, glatiramer acetate, natalizumab (currently not available), and mitoxantrone, among others. The proposed mechanisms of action for these medications include targeting the immune system (T cells, B cells, macrophages, and monocytes), in addition to tissues and chemicals within the CNS (myelin and axons) and periphery (leukocytes, cytokines, and integrins), and preventing breach of the blood-brain barrier. As we continue to learn more about the pathophysiology of MS, therapies will evolve through various stages of clinical development and/or clinical trials. Some of these treatments have presented challenges, raised concerns, and sparked controversies.

The complexities of treating MS in 2006 will be addressed in this issue of Johns Hopkins Advanced Studies in Medicine, including discussion of data from clinical studies of clinically isolated syndromes that point toward an early diagnosis of MS. Should we initiate therapy early on in these patients, or are we treating patients unnecessarily and exposing them to unnecessary costs and adverse effects, as some of them will not progress to CDMS? Is it possible to target therapies for this heterogeneous group of patients, potentially identifying subgroups of patients with MS who will respond best to certain medications? How can we best individualize and monitor therapy, what are the latest neuroimaging tools and disability scales, and what is the significance of neutralizing antibodies in patients taking immunomodulators? How can we continue to educate our patients to maximize adherence to therapy and assure optimal functioning for the maximum period of time in their lives?

What does the future hold? For example, in terms of designing future clinical trials, is it still appropriate and ethical to place patients in a placebo arm? Certainly, the goal of continued MS research is to gain an improved understanding of the disease through genomics, proteomics, and imaging. Specifically, it would be extremely beneficial to define subtypes of MS based on clinicopathologic correlations and/or biomarkers. Once the cause of each subtype of the disease is identified, specific therapies could be targeted toward these subpopulations, with the ultimate goal of a cure. In short, we have traveled far on a long road, but we still have much farther to go.

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


REFERENCES

1. National MS Society. Available at: http://www.nationalmssociety.org/Sourcebook-Epidemiology.asp. Accessed April 11, 2006.
2. Jacobs LD, Wende KE, Brownscheidle CM, et al. A profile of multiple sclerosis: the New York State Multiple Sclerosis Consortium. Mult Scler. 1999;5:369-376.

*Instructor, Department of Neurology, The Johns Hopkins Hospital, Baltimore, Maryland.
 Associate Professor, Neurology and Molecular Microbiology and Immunology, Director, Johns Hopkins Transverse Myelopathy Center, The Johns Hopkins Hospital, Baltimore, Maryland.
Address correspondence to: Benjamin M. Greenberg, MD, MHS, Instructor, Department of Neurology, The Johns Hopkins Hospital, 600 North Wolfe Street, Pathology 627C, Baltimore, MD 21287. E-mail: bgreenb7@jhmi.edu.





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