Mitchell T.Wallin, MD, MPH––Associate Director, Clinical Care,VA MS Center of Excellence–East, Associate Professor of Neurology, Georgetown University; John F. Kurtzke, MD––Professor Emeritus of Neurology, Georgetown University, Distinguished Professor of Neurology, Uniformed Services University of the Health Sciences, Consultant in Neurology and Neuroepidemiology,VAMC–Washington, DC

Introduction

Despite decades of research, the cause for multiple sclerosis (MS) remains unknown. Evidence points to one of several environmental agents that may trigger the disease in a genetically susceptible host. Epidemiologic studies have been helpful in discovering risk factors that are associated with developing MS as well as risk factors that influence the morbidity and mortality of the disease. Well-established risk factors for developing MS include female sex, white race, and high socioeconomic status (Wallin & Kurtzke, 2004). Each of these factors produces roughly a two-fold increased risk for developing MS. Recent research on the etiology of MS has focused both on genetic susceptibility and environmental susceptibility. The goal of this article is to briefly review some of the recent risk factors that have been highlighted in the literature.

Environmental Susceptibility in MS

Support for environmental susceptibility in the development of MS has come from a variety of sources. One such factor is the stratified worldwide prevalence of MS, which appears to be changing. The general worldwide distribution of MS may be described within three zones of frequency or risk: 1) a high-risk zone, with prevalence rates of 30 per 100,000; 2) a medium risk zone with prevalence rates between 5 to 29 per 100,000, and 3) a low prevalence zone with rates below 5 per 100,000. In the earlyto mid-20th century, a north-south grandient in MS prevalence was reported in the US and Europe. High prevalence regions included northern and central Europe into the former Soviet Union, the northern US, and Canada. This gradient has been shown to be diffusing in recent decades in the US, with higher risk for developing MS now in southern states (Wallin, Page, & Kurtzke, 2004—see Table 1, pg. 11) and in Europe, with higher risk for developing MS in Mediteranean countries (Kurtzke, 2005). While previously reporting prevalence rates within the low risk range, MS prevalence rates within Africa and South America appear to be increasing in recent years. When examining prevalence by sex, it is of interest that a number of studies have reported higher prevalence rates for women. These prevalence changes, however, have been observed within one or two generations, which is much too quick for genetic influence to be operative.

Several epidemics of MS have been reported in the literature. If there is evidence for a true outbreak, it is strongly suggestiveof an environmental agent that is operative in initiating MS. The best described epidemic of MS occurred in the Faroe Islands in the North Atlantic Ocean. As of 1998, 54 native resident Faroese were confirmed with onset of MS in the 20th century. There were none before 1943, but between 1943 and 1949, 17 patients had symptom onset in this populace of less than 30,000. The 17 with onset between 1943 to 1949 were then joined by four more of that age, whose onset was 1950 to 1961. These 21 patients constituted a type 1 point source epidemic of MS. Annual incidence rates rose steeply from 0 to over 10 per 100,000 in 1945, and then fell almost as steeply with a short tail. The other 33 patients were divided by when they too reached age 11, and in this way provided three more (type 2) epidemics of 10, 10, and 13 patients each. While there have been some challenges to the validity of this epidemic (Poser, Hibberd, BeneBenedikz, & Gudmundsson,
1988), the original investigators assail their thorough examination and confirmation of all MS cases, and the meticulous medical records and surveillance programs kept on the Faroese population through the Danish health system over the past century.

If the risk of MS is altered by a change of environments, MS must be largely driven by exogenous factors. In a number of studies of MS in migrants, there was a tendency for immigrants to retain much, but not all, of the risk of their birthplace. Evidence has supported that low- to high-risk migrants can increase their risk of MS (Martyn & Gale, 1997). On the other hand, more studies have shown changes in MS morbidity when moving from a high prevalence zone, to a low MS prevalence zone.

The influence of genetic and environmental risk factors were explored in a recent article examining prevalence of MS in new immigrants to Israel (Alter, Kahana, Zilber, & Miller, 2006).

Genetic Susceptibility in MS

A number of lines of evidence support genetic susceptibility for developing MS. Twin studies are a classic method to determine the influence of genetics on a particular disorder. One often measures the concordance rate in dizygotic and compares this rate to monozygotic twins. Concordance as used in genetics refers to the presence of the same trait in both members of a pair of twins, or in sets of individuals. The difference in concordance rates between monozygotic and dizygotic twins is primarily attributable to genetic factors. The maximum concordance rate for MS in monozygotic twins is 25% to 30% while the dizogotic twin concordance rate is 2% to 5% (Oksenberg & Hauser, 2005; Ebers, Sadovnick, & Risch, 1995). This indicates that although genes play a role in MS, the
maximal effect of genes is at most 30%.

