Epilepsia Open最新文献

{"title":"Artificial intelligence in the assessment of epilepsy-related genetic mutations: Learned from GABA_A receptors and GABA transporter 1.","authors":"Juexin Wang, Jing-Qiong Kang","doi":"10.1002/epi4.70259","DOIUrl":"https://doi.org/10.1002/epi4.70259","url":null,"abstract":"<p><p>This review examines how recent genetic and technological advances have transformed our understanding and treatment of genetic epilepsies (GEs), with a focus on disorders involving GABA_A receptors (GABRs) and the GABA transporter 1 (GAT-1) encoded by SLC6A1. About 1000 genes are associated with epilepsy, including ~100 directly linked to defined epilepsy syndromes. Many disease-causing variants affect ion channels and transporters, disrupting protein structure, trafficking, and synaptic function. These defects often underlie developmental and epileptic encephalopathies (DEEs). A key insight from recent studies is that endoplasmic reticulum (ER)-related pathology-such as protein misfolding, ER retention, and accelerated degradation, which are common consequences of those pathogenic variants. For example, mutations in SLC6A1 or GABRG2 lead to impaired trafficking and reduced surface expression of GAT-1 or GABR subunits, resulting in deficient inhibitory neurotransmission. These mechanisms have been validated using advanced cellular assays and mouse models, although such experimental approaches remain costly and labor-intensive. Artificial intelligence (AI) is emerging as a powerful complement to experimental studies. Computational approaches, including generative AI and protein language models, can predict mutation-induced changes in protein structure, stability, and interactions, aided by tools such as AlphaFold. These methods enable large-scale, system-level analysis of variants and hold promise for accelerating drug discovery. However, current AI models are limited by fragmented datasets and the inherent complexity of biological systems. Integrating AI with experimental research offers a scalable strategy to translate mechanistic insights across genetic epilepsies (GEs). For instance, 4-phenylbutyrate (PBA), tested in SLC6A1 and GABRG2 epilepsy mouse models and now in clinical trials (NCT04937062), shows promise for treating GEs and DEEs caused by ER-retained mutant proteins. AI-based prediction could help identify additional GEs likely to respond to similar therapeutic approaches. Overall, combining experimental and AI-driven methods represents a new frontier for advancing the diagnosis and treatment of GEs and DEEs. PLAIN LANGUAGE SUMMARY: Mutations in almost 1000 genes have been linked to epilepsies, including those affecting GABA signaling such as GABAA receptors and the GABA transporter. Using cell and mouse studies, we found that many of these gene mutations cause similar problems inside cells. Specifically, the mutant proteins get stuck inside the cell in a structure called the endoplasmic reticulum (ER) and cause ER stress. Importantly, an FDA-approved drug 4-phenylbutyrate (PBA) can reduce these problems. We propose using artificial intelligence (AI) to predict how different gene mutations affect protein function and to identify which patients are likely to benefit from PBA treatment.</p>","PeriodicalId":12038,"journal":{"name":"Epilepsia Open","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Postmortem MRI reveals distinct structural features in sudden unexpected death in epilepsy.","authors":"Andrea Hill, Fenglai Xiao, Maria Thom, David Maudgil, Hannah Bergman, John S Duncan, Owen J Arthurs, Josemir W Sander, Beate Diehl, Matthias J Koepp","doi":"10.1002/epi4.70276","DOIUrl":"https://doi.org/10.1002/epi4.70276","url":null,"abstract":"<p><p>Magnetic resonance imaging (MRI) abnormalities have been reported in individuals who later die from sudden unexpected death in epilepsy (SUDEP), but their specificity and predictive value remain uncertain. Postmortem MRI (PM-MRI) offers a unique opportunity to distinguish structural features associated with SUDEP from changes related to epilepsy, comorbid illness, or the postmortem interval. We performed PM-MRI in nine individuals: five with suspected SUDEP, two with epilepsy who died from non-seizure-related causes, and two without epilepsy who died from sudden cardiac