Epidemiology

Mary Ann Picone

Qibin Qi

Introduction

The etiology of multiple sclerosis (MS) is complex and not fully understood, but there have been various environmental and genetic factors associated with increased MS risk.¹ The prevailing thought is that MS is an autoimmune disorder whereby either viral or environmental agents, or both, trigger a T cell-mediated inflammatory attack, causing demyelination in the central nervous system (CNS). This is thought to result from a complex interplay between genes and the environment. The environmental factors most thought to be involved are vitamin D and Epstein-Barr virus (EBV). Obesity, particularly when present early in life, appears to play a role. Cigarette smoking also has been linked.¹ The aim of this chapter is to discuss genetic and environmental risk factors, both infectious and noninfectious, that are associated with MS development.

Demographics

MS is the most common cause of nontraumatic disability in young adults.¹,² The exact etiology remains unknown, but it is thought to be associated with genetic factors and environmental exposures with environmental factors playing a role in altering gene expression.³ Genes are needed for the development of MS, but the environment plays a predominant role in determining risk. These factors must act at an early age.

The National MS Society Prevalence Initiative, using administrative databases from a variety of sources including Medicare, Medicaid, Veterans Health Administration, and private insurers, estimated nearly 1.1 million people are living with MS in the United States.⁴ This is over twice the number reported since the late 1970s. Estimates of prevalence are important for public health initiatives regarding possible preventive strategies and cost to society, among others.

Lifetime risk for MS has a female predominance with an approximately three times greater risk in women than in men, and incidence of MS is approximately 1 in 200 for women.

The peak time for diagnosis is between 20 and 40 years of age. MS is less frequently diagnosed in childhood, and diagnosis tends to decline after 50 years of age.⁶⁶ It can begin within the first or second year of life and can also be diagnosed beyond the age of 70 years.⁵ Symptoms of the disease may often be present for years before a diagnosis is made. Critical exposure seems to occur before the age of 15 years, according to migration studies. The advent of magnetic resonance imaging (MRI) and improved diagnostic criteria throughout the years has led to earlier diagnosis of the disease.

Individuals of higher socioeconomic background have a greater risk than those of lower socioeconomic background. MS is more common in Caucasian population, whereas less frequent in African American and Asian populations. Studies have shown African American men to have an approximately 40% lower risk than white men.⁶ However, MS tends to have a more severe course in African Americans. It is rare in Inuits.

Life expectancy of patients with MS has increased in the recent years, and this can be one explanation for the increase in the prevalence seen.⁷ Increased awareness and diagnosis of the disease and improved access to neurologists can also increase incidence. One of the difficulties with ascertaining prevalence and incidence has been the problems encountered in consistency in the methodologies and quality of epidemiological studies which have been done.

A retrospective analysis done in the United States looking at commercially insured patient claims from 2008 to 2012 showed a prevalence of about 150 per 100,000 individuals. Females were three times more likely to have MS than males, and peak prevalence occurred at ages 45 to 49 years. Prevalence was relatively consistent during this time span.⁸ Population-based administrative data from British Columbia during the years 1991 to 2008 showed an increase in prevalence by 4.7% per year on average. This could be explained by increased peak prevalence of MS, longer survival rates for MS, and greater life expectancy of women compared with men.⁹ Recent data published from a prospective epidemiological Danish study looking at incidence of MS between 1950 to 1959 and 2000 to 2009 revealed an increased incidence of MS over a 60-year period, particularly
in women and older age-groups, ages 50 to 64 years. The study analyzed 19,536 cases of MS with onset between 1950 and 2009 that were recorded in the Danish registry. Prevalence of risk factors, smoking and obesity, increased during this time period in Denmark, but in females, hormonal factors seem to have played an even more important role. Increased incidence in females seemed to parallel age at first pregnancy and had a link to fewer pregnancies. For older patients, improved MRI diagnostic ability to distinguish between smaller vascular lesions and MS lesions could also contribute to the increased incidence seen.¹⁰,¹¹ Prevalence of MS in Norway has increased 10-fold over the past 50 years, and female-to-male sex ratio has increased. Changes in lifestyle and improved health services and life expectancy with MS could be contributing factors.¹⁰

Figure 1.1. Worldwide prevalence of multiple sclerosis (MS) in 2013. Reprinted with permission from Browne P, Chandraratna D, Angood C, et al. Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. Neurology. 2014;83(11):1022-1024. doi:10.1212/WNL.0000000000000768. See eBook for color figure.