The general population prevalence for MS is approximately 0.1%. This is in contrast to the familial MS recurrence risk for primary relatives: parents–3%, daughter –5%, son–1%; which is in turn slightly higher than that for extended relatives: uncles/aunts–2%, nieces/nephews–2%, first cousins–1% (Ebers, et al. 1995). The higher rate in MS prevalence for primary relatives compared with the general population implies genetic factors are operative. There continues to be a dilution of risk for MS with half-siblings: maternal or paternal half sister (1.3%–1.6%) and maternal or paternal half brother (0.5%–0.6%). As seen in the general population, a differential sex risk in familial recurrence exists with women having higher risk than men.

MS is considered a genetically complex disease with several genes likely involved in conferring risk. Family genetic linkage analysis has been performed in three large studies published over the past 10 years (Oksenberg, 2005). Over 60 candidate genomic regions have been identified. There has been consensus from these linkage analyses that the major histocompatabilitylocus is involved in MS. The HLA DR2 region on Chromosome 6p21.3 is felt to explain 15% to 60% of MS susceptibility. Other candidate regions that may be involved in genetic risk include chromosome 19q13 and chromosome 17q21-23.

Admixture mapping is novel technique used to localize disease-causing gene variants that differ in frequency between two historically separated populations. Near a gene that may predispose to a disease, patient populations descending from the recent mixing of two or more ethnic groups should have an increased probability of inheriting the alleles derived from the ethnic group that carries more disease susceptibility alleles. The African American population has had recent mixing of their gene pool making them an ideal population to study with this technique. Using the admixture mapping in a study sample of 605 African Amercan patients with MS and 1,043 controls, Reich and colleagues identified locus of genetic susceptibility on Chromosome 1 associated with MS (Reich et al., 2005).

Vitamin D and Sunlight

Vitamin D has a number of effects on the body, mediating cell maturation, calcium homeostasis, and immune system responses. Vitamin D is converted to its hormonally active form 1, 25-dihydroxyvitamin D3 through sunlight exposure in the skin and subsequent hydroxylation in both the liver and the kidney. In MS, Vitamin D is felt to be protective through its immunomodulating effects such as promoting antiinflammatory cytokines, stimulation of Th2 cells and inhibition of pathologic Th1 cells. Through decreased sun exposure or inadequate intake, Vitamin D deficiency states may increase the risk for MS or alter the course of the disease.

Patients with MS have been shown to be deficient in Vitamin D (Nieves, 1994). Vitamin D supplementation for 1 to 2 years was associated with a decrease in relapses and MS progression in one study (Goldberg, Fleming, & Picard, 1986). Munger and colleagues used dietary questionairres to prospectively assess information on Vitamin D intake in a large cohort of US Nurses (Munger et al., 2004). Women with the highest intake of Vitamin D had a 30% decreased risk for developing MS compared to women with the lowest intake.

Apart from its role in Vitamin D synthesis, solar UV light has immunosuppresive effects on the cell mediated immune system. Because MS is felt to be an autoimmune disease primarily mediated by patholgic T-cells, some investigators have proposed that the latitude gradients seen in MS may be reflective of differential exposure to sunlight. Ecologic studies have shown a negative correlation between UV radiation and MS prevalence (Van der Mei, Ponsonby, Blizzard, & Dwyer,
2001). Goldacre and colleagues used skin cancer as a surrogate for high sun exposure in a case-cohort study (Goldacre, Seagroatt, Yeates, & Acheson, 2004). Skin cancers were less common in patients with MS compared to matched controls and were found to be significantly protective in the development of MS.

Regarding MS morbidity, there is some evidence to suggest that UV light may be associated with a more aggressive course. Patients with MS in Los Angeles, CA progressed to higher disability levels and death more quickly than patients with MS in Seattle, WA (Detels et al., 1982). Tsunodo used an animal model of MS to evaluate the effects of UV light on both the development and progression of experimental allergic encephalomyelitis (EAE) (Tsunodo, Kuang,Igenge, Fujinama, 2005). UV radiation decreased the incidence of EAE, but it also increased the risk for conversion from a relapsing to a progressive form of EAE. This finding needs confirmation, but suggests that UV radiation may have a negative effect on MS morbidity.

While several studies have supported the Vitamin D and sunlight hypothesis in MS, there is some conflicting evidence. Firstly, migration studies have shown that populations can alter their risk for MS by moving within similar latitudes. Secondly, geographic gradients in the US and Europe are diffusing with time. Regions closer to the equator with greater sunlight exposure are reporting higher MS prevalence rates. Finally, high socioeconomic status is a risk factor for MS. One would expect such populations to have sufficient Vitamin D supplementation in Western societies and therefore be somewhat protected.

