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Multiple Sclerosis Re-Examined: Essential and Emerging Clinical Concepts

Magnetic resonance imaging brain lesions typical of multiple sclerosis.

Magnetic resonance imaging brain lesions typical of multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by exacerbations of neurological dysfunction due to inflammatory demyelination. Neurologic symptoms typically present in young adulthood and vary based on the site of inflammation, although weakness, sensory impairment, brainstem dysfunction, and vision loss are common. MS occurs more frequently in women and its development is complex—genetics, hormones, geography, vitamin D, and viral exposure all play roles. Early MS is characterized by relapsing-remitting course and inflammation of the white matter, although as patients age, the disease often transitions to a pathologically distinct secondary progressive phase with gradual disability accrual affecting gait, coordination, and bladder function. A minority of patients (10%) have disease that is progressive at onset. In the past decade, there has been a remarkable expansion in disease-modifying therapy for MS, but treatment of progressive disease remains a challenge. This article reviews foundational concepts in MS and emerging work that has reshaped understanding of the disease, providing new insight for therapeutic advance.


In 1868, Jean-Martin Charcot provided the first detailed anatomical illustrations of “la sclérose en plaques,” characteristic periventricular white matter lesions now appreciated as a pathological hallmark of multiple sclerosis (MS), the most common autoimmune demyelinating disease of the central nervous system. Although MS is commonly classified as “relapsing” or “progressive,” the disease is best understood as heterogeneous, with considerable overlap between stages. This is hypothesized as due to a complex immune response whereby the adaptive immune system drives pathology in early stages of disease but eventually wanes to be overtaken by other disease processes (mediated by the innate immune system, mitochondrial dysfunction, glutamate toxicity, and reduced compensatory ability, among other pathology), leading to gradual disability accumulation in older age.12 Treatment of MS remains a clinical challenge, as it is the most frequent cause of permanent disability in young adults, and annual health care costs total more than $10 billion in the United States.345


MS prevalence varies with geography: an estimated 400,000 people in the United States (150 people per 100,000) and 2.5 million people worldwide are affected.56 The mean age of diagnosis is 28 to 31 years, although patients may present from the first to the seventh decades of life.37 MS affects women disproportionately, with an estimated female-to-male incidence ratio of 2.3:1, skewing further toward female predominance in more recent studies for unclear reasons.89

MS prevalence increases the further one moves from the equator, hypothesized related to differences in genetic background, infection exposure, and vitamin D levels. In many countries with a high prevalence of MS (US, Northern Europe, Russia, Canada, and New Zealand) there is a latitude gradient of MS risk; however, in regions with lower prevalence this relationship does not always hold.9101112 Classic MS migration studies have shown that individuals moving from low- to high-prevalence regions after age 15 years maintain the low risk of the area that they migrated from, whereas individuals migrating before this age assume the risk of the region they move to.13 Several lines of evidence point to the importance of puberty in MS risk, potentially contributing to this effect: 1) increased female MS risk develops around age 11 years (near puberty onset); and 2) earlier menarche correlates with earlier MS onset in multicenter case-control studies of pediatric MS.14

Epstein-Barr virus exposure is a hypothesized trigger for the development of MS. Though Epstein-Barr virus infection is ubiquitous, studies have demonstrated near 100% seropositivity in MS patients, and in pediatric-onset MS there is an unexpectedly high rate of asymptomatic Epstein-Barr virus seropositivity.1516 Mononucleosis in adolescence is also associated with increased subsequent risk of MS (relative risk 2.3, 95% CI 1.7-3.0).17Epstein-Barr virus-mediated MS risk is hypothesized due to “molecular mimicry” (amino acid sequence homology between virus proteins and myelin basic protein causing auto-reactivity) and also infection of B cells, which may mediate chronic inflammation in MS.1819

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-Jonathan Zurawski, MD, James Stankiewicz, MD

This article originally appeared in the May issue  of The American Journal of Medicine.

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