Fine, Anthony L.

Low diagnostic yield of presurgical genetic testing in adult patients with epilepsy Jünemann C, Stuart A, Kaur N, Wiebe S, Jette N, Singh S, Borlot F, Knake S; Calgary Comprehensive Epilepsy Program Collaborators; Billie Au PY, Klein KM. Epilepsia . 2026 May 20. doi: 10.1002/epi.70291. Epub ahead of print. PMID: 42157695. Objective: To determine the diagnostic yield of genetic testing in patients undergoing presurgical evaluation for epilepsy. Methods: We conducted a cohort study including 115 adult patients who underwent presurgical evaluation in the Calgary Epilepsy Program between 2019 and 2023 and who had undergone research exome sequencing. A curated epilepsy gene panel comprising 765 Online Mendelian Inheritance in Man (OMIM)-listed epilepsy-associated genes was applied. Variants were classified according to American College of Medical Genetics and Genomics guidelines and assessed for clinical relevance and association with postsurgical outcomes. Results: Pathogenic or likely pathogenic variants in DEPDC5, NPRL2, KCNT2, and PRRT2 were identified, respectively, in 4 individuals (3.5%, 4/115). All variants met stringent quality criteria with high pathogenicity scores (Combined Annotation Dependent Depletion (CADD) 34–37) and absent or extremely low population frequencies in gnomAD v4.1. None of these patients had intellectual disability, and only 1 patient (PRRT2) had a positive family history. The patient with the KCNT2 variant underwent epilepsy surgery with good outcome (Engel class ID). Significance: This presurgical cohort demonstrates a low diagnostic yield of genetic testing in adult epilepsy surgery candidates. However, 3 of 4 patients with (likely) pathogenic variants did not have features that would have prompted clinical genetic testing, indicating that their genetic diagnosis would have been missed based on typical clinical genetic testing criteria in many jurisdictions.

Zorevunersen in Children and Adolescents with Dravet Syndrome. Laux L, Sullivan J, Perry MS, Brunklaus A, Desurkar A, Schreiber JM, Roberts CM, Knupp KG, Wheless JW, Wirrell EC, Ventola P, Wang F, Meena, Lynch J, Parkerson KA, Ticho B, Cross JH; MONARCH, ADMIRAL, SWALLOWTAIL, and LONGWING Study Groups. N Engl J Med. 2026 Mar 5;394(10):969–982. doi: 10.1056/NEJMoa2506295. PMID: 41780062. Background: Dravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency. Risks of sudden unexpected death in epilepsy and cognitive deficits are higher among patients with this syndrome than in the general population with epilepsy. The effects of zorevunersen, an antisense oligonucleotide designed to up-regulate Na V 1.1 sodium channels, in patients with Dravet syndrome are not known. Methods: We enrolled patients 2 to 18 years of age with Dravet syndrome who were receiving standard antiseizure medications in two phase 1–2a, open-label, multicenter studies (MONARCH and ADMIRAL). Patients were included in either a single-ascending-dose cohort, in which zorevunersen (10 to 70 mg) was administered on day 1 only, or a multiple-ascending-dose cohort, in which zorevunersen (20 to 70 mg) was administered two or three times in a 3-month period. Patients eligible for rollover to the two open-label extension studies (SWALLOWTAIL and LONGWING) continued to receive zorevunersen (≤45 mg) every 4 months. The safety and pharmacokinetics of zorevunersen were assessed in the primary analysis; clinical effects were also evaluated. Results: A total of 81 patients were enrolled in the phase 1–2a studies. As of May 30, 2025, a total of 75 patients had entered the extension studies. Most adverse events were mild or moderate. The most common adverse event was post-lumbar puncture syndrome (in 25% of patients) in the phase 1–2a studies and was an elevated protein level in cerebrospinal fluid (in 45%) in the extension studies. One patient had suspected unexpected serious adverse reactions, 1 had an adverse event that led to study withdrawal, 2 died from sudden unexpected death in epilepsy, and 1 died from malnutrition. Patients who received 70 mg of zorevunersen (one, two, or three doses) in the phase 1–2a studies, followed by up to 45 mg in the extension studies, had a median change from baseline in convulsive-seizure frequency ranging from −58.82% to −90.91% across 1-month intervals during the first 20 months of the extension studies. The data supported improvements in overall clinical status, quality of life, and adaptive behavior with continued treatment for up to 36 months in the extension studies. Conclusions: The safety profile and initial clinical improvement support the continued development of zorevunersen as a potential disease-modifying treatment for Dravet syndrome. (Supported by Stoke Therapeutics; MONARCH and SWALLOWTAIL ClinicalTrials.gov numbers, NCT04442295 and NCT04740476, respectively; ADMIRAL and LONGWING ISRCTN Registry numbers, ISRCTN99651026 and ISRCTN12811235, respectively.).