death. Hippocampal, amygdala, and subcortical volumes were quantified using validated segmentation methods and compared with 70 healthy in vivo controls. Compared with non-SUDEP cases, SUDEP cases showed significantly larger hippocampal (p = 0.014) and amygdala (p = 0.023) volumes, with most exceeding the healthy control mean, whereas non-SUDEP cases consistently demonstrated volume reductions. These findings parallel in vivo MRI observations in individuals at high risk of SUDEP and are consistent with transient peri- or postictal structural changes. In the context of recent large-scale studies showing few validated clinical SUDEP biomarkers beyond frequent generalized tonic-clonic seizures and sleeping alone, PM-MRI may provide an objective approach to positively identifying individuals who died from SUDEP. PLAIN LANGUAGE SUMMARY: We used magnetic resonance imaging (MRI) scans taken after death to study brain changes in people who died from sudden unexpected death in epilepsy (SUDEP). We found that certain brain areas involved in seizure control and automatic body functions, such as breathing and heart rate, were larger in people who died from SUDEP than in people who died from other causes. These changes were similar to those previously seen on brain scans of people with epilepsy who are known to be at higher risk of SUDEP while they were still alive. Our findings suggest that postmortem MRI may help identify brain changes linked to SUDEP.</p>","PeriodicalId":12038,"journal":{"name":"Epilepsia Open","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KCNQ2 neonatal epilepsy: Impact of prompt diagnosis and treatment, and early predictors of outcome severity.","authors":"Trupti Jadhav, Sophie E Bouffler, Emily Innes, Michael Fahey, Matthew Hunter, Kavitha Kothur, Sebastian Lunke, Matthew Lynch, Emma Macdonald-Laurs, Elizabeth Emma Palmer, Chirag Patel, Jason Pinner, Kate Riney, Rani Sachdev, Sarah A Sandaradura, Ingrid E Scheffer, Zornitza Stark, Katherine B Howell","doi":"10.1002/epi4.70266","DOIUrl":"https://doi.org/10.1002/epi4.70266","url":null,"abstract":"<p><strong>Objective: </strong>To determine whether prompt genetic diagnosis in children with KCNQ2 neonatal epilepsy enabling targeted therapy is associated with improved outcomes, and identify early predictors of developmental outcomes.</p><p><strong>Methods: </strong>Thirty-seven children with KCNQ2 neonatal epilepsy were recruited from five pediatric centers. We reviewed demographic, clinical, EEG, and genetic data. We determined differences in outcomes between individuals with prompt (greater than 30 days from seizure onset) and later genetic diagnosis, and we identified neonatal factors associated with developmental outcome.</p><p><strong>Results: </strong>Baseline characteristics were similar between children with prompt (n = 6, median age at genetic diagnosis 15 days) and later (n = 31, median age 309 days, p < .05) diagnosis. All with prompt diagnosis received sodium channel blocking (SCB) anti-seizure medication (ASM) in the neonatal period compared with 15/31 (48%) in the later diagnosis group. Children with prompt diagnosis had higher rates of seizure freedom at age 12 months than those with later diagnosis (6/6 [100%] vs. 17/31 [54%]; p .049], and lower number of emergency department representations (median 0 vs. 2), and hospital readmissions (median 0 vs. 1). Factors in the neonatal period associated with abnormal developmental outcome included neurological abnormalities (e.g., abnormal tone) and markedly abnormal neonatal EEG background (11/11 [100%] with markedly abnormal EEG vs. 11/24 [46%] with normal to moderately abnormal EEG).</p><p><strong>Significance: </strong>Prompt genetic diagnosis was associated with targeted therapy, resulting in improved seizure control and reduced hospital representation. Clinical features present in the neonate assist in predicting outcome severity, which is critically important in counselling families receiving a KCNQ2 diagnosis soon after seizure onset.