Where in the World Does MS Typically Occur?

MS is most common in the northern parts of North America and Europe (Figure 1.1).¹² Prevalence in these areas is between 0.1% and 0.2% of the population. Incidence is approximately 5 to 6 per 100,000 yearly.¹³ Incidence being the risk of contracting the disease, and prevalence the proportion of cases in the population at any one time.

Geographic distribution appears to inversely parallel that of regional ultraviolet radiation with low incidence in subtropical and tropical regions and higher incidence with increasing latitudes both north and south of the equator,³ with higher incidence in the northern parts of
North America and Europe, where the prevalence is between 0.1% and 0.2% of the population, and the incidence is about 5 to 6 per 100,000 population per year.¹⁴ Because of this observation, it has been proposed that exposure to sunlight and higher vitamin D levels may have a protective effect.⁶⁹

MS is rare in Asia, where the demyelinating disorder more commonly seen is neuromyelitis optica.

Migration effects: MS risk appears to decrease when people migrate from an area of higher incidence to that of lower incidence, particularly before the age of 15 years. When individuals move before their teenage years from an area of high MS prevalence to an area of low MS prevalence, their MS risk becomes similar to the region in which they moved. Children of immigrants from lower MS-prevalent regions born in a higher MS-prevalent region have a risk similar to those in the country of birth. Opposite migration does not appear to increase risk.³,⁶

Environmental Factors (Noninfectious)

Genetic factors are needed for MS to develop, but environmental factors play an important role in determining MS risk, particularly at an early stage in life.

Latitude

In temperate climate regions, MS incidence and prevalence increase with latitude.⁶ Latitude appears to be the strongest risk factor for MS. In the northern hemisphere, MS prevalence tends to follow a north-south gradient and in the Southern hemisphere, a south-north gradient. However, this gradient appears to be decreasing. Over the last few decades, relative risk of MS was 2.02 comparing residence in northern US states to southern states for Vietnam veterans.⁶

For earlier born World War II veterans, the risk was 2.64. Recent studies have shown that the prevalence of MS in formerly considered low-risk areas such as South America and regions closer to the equator is increasing.⁶ MS prevalence decreases with increasing light exposure.

Month and Place of Birth

Studies from Canada, Australia, and northern Europe¹,⁶,¹⁵ showed latitude-related increased risks for spring births that may reflect lower maternal vitamin D levels in winter pregnancies. During winter months at latitudes >42°N, most ultraviolet B (UVB) radiation is absorbed by the atmosphere with little production of vitamin D in the skin.

High-Salt Diets

Diet has been discussed as a potential risk factor for MS in developed countries. With increased adoption of the western diet and use of more processed food, salt intake has increased, and this can play a role in MS pathogenesis.¹⁶ Salt intake has been shown to participate in modulating the differentiation of human and mouse Th17 cells. Mice fed a high-sodium diet had more aggressive courses of experimental autoimmune encephalomyelitis associated with increased IL-17. Increased sodium intake can boost the induction of IL-17-producing CD4+ helper T cells, which have been shown to be involved in MS pathogenesis. High-salt diets also affect the renin-angiotensin aldosterone system, which potentially can modulate immune responses.

Sodium intake has been associated with increased disease activity in MS.¹⁷ Farez and colleagues found a positive correlation between exacerbation rates and sodium intake.¹⁷ Increased radiological disease activity was also noted.

