For unclear reasons, the incidence of MS is two to three times higher in women than in men, but it is largely thought to be due to the higher susceptibility of women to autoimmune and inflammatory diseases. Although the etiology of MS remains unclear, there have been a number of established epidemiological associations. While its prevalence is reported as 1 per 100,000 in equatorial areas of the world, it increases to 6 to 14 per 100,000 in the southern US and Europe; 30 to 80 per 100,000 in Canada; northern US and northern Europe and as high as 177 per 100,000 in Minnesota; suggesting a gradient in the Northern hemisphere [4]. Recent research suggests that MS might be associated with the lack of sun exposure and reduced levels of vitamin D [5] which could partially explain the latitudinal gradient. Analysis of groups that had migrated from high to low prevalence zones suggests that at least part of the risk for developing MS depends on when the migration occurs. It has been observed that people who immigrate before the age of 15 have the same risk as people born in that area, whereas people who immigrate at a later age retain the risk associated with the region of their birthplace [6]. Although it has been suggested that possible exposure to various infections including specific viral agents is a risk factor for the development of MS, no studies have shown relevant evidence of a possible culprit [7].

Familial aggregation and heritability have also been implicated in multiple studies, with observed higher prevalence of MS in full siblings when compared to half siblings [8], as well as in monozygotic versus dizygotic twins. A genetic component is further supported by the presence of increased frequency of certain histocompatibility locus antigen (HLA) subtypes within patients with MS, namely HLA-DR6 and HLA-DR2, which are thought to be markers for “MS susceptibility” [7]. Although the presence of these HLA types is not specific for MS, those who have these genetic markers have an increased risk of developing MS by three- to fivefold [7].

Given the higher predisposition observed in patients with pars planitis to develop MS, Raja et al. evaluated a group of 53 patients with pars planitis looking for MS prevalence as well as possible genomic associations. Of 37 patients with pars planitis who underwent neurologic evaluations, 6 (16.2 %) developed multiple sclerosis. The HLA-DR15 allele, coding for one of the two HLA-DR2 subtypes, was associated with pars planitis (odds ratio = 2.86, P = 0.004). In addition, there was a suggestion that the association with HLA-DR15 was greater in patients with both pars planitis and multiple sclerosis, with three of the five patients with multiple sclerosis, pars planitis, and HLA typing expressing the HLA-DR15 allele [9].

Traditionally, MS was diagnosed after a patient experienced two separate clinical attacks in two distinct areas of the CNS separated by at least 6 months. Today, the diagnosis is based on the widely accepted McDonald criteria in which MRI brain imaging and/or spinal fluid analysis can serve as objective clinical evidence of the disease [10]. A recent revision of this criterion by Polman et al. [11] includes the advent of refined neurological imaging, in which the presence of older lesions identified by MRI is adequate to satisfy this criterion, and the physician does not necessarily need to wait for new clinical events to establish the diagnosis of MS.

Retinal venous sheathing in association with multiple sclerosis (Fig. 29.2) was first reported by Rucker in 1944 and subsequently followed by case reports describing similar findings [12]. Archambeau et al. [13] in 1965 reported the presence of vitreous cells in 10 patients with multiple sclerosis. One year later Breger et al. [14] evaluated patients with uveitis and MS and described retinal vein exudation associated with retinal ischemia and neovascularization.

Nearly two decades later Arnold et al. [15] described autopsy findings in 47 MS patients, including granulomatous retinal periphlebitis in four cases (7 eyes) and focal lymphocytic or granulomatous retinitis in three cases (5 eyes). Chester et al. [16] evaluated a cohort of 51 patients with pars planitis and found eight (16 %) cases of demyelinating disease (MS or optic neuritis), although the timing of the diagnosis in relation to the uveitis is unclear. Additional larger case series have continued to demonstrate the relationship between MS and ocular inflammation, particularly chronic anterior uveitis, intermediate uveitis, and retinal vasculitis [17].

Multiple population studies have investigated the prevalence of uveitis and other ocular disorders in patients with MS with varying results.

One large retrospective study of 4300 patients using the Lyon MS database found 28 patients with uveitis, with a prevalence of uveitis of 0.65 % (28/4300). Uveitis preceded the onset of MS in 46 % of the patients, occurred simultaneously in 18 % and presented following the diagnosis of MS in 36 % of cases. The area of ocular involvement and timing of uveitis were not associated with any significant difference in MS course and prognosis. There was also no difference in the course and prognosis of the CNS disease in patients with or without uveitis. The prevalence of uveitis (from all causes) in that local area was reported as 38 cases per 100,000; uveitis was 17 times more common in MS patients when compared to the general population [18].

A smaller prospective study performed in Croatia followed 42 patients with multiple sclerosis and identified intermediate uveitis in 28.5 % of these patients. This is a much higher prevalence of uveitis than previously reported in other published reports. This population also included a high number of patients with optic neuritis as a manifestation of MS. It was unclear why this cohort of patients had significantly greater ocular manifestations [19].

The neuro-ophthalmology group from Emory University evaluated patients in two large clinics, one with MS patients and the other with uveitis patients, and identified 28 patients with concomitant disease (20 women and 8 men; mean age, 47 years; range, 28 to 67 years) out of a total of 2628 patients (1 %). The mean age at onset of neurologic symptoms was 34.2 years (range, 15–55 years). MS was relapsing remitting in 19 of 28 patients (67.8 %), secondary progressive in 8 of 28 patients (28.6 %), and primary progressive in one patient [20].

A German uveitis center performed a similar retrospective evaluation of 1916 uveitis patients and found 3.1 % to also have MS. Of those, 74.6 % were female, highlighting the gender disparity of the underlying autoimmune disease [21].

Zein et al. evaluated 1254 patients with uveitis at a large tertiary care center in Boston and reported 16 cases of MS (0.013 %). Most of the patients with MS-associated uveitis were white females (88 %) between 20 and 50 years of age. The onset of uveitis fell within 5 years of the diagnosis of MS in 63 % of the patients; nine had MS diagnosed prior to the onset of uveitis by an interval of 1–19 years. Uveitis and MS were diagnosed concurrently in three patients. Interestingly, they have also observed that optic neuritis was one of the most common neurological manifestations, present in 44 % of those patients [1].