To yield useful data epidemiological studies must be carried out by trained personnel in large populations with good access to good medical care. A number of good studies have been performed, and there is evidence indicating that incidence rates for MS may be increasing.

Age and Sex Distribution Multiple sclerosis of the relapsing-remitting type is more common in women, about 70% of all patients in most recently studied populations, including our large southern population, with onset of illness in both sexes by the age of 30 in two-thirds [11]. Primary progressive MS is slightly more common in men and typically begins in midlife.

Incidence of MS Incidence is the rate of occurrence of newly diagnosed (MS) cases per unit of population (usually described per million) per time period, usually reported on an annual basis. The incidence of MS is relatively low (1-5 per million) but seems to have increased over the last century [11]. In the United States the most useful current data comes from Olmsted County, Minnesota, where the incidence rate increased during the last century from two per million to three times that incidence [11].

A number of confounding factors influence incidence figures. Over the last half century, there has been a dramatic increase in the number of trained neurologists. With the advent of effective therapies, more neurologists are interested in MS and many trained in this subspecialty. Consistent easily interpreted diagnostic criteria, and improved diagnostic testing (especially MRI), have greatly facilitated making the diagnosis. Undoubtedly, these factors partly account for the apparent increased incidence of multiple sclerosis. If we can extrapolate from the experience of neuropathologists, and as reported from Stanford, 1-2% of postmortem examinations reveal tissue evidence of “demyelinating disease” in the absence of a clinical history [66, 67]. It is possible that now, given the availability of neurologists, the increasing awareness of MS, and the diagnostic facilities available, many clinically undiagnosed cases in the past would be labeled as having MS.

Despite the low incidence of MS, this illness is the most common cause of chronic disability in young adults because of the minimal impact on the longevity currently. The observations in Olmsted County, Minnesota, clearly indicate a real increase in the incidence, as well as its prevalence, of MS [9].

It is often stated that there are 250,000-350,000 MS patients in the United States [11]. Figures currently used, however, are not based on any current national epidemiological studies. When prevalence figures were reported to be low for the Southern United States, except for California, there were no neurologists in the South. In Florida, for example, the first neurologist established a practice in Florida in 1953 but then entered the military service, a situation similar to many other areas in the South. The appearance of neurologists in the South since that time, as in virtually all under-serviced communities in the United States, is bound to have had a dramatic impact on the recognition and diagnosis of nervous system disease, especially MS. The impact of MRI on the recognition of neurological disease has been dramatic, especially for MS. Considering the increased availability of neurological consultation, improved diagnostic criteria and the availability to MRI, and improved CSF examination, that larger numbers of MS patients will be recognized in life. The quoted prevalence of MS appears to be unrealistically low.

Environmental Factors Myriad environmental risk factors for MS have been studied with varying degrees of validation. The most robust data supports the association of prior Epstein-Barr virus infection and smoking and development of MS [68]. The significant detrimental effect of smoking has been identified in numerous studies, with a dose-response relationship [69, 70]. Previous infection with EBV and high antibody titers to Epstein-Barr early nuclear antigen are well- established risk factors for MS, especially when contracted as an adolescent or young adult [71, 72].

Other epidemiological factors, which may be associated with an increased risk of MS, include increased salt intake. Kleinewietfeld et al. demonstrated that elevated sodium chloride concentrations in human (dietary) and mouse (tissue culture followed by studies of dietary intake) models increase proinflammatory Th17 cells [73, 74]. Vitamin D may be an early predictor MS activity and progression, though identification of the optimal Vitamin D supplementation strategies remains undetermined [75]. Unpublished follow-up data beyond 10 years of Aschiero’s study group of vitamin D shows maintenance of long-term benefit with vitamin D levels greater than 50 nmol/L. High-dose supplementation with 10,400 IU cholecalciferol daily has been reported as safe [76]. Adolescent obesity, defined as a BMI of > 27 kg/m2 at age 20, is associated with a twofold increased risk of developing MS. Further study has indicated an interaction between adolescent obesity and HLA risk genes in MS [77, 78].

There is a geographical pattern distribution of MS, with higher disease incidence in higher latitudes, though this has become less apparent in recent years in the setting of globalization [79]. In this context, the “hygiene hypothesis” was introduced by Strachan in the 1980s. It proposes that persons with less exposure to microbes early in life are more likely to develop autoimmune disorders, including MS [80]. This hypothesis has fallen out of favor, however, as a result of several studies evaluating MS incidence and helminthic infection, and the role of the gut micro- biome in MS has become a focus of research. Nonpathogenic intestinal microflora may be mediators of autoimmunity in MS [81-85]. There is no longer evidence for a north-south gradient for MS in the United States.

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