Smoking and MS

There is growing evidence that smoking may increase the risk for developing MS and negatively impact the disease course. Smoking has been associated with worsening MS symptoms in isolated case reports. Casecontrol studies have produced variable results, but tend to support an increased risk for MS among smokers. Proposed mechanisms that may be implicated in the association between MS and smoking include immunomodulation, cyanide toxicity, free radical formation, and an increased risk for infection in smokers.

Two prospective studies based in the UK found an elevated relative risk for developing MS in individuals smoking greater than 15 cigarettes per day (Villard-Mackintosh & Vessey, 1993; Thorogood & Hannaford, 1998). The results, however, were not statistically significant. Using the Nurses Health Study II, Hernan and colleagues found a 60% increased rate of developing MS among current smokers compared to never smokers (Hernan, Olek, & Ascherio, 2001). These results did reach statistical significance. Corroborating evidence for an increased risk for MS in smokers was found in a nested case control study based in the UK showing a 30% increased risk in ever versus never smokers (Hernan, 2005). This same study showed that ever versus never smokers had a 3.6-fold higher risk for converting from relapsing-remitting MS. These prospective studies are less prone to bias compared to association studies and case-control studies and offer support for the associaton between smoking and development of MS. More research in this area needs to be done to show cause and effect relationship between smoking and MS.

Viral Triggers and MS

Viral infection has long been proposed as a mechanism to trigger MS in a susceptible host. Similar to polio, MS may be precipitated by a widespread infection acquired in childhood or adolescence with the risk of acquiring disease increasing with higher age of infection. Several lines of evidence support a viral hypothesis in MS. Firstly, there are high concentrations of antibodies produced in the cerebrospinal fluid in patients with MS. While the target of these antibodies is still unclear, it suggests a response to an underlying infection. Secondly, most chronic inflammatory diseases of the central nervous system are infections. Finally, viruses are associated with demyelination in humans (e.g., acute demyelinatingencephalomyelitis) and animals (e.g., Theiler’s virus infection in mice).

A number of viruses have been implicated in MS including HTLV-1, measles, mumps, Canine distemper, and Corona viruses. Many viral associations with MS have been disproven, however, by well-controlled studies. Interest in viruses within the herpes family remains high due to their ubiquitous nature and neurotropism. The Epstein-Barr virus (EBV) and Human Herpes virus 6 are two viruses within the Herpes family that have received recent attention in the literature.

EBV is the virus that causes mononucleosis. It is acquired in childhood or adolescence and the general population has a 90% to 95% positive seroprevalence. Patients with MS uniformly have EBV antibodies in their serum. Because EBV infection in the general population is so common, showing a differential change in antibody titers in MS compared to controls can be challenging. A recent meta-analysis of 14 studies showed a highly significant risk (Relative Risk: 2.3) for devloping MS based on history of EBV infection (Thacker, Mirzaei, & Ascherio, 2006). A history of infectious mononucleosis based on a questionaire interview was associated with a two-fold increased risk for developing MS in the Nurses Health Study. An interesting study utilizing pre-illness serum on patients with MS demonstrated a significant antibody rise in EBV antibody titers prior to the onset of MS (Levin, 2005). These studies suggest EBV is associated with MS, but it remains unclear if EBV is causative or simply being reactivated with the onset of MS.

HHV-6 is a double stranded DNA virus and was initially isolated in 1986. There are two forms of the virus: HHV-6A and
HHV-6B. HHV-6B is the causative agent of the common childhood disease roseola. HHV-6A has been associated with MS. A recent review found 13 of 29 studies that support significantly higher levels of HHV6 DNA (serum, CSF, and brain) in MS compared with controls (Fotheringham & Jacobson, 2005). Five of nine antibody studies (serum and CSF) were also supportive of higher titers in patients with MS compared to controls. A variety of techniques were used to measure HHV6 antibodies and DNA which likely produced some of the variation in studies. Simliar to EBV, it is unclear if the detection of HHV6 DNA implicates a direct association with MS or merely reactivation of previous HHV6 infection within brain and immune cells. More research using more powerful molecular detiction techniques and larger MS study populations will be needed to confirm these results.

Summary
Environmental risk factors continue to be important in understanding the etiology of MS. While genes play a role in determining MS susceptibility, current evidence supports the dominance of environmental triggers initiating the disease. Recent studies have shown smoking, vitamin D deficiency, and lack of sunlight to be associated with MS onset. There is solid support for viral triggers in MS and hopefully improved molecular techniques will help to confirm one or more viruses as a risk factor. To explore the role of both genetics and environmental factors in MS susceptibility, larger longitudinal studies will be required. A better understanding of MS suscceptibility factors will ultimately lead to improved treatments and prevention of the disease.

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