Encephalopathy Post CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma: Beyond ICANS

Human herpesvirus 6 (HHV-6) reactivation is a rare but serious complication of chimeric antigen receptor T-cell (CAR-T) therapy that can overlap with immune effector cell-associated neurotoxicity syndrome (ICANS) or cytokine release syndrome (CRS), making diagnosis and management challenging. We describe a 68-year-old man with relapsed/refractory IgA kappa multiple myeloma who received multiple prior therapies, including CyBorD, mVRD-lite, Dara-CyBorD, VD-ACE, and KPd, before undergoing lymphodepleting chemotherapy and CAR-T infusion. Early after infusion he developed grade 2 CRS and ICANS that improved with tocilizumab and corticosteroids, followed by recurrent encephalopathy with progressive neurologic decline. Initial infectious evaluation was negative, but repeat cerebrospinal fluid (CSF) and plasma polymerase chain reaction testing revealed HHV-6 reactivation. Antiviral therapy with foscarnet, later switched to ganciclovir, was initiated with corticosteroids and intravenous immunoglobulin. Although repeat CSF testing showed transient viral clearance, neurologic function continued to decline, and brain MRI demonstrated findings consistent with ICANS, including scattered white matter signal abnormalities and dural enhancement. Despite aggressive management, the patient developed multiorgan failure and died. This case illustrates the diagnostic complexity of HHV-6 reactivation during CAR-T therapy, where overlapping clinical and radiologic features with ICANS can obscure recognition; profound immunosuppression from prior treatment and CAR-T-induced immune dysregulation likely predisposed to viral reactivation. HHV-6 reactivation is a critical, underrecognized cause of neurotoxicity after CAR-T therapy, and clinicians should maintain a high index of suspicion in patients with delayed or atypical neurotoxicity, since early virologic testing and prompt antiviral therapy may improve outcomes in this vulnerable population.