Pilotto et al reported a patient with severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) infection presenting as mild respiratory distress who developed encephalopathy characterized by akinetic mutism. 1 The patient’s prompt clinical response and stabilization of cerebrospinal fluid (CSF) cytokines to high-dose steroids led the authors to propose a cytokinemediated neuroinflammatory response induced by SARS-CoV-2. Encephalopathy is emerging as a recurrent complication of COVID-19 yet remains poorly characterized. In a subgroup of patients, central nervous system (CNS) invasion by SARS-CoV-2 might not have direct pathogenicity. 1 Cytokine-mediated neuroinflammation has a primary pathogenic role in immune effector cell–associated neurotoxicity syndrome (ICANS), 2, 3 where it is induced by chimeric antigen receptor T-cell (CAR-T) therapy, a novel and highly effective treatment for refractory hematological malignancies. 2 Cytokine release syndrome (CRS) is commonly associated with this therapy, 2 and notably presents in a subgroup of COVID-19 patients. 4 ICANS severity frequently correlates with CRS, yet may also occur with minimal systemic inflammation. 2, 3 ICANS is a neuropsychiatric syndrome with heterogeneous clinical manifestations; however, akinetic mutism is a recurrent and specific feature that might help discriminate it from other encephalopathies. 2, 3 Interestingly, we observed 3 COVID-19 patients presenting with a similar phenotype to Pilotto et al’s case, including transitory akinetic mutism, where other likely causes were reasonably excluded and SARS-CoV-2 real-time polymerase chain reaction in CSF tested negative (unpublished data).