Abstract Background Genetic testing is increasingly used in presurgical evaluation, but the yield of resection across germline genetic epilepsies remains uncertain. Methods We conducted a systematic review of MEDLINE (PubMed) and Scopus and added cases from three institutional cohorts and the Pediatric Epilepsy Research Consortium (PERC) databases, including individuals with pathogenic/likely pathogenic germline variants besides tuberous sclerosis and neurofibromatosis who underwent resection or laser ablation. Etiologies were grouped into biologically informed categories (GATORopathies, vascular, overgrowth, CNVs, channelopathies, synaptopathies, other). Primary outcome was seizure freedom (Engel I) at last follow-up. Group comparisons used Fisher’s 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 223 literature cases (64 studies), 35 institutional cases, and 11 PERC cases (n=269). Median follow-up was 24 months (IQR 12–48.0). Seizure freedom was achieved in: vascular disorders 14/19 (73.6%), GATORopathies 79/120 (67.5%), CNVs 18/31 (66.7%), overgrowth 7/13 (53.8%), other 16/25 (41.7%), channelopathies 13/43 (33.3%), and synaptopathies 4/18 (22.2%) (overall p<0.001). Among cases with known imaging, 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 (2.66-fold, 95% CI 0.87–9.72) and GATORopathies (2.46-fold, 95% CI 1.46–4.18), and lower for synaptopathies (∼4.2-fold lower, OR 0.24, 95% CI 0.05– 0.78) 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). Conclusions 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, pathology) and time-to-event outcomes are needed to refine the selection of surgical candidates and quantify seizure and non-seizure-related outcomes.

Pathways Linking Parental Social Support and Decision-Making Participation to Medication Adherence in Children With Epilepsy: The Moderating Role of Parental Anxiety. Yang C, Huang R, Tao Q, Hao Z, Zhao L, Zhang L. Depress Anxiety . 2025 Sep 16;2025:7159579. doi: 10.1155/da/7159579. PMID: 40995429; PMCID: PMC12457068. Background: Medication adherence among pediatric epilepsy patients is frequently suboptimal, and the complex interplay between parental social support, decision-making participation, treatment satisfaction, and parental anxiety in influencing medication adherence remains underexplored. This study investigates both the direct and indirect pathways linking these factors to medication adherence and examines the mediating role of treatment satisfaction and the moderating role of parental anxiety. Methods: A cross-sectional study was conducted at three medical institutions between January 2020 and June 2024. Data on patient demographics and standardized scales measuring medication adherence, social support, communication and decision-making participation, treatment satisfaction, and parental anxiety were collected. Relationships among these variables were analyzed using structural equation modeling (SEM) and moderation analysis. Results: A total of 1056 patients were included in the study, with a mean age of 8.86 ± 3.99 years; 51.7% were male. Path analysis showed that parental social support (STD = 0.344, p < 0.001), communication and decision-making participation (STD = 0.392, p < 0.001), and treatment satisfaction (STD = 0.090, p < 0.05) had significant positive effects on medication adherence. Parental social support (STD = 0.483, p < 0.001) and communication and decision-making participation (STD = 0.203, p < 0.001) also strongly influenced treatment satisfaction. The indirect effects of social support and decision-making participation on medication adherence, mediated through treatment satisfaction, were statistically significant ( p < 0.05). Parental anxiety, as a moderating factor, weakened the positive effects of social support, decision-making participation, and treatment satisfaction on medication adherence ( p < 0.05). Conclusion: This study systematically develops an integrated model linking parental social support, communication and decision-making participation, treatment satisfaction, and anxiety to medication adherence in pediatric epilepsy. It highlights the mediating role of treatment satisfaction and the moderating role of parental anxiety. Enhancing parental social support and communication, improving treatment satisfaction, and addressing parental anxiety are key strategies to promote medication adherence.

