Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition predominantly affecting females in an 8:2 ratio¹ characterized by neuropsychiatric symptoms with CSF antibodies against the NMDAR-GluN1 subunit.

A 49-year-old transgender male-to-female on estrogen presented with subacute behavioral changes, suicidal ideation, and hallucinations. Exam was notable for speech arrest, catatonia, waxing flexibility, and diminished executive functioning, memory, strength, and coordination. Encephalopathy panel, autoimmune workup, and CT chest/abdomen/pelvis were unremarkable. MRI Brain revealed subtle right cortical and subcortical FLAIR/T2 hyperintensities without enhancement. Video encephalogram demonstrated right hemispheric delta slowing with occasional superimposed low amplitude fast activity, and rare sharp waves. CSF was negative for HSV/VZV, but remarkable for NMDAR antibodies, confirming NMDAR encephalitis. She was treated with IV methylprednisolone, IVIG, and rituximab with improvements in strength, coordination, visual-spatial processing, and cognition. Repeat MRI Brain showed resolution of the right temporal and insular cortical hyperintensities.

To our knowledge, our case represents the first report of transgender male-to-female NMDAR encephalitis on estrogen, though the incidence may be underreported due to the atypical presentation and challenges in diagnosing patients with gender dysphoria, which may suggest a psychiatric etiology. Males with NDMAR encephalitis typically present with partial seizures followed by cognitive symptoms compared to females who first present with behavioral symptoms.² Our patient presented with behavioral symptoms similar to females. Estrogen mediates NMDAR conductance³ and inhibits GABA transmission, which propagates neuronal dendritic spines,⁴ increasing seizure susceptibility. However, estrogen is neuroprotective against NMDA-induced seizures in animal models,⁵ possibly through the interplay of progesterone and androgens, which have anticonvulsant effects.^6,7 NMDAR encephalitis seizures decrease with age after puberty, suggesting that hormonal imbalances account for seizure propensity.⁸ Our case highlights the importance of maintaining a high index of suspicion for NMDAR encephalitis in patients on hormone therapy, as early recognition and treatment is essential for optimizing prognosis.