Ivaniuk, Alina

Abstract Objective This study was undertaken to provide an overview of the research landscape and evaluate the impact of lifestyle modifications on seizure reduction and quality of life in people with epilepsy receiving standard medical treatment. Methods Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines, we conducted a systematic review of major databases (Medline, Embase, American Psychological Association PsycInfo, Cochrane Library, and Web of Science) through November 2025. After screening 5151 articles, 118 studies met inclusion criteria: prospective trials reporting seizure frequency in adults or mixed populations with epilepsy. Four epilepsy‐trained reviewers independently assessed studies. A random‐effects meta‐analysis was performed on studies reporting ≥50% seizure reduction or data allowing its calculation. Short‐term response was defined as the earliest postintervention time point, and long‐term response as the final reported time point. Results The 118 studies covered diet ( n = 33), supplements ( n = 20), biofeedback ( n = 14), psychosocial/behavioral therapy ( n = 13), yoga/meditation/mindfulness ( n = 8), music therapy ( n = 7), and others. Fifty‐two (44%) included control groups, whereas 91 (77%) reported statistical analysis of seizure frequency. Among those, 68% showed significant seizure reduction. Quality of life was assessed in 31 studies, 68% reporting improvement. Seventy‐one studies (60%) were included in the meta‐analysis. Overall, the ≥50% seizure reduction response rate was 44% for short‐term outcomes (95% confidence interval [CI] = 38%–50%) and 50% for long‐term outcomes (95% CI = 44%–56%). Dietary interventions had the largest evidence base ( n = 33), with short‐ and long‐term response rates of 40% and 51%, respectively. Meditation/yoga/mindfulness had the highest response rate (62% short term, 79% long term), whereas exercise and supplements had the lowest (30%–35%). Significance Lifestyle modifications may offer beneficial, adjunctive effects on seizure control. However, the current evidence is limited by variability in study design and quality. Larger, well‐designed trials with standardized outcomes are needed to clarify how these interventions can complement epilepsy treatment. This systematic review and meta‐analysis serves as a foundation for future research to better define the role of lifestyle interventions in epilepsy care.

Abstract Epilepsy affects more than 50 million individuals globally and has a substantial genetic component that remains to be completely understood. Traditional studies have focused on severe, early onset cases enrolled through clinical or research settings. Recent biobank‐based approaches, leveraging large‐scale population datasets, offer opportunities to explore genetic associations in broader epilepsy phenotypes, including milder, later onset forms. We analyzed data from more than 750 000 individuals across the UK Biobank, All of Us, and Massachusetts General Brigham Biobank, including 20 026 individuals with epilepsy. Rare coding variant burden testing revealed a significant association with LGI1 , a known epilepsy gene. Among the other top 10 associated genes, seven had prior evidence linking them to epilepsy ( GABRG2 , ATP1A3 ), neurological disorders with comorbid seizures ( HTRA2 , KRIT1 , STAG1 ), possible involvement in seizure phenotypes ( ADAM23 ), or roles in neuronal function ( PDCD4 ). Thus, we provide the first statistical evidence for ADAM23 as a candidate gene for epilepsy, based on the suggestive association signal combined with prior biological evidence from both animal (canine and murine) and one recent human epilepsy case study, potentially contributing to human epilepsy through its direct interaction with LGI1 . Phenome‐wide analyses highlighted the pleiotropic effects of epilepsy genes, with LGI1 and ADAM23 predominantly associated with epilepsy, whereas other genes such as KRIT1 , TSC1 , and TSC2 exhibited broader systemic involvement. Our study shows the potential of population‐scale genomic data and suggests that integrating these datasets with deep phenotyping will uncover more novel insights into epilepsy genetics in the future.

