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Improving Clinical and Economic Outcomes in Multiple Sclerosis

Overview of the Epidemiology, Diagnosis, and Disease Progression Associated With Multiple Sclerosis

Mark J. Tullman, MD
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that affects approximately 400,000 people in the United States. The etiology of MS is unknown, but it is likely the result of a complex interaction between genetic and environmental factors and the immune system. The clinical manifestations of MS are highly variable, but most patients initially experience a relapsing-remitting course. Patients accumulate disability as a result of incomplete recovery from acute exacerbations and/or gradual disease progression. This article briefly reviews the immunopathology of MS, the symptoms and natural course of the disease, and the recently revised MS diagnostic criteria.

(Am J Manag Care. 2013;19:S15-S20)
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The cause of MS is unknown. Most patients with MS initially experience relapses with complete or near-complete recovery interspersed with periods of clinical remission. Although some patients have only minimal symptoms, the majority ultimately develop disability over time as a result of incomplete recovery from relapses and/or conversion to a progressive phase of the disease. However, MS is an extremely variable illness and the course of the disease is essentially impossible to predict in an individual patient. Consequently, counseling patients early in the course of the disease about the variable nature of MS and determining the most appropriate treatment options among the increasing number of available agents are often challenging for clinicians.1,2 This article addresses the current understanding of the epidemiology, pathophysiology, and diagnosis of MS, and discusses treatment and managed care implications.


MS affects approximately 400,000 people in the United States and 2.5 million worldwide. More than 200 people are diagnosed with MS each week in the United States.1 MS typically begins between the ages of 20 and 40 years and it is the leading cause of non-traumatic disability in young adults. Initial symptoms rarely occur before age 10 years or after age 60 years. Women are affected approximately twice as often as men, except in individuals with the primary-progressive form of the disease, where there is no gender preponderance.1

The etiology of MS is unknown. It likely results from complex interactions between environmental and genetic factors, which lead to an aberrant immune response and damage to the myelin sheath, oligodendrocytes, axons, and neurons. A number of factors appear to influence the risk of MS. The strongest known genetic factor affecting MS susceptibility is the HLA-DRB1*1501 haplotype. However, it is not essential for the development of MS, as it only increases the risk by 2- to 4-fold and is present in approximately 20% to 30% of healthy individuals. Additional evidence for a genetic predisposition includes a 20- to 40-fold increased risk of MS in first-degree relatives of patients with MS and a 25% to 30% concordance in monozygotic twins, compared with only 5% in dizygotic twins. However, approximately 70% of identical twins are discordant for MS, so environmental factors and other unknown influences most likely contribute to disease susceptibility.1,3

The prevalence rates of MS have been reported to vary by continent and geographical latitude. The condition is of high prevalence (>30 per 100,000) in northern parts of Europe and North America; medium prevalence (5-30 per 100,000) in southern Europe and southern United States; and Central and South America (10-20 per 100,000); and low prevalence (<5 per 100,000) in Asia and South America.3

Koch-Henriksen and Sørensen conducted an extensive literature search and meta-regression analysis to evaluate the changes in MS incidence and prevalence worldwide.3 Their analysis indicated that the prevalence and incidence of MS are increasing over time. The increase in prevalence was presumed to be due to prolonged survival of patients with MS, while the increase in incidence was thought to be due to a number of factors. In particular, the ratio of disease in women to men has increased over time from less than 1.5 to greater than 2. This increase in MS among females appears to be driving the increase in incidence, and may be due to changes over time in occupation, cigarette smoking, obesity, birth control, and later childbirth. Furthermore, the previously proposed latitude-related differences in prevalence were dispelled in the northern hemisphere but supported in the southern hemisphere. MS is fairly common in Caucasians of northern European ancestry, but less common where non-Caucasians live, in low-income countries, and in tropical zones. Thus, factors which influence MS incidence include population genetics, the interplay between genes and a geographically determined physical environment, and socioeconomic structure, including availability of medical facilities.1,3

Other environmental factors which may relate to MS are sunlight and ultraviolet radiation exposure, vitamin D, Epstein-Barr virus (EBV) and other viruses, and other infective agents.4 The hypothesis that higher exposure to sunlight, and consequently ultraviolet radiation, is associated with a lower incidence of MS tends to conveniently fit with the latitude-based observations; however, exceptions exist. Israeli-born individuals of African descent have higher MS rates than their immigrant predecessors, although it is unlikely that their exposure to sunlight was different. For the same reasons, the relationship between vitamin D and MS is unclear. Although epidemiologic studies correlated increased vitamin D intake with decreased MS incidence, exceptions among Israeli-born individuals do not support the association. Exposure to EBV at an early age in children has been linked to reduced incidence of MS, while exposure in the form of infectious mononucleosis later in life (late adolescence) is linked to an increased risk. EBV prevalence also appears to correlate with the observed differences in MS based on latitude and socioeconomic structure. It has also been postulated that the lower rate of herpes simplex virus (HSV) in patients with MS may suggest a protective effect of HSV, or an immunomodulatory effect on the outcome of EBV. Exposure to certain bacteria (ie, Acinetobacter species, Chlamydia pneumonia, Pseudomonas aeruginosa), mycobacteria, or helminthes has also been linked to MS, although the data are not strongly associated.


