Current Issues and Ongoing Challenges in MS: Neurodegeneration and Neuroprotection
Arun Venkatesan, MD, PhD,* and Michael K. Racke, MD †
Multiple sclerosis (MS) is a chronic, progressive, disabling condition that is characterized by inflammation and demyelination of central nervous system (CNS) axons. Individuals with MS typically begin to exhibit significant impairment in the ability to walk without aid approximately 10 to 12 years after diagnosis, and many are essentially confined to a wheelchair within 25 to 30 years.1 Due to the relatively young age at the time of diagnosis (typically between the ages of 20 and 50) and the potential for permanent neurologic impairment, MS is a major cause of disability in developed nations. Disability associated with MS also creates a significant economic burden for most patients, who often experience sustained loss of income and unreimbursed expenses associated with medical or nursing care.2
Most patients with MS initially experience discrete episodes of CNS inflammation and a return to normal or near-normal function between episodes. Inflammatory lesions occur throughout the brain and spinal cord, and the disease therefore produces a variety of non-specific signs and symptoms that may include pain, muscle weakness, spasticity, visual disturbances, paresthesia, sexual dysfunction, or cognitive impairment. Disease-modifying therapies that suppress CNS inflammation have been shown to significantly reduce relapse rates, disease progression, and magnetic resonance imaging (MRI) evidence of disease activity in patients with MS, and 4 immunomodulators are considered first-line treatment options (2 formulations of interferon ß-1a, interferon ß-1b, and glatiramer acetate).3 Although these agents are effective for individuals with relapsing forms of MS, many patients continue to exhibit significant disease activity despite first-line therapy. In addition, most patients with MS eventually develop irreversible and progressive neurologic impairment that is less responsive to treatment with the approved MS therapies.3
Although MS has traditionally been viewed as a disorder of CNS inflammation and demyelination, a growing body of evidence has demonstrated that axonal damage and progressive neurodegeneration are also important in the pathogenesis of MS. Neurodegeneration has been identified at even the earliest stages of MS, and is thought by many experts to be an important contributor to the long-term progression of disability.4,5 Several mechanisms have been hypothesized to account for axon loss in MS, including increased vulnerability to the effects of inflammatory mediators following demyelination, the loss of myelin-derived substances that support neuronal survival, and neuronal toxicity due to intracellular calcium overload. These observations suggest that treatment strategies that are designed to prevent neurodegeneration may provide entirely new approaches to the treatment of MS. Several recent studies have examined the potential neuroprotective effects of current MS therapies and have explored novel approaches to reduce neurologic injury. In addition, conventional imaging technologies may not be sensitive to neurodegeneration, and new imaging techniques may be required to identify and quantify neurodegeneration in clinical practice and in clinical trials of potential neuroprotective therapies.6
This issue of Johns Hopkins Advanced Studies in Medicine includes proceedings from The 6th Annual Johns Hopkins MS Symposium, and will provide an overview of the opportunities and challenges of neuroprotective strategies in MS therapy. In the first article, Bruce D. Trapp, PhD, discusses some of the pathologic evidence that neurodegeneration is an important contributor to the pathogenesis of MS and examines the relationship between chronic axonal demyelination and neurodegeneration. Benjamin Greenberg, MD, MHS, describes research supporting a role for neurodegeneration that is independent of inflammation and reviews findings suggesting that current MS therapies may produce direct or indirect neuroprotective effects. Peter A. Calabresi, MD, discusses the limitations of current MRI techniques for the assessment of neurodegeneration and describes newer imaging technologies to quantify neuronal and axonal loss. Clyde E. Markowitz, MD, examines important issues in the management of breakthrough disease and reviews the importance of identifying and overcoming barriers to treatment adherence. Dr Markowitz also summarizes recent research regarding the use of several medication strategies for patients with continued MS activity despite disease-modifying therapy. Michael K. Racke, MD, presents an excerpt from a case-based clinical decision-making exercise on the use of MRI that was conducted with clinicians who treat MS. This issue concludes with highlights from the question and answer sessions that took place at the meeting.
This educational activity is designed to provide neurologists, MS specialists, neuroscience nurses, and other clinicians who care for patients with MS with an update on the role of neurodegeneration in the pathophysiology and treatment of MS. Participants who complete this educational activity will be better able to describe the significance of neurodegeneration for the long-term course of MS, identify and overcome barriers to treatment adherence, and manage patients with continued disease activity despite therapy with first-line agents. In addition, participants will be prepared to interpret the results of new CNS imaging techniques that are designed to assess neurodegeneration and neuroprotection, and to incorporate the results of clinical trial data from neuroprotection studies into clinical practice.
1. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343:1430-1438.
2. Whetten-Goldstein K, Sloan FA, Goldstein LB, Kulas ED. A comprehensive assessment of the cost of multiple sclerosis in the United States. Mult Scler. 1998;4:419-425.
3. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58:169-178.
4. De Stefano N, Narayanan S, Francis GS, et al. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol. 2001;58:65-70.
5. Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci. 2003;206:165-171.
6. Meier DS, Weiner HL, Khoury SJ, Guttmann CR. Magnetic resonance imaging surrogates of multiple sclerosis pathology and their relationship to central nervous system atrophy. J Neuroimaging. 2004;14(3 suppl):46S-53S.
*Assistant Professor of Neurology, Department of Neurology, The Johns Hopkins Medical Institute, 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: Arun Venkatesan, MD, PhD, Assistant Professor of Neurology, The Johns Hopkins University School of Medicine, Department of Neurology, 600 North Wolfe Street, Pathology 509, Baltimore, MD 21287. E-mail: firstname.lastname@example.org.
The content in this monograph was developed with the assistance of a medical writer. Each author had final approval of his article and all its contents.