A viral infection can initiate an immunological cascade, which – after a latency period – can trigger MS.5 The strongest known viral risk factor is infection with EBV. There is a dose–response relationship between MS risk and antibody titer – especially antibodies to the EBV nuclear antigen-1.6 Compared with uninfected individuals, the hazard of developing MS is approximately 15-fold higher among individuals infected with EBV in childhood and about 30-fold higher among those infected with EBV in adolescence or later in life.7

There are differences in EBV activity between risk of RRMS and PPMS, with higher antibodies to EBV more commonly associated with RRMS than with PPMS.2 A five-year longitudinal study examined the sera of 25 RRMS and 25 PPMS patients and found significantly increased median titers of anti-EBV nuclear antigen-1 (EBNA-1) IgG in RRMS, compared to PPMS.8 Another study comparing 46 RRMS, 11 SPMS, and 21 PPMS patients found seroprevalence to anti-EBV IgG levels to be significantly higher among RRMS and SPMS patients, compared to PPMS patients.9

Cigarette Smoking

There is a dose-response effect between cigarette smoking and increased MS susceptibility, as well as more rapid disease advancement. The relative risk for MS development is approximately 1.5 for smokers compared with nonsmokers.10 Unlike EBV, however, there appear to be no significant difference between RRMS and PPMS, in the impact of cigarette smoking.2,11,12

The impact of smoking on patients being treated with immunomodulatory therapy (IMT) is controversial.  A recent study found no correlation between smoking and disease progression, or formation of anti-IMT neutralizing antibodies in IMT-treated patients. The authors admit that these results “conflict with previous studies,” noting that further research is needed.13