</p><p><strong>Plain language summary: </strong>In KCNQ2 neonatal epilepsy, sodium channel blocking antiseizure medicines are recommended, but the benefits of starting treatment early have been uncertain. Our findings show that prompt genetic diagnosis enabled early targeted treatment, with potential to improve outcomes. Specifically, prompt genetic diagnosis was associated with improved seizure control and reduced hospital visits compared with delayed diagnosis. However, a prospective, long-term study is needed to determine whether early treatment also improves developmental outcomes. Predicting outcome severity in newborns remains challenging, although abnormal neurological examination and markedly abnormal EEG in the newborn period were linked to abnormal developmental outcomes.</p>","PeriodicalId":12038,"journal":{"name":"Epilepsia Open","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroanatomical correlates of neuropsychological dysfunction in pediatric pharmacoresistant epilepsy due to focal cortical dysplasia type II.","authors":"Ana Arenivas, Spencer Morris, Brittany Lapin, Yadi Li, Lisa Ferguson, Stephen E Jones, Ingmar Blümcke, Imad Najm, Robyn M Busch, Zhong Irene Wang","doi":"10.1002/epi4.70268","DOIUrl":"https://doi.org/10.1002/epi4.70268","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Children and adolescents with pharmacoresistant epilepsy (PRE) show marked individual cognitive and emotional variability not fully accounted for by demographic or clinical variables. This exploratory pilot study characterizes neuroanatomical abnormalities and their relationships with neuropsychological functioning in a pediatric patient cohort with PRE due to type II focal cortical dysplasia (FCD).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Retrospective data were obtained from patients with histopathologically confirmed FCD II who completed presurgical evaluations including high-resolution 3T MRI and neuropsychological assessment. Voxel-based morphometric MRI postprocessing using the Morphometric Analysis Program (MAP18) provided age-adjusted quantitative characterizations of within-lesion MRI features [Junction (gray-white matter junction blurring), Extension (abnormal gyration), and Thickness (cortical thickening in the regional lesion)]. Associations between MRI feature z-scores and cognitive domain composite scores were evaluated using Pearson correlation coefficients and multivariable linear and logistic regression models, controlling for seizure side and site. Lesion ROI volumes were also analyzed to evaluate their associations with MRI feature z-scores and neuropsychological function.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We included 24 patients [mean age = 13.8; 58% male] with FCD IIa (n = 8; 33%) or FCD IIb (n = 16; 67%). Patients with FCD IIb had higher mean and maximum Junction z-scores compared to those with FCD IIa (Cohen's d = 1.00 and 1.07). Mean and maximum Thickness z-scores were negatively associated with attention (r = -0.32; r = -0.47) and general cognitive ability (GCA; r = -0.46; r = -0.41). Mean Thickness z-scores were also negatively associated with visuospatial skills (r = -0.34). In regression models, higher mean and maximum Thickness were associated with poorer GCA scores (estimate (se): -14.98 (6.88), p = 0.042; -5.76 (2.41), p = 0.027, respectively), and higher maximum Thickness was associated with worse attention scores (estimate (se): -6.02 (2.60), p = 0.032). Lesion volumes were not associated with MRI feature z-scores, cognition, self-reported mood or anxiety.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Significance: &lt;/strong&gt;Our findings showed that lesional neuroanatomical abnormalities, particularly increased cortical thickness, were associated with poorer cognitive performance in pediatric patients with FCD II. Future research in larger, more diverse samples is needed to identify other factors contributing to neuropsychological variability in this population.