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

      Highlights

      • 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.

      Abstract

      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.

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