To report a rare case of anti–neuronal nuclear antibody type 1 (ANNA-1)–associated paraneoplastic autoimmune encephalitis in a patient with metastatic prostate adenocarcinoma.

ANNA-1 antibodies are classically associated with paraneoplastic neurologic syndromes, most often in small-cell lung carcinoma. Association with prostate adenocarcinoma is uncommon. These syndromes are typically linked to intracellular antigens and are often less responsive to immunotherapy than encephalitides mediated by neural surface antibodies. Despite prostate cancer being a prevalent malignancy among men, its association with ANNA-1 encephalitis is rare. 

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A 73-year-old man developed a subacute progressive neuropsychiatric syndrome characterized by cognitive decline, behavioral disinhibition, agitation, fluctuating encephalopathy, and complex visual hallucinations, leading to multiple hospitalizations. Brain MRI showed no acute or interval abnormalities, including no limbic T2 hyperintensities. Serial EEGs demonstrated diffuse theta slowing and triphasic waves without seizures. CSF showed mildly elevated protein, 8 unmatched oligoclonal bands, and elevated ANNA-1 titers (1:30,720). Malignancy evaluation identified biopsy-confirmed prostate adenocarcinoma with metastases to the spine and femur. Small-cell lung carcinoma was excluded. Initial treatment with intravenous methylprednisolone followed by intravenous immunoglobulin led to partial improvement, though relapsing neuropsychiatric symptoms required additional IVIG, after which mental status, mood, and agitation improved, although cognitive deficits persisted. Management also included cancer-directed therapy with radiation.  

This case expands the clinical spectrum of ANNA-1-associated encephalitis in the setting of metastatic prostate adenocarcinoma. The absence of limbic MRI abnormalities and limited CSF inflammatory findings should not preclude consideration of this diagnosis in the appropriate clinical setting. The observed partial but clinically meaningful response to repeated immunotherapy is notable in an intracellular antigen-mediated paraneoplastic encephalitis, which is typically less treatment-responsive. This reinforces the need for early antibody testing and prompt malignancy evaluation in atypical subacute encephalopathy.