To the Editor:
In a recent paper, Marrie et al.1 used a case-control methodology to investigate a possible relationship between MS and infectious mononucleosis (IM). The study involved 225 subjects with MS and 900 controls matched for age, sex, and physician practice, with all subjects being from the United Kingdom. Marrie et al., on the basis of a significantly higher rate of IM in cases (5 of 225) than in controls (6 of 900), interpreted that contracting IM is a risk factor for MS.
I believe that their data are not sufficient to draw such a conclusion. Infection with Epstein-Barr virus (EBV), regardless of timing, is a putative risk factor for MS because almost all persons with MS have been previously infected with EBV.2,3⇓ Experimental work has revealed that EBV could theoretically participate in MS etiology by providing one or more molecular mimics of myelin antigens.4,5⇓ Thus, a previous infection with EBV, regardless of an early or late IM timing of the infection, is enough to explain the occurrence of MS in the cases. A standard case-control study cannot provide further insight into specifics of an EBV infection for affecting MS risk.
To investigate whether timing is a significant part of the EBV risk factor, it would be necessary to have controls and cases who are all genetically susceptible to MS and had also all been previously infected with EBV. Then, and only then, could a worthwhile conclusion be drawn regarding the potential for a late infection IM to be a risk factor for MS. Given that it is most likely that the vast majority of the controls (estimated 99+%) in the Marrie et al. study are not genetically susceptible to MS, a comparison of rates of IM between the cases and controls adds nothing to the problem of whether a late infection with EBV is an additional risk factor. Finally, even if a properly controlled future study reveals that IM is indeed a risk factor for MS, the fact that Marrie et al. found that only 2% of the cases in their study had IM before MS onset suggests that IM would be an exceedingly minor factor at best.
Reply from the Authors:
Embry has argued that case control methodology is inappropriate for investigating the role of timing of EBV infection as a putative risk factor for the onset of MS, partly because most studies indicate that the majority of the population has been exposed to EBV infection by adulthood. We disagree with this criticism of case control methodology. By examining exposure to a putative risk factor during different time periods before onset of disease, it is certainly possible to obtain useful information even if all cases and controls had been exposed. Indeed, the consideration of a history of exposure during a time period that is not etiologically relevant can lead to the attenuation of the effect estimate.6 Thus careful attention to the timing of the exposure relative to onset is critical.
In our study we demonstrated an association between IM and subsequent risk of MS (OR = 5.5 [95% CI 1.5–19.7]), with an increased risk associated with IM occurring after age 17 years (OR = 6.0 [95% CI 1.4–25.4]).1 This suggests that late infection, not simply EBV infection, is a risk factor for MS. This is not a definitive study, as we stated in our article, but it adds to the current body of evidence available.
Embry also suggests that establishing EBV as a risk factor for MS is of minimal importance, as it would explain only a small proportion of MS cases. It is generally accepted that MS is a disease with a multifactorial etiology; thus, we agree with Embry in terms of the ability of EBV exposure to account for a large proportion of MS cases. However, by adding to the body of evidence about the role of EBV in the etiology of MS, we set the stage for larger, more focused epidemiologic research that will include rigorous study of only those factors for which there is strong basic science and epidemiologic evidence.7
Footnotes
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Copyright © 2001 by the American Academy of Neurology
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