Short communicationMassive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal

•Post-mortem brain from an unusual, fulminant case of MS after natalizumab withdrawal is analyzed.•Widespread EBV latent and lytic infection is found in multiple white matter lesions.•EBV lytically infected cells and granzyme B+ CD8+ T cells are more frequent in active lesions.•Uncontrolled EBV reactivation in the CNS during natalizumab therapy causes hyperinflammation after drug discontinuation.

Rebound of disease activity in multiple sclerosis patients after natalizumab withdrawal is a potentially life-threatening event. To verify whether highly destructive inflammation after natalizumab withdrawal is associated with Epstein-Barr virus (EBV) reactivation in central nervous system infiltrating B-lineage cells and cytotoxic immunity, we analyzed post-mortem brain tissue from a patient who died during a fulminating MS relapse following natalizumab withdrawal. Numerous EBV infected B cells/plasma cells and CD8 + T cells infiltrated all white matter lesions; the highest frequency of EBV lytically infected cells and granzyme B + CD8 + T cells was observed in actively demyelinating lesions. These results may encourage switching to B-cell depleting therapy after natalizumab discontinuation.

Graphical abstractHypothetical model of EBV-driven CD8 + T-cell mediated CNS hyperinflammation in lethal multiple sclerosis relapse after natalizumab withdrawal.Download high-res image (385KB)Download full-size image