Abstract The International League Against Epilepsy (ILAE) is a global organization dedicated to improving the lives of people with epilepsy through education, research, and advocacy. Recognizing the need for broader engagement and multidisciplinary collaboration, the ILAE has established five sections: Young Epilepsy Section (YES), Nursing, Social Work and Social Services (SWSSS), Neurotechnology, and Pharmacy. These sections aim to strengthen professional networks, enhance education, and promote innovation in epilepsy care. YES fosters leadership and participation among early‐career professionals, whereas the Nursing Section addresses gaps in epilepsy‐specific training and competency development. SWSSS emphasizes psychosocial care, advocacy, and health equity, supporting Intersectoral Global Action Plan (IGAP) objectives through culturally sensitive interventions. The Neurotechnology section advances the integration and development of innovative tools for diagnosis and treatment, and the Pharmacy section focuses on optimizing medication management and access to antiseizure medications globally. Collectively, these sections contribute to the WHO IGAP by improving policy, care delivery, research, and public health responses. Looking ahead, ILAE seeks to expand multidisciplinary participation, encourage cross‐sectional collaboration, and maintain its role as a leading force in global epilepsy care. Through these initiatives, ILAE continues to build capacity, foster inclusivity, and drive progress toward equitable, comprehensive epilepsy services worldwide. Plain Language Summary The International League Against Epilepsy (ILAE) is the global organization responsible for all healthcare professionals involved in the care of those with epilepsy. Recognizing the increasing number of different disciplines now contributing to epilepsy care, and the need to develop professionals of the future, the ILAE has recognized “sections” of like‐minded individuals to encourage networking and communication. Together, these sections contribute to the WHO Intersectoral Global Action Plan (IGAP) by improving policy, care delivery, research, and public health responses. Moving forward, the ILAE seeks to expand multidisciplinary participation, encourage collaboration, and maintain its role as a leading force in global epilepsy care.

ABSTRACT The TLK2 gene encodes a serine/threonine kinase essential for chromatin assembly. Loss‐of‐function heterozygous variants were recently identified as a cause of a rare neurodevelopmental disorder ( TLK2 ‐NDD) characterized by a variable spectrum of developmental delay, autism, behavioral issues, and severe constipation. We describe two unrelated young adult females presenting with neurodevelopmental delay, neurobehavioral abnormalities, and constipation since infancy secondary to truncating TLK2 variants. Case 1 is a 26‐year‐old female who was referred to our clinic for extended assessment of new‐onset psychosis and concern for seizures. She has been diagnosed with autism spectrum disorder and has a history of developmental delay, constipation, and aggressive outbursts since early childhood. At the age of 24 years, she developed an acute onset of persistent daily auditory hallucinations with threatening content that was refractory to medical and electroconvulsive therapy. Video‐ EEG assessment found no correlates for hallucinations. Trio whole genome sequencing revealed a heterozygous de novo pathogenic TLK2 variant, NM_006852.6:c. 367C >T (p. Arg123Ter ). Case 2 is a 19‐year‐old female who was evaluated for developmental delay and intellectual disability. Her phenotype was also notable for constipation since infancy and suggestive hypothalamic features with obesity, metrorrhagia, and hypersomnia. Trio whole genome sequencing revealed a likely pathogenic heterozygous TLK2 variant NM_006852.6:c.587del(p.Ser196ThrfsTer19) inherited from an asymptomatic, mosaic father. We present the adult phenotype of two young females with truncating variants in TLK2 and unusual phenotypic features of refractory hallucinations and possible hypothalamic syndrome. While both features may be independent of TLK2 ‐NDD, evidence from schizophrenia genome‐wide association studies and tissue expression data indicates that these features might be a part of longitudinal phenotype development. Long‐term follow‐up studies are required to unfold the phenotypic spectrum of TLK2 ‐NDD and to better understand the implications of these findings for management and prognosis.

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.

