Neurosyphilis and limbic encephalitis: practical guidance for diagnosis and treatment sequencing at an...

Syphilis remains a re-emerging global infection with protean neurologic manifestations. Although neurosyphilis has long been framed as a direct infectious involvement of the central nervous system, an emerging case-based literature suggests that, in selected patients, Treponema pallidum infection may intersect with autoimmune limbic encephalitis, including anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. We conducted a structured narrative synthesis of published reports describing neurosyphilis presenting with a limbic encephalitis phenotype and reports documenting neuronal surface antibodies in the context of neurosyphilis. Across published reports, a recurrent phenotype is described: subacute psychiatric symptoms, memory impairment, seizures, mesial temporal abnormalities, and inflammatory cerebrospinal fluid profiles that do not reliably discriminate between infection and autoimmunity. While neurosyphilis can convincingly mimic autoimmune limbic encephalitis, a small number of observations describe limited improvement with antimicrobial therapy alone and more substantial recovery after immunomodulation, raising the possibility of an overlap phenotype in a minority of patients. Taken together, these case-based findings support a parallel diagnostic posture, securing antimicrobial coverage when neurosyphilis is supported, while preserving timely autoimmune phenotyping and treatment escalation when objective features suggest immune-driven persistence.