SUDEP risk is influenced by longevity genomics: A polygenic risk score study Martins H, Mills JD, Pagni S, Gulcebi MI, Vakrinou A, Moloney PB, Clayton LM, Bellampalli R, Stamberger H, Weckhuysen S, Striano P, Zara F, Bagnall RD, Harris RV, Lawrence KM, Sadleir LG, Crompton DE, Friedman D, Laze J, Li L, Berkovic SF, Semsarian C, Scheffer IE, Devinsky O, Kuchenbaecker K, Balestrini S, Sisodiya SM. EBioMedicine. 2025 Aug;118:105841. doi: 10.1016/j.ebiom.2025.105841. Epub 2025 Jul 28. PMID: 40731221; PMCID: PMC12368338. Background: Sudden Unexpected Death in Epilepsy (SUDEP) is a rare and tragic outcome in epilepsy, identified by those with the condition as their most serious concern. Although several clinical factors are associated with elevated SUDEP risk, mechanisms underlying SUDEP are poorly understood, making individual risk prediction challenging, especially early in the disease course. We hypothesised that common genetic variation contributes to SUDEP risk. Methods: Genetic data from people who had succumbed to SUDEP was compared to data from people with epilepsy who had not succumbed to SUDEP and from healthy controls. Polygenic risk scores (PRSs) for longevity, intelligence and epilepsy were compared across cohorts. Reactome pathways and gene ontology terms implicated by the contributing single nucleotide polymorphisms (SNPs) were explored. In the subset of SUDEP cases with the necessary data available, a risk score was calculated using an existing risk prediction tool (SUDEP-3); the added value to this prediction of SNP-based genomic information was evaluated. Findings: Only European-ancestry participants were included. 161 SUDEP cases were compared to 768 cases with epilepsy and 1153 healthy controls. PRS for longevity was significantly reduced in SUDEP cases compared to disease (P =0.0096) and healthy controls (P=0.0016), as was PRS for intelligence (SUDEP cases compared to disease (P=0.0073) and healthy controls (P=0.00024)). The PRS for epilepsy did not differ between SUDEP cases and disease controls (P =0.76). SNP-determined pathway and gene ontology analysis highlighted those related to inter-neuronal communication as amongst the most enriched in SUDEP. Addition of PRS for longevity and intelligence to SUDEP-3 scores improved risk prediction in a subset of cases (38) and controls (703), raising the area-under-the-curve in a receiver-operator characteristic from 0·699 using SUDEP-3 alone to 0·913 when PRSs were added. Interpretation: Common genetic variation contributes to SUDEP risk, offering new approaches to improve risk prediction and to understand underlying mechanisms.

Abstract Objective The objective of this study is to characterize contemporary surgical management practices and factors influencing surgical decision‐making in the management of Lennox–Gastaut Syndrome (LGS) across pediatric epilepsy centers in the United States. Methods A 45‐item cross‐sectional survey was developed and distributed to Pediatric Epilepsy Research Consortium centers. Domains included institutional demographics, surgical evaluation timing and goals, presurgical workup, procedural utilization and outcomes, and barriers to surgery. Descriptive statistics and thematic analysis were performed. Results Thirty‐two pediatric epilepsy centers participated (38% response), the majority comprising pediatric epileptologists at Level 4 National Association of Epilepsy Centers. Most centers (66%) considered surgery after failure of 3–4 antiseizure medications. Presurgical workup typically included brain magnetic resonance imaging (MRI), long‐term electroencephalography (EEG) monitoring, and neuropsychological assessment, while use of functional imaging, magnetoencephalography, and intracranial EEG varied considerably. All centers offered vagus nerve stimulation and corpus callosotomy; 80%–90% offered resection, hemispherectomy, responsive neurostimulation (RNS); 60%–65% offered deep brain stimulation (DBS) and laser ablation. Among centers offering RNS, half targeted thalamic structures exclusively, and the remainder targeted cortical or combined cortical‐thalamic structures; the centromedian nucleus was the preferred thalamic target for RNS and DBS. Surgical decision‐making was influenced by patient characteristics, procedural considerations, and systemic factors. Seizure frequency, family preference, and multidisciplinary input were highly rated across all interventions. Etiology was critical for resection and hemispherectomy, while financial constraints, insurance barriers, and the need for future neuroimaging impacted neuromodulation selection. Scenario‐specific trends included less frequent consideration of DBS and RNS in children under five years, less use of hemispherectomy in older children, preference for corpus callosotomy in children with predominantly drop seizures, and procedural selection based on MRI findings. Significance Substantial variability exists in the surgical management of LGS. These findings highlight critical opportunities to harmonize practices, reduce disparities, and guide comparative effectiveness research to optimize outcomes. Plain Language Summary Lennox–Gastaut Syndrome (LGS) is a severe form of epilepsy that may require surgery when medications are not effective. This study found that surgical care for LGS varies widely across pediatric epilepsy centers in the United States, including when surgery is recommended, how patients are evaluated, and which procedures are available. Newer approaches such as brain stimulation are being used more often, although access remains inconsistent. These findings highlight the need for clearer treatment pathways to ensure that children with LGS have equitable access to the best possible care.

