Multiple sclerosis (MS) is a disease of the central nervous system characterized 
by inflammation, demyelination, and neuronal damage. Environmental and genetic 
factors are associated with the risk of developing MS, but the exact cause still 
remains unidentified. Epstein-Barr virus (EBV), vitamin D, and smoking are among 
the most well-established environmental risk factors in MS. Infectious 
mononucleosis, which is caused by delayed primary EBV infection, increases the 
risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by 
activating silent human endogenous retrovirus-W. The emerging B-cell depleting 
therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well 
as the fully human ofatumumab, have shown promising clinical and magnetic 
resonance imaging benefit. One potential effect of these therapies is the 
depletion of memory B-cells, the primary reservoir site where EBV latency 
occurs. In addition, EBV potentially interacts with both genetic and other 
environmental factors to increase susceptibility and disease severity of MS. 
This review examines the role of EBV in MS pathophysiology and summarizes the 
recent clinical and radiological findings, with a focus on B-cells and in vivo 
imaging. Addressing the potential link between EBV and MS allows the better 
understanding of MS pathogenesis and helps to identify additional disease 
biomarkers that may be responsive to B-cell depleting intervention.