Background: Mpox, formerly known as monkeypox, is an infectious disease caused by the mpox virus. Systemic involvement is rare and mpox-associated meningoencephalitis is an uncommon clinical presentation. Because mpox-associated meningoencephalitis is characterized by nonspecific clinical and incidental imaging findings, the disease is difficult to diagnose.

Methods: We present a case of fatal mpox-associated meningoencephalitis with negative polymerase chain reaction in cerebrospinal fluid (CSF) diagnosed at autopsy. A young immunocompetent patient with no significant medical history initially presented with genital mpox infection. Within 48 hours, he showed neurologic involvement requiring orotracheal intubation. His condition deteriorated rapidly, progressing to cerebral edema and brain death consistent with meningoencephalitis. Despite negative testing for mpox virus in CSF, the diagnosis was confirmed posthumously by autopsy, where histological examination revealed the presence of mpox virus in brain tissue.

Conclusions: Mpox-associated meningoencephalitis should be considered as a potential diagnosis even in the absence of the mpox virus genome in CSF.