Germline Genetic Variants and Epilepsy Surgery Response: Individual Participant Pooled Analysis of 272 Patients
In brief
Surgery freed 66% of patients with GATORopathies, but only 22% with synaptopathies
In a pooled analysis of 272 people with germline genetic epilepsies, seizure freedom after resection or laser ablation varied by genetic pathway: rates were highest for GATORopathies and vascular disorders, and lowest for synaptopathies and channelopathies. Even when MRI showed a lesion, outcomes remained lower for the latter groups; prospective studies are needed to guide surgical selection.
- Journal
- Neurology (Q1)
- Published
- 2 November 2026
- Study design
- Systematic review of cohort studies
- Evidence level
- Level 2, Moderate (CEBM 2a)
- Authors
- Alina Ivaniuk, Sunanjay Bajaj, Christian M Boßelmann, Hyun Yong Koh, Elia M Pestana Knight, Xiaoming Xz Zhang, et al.
- PMID
- 42970749
- DOI
- 10.1212/WNL.0000000000218687
Why clinicians should know about it
- Picked for Genetics (clinical) (paper of the day, 3 November 2026): Germline diagnoses guide seizure surgery prognosis and counseling
Abstract
BACKGROUND AND OBJECTIVES: Genetic testing is increasingly used in presurgical evaluation, but the yield of resection and ablation across germline genetic epilepsies remains uncertain. METHODS: We conducted a systematic review of MEDLINE (PubMed) and Scopus and added cases from 3 institutional cohorts and the Pediatric Epilepsy Research Consortium (PERC) databases, including individuals with pathogenic/likely pathogenic germline variants besides tuberous sclerosis who underwent resection or laser ablation. Etiologies were grouped into biologically informed categories (GATORopathies, vascular, overgrowth, copy number variants (CNVs), channelopathies, synaptopathies, and other). Primary outcome was seizure freedom (Engel I) at the last follow-up. Group comparisons used Fisher exact and Kruskal-Wallis tests (α = 0.05; Bonferroni when applicable). Prespecified sensitivity analyses stratified by lesional status, excluded GATORopathies, and restricted to literature-only cases. RESULTS: We included 224 literature cases (65 studies), 36 institutional cases, and 12 PERC cases (n = 272). The median follow-up was 24 months (interquartile range 12-48.0). Seizure freedom was achieved in vascular disorders 14/19 (73.6%), GATORopathies 79/120 (65.8%), CNVs 18/31 (58.0%), overgrowth 9/16 (56.6%), channelopathies 13/43 (30.0%), synaptopathies 4/18 (22.2%), and other 11/25 (44.0%) (overall p < 0.001). Among cases with available imaging results, 208/253 (82.2%) had epileptogenic MRI lesions, including 64% of channelopathies and 80% of the synaptopathies. In univariate contrasts (each category vs all others), odds of seizure freedom were higher for vascular disorders (2.64-fold, 95% CI 0.87-9.65) and GATORopathies (2.41-fold, 95% CI 1.44-4.09), and lower for synaptopathies (∼4.2-fold lower, OR 0.23, 95% CI 0.05-0.77) and channelopathies (∼4.5-fold lower, OR 0.22, 95% CI 0.09-0.48). Direction and magnitude were consistent across prespecified sensitivity analyses (lesional only, literature only, exclusion of GATORopathies). DISCUSSION: Resective surgeries can be effective in germline genetic epilepsies, but outcomes vary by pathway. Disorders with discrete, lesional substrates (GATORopathies, vascular) show the highest likelihood of seizure freedom, whereas channelopathies and synaptopathies, despite the presence of MRI lesions, have substantially lower yields even in lesional cases. Prospective, genotype-aware surgical registries with standardized reporting (EEG, imaging, and pathology) and time-to-event outcomes are needed to refine the selection of surgical candidates and quantify seizure and non-seizure-related outcomes.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.