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Epidemiology and Natural History of Multiple Sclerosis
Marcus W. Koch
KEY POINTS FOR CLINICIANS
• The incidence and prevalence of multiple sclerosis (MS) varies between different geographical regions and ethnicities.
• MS is a lifelong disease; the overall survival of patients with MS is about 6 years shorter than that of the general population.
• The environmental risk factors, vitamin D (deficiency), and smoking influence the risk of developing MS, as well as the disease course.
• Sex, age at onset, and onset symptoms cannot reliably predict the disease course.
• The times to landmark disability have recently been found to be longer than initially reported, with a time to Expanded Disability Status Scale (EDSS) 6.0 of about 30 years overall and about 15 years in primary progressive MS. There is a significant interindividual variation in the time to reach this landmark.
EPIDEMIOLOGY, SURVIVAL, INCIDENCE, AND PREVALENCE OF MULTIPLE SCLEROSIS
Compared to other diseases of the central nervous system such as stroke, epilepsy, and traumatic brain injury, MS is a relatively uncommon disease. MS has a protracted disease course, with often long periods of clinical stability, and can be viewed as a lifelong condition; the overall survival of patients with MS is about 6 years less than that of the general population (1).
People with MS die about 6 years earlier than the general population.
MS is newly diagnosed in about one in 20,000 people per year (incidence) and affects about one in 1,000 people (prevalence) (2). The incidence and prevalence of MS are, however, highly variable between different geographical areas. The prevalence of MS increases with latitude, such that the countries farthest from the equator have the highest prevalence of MS, whereas countries closer to the equator have a lower prevalence. For example, MS affects about one in 400 people in Canada (3), but only one in 5,000 people in Brazil (4). Several factors are believed to contribute to this latitudinal difference. The influence of increased vitamin D production due to a greater exposure to sunlight in countries closer to the equator is one explaining factor (see following discussion on environmental risk factors). Ethnic differences between countries could also contribute. It has classically been thought that people of European descent may be especially susceptible to MS, whereas those of Asian and African descent may be less susceptible. This is illustrated best by epidemiological studies from around the world, which compare the prevalence of MS among different ethnic groups living together in the same area: one study in Israel, for instance, showed that Jews of European extraction had a much higher prevalence of MS (68 per 100,000) than Arabs (11 per 100,000). A South African study showed that whites had a much higher prevalence (26 per 100,000) than both Indians (8 per 100,000) and blacks (0.22 per 100,000) (5). Similar findings were also seen in New Zealand, where the prevalence of MS among people of European descent was much higher (103 per 100,000) than that among the Maoris (16 per 100,000) (6). MS is rare in Southeast Asia, with prevalence in the range of 1.4 per 100,000 in Shanghai, China (7) to 3.6 per 100,000 in South Korea (8). More recent research into the influence of ethnicity on MS incidence in the United States, however, has challenged these classical population-based studies. Two large studies based on an investigation of a large population of members of a health insurance in 23southern California showed that the incidence of MS and other demyelinating diseases was higher in blacks than in other ethnic groups in both adults and children (9,10). One reason for this difference in MS incidence may lie in the differences in vitamin D levels among ethnicities, as the National Health and Nutrition Examination Survey, a U.S. study tracking nutritional status, including vitamin D levels, in the U.S. population since 1988, has consistently shown blacks to have lower levels of vitamin D compared to other ethnic groups (11,12). The reason for the influence of ethnicity on MS incidence and prevalence across many populations, however, is not fully understood.
The prevalence of MSdiffers between geographical locations and ethnicities. For example, MS affects about one in 400 people in Canada, but only one in 5,000 people in Brazil.
In the vast majority of patients, MS presents with a relapse, and the subsequent disease course is characterized by relapses and remissions: relapsing–remitting MS (RRMS). In about 10% of all patients with MS, the disease begins with a slow and relentless accumulation of disability, usually without any relapses. This form of the disease is called primary progressive MS (PPMS). In the longer term, most patients with RRMS experience a change in their disease course from the period with relapses and remissions to a more uniform and slow worsening of symptoms. This is called secondary progressive MS (SPMS). SPMS patients may continue to have relapses or cease having relapses, but the relapse rate tends to be less later in the disease course.
The median age at disease onset is around 30 years in RRMS and around 40 years in PPMS, the conversion to SPMS also occurs around a median age of 40 years. Women have a slightly, up to several years, earlier onset than men.
RRMS occurs more commonly in women, with a female-to-male ratio that was classically given as about 2. Recently, it has been found that this sex ratio of MS has changed in the last decade, so that it is now even more common in women, with the ratio of women-to-men with MS increasing from 1.4 in 1955 to 2.3 in 2000 (13). The reason for this increase is unknown. PPMS affects men and women equally.
