Multiple Sclerosis Update

Published Online: November 24, 2013
Clyde E. Markowitz, MD
Multiple sclerosis (MS) is a chronic but incurable disease of the central nervous system (CNS) that is often diagnosed in the second or third decade of life. It is more common among women than men, significantly impairs patient quality of life, and is associated with substantial costs to patients, healthcare systems, and society. Of the approximately 2.3 million individuals worldwide that have MS, more than 400,000 reside in the United States. Although the etiology of MS is not completely understood, a great deal of evidence suggests a complex relationship between environmental and genetic factors. The pathophysiology of MS involves an aberrant attack by the host immune system on oligodendrocytes, which synthesize and maintain myelin sheaths in the CNS. There are 4 identified disease courses in MS, and approximately 85% of people with MS present with relapsing-remitting MS, which is characterized by discrete acute attacks followed by periods of remission. Signs and symptoms of MS are dependent on the demyelinated area(s) of the CNS and often involve sensory disturbances, limb weakness, fatigue, and increased body temperature. The criteria for a diagnosis of MS include evidence of damage in at least 2 separate areas of the CNS, evidence that the damage occurred at different time points, and the ruling out of other possible diagnoses. Diseasemodifying drugs (DMDs) that reduce the frequency of relapses, development of brain lesions, and progression of disability are the standard of care for relapsing forms of MS, and the use of DMDs should be initiated as early as possible.

(Am J Manag Care. 2013;19(16):S294-S300)
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) in which inflammation and breakdown occur in the protective insulation that surrounds nerve fibers (myelin), thereby disrupting signals from within the brain, as well as between the brain and the host body. It results in a variety of neurological symptoms that depend upon which pathways are disrupted.1,2 While the onset of MS for most individuals typically occurs between their 20s and 50s, with 2 to 3 times as many women as men being diagnosed with MS, approximately 2% and 5% of patients encounter disease onset before the ages of 10 and 16 years, respectively.2,3 Although life expectancy with MS is at least 25 years from disease onset, with most patients dying from unrelated causes,3 those with MS have worse health-related quality-of-life scores than the general population with regard to physical functioning, vitality, and general health.4-6 Additionally, several studies have evaluated the economic burden associated with MS in the United States, with results indicating that MS is very costly to individuals, healthcare systems, and society.7-10


Approximately 2.3 million individuals worldwide have MS, which includes more than 400,000 in the United States.2 In addition, an estimated 200 persons are diagnosed with MS each week in the United States, which translates to roughly 1 diagnosis of MS every hour.2 The largest and most recent examination of the worldwide prevalence of this often unpredictable and debilitating disease was conducted in a large international study from 2005 to 2007, and included over 100 countries that spanned all World Health Organization (WHO) regions and continents.11

Data from the WHO study indicated that the global median estimated prevalence of MS was 33 cases per 100,000 persons. While MS is present in all regions of the world, its prevalence varies greatly; the highest rates per 100,000 persons were found in North America (140) and Europe (108), and the lowest rates were found in sub-Saharan Africa (2.1) and East Asia (2.2).11 Furthermore, the prevalence of MS may also vary substantially within each region; for instance, in Europe, the highest prevalence per 100,000 persons is found in Sweden (189), whereas the lowest is found in Albania (22).11 Reasons for the observed variation in worldwide prevalence and incidence of MS are not well understood, and although environmental and genetic explanations have been offered, it is widely accepted that both factors likely play important roles.

Etiology and Pathophysiology

The etiology of MS is not completely understood, but epidemiological and association studies do suggest a relationship between multiple environmental and genetic factors.3,12 Several environmental risk factors for MS that have been identified include high Epstein-Barr virus immunoglobulin G antibody titers, low levels of vitamin D and/or ultraviolet radiation exposure, and cigarette smoking.12-14 In addition to these environmental factors, genetic components are thought to be involved in the etiology of MS. The disease is known to aggregate in families,15 and has higher concordance rates in monozygotic twins (up to 30.8%) compared with dizygotic twins (2.4%-4.7%), ordinary siblings (3%),16,17 or half-siblings (1.32%).18 Although children of 2 parents with MS have a 5.8% chance of developing MS,19 no increased risk was observed among adoptive relatives.20

Multiple sclerosis is characterized by acute focal inflammatory demyelination and axonal loss with limited remyelination, which results in chronic multifocal sclerotic plaques. The atrophy and accelerated loss of brain gray matter has also been correlated with disability progression in MS.3,21 Regarding the pathophysiology of MS, oligodendrocytes, which synthesize and maintain the myelin sheath of up to 40 neighboring nerve axons in the CNS, is the principal target of immune attacks in MS.3 The breakdown of immune regulation in autoimmune diseases such as MS is thought to be attributable to molecular mimicry, in which a peptide presented to the peptide-binding groove of a specific class II molecule is immunologically indistinguishable from a self-antigen. Therefore, in MS, an appropriate immunological response to infection can inadvertently generate inappropriate inflammation against a component of the oligodendrocyte-myelin unit, which results in temporally and spatially segregated inflammatory lesions. This breakdown of host immune regulation can lead to the proliferation and activation of autoreactive T cells and their subsequent entry into circulation. These cells can express adhesion molecules and induce reciprocal changes in endothelia, allowing the T cells to cross the blood-brain barrier (BBB) into the CNS. Once within the host CNS, the activated T cells initiate a proinflammatory loop by re-encountering the antigen and activating the microglia, causing the expression of class II molecules and re-presenting of antigen to T cells. Toxic inflammatory mediators are then released, sustaining a breakdown of the BBB and leading to injury of axons and glia. Although cytokines and growth-promoting factors, which are released by reactive astrocytes and microglia as part of the acute inflammatory process, can promote endogenous remyelination, astrocyte reactivity and gliosis can lead to a physical barrier that prevents further remyelination.3

Clinical Course and Diagnosis

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