Diet and Gut Microbiome

Specific gut bacteria seem to be more common in MS patients than in controls, and pro-inflammatory responses in human blood mononuclear cells could be produced by these bacteria and trigger experimental allergic encephalomyelitis, an animal model of MS.¹⁸ Bacteria in the gut have been suggested to interact with myelin antigens to trigger autoimmune responses.¹⁹,²⁰

The cause-and-effect relationship between dysfunctional gut bacteria and MS is still uncertain. In a case-control study in Canada, authors reported increased risk of MS in persons whose diet was higher in animal fats and lower risk in persons with diet consisting of more vegetables and higher dietary fiber. Eating a high-fiber diet helps to promote microbial diversity particularly species within the firmicutes and bacteroidetes phyla.¹⁸ Low dietary polyunsaturated fatty acids may also be another modifiable risk factor for MS.²¹

Vitamin D

Vitamin D levels can play a role in decreasing MS risk. Exposure to sunlight and greater vitamin D absorption in latitudes closer to the equator may help explain the relatively low prevalence of MS in these areas. The incidence of MS diagnosis appears to be the lowest near the equator and increases with increasing latitude. Migration studies have shown that moving from areas of higher to lower incidence appears to decrease future risk of developing MS, with the change in MS risk being most significant when migration occurs
in childhood and early adolescence. These areas of low MS prevalence are noted to be areas with higher sunlight exposure, sunlight being the principal inducer of Vitamin D synthesis. Vitamin D has been shown to have immunomodulatory effects, mediating a shift to a more anti-inflammatory immune response by increasing Th2 and regulatory T cell functionality. In its hormonal form, it has been shown to prevent experimental autoimmune encephalomyelitis, an animal model of MS.²²

Low vitamin D levels in early life in individuals who bear HLA-DRB1*15, a genetic variant associated with increased MS risk, could allow autoreactive T cells to escape deletion by the thymus.²³ This has prompted the question of whether exposure to sunlight and higher vitamin D levels earlier in life confer a protective effect for MS. A study done by Munger supported this view, showing a strong protective effect of 25-hydroxy vitamin D levels of 100 nmol/L or higher before the age of 20 years.²⁴ Patients with MS studied prospectively had significantly lower levels of vitamin D during adolescence before disease onset.²⁴ A cross-sectional study by Laursen suggested that shorter amount of sun exposure during adolescence as well as higher body mass index (BMI) at the age of 20 years were associated with an earlier age of onset of MS.²⁵ Increased time spent in the sun during childhood has also been shown to be associated with decreased risk of MS.²⁵ Exposure to sunlight is the major source of vitamin D for many people. Sunscreen use has increased, so there is less UVB absorption. In addition, people with MS are likely to spend more time indoors because of heat sensitivity, as heat can often exacerbate symptoms. UVB radiation converts cutaneous 7 dehydrocholesterol to previtamin D3, which isomerizes to vitamin D3. Vitamin D3 hydroxylizes first to 25 hydroxyvitamin D3 (25(OH)D3) and then to 1,25, dihydroxyvitamin D3, which is the biologically active hormone. At higher latitudes, >42°N, very little vitamin D is absorbed by the skin because most UVB is absorbed by the atmosphere, especially in the winter months.²⁶ One recent study examining Finnish women of reproductive age showed that women who had deficient levels of vitamin D (i.e., <30 nmol/L) had a 43% higher risk of MS compared with women who had adequate levels of vitamin D (i.e., >50 nmol/L).²⁷

Average diet and supplement intake in the United States is <400 IU/d. Studies done in vitamin D-deficient mice treated with vitamin D supplements have shown induction of regulatory T cells. Reduction in risk for developing MS with 25(OH)D levels > 100 nmol/L was stronger before the age of 20 years than at age 20 years or older.

Vitamin D supplementation and increase in blood levels are also beneficial in patients who already have the disease. Serum levels tend to increase by 0.8 to 1 nmol/L for every 1 µg ingested. In a study done by Munger et al examining vitamin D levels and MS risk, among whites, there was a 41% decrease in MS risk for every 50 nmol/L increase in 25 hydroxyvitamin D.²⁸

Stress and Trauma

Regarding physical trauma and its association with development of MS, studies have not shown evidence to support a relationship between MS and trauma. The relationship between MS and psychologic or emotional stress, however, is possible.¹ An MRI prospective study done by Mohr et al. looked at life stress and new brain lesion formation. It reported that new MRI lesions increased after a lag of 8 weeks following increase in stress such as family or job conflict or changes in routine but not after major stressful events and that the MRI changes were not associated with clinical changes.²⁹

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