RRMS occurs about twice as often in women than in men. PPMS affects men and women equally.
ENVIRONMENTAL RISK FACTORS FOR MS
While research on environmental risk factors for MS is ongoing and many possible risk factors are being investigated, three environmental risk factors, vitamin D, Epstein–Barr virus (EBV) infection, and smoking, currently have the most convincing evidence to support them.
Vitamin D has recently been found to influence the risk of developing MS. The best evidence for this comes from an investigation of routine blood samples in U.S. military personnel. Routine medical examinations for U.S. military personnel include the drawing of a blood sample, which is then stored. One study investigated 25-hydroxyvitamin D levels in these blood samples and related the vitamin D level to the subsequent risk of developing MS in a nested case-control study. This included 257 people who developed MS and two matched controls per case drawn from over 7 million people registered in the U.S. Department of Defense Serum Repository. In the study, it was found that the risk of developing MS decreases with rising serum vitamin D levels (odds ratio 0.59 per 50 nmol/L increase in vitamin D serum level) (14). Further studies suggest an association of vitamin D levels and the risk of developing MS with exposure to ultraviolet light: a retrospective Australian study showed that actinic skin damage (which occurs as a consequence of too much exposure to ultraviolet light), as well as the (remembered) time spent in the sun during childhood were associated with a lower risk of developing MS (15). The reason for the latitudinal variation in MS risk is most likely the lower exposure to ultraviolet light at higher latitudes, and the subsequent lower levels of vitamin D.
A low serum level of vitamin D is a risk factor for MS.
Studies on the influence of infections with EBV on MS risk are made difficult by the fact that the great majority (around 95%) of adults is seropositive for EBV, which makes for large required sample sizes. A recent meta-analysis on EBV and MS risk including 1,779 people with MS and 2,526 control persons showed that seronegativity for EBV is associated with a very low risk of developing MS (odds ratio of 0.06) (16). Another large meta-analysis showed that a history of infectious mononucleosis (symptomatic EBV) was associated with a roughly doubled risk of developing MS (relative risk 2.17) (17). An analysis from a clinical trial cohort showed no important impact of EBV antibody levels on the risk of developing MS in a cohort of patients with clinically isolated syndrome (CIS). The BENEFIT study included 468 people with CIS, 448 were positive for EBV antibodies. In this study, the EBV-positive patients were divided into quartiles by the 24height of their EBV antibody titer, and there were no significant differences between these quartiles with regard to the risk of developing clinically definite MS during the 5-year follow-up period, or to clinical or MRI disease activity. Interestingly, the two patients who were consistently found to be EBV antibody negative, though they were not included in the analyses, did not go on to develop MS (18).
The reason for the latitudinal variation in MS risk is most likely the exposure to ultraviolet light at higher latitudes and the subsequent lower levels of vitamin D.
Good evidence for the influence of smoking on the risk of developing MS comes from the two Nurses’ Health Studies, each including more than 100,000 women. An analysis of these studies showed an increased risk of MS among current (relative incidence rate compared to nonsmokers: 1.6) as well as former smokers (relative incidence rate: 1.2). There also was a suggestion of dose dependency, with the relative incidence increasing with increasing pack years (19). Further studies have since shown that secondhand smoke is associated with a higher risk of MS among children (20) and adults (21). The aforementioned analysis of the BENEFIT trial cohort, however, failed to show an important impact of cigarette smoking on the risk of developing clinically definite MS in a cohort of people with CIS. In this study, elevated blood levels of cotinine, a nicotine metabolite and reliable marker of current or recent tobacco use, were unrelated to the risk of developing clinically definite MS, or to the clinical or MRI disease activity during the 5-year follow-up period (18).
Smoking and secondhand smoke are risk factors for MS.
THE NATURAL HISTORY OF MS
Studies on the natural history of MS have usually investigated how certain risk factors are related to the arrival at certain landmark disability levels. Typically, the time to a landmark disability score (such as EDSS 6.0, when patients need a cane for walking) was measured from disease onset. Early studies reported a relatively quick progression from disease onset to EDSS 6.0, with a median time from disease onset of RRMS in the range of 15 (22) to 20 (23) years, but newer studies have corrected these estimates to a median time from onset of around 30 years (24,25). Early studies on the natural history of PPMS reported very short median times to EDSS 6.0 of less than 10 years (22,23). More recent studies have corrected these to a median time from disease onset of around 15 years (26). It should be noted that there is a very wide interpersonal variation in the progression of MS. Even within PPMS, which is thought to be the most uniform of the disease courses, the time to EDSS 6.0 ranged from around 8 years in 25% of patients with the quickest progression to more than 25 years in the 25% with the slowest progression (26).
