Epstein-Barr virus-associated immune reconstitution inflammatory syndrome as possible cause of fulminant multiple sclerosis relapse after natalizumab interruption

Abstract Studying rebound mechanisms in MS patients after interruption of natalizumab may advance our understanding of MS pathogenesis. To verify the role of Epstein-Barr virus (EBV) infection and anti-EBV immunity in post-natalizumab rebound, we analyzed postmortem brain tissue of a case of fatal MS relapse. Using immunohistochemistry, EBV latent, early and late lytic proteins and CD8+ T cells sticking to EBV lytically-infected cells were detected in multiple inflammatory white matter lesions. Using the pentamer technology on brain sections, EBV-specific CD8+ T cells were observed perivascularly. Cell-free EBV DNA was detected in cerebrospinal fluid. These findings confirm and extend the results obtained in another case of post-natalizumab fatal MS relapse, suggesting that this condition represents an EBV-associated immune reconstitution inflammatory syndrome.