Abstract Objective To assess the localization and lateralization values of ictal emotional features and ictal defensive behaviors in pediatric and young adult patients with frontal lobe epilepsy (FLE). Methods Children and young adults with FLE were identified from a single institution's epilepsy surgery database. Two epileptologists determined by consensus the presence of ictal emotional features (positive‐ smile, laughter, humming, singing; negative‐ fear, crying, anger, disgust, contempt, sadness) and ictal defensive behaviors (freezing with a fearful facial expression, shielding the face with hands, burying the face in a pillow, or exhibiting hyperkinetic motor behaviors like attempting to escape from bed or resisting restraint) in each patient's first video EEG (vEEG). Historic seizure semiology and vEEG reports were compared with the consensus vEEG analysis. Longitudinal changes in ictal emotional features were defined by the emergence or resolution of ictal emotional features between historic seizure semiology and re‐review of presurgical vEEG analysis. Subgroup analyses were conducted according to the seizure lateralization (left vs. right) and sublobar localization (precentral, medial, lateral, extensive) based on surgical extent. Results Twenty‐three FLE patients were included (female 39%; mean age at vEEG analysis: 11.28 years, range 1.75–20.17). The inter‐rater reliability was very good for both ictal emotional features ( κ = 0.81, 95% CI: 0.59–1) and ictal defensive behaviors ( κ = 0.91, 95% CI: 0.79–1). Ictal emotional features were observed in 10 patients (43.4%), with negative emotions present in 70% (7/10) of these cases. vEEG reports lacked documentation of ictal emotional features in two patients. Although ictal emotional features showed no statistical correlation by sublobar regions, ictal defensive behaviors were consistently seen in medial compared to lateral FLE (100% vs. 16.6%; p = 0.004). Longitudinal changes in ictal emotional features were observed in 8 (34.7%) patients. Significance Ictal emotional features were common in pediatric and young adult FLE patients and were mainly negative. Ictal defensive behaviors were more likely associated with medial FLE. Longitudinal changes in ictal emotional features occurred in about a third of pediatric and young adult patients with FLE. Plain Language Summary This study examined emotional features and defensive behaviors during seizures in children and young adults with FLE. Negative emotions were commonly seen during seizures. Ictal defensive behaviors were more frequently observed in patients with medial FLE, and recognizing these signs could help clinicians localize the seizures. Changes in emotional features were seen over time in about one‐third of children and young adult patients.

Original Article Citation Mithani K, Niazi F, Suresh H, Alrumayyan Y, Rayco ER, Ochi A, Otsubo H, Kerr E, Breitbart S, LeBlanc-Millar A, Gadgil N, Raskin JS, Weil AG, Hadjinicolaou A, Iorio-Morin C, Weiss S, Jain P, Sham L, Donner E, Fasano A, Gorodetsky C, Ibrahim GM. Deep brain stimulation of the centromedian nucleus for drug-resistant epilepsy in children: Quality-of-life and functional outcomes from the CHILD-DBS registry. Epilepsia. 2025 Apr 1. doi: 10.1111/epi.18393. Epub ahead of print. PMID: 40167366. Objective: Deep brain stimulation of the centromedian nucleus of the thalamus (CM-DBS) is an investigational, off-label treatment for drug-resistant epilepsy (DRE) in children. Although emerging evidence supports its safety and efficacy for select indications, the effect of CM-DBS on quality of life and functional outcomes such as school attendance has not been studied. Here, we analyzed data from the prospective CHILD-DBS (Child and Youth Comprehensive Longitudinal Database for Deep Brain Stimulation) to examine the impact of CM-DBS on patient- and caregiver-reported outcomes. Methods: Twenty-two children and youth underwent bilateral CM-DBS. Caregiver–child dyads completed surveys related to seizure frequency, seizure severity, quality of life, and school attendance at baseline, 6 months, and 1 year postsurgery. Simulated volumes of tissue activation were analyzed to identify optimal stimulation targets associated with treatment outcome. Results: Of 22 children, 10 experienced ≥50% reduction in seizure frequency (mean reduction = 66.7 ± 17.3%), one exhibited a modest benefit (37.5% reduction), and the remaining 11 experienced no change. The majority (73% of patients) exhibited a clinically important reduction in seizure severity, including six children who did not demonstrate any change in seizure frequency. Only those who experienced a reduction in seizure frequency demonstrated significant improvements in general health and overall quality of life. Furthermore, we observed an increase in school attendance across participants 1 year after CM-DBS. Significance: CM-DBS can lead to reduction in seizure burden concurrent with improvements in quality of life and relevant functional outcomes in children with DRE. These findings further our understanding of the impact of CM-DBS on meaningful outcomes for children and caregivers.