Unclassified Neuronal Antibodies in Suspected Autoimmune Encephalitis: A Report of Two Cases

Autoimmune encephalitis (AE) is an important and potentially reversible cause of subacute cognitive and neurological decline. A significant proportion of patients remain seronegative for known neuronal antibodies or harbor unclassified antibodies, posing diagnostic challenges. We report two cases of suspected AE associated with unclassified neuronal antibodies. The first case involved a 42-year-old male presenting with focal seizures followed by rapidly progressive cognitive decline, mutism, and spasticity. Magnetic resonance imaging revealed multifocal cortical-subcortical T2-FLAIR hyperintensities, while cerebrospinal fluid (CSF) and conventional autoimmune and paraneoplastic antibody panels were noncontributory. The second case was a 70-year-old male with insidious cognitive decline, Parkinsonism, autonomic dysfunction, and fluctuating cognition. Neuroimaging was unremarkable, and CSF showed elevated protein with lymphocytic predominance. In both cases, serum testing demonstrated unclassified neuronal antibodies. Both patients received immunomodulatory therapy including high-dose corticosteroids, intravenous immunoglobulin, rituximab, and plasmapheresis, resulting in clinical stabilization and cognitive improvement. These cases emphasize the importance of considering autoimmune encephalitis in patients presenting with gradually worsening cognitive and neurological symptoms, despite negative routine antibody panels. Early clinical suspicion and prompt immunotherapy are crucial for improved outcomes.