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Plain language summary: &lt;/strong&gt;We studied 24 pediatric patients with pharmacoresistant epilepsy (PRE) and a confirmed diagnosis of focal cortical dysplasia type II (FCD II) to examine how MRI findings relate to thinking abilities. Patients with FCD IIb showed more pronounced MRI abnormalities than FCD IIa. Greater cortical thickening within the lesion w","PeriodicalId":12038,"journal":{"name":"Epilepsia Open","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trends in antiseizure medication monotherapy for pediatric epilepsy in the United States.","authors":"Adam P Ostendorf, Mariah Eisner, Mahmoud Abdel-Rasoul, Stephanie M Ahrens, Jaime D Twanow, Howard P Goodkin, Christopher W Beatty","doi":"10.1002/epi4.70273","DOIUrl":"https://doi.org/10.1002/epi4.70273","url":null,"abstract":"<p><strong>Objective: </strong>National prescribing trends for antiseizure medication (ASM) in children with epilepsy over the past decade are unclear. Despite the 2021 SANAD II trials supporting lamotrigine and valproate for focal and generalized epilepsies, respectively, it is unknown if their use increased. This study evaluated ASM prescriptions in the U.S. before and after publication of high-quality clinical trials.</p><p><strong>Methods: </strong>A retrospective cross-sectional cohort study was conducted using the Epic Cosmos Dataset, a national electronic health record repository covering over 300 million patients. Children with epilepsy aged 4-18 years prescribed their first ASM between 2015 and 2024 were included, excluding those with absence epilepsy. The primary outcome was the prescribed ASM, analyzed by year and patient demographics.</p><p><strong>Results: </strong>Among 146 395 children with a single ASM prescription, levetiracetam was most common (58%), increasing from 47% in 2015 to 66% in 2024. Lamotrigine and valproate declined (10%-5.5% and 12%-7.5%, respectively). Females were prescribed less valproate (5% vs. 12% in males). Odds of lamotrigine prescription (OR, 95% CI) were lowest among patients in the highest social vulnerability index quartile (0.71, 0.67-0.75), Black (0.39, 0.36-0.42), Asian (0.49, 0.42-0.57), Hispanic/Latino (0.60, 0.56-0.64), and male (0.60, 0.57-0.62) patients.</p><p><strong>Significance: </strong>While a reduction in valproate was anticipated given increasing teratogenic concerns, lamotrigine prescriptions for children in the U.S. declined despite evidence of its superiority over other commonly used ASMs. This trend is more prominent in racial and ethnic minorities and those with higher social vulnerability. Interventions are needed to ensure children receive evidence-based, equitable care.</p><p><strong>Plain language summary: </strong>Some seizure medications work better than others, and clinical trials have shown lamotrigine to be among the most effective and best-tolerated first treatments for children with epilepsy. Using a large national database of over 146 000 children, we found that lamotrigine prescriptions declined steadily from 2015 to 2024, while the use of levetiracetam, a less effective alternative, continued to rise. This trend was most pronounced in Black, Hispanic, and socially vulnerable children, suggesting that many children are not receiving evidence-based care and that existing inequities in epilepsy treatment are worsening.</p>","PeriodicalId":12038,"journal":{"name":"Epilepsia Open","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Widening participation in the International League Against Epilepsy: Looking to the future.","authors":"J Helen Cross, Lauren Coleman, Sebastian Oritz, Alina Ivaniuk, Cecilie Gjessing Nome, Eugenia Roza, Patricia O Shafer, Jane von Gaudecker, Chris Ryan, Benjamin H Brinkmann, Caroline Neuray, Tim Welty, Samuel Wiebe, Alla Guekht","doi":"10.1002/epi4.70272","DOIUrl":"https://doi.org/10.1002/epi4.70272","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12038,"journal":{"name":"Epilepsia Open","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Energy metabolism, adenosine, and glutamate signaling reprogramming by decanoic acid in Glut1 disorder syndrome.","authors":"Erwann Pain, Yatra Kapatel, Pankaj K Singh, Katie Lloyd Jones, Jamuna Selvakumaran, Alberto Malerba, Walter Lucchesi, Tricia Rutherford, Christina A Gurnett, Matthew C Walker, Robin S B Williams","doi":"10.1002/epi4.70263","DOIUrl":"https://doi.org/10.1002/epi4.70263","url":null,"abstract":"<p><p>Glut1 deficiency syndrome (Glut1DS) leads to neurological and cognitive symptoms and is primarily treated using carbohydrate-restricted ketogenic diets. However, a recent clinical trial of a less restrictive, non-ketogenic, medium chain triglyceride (MCT) diet with a high decanoic acid content suggests efficacy in Glut1DS treatment. Here, we employ human Glut1DS-derived iPSCs to investigate a role for these medium chain fatty acids