Drug-resistant epilepsy (DRE) may lead to substantial morbidity, impaired quality of life (QoL), and increased mortality. Clinicians increasingly use surgical interventions to manage DRE, but uncertainty remains regarding their comparative benefits and harms across epilepsy syndromes. We conducted 4 systematic reviews and meta-analyses to inform the American Epilepsy Society (AES) and Congress of Neurological Surgeons (CNS) guidelines on surgical management of DRE. We searched MEDLINE, Embase, and CENTRAL from inception to August 2024 for randomized controlled trials (RCTs) and nonrandomized studies (NRS). We evaluated (1) resective or ablative surgery versus medical therapy in drug-resistant mesiotemporal lobe epilepsy (DR-MTLE); (2) resective or ablative surgery versus medical therapy in drug-resistant neocortical epilepsy (DR-NE); (3) callosotomy versus vagus nerve stimulation (VNS) in developmental and epileptic encephalopathies (DEEs) with drop attacks; and (4) ablative versus resective surgery in hypothalamic hamartoma (HH). The panel prioritized the following critical outcomes: seizure freedom, QoL, neuropsychological, neuropsychiatric, and social outcomes, and serious adverse events. We assessed certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. We included 59 studies comprising 4868 participants. In DR-MTLE, moderate-certainty evidence from RCTs showed that anterior temporal lobectomy (ATL), compared with medical therapy, probably increases seizure freedom and improves QoL. The evidence was very uncertain regarding the effects of selective amygdalohippocampectomy, laser interstitial thermal therapy (LITT), and radiosurgery in patients with DRE. In DR-NE, very low-certainty evidence suggested that seizure freedom may occur after resective surgery. However, we did not identify any eligible studies evaluating ablative surgery in this population. In DEE, very low-certainty evidence suggested that, when compared to VNS, callosotomy may improve seizure outcomes but may also increase serious adverse events. In HH, evidence for LITT and radiosurgery was found to be very uncertain. Across reviews, the most common reason for downgrading the certainty of evidence was risk of bias and imprecision. Moderate-certainty evidence supports ATL in selected patients with DR-MTLE. For other surgical approaches and epilepsy syndromes, the evidence remains very uncertain, highlighting the need for better comparative studies.
Normal brain function relies on coordinated oscillations within and across neural circuits. In epilepsy, disruption of these oscillations may reflect pathological excitability associated with seizure generation and/or the emergence of comorbidities. Among these oscillatory activities, high-frequency oscillations (HFOs, typically within 80-500 Hz) are increasingly considered promising electrophysiological biomarkers of epileptogenicity. Preclinical models provide a powerful platform for elucidating the mechanisms underlying HFO generation and for evaluating candidate therapeutic strategies. However, substantial heterogeneity persists across preclinical HFO studies in recording techniques, signal definitions, and reporting practices. This variability limits reproducibility and hampers comparisons between preclinical findings and human data, highlighting the need for greater harmonization. To that end, we propose a set of common data elements (CDEs) organized across 4 domains: (1) HFO recording, (2) HFO definition and detection, (3) HFO reporting and quantification, and (4) biological and disease context CDEs to capture subject- and model-specific parameters that may affect HFO interpretation and comparisons across studies. CDEs are classified as either core, representing the essential information recommended for all HFO studies; or optional, representing additional information recommended when relevant to the experimental design or research question. For practical implementation, CDEs are operationalized through structured case report forms that can be integrated into Research Electronic Data Capture systems for scalable implementation. By promoting harmonized practices, HFO CDEs aim to facilitate a common reporting language in preclinical and translational HFO research in epilepsy, enhance methodological rigor and transparency, and facilitate comparisons across laboratories and experimental models.
AAV-mediated gene therapy in a model of SLC13A5 citrate transporter disorder rescues epileptic and metabolic phenotypes Bailey LE, Adams RM, Schackmuth MK, Garza IT, Knight K, Holmes SK, Eller MM, Lee M, and Bailey RM. J Clin Invest . 2026 Feb 19;136(8):e197503. doi: 10.1172/JCI197503. PMID: 41712282; PMCID: PMC13078891. SLC13A5 citrate transporter disorder is a rare epileptic encephalopathy caused by loss-of-function pathogenic variants in the SLC13A5 gene. Loss of sodium/citrate cotransporter function causes a severe early-life epilepsy resulting in lifelong developmental disabilities and increased extracellular citrate. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and neurodevelopmental SLC13A5 phenotype. We performed preclinical studies in SLC13A5-deficient (KO) mice evaluating phenotype rescue with adeno-associated virus (AAV) vector carrying a functional copy of the human SLC13A5 gene (AAV9/SLC13A5). Cerebrospinal fluid delivery of AAV9/SLC13A5 decreased extracellular citrate levels, normalized electrophysiologic and sleep architecture abnormalities, and restored resistance to chemically induced seizures and death. Treatment benefits were achieved with administration during early brain development and in young adult mice, indicating therapeutic efficacy across developmental and postdevelopmental stages. Comparison of delivery routes in young adult KO mice showed that higher brain targeting achieved with intracisterna magna delivery resulted in greater treatment benefit as compared with intrathecal lumbar puncture delivery. Together, these results support further development of AAV9/SLC13A5 for treating SLC13A5 citrate transporter disorder.
Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Late Onset Epilepsy: A Real-World Cohort Study Lin BH, Huang HM, Lin HA, Lin SF. Epilepsia . 2026;67(7):3444–3456. doi:10.1002/epi.70239. Objective: Late onset epilepsy (LOE) is associated with substantial morbidity. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may exert neuroprotective effects. This study evaluated the association between SGLT2i and risk of LOE among older adults with type 2 diabetes mellitus. Methods: This retrospective cohort study was conducted between 2013 and 2025 with a 3-year follow-up using the TriNetX global network. Patients ≥ 60 years old with type 2 diabetes mellitus were classified into two cohorts—new SGLT2i users and new dipeptidyl peptidase-4 inhibitors users—following a 6-month washout of other antihyperglycemic agents except metformin. Patients with major neurological diseases or contraindications to SGLT2i were excluded. Propensity score matching was used to balance baseline characteristics between two cohorts. The primary outcomes were incident LOE, status epilepticus, and initiation of antiseizure medications. Unadjusted Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence interval (CIs). Results: A total of 1435648 patients were identified. After matching, 60203 patients were included in the SGLT2i cohort (mean age = 67.7 years, 42.3% female) and 60203 in the control cohort (mean age = 67.7 years, 41.7% female). SGLT2i use was associated with lower risk of LOE (HR = .55, 95% CI = .44–.68), status epilepticus (HR = .38, 95% CI = .21–.69), and antiseizure medication initiation (HR = .63, 95% CI = .58–.69). SGLT2i reduced LOE risk in patients with stroke (HR = .69, 95% CI = .42–.88) and dementia (HR = .44, 95% CI = .25–.78) but not in those with traumatic brain injury or brain tumors. Significance: SGLT2i use was associated with reduced risk of LOE among selected patients, supporting its role in an etiology-specific therapeutic approach for older adults at risk of epilepsy. Semaglutide and Risk of Adult-Onset Seizure: A Target Trial Emulation Eun Y, Bong S, Koh HY, Trousdale RK, Cho YM, Jang Y, Lee ST. Neurology. 2026 Jul 14;107(1):e218174. doi: 10.1212/WNL.0000000000218174. Epub 2026 Jun 17. PMID: 42308439; PMCID: PMC13278381. Background and objectives: Adult-onset seizure reflects the burden of acquired brain insults, but established disease-modifying preventive strategies are limited. We evaluated whether semaglutide initiation is associated with a lower incidence of adult-onset seizure compared with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other glucose-lowering drugs (GLDs) in adults with type 2 diabetes. Methods: Using the All of Us Research Program, we emulated a population-based target trial in new-user, active-comparator cohorts from January 2018 to October 2023. We compared semaglutide vs other GLDs and semaglutide vs SGLT2i. Incident epilepsy or seizure was identified from diagnostic codes. Effects were estimated using inverse probability of treatment weighting with weighted Cox models and targeted maximum likelihood estimation (TMLE). Subgroup and sensitivity analyses with multiple outcome definitions and analytic approaches were conducted to assess the robustness of findings. We evaluated mediation through hemoglobin A1c (HbA1c) and body mass index (BMI) using the longitudinal Vansteelandt framework. Results: We analyzed 10,213 patients in the semaglutide (n = 2,586, mean age, 60.1 years; 56.8% female) vs other GLDs cohort (n = 7,627, mean age, 63.7 years; 54.2% female) and 8,605 patients in the semaglutide (n = 2,814, mean age, 60.5 years; 66.2% female) vs SGLT2i cohort (n = 5,791, mean age, 64.4 years; 47.3% female). Semaglutide was associated with a lower risk of adult-onset seizure compared with other GLDs (weighted HR 0.44 [95% CI 0.25-0.79]; 4-year risk difference -1.78% [95% CI -2.58 to -0.98]) and SGLT2i (weighted HR 0.48 [95% CI 0.27-0.85]; 4-year risk difference -1.46% [95% CI -2.41 to -0.51]). TMLE estimated risk differences per 1,000 persons of -14.20 (95% CI -18.33 to -10.07) vs other GLDs and -7.62 (95% CI -11.65 to -3.60) vs SGLT2i, corresponding to numbers needed to treat of 70 and 131, respectively. Mediation was minimal for HbA1c (2.4% vs other GLDs; 6.5% vs SGLT2i) and BMI (0% vs other GLDs; 0.7% vs SGLT2i). Discussion: Semaglutide initiation was associated with a lower risk of adult-onset seizure compared with SGLT2i and other GLDs in patients with type 2 diabetes, independent of glycemic and weight effects. Residual confounding, low event counts, and shorter follow-up limit causal interpretation. Classification of evidence: This study provides Class II evidence that semaglutide use was associated with a lower risk of adult-onset seizures compared with other GLDs and SGLT2i.