Abstract Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

Abstract Rationale Neurodevelopmental disorders (NDDs) are characterised by significant challenges in communication, social interaction, and adaptive function, often impacting quality of life. Previous studies support genetic influences on the communication abilities of individuals with NDD, but were either limited to single genetic conditions or to small cohorts with a limited selection of communication measures. Methods We analysed caregiver-reported communication abilities in 79,518 individuals with NDD from the Simons Searchlight and SPARK registries: 4,439 with a CNV-based or monogenic NDD and 75,079 with autism spectrum disorder (ASD) without a known genetic cause (idiopathic ASD) as controls. For analysis, we a priori selected 10 communication-related measures based on their availability in the study cohorts, coverage of distinct communication aspects, and their frequent use in neurodevelopmental phenotyping, yielding 177,328 data points across all study cohorts. The individuals in the Searchlight registry were divided into a Discovery cohort (the 15 most prevalent genetic NDD conditions) and a Confirmation cohort (all other genetic NDD conditions). A second Confirmation cohort was generated using all individuals with genetic ASD forms from the SPARK registry. We then tested each of the three case cohorts and each genetic condition represented in the Discovery cohort against the ASD control cohort. Developmental trajectories were assessed through testing of participants grouped by age at evaluation. Results Measure-level analyses demonstrated significant associations between genetic status and communication abilities, differences in communication abilities between classes of genetic variants (monogenic vs. CNV-based NDDs), and variability between specific genetic NDD conditions. CNV-based NDDs showed milder communication impairment, outperforming idiopathic ASD controls in 9/10 communication measures, whereas monogenic NDD conditions had more pervasive impairments, especially in verbal communication. Although impaired in verbal communication, five monogenic NDD conditions showed at least suggestive strengths in nonverbal and social communication relative to idiopathic ASD controls ( CSNK2A1 , CTNNB1 , SETBP1 , MED13L , and PPP2R5D ), specifically in using gestures. Developmental trajectory analyses revealed STXBP1 as the gene group at highest risk of developmental stagnation in communication abilities. Conclusions These findings underscore the potential of precision speech-language pathology (SLP) approaches tailored to the specific verbal and nonverbal communication strengths and weaknesses of genetic groups. We also provide evidence for measurable improvements and declines in communication abilities with age at the group level, highlighting the need for developmentally informed care. By integrating genetic insights into clinical practice, precision SLP approaches may enhance communication outcomes and developmental progress and improve quality of life for individuals with genetic NDDs.

Abstract Motivation: Epilepsy is a diverse group of neurological disorders affecting over 50 million people worldwide. While common epilepsy types are well studied, rare epilepsies—often severe and genetically complex—pose significant challenges in diagnosis, research, and treatment. Accurate and interoperable etiology and disease classifications are critical for improving data sharing, supporting clinical decision-making, and advancing rare disease research. Results: To enhance the accuracy of epilepsy-related disease concept representation within the Mondo Disease Ontology (Mondo), we conducted a series of expert-driven workshops in collaboration with the team from the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP). Specialists in epileptology, genetics, neurodevelopment, biomedical ontology, and patient community advocates systematically reviewed and revised the epilepsy hierarchy in Mondo, aligning it with the International League Against Epilepsy (ILAE) classification system. These updates include reclassification of epilepsy subtypes, including syndromes, age-related epilepsies, and developmental epileptic encephalopathies, resulting in a more granular, standardized, and clinically relevant structure. Mondo now offers an enhanced framework for integrating epilepsy data across resources, enabling improved interoperability and facilitating rare disease research and data curation, with continued efforts underway to further refine and expand this integration.

Abstract Aim To assess the long‐term efficacy of vagus nerve stimulation (VNS) in Dravet syndrome and identify key factors influencing treatment response. Method We conducted a two‐center, retrospective cohort study of 15 patients (six females, nine males; median age at seizure onset 4 months [range 2–12 months]) with Dravet syndrome who underwent VNS implantation. Seizure frequency was evaluated over 12 months and up to 10 years after implantation. Linear mixed‐effects regression was used to analyze the impact of antiseizure medications (ASMs) and VNS parameters on seizure outcomes. Results A 50% or greater reduction in seizure frequency was observed in 93.3% (14 of 15) of patients at 12 months and 86.7% (13 of 15) of patients across the 10‐year follow‐up. This seizure reduction was independent of ASM use; the VNS duty cycle was a significant predictor of seizure reduction. Two individuals (13.3%) experienced minor adverse events. Interpretation VNS provides durable seizure reduction in Dravet syndrome, independent of ASM adjustments. These findings highlight the importance of early VNS initiation and parameter optimization in managing genetically defined epilepsy syndromes.