in the regulation of gene expression as a proxy for metabolic reprogramming. We show that the new high decanoic blend reproduces many therapeutic changes in energy metabolism-related gene expression seen during glucose-restricted ketogenic diets, including enhanced expression of β-oxidation, TCA cycle, and oxidative phosphorylation-related genes, but under high glucose conditions. These treatments also unexpectedly regulate transcription of adenosine signaling and synaptic transmission-related genes. This study thus identifies potential molecular mechanisms of decanoic acid that may underlie its clinical benefit in Glut1DS and expands its role to other genetic epilepsies. PLAIN LANGUAGE SUMMARY: Ketogenic diets provide the first-choice treatment for glucose transporter type 1 deficiency syndrome (Glut1DS), where reduced carbohydrate intake triggers the production of ketones as the therapeutic mechanism. Alternatively, a new, flexible medium chain triglyceride diet has been developed that does not involve reduced carbohydrate restriction nor ketone production. This study investigates the metabolic mechanisms underlying this diet in Glut1DS patient-derived stem cells. Interestingly, the diet mimicked the beneficial effects of ketogenic diets to improve energy metabolism, and surprisingly indicated new ways that the diet may provide therapeutic benefit in Glut1DS treatment.</p>","PeriodicalId":12038,"journal":{"name":"Epilepsia Open","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-30a-5p mediates epileptogenesis in epilepsy models by targeting SOX4 to regulate the Wnt/β-catenin pathway.","authors":"Zhenlin Yang, Xu Zhang, Jingjing Guo, Yuanxin Wei, Jinzi Li","doi":"10.1002/epi4.70270","DOIUrl":"https://doi.org/10.1002/epi4.70270","url":null,"abstract":"<p><strong>Objective: </strong>The pathogenesis of epilepsy is closely associated with neuronal synaptic plasticity. MicroRNAs (miRNAs) can regulate various biological processes by binding to specific sequences on target genes. This study employs bioinformatics, molecular dynamics, and experimental approaches to investigate the mechanism by which MiR-30a-5p treats epilepsy through targeting SOX4 and regulating the Wnt/β-catenin signaling pathway.</p><p><strong>Methods: </strong>Performed bioinformatics analysis to predict the signaling pathways involved in miRNA-30a-5p-mediated intervention in epilepsy. RT-qPCR was used to detect the expression levels of miR-30a-5p in the hippocampal tissues of epileptic rats and in primary hippocampal neurons subjected to Mg²⁺-free treatment. The effects of miR-30a-5p inhibition on synaptic plasticity were assessed using EEG, the Morris water maze test, Golgi staining, Sholl analysis, and Western blotting. TargetScan and miRTarBase were employed to predict the target genes of miR-30a-5p. The interaction was validated through dual-luciferase reporter assays, IHC, IF, and Western blotting, and the effect of SOX4 inhibition on synaptic plasticity was evaluated. The involvement of the Wnt signaling pathway was assessed by Western blotting.</p><p><strong>Results: </strong>The expression level of miR-30a-5p was significantly elevated in the hippocampal region of epileptic rats and in magnesium-depleted hippocampal neuronal cultures. SOX4 was identified as a direct target of miR-30a-5p. Inhibiting miR-30a-5p reduces the expression of synapse-associated proteins (SYP/CaMKII/PSD95), while upregulating SOX4 and downregulating the levels of Wnt3a, β-catenin, and cyclin D1. miR-30a-5p may participate in alterations of neuronal synaptic plasticity by directly targeting and inhibiting SOX4 expression, thereby activating the Wnt/β-catenin signaling pathway.</p><p><strong>Significance: </strong>This study provides evidence that miR-30a-5p participates in the process of synaptic plasticity impairment in epileptic neurons. The study confirms a direct interaction between miR-30a-5p and SOX4. Furthermore, miR-30a-5p regulates the Wnt/β-catenin signaling pathway by targeting SOX4, thereby influencing neuronal synaptic plasticity impairment. This discovery provides a novel potential therapeutic target for delaying epilepsy progression.