Temporal Lobe Epilepsy With GAD Antibodies—Time to Give Up, or Time to Double Down?

Temporal Lobe Epilepsy Associated With Glutamic Acid Decarboxylase Antibodies: Defining a Distinct Epilepsy Syndrome Rada A, Reisch LM, Hagemann A, Woermann FG, Bien CG. Neurol Neuroimmunol Neuroinflamm . 2025;12(4): e200422(1)-e200422(13). doi: 10.1212/NXI.0000000000200422 Background and Objectives: Epilepsy associated with glutamic acid decarboxylase antibodies (GAD-abs) often presents as temporal lobe epilepsy (TLE). However, detailed data on this condition are lacking. The aim of this study was to demonstrate that TLE with GAD-abs (GAD-TLE) is distinct from other forms of TLE and to describe the subgroup of patients with epilepsy and GAD-abs but no evidence of TLE. Methods: Inpatients from 2011 to 2022 with high serum GAD-abs (≥1:80, confirmed by a cell-based assay and typical staining pattern on a tissue-based assay) were included. The control group comprised patients with mesial TLE (EMU-mTLE) with hippocampal sclerosis or nonlesional epilepsy diagnosed on the epilepsy monitoring unit (EMU) and having negative results on a broad panel of neural antibodies. Data were retrospectively collected from first admission (visit 1 [V1]) and most recent follow-up (visit 2 [V2]). Parameters included demographic data, comorbidities, seizure characteristics, electroencephalography findings, MRI results, verbal memory performance, GAD-ab titers (V1), therapies, seizure and memory outcomes, and occupational status (V2). Results: Of 81 GAD-ab–positive patients, 71 (88%) had TLE. Compared with 40 EMU-mTLE controls, patients with GAD-TLE were more often female (84% vs 33%, p < 0.001), more frequently had autoimmune comorbidities (46% vs 2.5%, p < 0.001), musicogenic seizures (18% vs 0%, p = 0.004), and seizure clusters (25% vs 5%, p = 0.002) but less frequently had hippocampal sclerosis (25% vs 54%, p = 0.007). At follow-up (GAD-TLE: median 5 years; EMU-mTLE: 2 years), only 14% of patients with GAD-TLE were terminally seizure-free for ≥1 year, compared with 39% of patients with EMU-mTLE (p = 0.04). Verbal memory remained stable, and occupational status was unchanged. Ten GAD-ab–positive cases without evidence of TLE were identified, including 3 with generalized features. Discussion: Epilepsy associated with GAD-abs predominantly manifests as TLE and as such is an epilepsy syndrome (GAD-TLE). In comparison with EMU-confirmed patients with mTLE without GAD-abs, the seizure outcome is inferior but the neuropsychological performance is usually normal and remains stable. A subset of patients with epilepsy with high-titer GAD-abs do not have TLE, some presenting with generalized features.