Britton, Jeffrey W

Abstract High‐titer glutamic acid decarboxylase 65 (GAD65) antibodies (>20 nmol/L) are linked to chronic focal epilepsy, usually of temporal regional onset. Identification of these antibodies has treatment and prognostic implications. We compared patients with drug‐resistant epilepsy and high‐titer GAD65 antibodies to an age‐ and sex‐matched control group with drug‐resistant GAD65 antibody–negative temporal lobe epilepsy. From 1432 patients presented at a single‐center surgical epilepsy conference (2007–2024), we identified 15 patients (1% from surgical epilepsy conference: 13 female, 86.7%) with high‐titer serum GAD65 antibodies (median serum titer = 960 nmol/L; range 34–4678). The median age at epilepsy onset was 25 years (range 4–44). All had temporal regional‐onset epilepsy; 53% had bitemporal seizures. Three patients had limbic encephalitis, and three developed mesial temporal sclerosis. Those with GAD65 antibody–associated epilepsy were more likely to have depression and/or anxiety and less likely to undergo resection after evaluation than those in the control group. Although seizure types, electroencephalography (EEG), imaging, and autoimmune history were not statistically significantly different from the control group, we found that musicogenic seizures, limbic encephalitis, and type 1 diabetes occurred only in GAD65‐positive patients. These features, when present, may suggest an autoimmune etiology and warrant antibody testing. Identifying patients with GAD65 antibody–associated epilepsy is important due to its drug resistance, lower rate of satisfactory surgical outcomes, and potential responsiveness to immunotherapy. Further research is needed to define the optimal treatment and distinguish this subgroup from other causes of drug‐resistant epilepsy.

Abstract Objectives γ‐Aminobutyric acid B receptor (GABA B R)‐IgG (immunoglobulin G) is an intermediate‐risk paraneoplastic autoantibody often associated with seizures. We aimed to assess the clinical and oncological features of GABA B R‐IgG autoimmune encephalitis (AE) and evaluate the performance of antibody testing. Methods Patients testing positive for GABA B R‐IgG in serum/cerebrospinal fluid (CSF) at Mayo Clinic Neuroimmunology Laboratory were identified. Archived sera were retested by cell‐based assay (CBA) at 1:100 and 1:200 dilutions. A live‐cell flow cytometry–based assay (LCFBA) was developed and validated using archived sera and CSF. True positivity included patients with classic presentations of GABA B R‐IgG AE or oncological explanations for antibody presence. Results Eighty‐six patients (median age 63 years; 43 female) presented with classic presentations of GABA B R‐IgG AE: encephalopathy with prominent seizures ( n = 55), status epilepticus ( n = 23), and rapidly progressive dementia ( n = 8). In addition, 44 patients (33%) had a false‐positive result for GABA B R‐IgG characterized by non‐specific symptoms/alternate diagnoses. Malignancy was identified in 78% of true‐positive patients, predominantly small cell lung carcinoma (SCLC). Testing serum at 1:100 dilution on CBA and using tissue immunofluorescence assay (IFA) in serum and CSF improved the identification of true‐positive patients ( p < 0.001). CBA at 1:100 dilution performed better than conventional CBA (at 1:10 dilution, p < 0.001) and tissue IFA ( p = 0.031). An in‐house LCFBA showed 100% sensitivity and specificity in CSF, performing similarly to conventional CBA ( p = 0.125) in CSF, but better than tissue IFA ( p = 0.031). Furthermore, serum LCFBA performed better than conventional CBA ( p = 0.022) and tissue IFA ( p = 0.006). LCFBA had the highest diagnostic accuracy and was closely followed by CBA at 1:100 dilution. Significance GABA B R‐IgG AE often presents as encephalopathy with seizures or status epilepticus in the context of an underlying SCLC. Multimodal evaluation using tissue IFA and fixed CBA at higher dilutions improves detection of true cases. LCFBA performs very well as a diagnostic test with very high sensitivity and specificity.

The 2023 American Epilepsy Society Annual Course “It’s About Time” addressed timing in epilepsy evaluation and treatment with respect to health disparity and vulnerable populations and diagnostic, clinical, and epilepsy surgery evaluation. This comprehensive course included topics on gaps in epilepsy care and optimization of behavioral health for patients with epilepsy. The summary details current knowledge in areas of seizure forecasting and epileptogenesis. Intricacies and controversies over timing were discussed for treatment of nonconvulsive seizures and ictal-interictal patterns, acute symptomatic seizures, neuromodulation versus surgery, and epilepsy surgery in status epilepticus. Timing regarding clinical care in autoimmune-associated epilepsy, developmental and epileptic encephalopathy, and dietary therapy were examined. Additionally, salient topics on using novel biomarkers and collaboration with neuropsychological outcomes were also tackled in this all-encompassing lecture series.