Environmental Risk Factors for Pediatric Multiple Sclerosis
A higher prevalence of anti-EBV-VCA antibodies in adult MS patients, as compared to healthy controls, was described in a US study in 1976.86 Although this initial study did not reach statistical significance, an expansion of the study to include 157 adult-onset MS patients and 81 control subjects found anti-EBV-VCA antibodies to be significantly more prevalent in MS patients (98.7%) compared with controls (93.8%), with higher geometric mean titers of EBV-VCA antibodies significantly elevated in MS patients.87
Many subsequent studies have reported that
adult MS patients are more likely than control subjects to have both anti-EBV-VCA and EBNA antibodies with elevated titers.82,88–95 Seroprevalence studies show that nearly 100% of adult-onset MS patients compared with 95% of controls have antibodies for one or more EBV antigens with an odds ratio for MS in seronegative compared with seropositive individuals of 0.06 (95% CI 0.03–0.13).9
In childhood, three case-control studies have shown that EBV seropositivity is more common in pediatric-onset MS patients than in healthy age-matched and regionally matched children. A single-center Canadian study reported that serologic evidence of remote EBV infection was present in 83% of children with MS (n=30) compared with 42% of healthy age-matched controls (n=90, OR 8.7, 95% CI 2.5–30.3; p<0.01).96
A
multinational study that enrolled children with MS and matched controls from Canada, the US, South America, and Europe reported serologic evidence of remote EBV infection in 86% (108 of 126) of children with MS compared with 64% (61/96) of control participants (p=0.025).39
Among
seropositive children, mean EBNA1 titers in 73 children with MS were significantly higher than in 54 EBV-positive children without MS (187.4 ± 59.5 versus 152.5 ± 70.1; p=0.006).39
The association of remote EBV
infection and pediatric MS was further strengthened by a German study of 147 children with MS and 147 paired sex- and age-matched controls in which remote EBV infection was more common in MS patients than in healthy controls (84 versus 56%; p=0.0033).97
Median anti-EBV-VCA and
anti-EBNA1 antibody titers were significantly higher in seropositive MS patients compared with seropositive control children (anti-EBV-VCA 62 versus 44; p=0.0002; anti-EBNA1 36 versus 14; p=0.003). To date, none of the pediatric MS studies have found differences in seroprevalence rates for other common childhood viruses studied, including herpes simplex virus, cytomegalovirus, varicella zoster virus, or Parvovirus B19.
In adults with established MS two studies have demonstrated active EBV replication during relapses but not during periods of clinical quiescence;98,99
however, two others have not.88,100 A multinational study
of childhood MS found no correlation between mean relapse rates and EBV seropositivity (mean relapse rate in EBV positive patients of 1.18 ± 0.7 versus mean relapse rate in EBV negative patients of 1.01 ± 0.6; p=0.49), but these results may have been confounded by age.39
Anti-EBV antibody titers may correlate with disease activity on MRI. A recent study of 50 adults with MS showed that anti-EBV-VCA antibody titers were inversely correlated with MRI measures of gray-matter atrophy in the following three years.101
A study from the UK of 50
patients with a clinically isolated syndrome (CIS), 25 patients with relapsing–remitting MS (RRMS), and 25 patients with primary-progressive MS showed that participants with at least one gadolinium-enhancing lesion on MRI had higher median EBNA1 titers than those who did not (791 [95% CI 414–1704] versus 251 [95% CI 82–599]; p<0.001). There was
US NEUROLOGY
also a positive linear correlation between EBNA1 IgG concentration and number of gadolinium-enhancing lesions (Spearman r=0.33; p<0.001).102
Pathobiologic Insights
The underlying biological mechanisms responsible for the observed epidemiologic associations between MS risk and EBV infection remain to be fully explained. Several studies in adults have shown elevated levels of intrathecal anti-EBV-VCA antibodies,91
anti-EBNA1 antibodies,103 antibodies directed against the EBV protein BRRF2 in MS patients.104
and EBV
may influence MS pathogenesis through cellular immune mechanisms. A study of 20 EBV seropositive MS patients and 20 seropositive healthy controls showed an increased frequency of memory CD4+
T cells,
Several studies have noted T-cell cross reactivity between EBV antigens and autoantigens, including myelin basic protein.106–109 These results would support the hypothesis that there is cross-reactivity between EBV viral epitopes and self-antigens.110
enhanced proliferation of CD4+ cells, and increased production of the proinflammatory cytokine interferon gamma in samples from MS patients.105
Other Viruses
There has been interest in other potential viral etiologies for MS, including varicella zoster virus (VZV) infection.9,111,112
Several case-control
but the young age of VZV acquisition leads to a high seroprevalence rate even in healthy children. A French study of 137 children with clinically definite MS and 1061 matched control children found that a history of clinical chickenpox was present in fewer children with MS compared with healthy controls (76.6 versus 84.9%; adjusted OR 0.58, 95% CI 0.36–0.92).115
studies in children have largely shown no differences in the presence of anti-VZV antibodies in serum or CSF between children with MS and controls,39,96,113,114
We would hypothesize that the
lower frequency of VZV infection in pediatric MS patients indicates limited exposure to childhood infections and that delayed exposure to common infectious agents could render an individual particularly prone to aberrant immune responses to other key environmental triggers such as EBV. Recent VZV vaccination also confounds studies of VZV infection rates in pediatric MS.
Cigarette Smoke Epidemiology
Increased risk for adult-onset MS in individuals who report a history of smoking has been found in several case-control and prospective studies116–121
A meta-analysis of six retrospective and prospective studies reported a pooled odds ratio of 1.34 (95% CI 1.17–1.54) for MS in smokers versus non-smokers.122
and the relative risk for MS in patients with a past or current smoking history versus those with no smoking history has been estimated to be 1.2 (95% CI 0.9–1.6) and 1.4 (95% CI 1.2–1.7), respectively.11
A French study of 129 children diagnosed with MS before 16 years of age and 1,038 matched population controls reported exposure to parental smoking in 62% of children with MS compared with 45.1% of control children (adjusted relative risk for MS 2.12, 95% CI 1.43–3.15).123 When stratified by age, adjusted relative risk for children over 10 years of age (2.49, 95% CI 1.53–4.08) was higher than that for children under 10 years of age (1.47, 95% CI 0.73–2.96), which may reflect a longer duration of exposure.
99
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