Studies in experimental allergic encephalomyelitis (EAE), histopathological studies of MS lesions, and immunologic markers in serum and cerebrospinal fluid of MS patients suggest that MS is an immune-mediated disease. A virus, bacterium, or other environmental toxin might induce an immune response in genetically susceptible persons.5,6

Antigen-presenting cells (APCs) provide relevant antigens to CD4+ T helper cells in the periphery, which lead to their activation and the subsequent generation of autoreactive pro-inflammatory T helper (Th) 1 and 17 subsets.5 B cells and monocytes are also activated. These autoreactive T cells interact with adhesion molecules on the endothelial surface of CNS venules and, with antibodies and monocytes, cross the disrupted blood-brain barrier with the aid of proteases (eg, matrix metalloproteinases) and chemokines. Within the CNS, target antigens are recognized (putative antigens include myelin basic protein, myelin-associated glycoprotein, myelin-oligodendrocyte glycoprotein, proteolipid protein, aB-crystallin, phosphodiesterases, and S-100 protein), T cells are reactivated, and the immune response is amplified. Pro-inflammatory Th cells proliferate and B cells continue their maturation to antibody-secreting plasma cells, while monocytes become activated macrophages.7 Together, these immune cells produce inflammatory cytokines (eg, IL-12, IL-23, interferon g, tumor necrosis factor a), proteases, free radicals, antibodies, nitric oxide, glutamate, and other stressors that collectively lead to damage of myelin and oligodendrocytes. In the appropriate cytokine milieu, CD4+ Th2 cells proliferate and secrete anti-inflammatory cytokines (eg, IL-4, Il-5, IL-13) and transforming growth factor β that suppress the immune response. Depending on the location and extent of damage, demyelination may impair or block nerve conduction and result in neurologic symptoms.8-10 With a loss of trophic support from oligodendrocytes, axons may degenerate to cause irreversible neurological deficits. Spontaneous improvement of symptoms is attributed to resolution of inflammation, adaptive mechanisms (eg, reorganization of sodium channels), or remyelination.

It had long been thought that Th1 and Th2 subsets arose from the terminal differentiation of the CD4+ T cells. However, a third pathway has been identified, induced by IL-1, IL-6, and transforming growth factor b, and then expanded and maintained by IL-23, which is secreted by APCs. This third subset, a pro-inflammatory T helper cell, is known as Th17 because it produces IL-17. Th17 cells secrete a number of cytokines, including tumor necrosis factor a and GM-CSF, which are critical for the development of EAE. Patients with MS have monocyte-derived dendritic cells that secrete higher levels of IL-23 than healthy people.5,11,12 Higher levels of IL-17 mRNA-bearing mononuclear cells are found in the serum of patients with MS experiencing relapses than in those with MS in remission.

Although MS is typically considered a T cell–mediated disease, a growing body of evidence supports a pathogenic role of B cells, including the frequent observation of intrathecal production of immunoglobulin in patients with MS, identification of antibodies that react to specific myelin antigens within MS lesions, a pathological pattern of MS characterized by antibody-associated demyelination (see below), and the discovery of B cell follicles in the meninges of patients with secondary-progressive MS.13 Furthermore, B cells are efficient antigen-presenting cells, and B cell depletion is a promising therapeutic approach in MS.

Acute MS lesions have indistinct margins, hypercellularity, intense perivascular infiltration by lymphocytes, parenchymal edema, loss of myelin and oligodendrocytes, widespread axonal damage, plasma cells, myelin-laden macrophages, hypertrophic astrocytes, and little astroglial scarring.4 Chronic MS lesions have sharp edges, with a perivascular cuff of infiltrating cells, lipid-laden and myelin-laden macrophages, hypertrophic astrocytes, some degenerating axons, dissolution of myelin into droplets which are phagocytized by macrophages, and demyelination associated with immunoglobulin deposition. Chronic lesions may also exhibit an increase in oligodendrocytes and remyelination.5

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