2022 Top Story in Neurology: Multiple Sclerosis—The Tale of Two Viruses

As the COVID-19 pandemic enters the fourth year, there have been a series of publications suggesting that patients on B-cell–depleting and sphingosine-1-phosphate receptor modulator therapies are at an increased risk for complications associated with COVID-19 and are also at a higher risk for contracting the illness.¹ This poses a major dilemma because these therapies are two of the most effective therapies in controlling the relapses and progression of the illness. Vaccination is a major preventive measure besides the public health precautions. However, the vaccines may not mount an adequate immune response if they are not given at the appropriate timing. One study found that serum ocrelizumab concentrations may be an alternative to B-cell counts as a biomarker of vaccine responsiveness to guide clinical decisions with respect to the timing of vaccination.² This could particularly be useful in resource-limited areas, and the concentrations can be mathematically modeled. However, a recent study presented at the ECTRIMS suggested that, despite vaccination, individuals on disease-modifying drugs such as ocrelizumab and fingolimod may be at an increased risk for developing COVID-19 and an increased risk for hospitalization.³ This suggests that suboptimal vaccination is associated with the increased risk. Delaying B-cell–depleting therapies after vaccination provides the most optimal antibody response to the vaccine. In contrast, a recent study suggests that cell-mediated immune responses are most optimal if the vaccine is given soon after the B-cell–depleting treatment.⁴ This might be somewhat counterintuitive, but it might suggest the need for studies to determine whether additional boosters early and late in the course of therapy may provide better protection. The possibility that the vaccine itself may induce demyelinating diseases has also been studied. Data from the WHO pharmacovigilance database suggest that there is a weak increased risk of such complications, but no increased risk was noted when compared with other viral vaccines.⁵

The possibility that a viral infection may be the cause of MS or may play a major role in the pathophysiology of MS has long been considered. Although several viruses and pathogens have been implicated, none has stood the test of time or rigor of analysis. A recent paper published in Science reported a strong epidemiological association between the Epstein–Barr virus (EBV) and MS has received a lot of attention.⁶ The potential association of EBV and MS is not new. It has been known that patients with MS often report severe forms of infectious mononucleosis and often get infected later in life (mostly in their teenage years). However, such studies are subject to recall bias. EBV has been detected in the brains of patients with MS but also in healthy controls. Others have failed to detect the virus in the brain. The current study used stored serum samples obtained from a large population of military recruits. They joined the military at a young age, and the samples were collected as part of their annual checkup. This allowed the authors to identify individuals who were seronegative for EBV and later developed MS. From a cohort of 10 million individuals, they identified 30 such individuals. They found that all but 1 patient had also undergone EBV seroconversion before developing MS. Of 90 other individuals who were seronegative for EBV and did not develop MS, only 60 had seroconverted. However, both groups had similar proportions of patients who were seropositive for cytomegalovirus. Neurofilament levels also increased in some of the patients before they developed MS. The authors concluded that their findings suggested that EBV is the leading cause of MS. Another study published soon after suggested that there was molecular mimicry between the EBV antigens and a molecule called GlialCAM. Thus, an immune response to EBV could potentially lead to an autoimmune response targeted against the glial cells causing demyelination.⁷ However, the results of these studies should be interpreted with caution. Ongoing studies regarding EBV vaccination and therapeutics targeted against EBV reservoirs may shed additional light on the potential role of this virus in mediating MS.