Elsevier

Neurologic Clinics

Volume 29, Issue 2, May 2011, Pages 233-255
Neurologic Clinics

Individual and Joint Action of Environmental Factors and Risk of MS

https://doi.org/10.1016/j.ncl.2010.12.007Get rights and content

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A causal pie model for multiple sclerosis

MS is a complex multifactorial disease wherein a variety of environmental and genetic factors interplay to manifest in the clinical disorder recognized by all neurologists. Rothman’s “Causal Pie Model”1 is a useful framework to understand this interplay of etiological factors, allowing a structure wherein individual components can act together to cause disease. These components may be simplified as “slices of a pie” (Fig. 1), with a given causal mechanism requiring the joint action of many

Epstein-Barr virus

Infections are usual suspects among potential etiological factors in autoimmune disease, thought to act by molecular mimicry, for example, Campylobacter and Guillain-Barré syndrome, or by passive changes in immune modulation. EBV is the only viral agent with convincing and consistent evidence for an association with MS onset. EBV is a member of the Herpesviridae group. Whereas primary EBV infection in childhood is normally asymptomatic, infection at or after adolescence often results in

Sun exposure/vitamin D

It has long been recognized that MS has a distinct geographic variability in its distribution, with the frequency of MS increasing with increasing latitude,29, 30 and this gradient has been borne out in meta-analyses of MS prevalence and incidence.31, 32 Of interest, a recent study conducted in Australia found a latitudinal gradient in the incidence of first demyelinating events, with the incidence rate increasing by 9.55% per degree increase in latitude.33 Although differences in allele

Smoking

A large number of studies, including prospective studies,98, 99, 100, 101 have found a positive association between smoking and MS. The results have been very consistent in that few have reported a null finding and none an inverse association. The magnitude of effect is modest, with a 2007 meta-analysis of 6 epidemiologic studies finding a pooled estimate for ever smoking versus never smoking of 1.34 (1.17–1.54).102 Of note, the 3 retrospective studies provided a slightly stronger risk estimate

Infections as a protective factor

Infections might also play a protective role. Bach119 demonstrated that the increased incidence over time of autoimmune and allergic diseases such as MS, type 1 diabetes, Crohn disease, and asthma coincided with the decrease in incidence of measles, mumps, rheumatic fever, hepatitis A, and tuberculosis. These observations might be related to infection load during early childhood. In atopic disease, there is evidence for the so-called Hygiene Hypothesis, where increased hygiene and smaller

Other factors

Several studies have investigated the relationship between human herpes virus (HHV)-6 and MS, but the results have been mixed. A systematic review of the literature between 1965 and 2001, which included 28 studies of serum, CSF, and/or pathology for the presence and quantity of serologic and/or direct evidence of HHV-6 infection, found no conclusive evidence of a difference in HHV-6 infection between cases and controls and thus, no association between HHV-6 and MS.126 Subsequent studies have

The joint action of risk factors

Recently, an increasing number of research groups has examined the combined action of 2 or more risk factors. In the most general sense, two risk factors are said to interact with one another if the effect of the first factor on disease risk depends on the level of the second factor, and vice versa. For gene-environment interaction, attention has largely focused on the major genetic risk factor HLA-DR15. Thus, the effect of an environmental exposure on MS might depend on whether a person is

Summary

The etiology of MS is a complex story with multiple factors playing a role at different times during life, interacting with each other to ultimately manifest in MS. Using the Rothman Causal Pie Model helps demonstrate that the way these factors come together to cause disease is somewhat idiosyncratic, with different individuals having different paths to disease; this complicates the task of epidemiologists. Defining causal associations is only a part of the whole equation. Knowing how causal

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      Although a recent study has questioned whether the season/month of birth effect in diseases such as MS is actually an artifact, or chance finding, related to natural variation in both regional and temporal months of birth in any underlying (control) population (Fiddes et al., 2013). Much discussion has surrounded the possible timing of environmental exposures after birth which might trigger MS onset, with no definitive answers (Handel et al., 2010b; van der Mei et al., 2011). Evidence from studies included in our review suggested that early childhood through until adolescence represent ‘at risk’ periods, with increased sun exposure, vitamin D intake or exposure to infant siblings during these times associated with a reduced risk of multiple sclerosis (Islam et al., 2007; Dalmay et al., 2010; van der Mei et al., 2003; Ponsonby et al., 2005; McDowell et al., 2010).

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    Financial disclosures and/or conflicts of interest: The authors have nothing to disclose.

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