To define neuropsychological deficits in GAD65-IgG autoimmune epilepsy and assess associations with quantitative MRI and serum neural injury biomarkers.

GAD65-IgG autoimmunity causes adult-onset, often pharmacoresistant epilepsy. However, the neuropsychological profile and its relationship to MRI volumetry and serum biomarkers remain incompletely defined.

We retrospectively studied 51 patients with autoimmune epilepsy associated with high-titer GAD65-IgG who underwent comprehensive neuropsychological testing at Mayo Clinic (2000-2025). Test performance was summarized using t-scores across 28 measures. Brain MRI volumetry was performed. Serum NfL and sTREM2 were quantified (Ella, Biotechne). Associations between cognition, brain volumes, and biomarkers were analyzed.

Fifty-one patients were included (78% female; median onset age 27 years, IQR 18–37). Half met definite autoimmune limbic encephalitis criteria; 69% received immunotherapy. Neuropsychological testing occurred a median of 6 years after onset (IQR 1–15); 88% had ongoing seizures and 78% were on antiseizure polytherapy. Verbal memory (LISTDEL = 34) and language (BNT = 36) were the most impaired domains. Seventy-five percent of patients reported psychiatric comorbidities, including depression (87%), anxiety (42%), and sporadically irritability, apathy, and emotional lability. Compared with individuals tested <2 years from onset, immunotherapy-naïve patients assessed ≥2 years after onset (n=23) demonstrated worse naming (BNT 32 vs. 45; p=0.01) and greater memory impairment, particularly verbal delayed recall. MRI volumetry (n=33) showed predominant mesial temporal involvement (mean z-score 0.90) with hippocampal asymmetry correlating with naming deficits (r=-0.44, p=0.03). Serum NfL and sTREM2 were higher in patients (n=38) (median NFL 18.9 vs 4.96 pg/mL, p=<0.01; median sTREM2 21.687 vs 14.394 pg/mL, p=0.02). Before immunotherapy (n=20), higher NfL correlated with worse visuospatial (r=-0.7, p=0.02) and premorbid abilities (r=-0.5, p=0.04).

GAD65-IgG autoimmune epilepsy is associated with persistent cognitive impairment, particularly in naming and verbal memory, corresponding to mesial temporal structural changes. Elevated NfL correlates with worse cognition; the role of increased sTREM2 requires further investigation.