</p><p><strong>Plain language summary: </strong>Epilepsy is a common brain disorder that affects millions of people worldwide. This study found that a small molecule called miR-30a-5p increases in the brain during epilepsy and disrupts normal communication between neurons. By blocking this molecule in laboratory experiments, we were able to improve neuron function and reduce damage. These findings suggest that targeting miR-30a-5p could lead to new treatments to slow down the progression of epilepsy.</p>","PeriodicalId":12038,"journal":{"name":"Epilepsia Open","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic sleep deprivation promotes drug-resistant epilepsy via the BMAL1-mTOR-P-gp axis.","authors":"Xiaomeng Wang, Rui Li, Yuzhu Zhang, Yi Hu, Jingjiao Chen, Sijia Tian, Dong Zhou, Xiaosa Chi","doi":"10.1002/epi4.70271","DOIUrl":"https://doi.org/10.1002/epi4.70271","url":null,"abstract":"<p><strong>Objective: </strong>The interplay between chronic sleep deprivation and drug-resistant epilepsy (DRE) has gained increasing attention. Brain and muscle Arnt-like protein 1 (BMAL1), which is implicated in sleep disturbance, has an unclear role in DRE. We aimed to investigate the role of BMAL1 in sleep deprivation-induced DRE.</p><p><strong>Methods: </strong>A pentylenetetrazole (PTZ) kindling epilepsy model was established to explore the impact of chronic sleep deprivation on pharmacoresistance and related molecular expression. BMAL1 was either overexpressed or knocked down in epileptic rats using adeno-associated viral vectors, and pharmacoresistance together with hippocampal protein levels were assessed. Complementary in vitro experiments in brain endothelial cells and astrocytes further evaluated the effects of BMAL1 on Per2, P-S6, and P-gp.</p><p><strong>Results: </strong>Chronic sleep deprivation significantly increased pharmacoresistance, accompanied by reduced BMAL1 and Per2, elevated P-S6, and increased P-glycoprotein (P-gp) expression in the hippocampus. In vitro experiments confirmed that BMAL1 regulates P-gp through the mTOR pathway. In vivo, BMAL1 overexpression attenuated chronic sleep deprivation-induced pharmacoresistance, restoring Per2, inhibiting the mTOR pathway, and reducing P-gp levels. Conversely, BMAL1 knockdown promoted pharmacoresistance in epileptic rats with normal sleep, with decreased Per2, increased P-S6, and elevated P-gp.</p><p><strong>Significance: </strong>These findings indicate that BMAL1 is an important mediator linking chronic sleep deprivation to pharmacoresistance in epilepsy, and suggest the BMAL1-mTOR-P-gp axis as a potential therapeutic target for drug-resistant epilepsy.</p><p><strong>Plain language summary: </strong>Drug-resistant epilepsy remains a major clinical challenge, and sleep loss increases its risk. We found that chronic sleep loss reduces BMAL1, a protein that helps regulate sleep. In experiments with rats and brain cells, altering BMAL1 levels changed P-glycoprotein via the mTOR pathway. These changes in P-glycoprotein then influenced the response to anti-seizure medicines. The study showed that targeting BMAL1 may be a new treatment for drug-resistant epilepsy.</p>","PeriodicalId":12038,"journal":{"name":"Epilepsia Open","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world effectiveness of highly purified cannabidiol in epilepsy associated with 15q11.2-q13.1 duplication and deletion syndromes: A multicenter study.","authors":"Emanuele Cerulli Irelli, Adolfo Mazzeo, Marco Perulli, Georgia Ramantani, Domenica Battaglia, Irene Bagnasco, Erica Cognolato, Pasquale Striano, Susanna Negrin, Alberto Danieli, Paolo Bonanni, Francesca F Operto, Carlo Di Bonaventura, Antonietta Coppola, Alessandro Orsini","doi":"10.1002/epi4.70241","DOIUrl":"https://doi.org/10.1002/epi4.70241","url":null,"abstract":"<p><p>This multicenter retrospective study evaluated the effectiveness and safety of highly purified cannabidiol (CBD) in 22 patients with 15q11.2-q13.1 duplication or deletion syndromes (15q-DDS), including 12 with 15q duplication syndrome (dup15q) and 10 with Angelman syndrome (AS). Median (interquartile range [IQR]) age at CBD initiation was 14.5 (10-22.5) years, with a median (IQR) follow-up of 21 (14-33) months. All dup15q and two AS patients presented with a Lennox-Gastaut phenotype. At last observation, mean seizure reduction was 55.7% (95% confidence interval 38.7-72.7), with 63.6% patients achieving ≥50% reduction, 40.9% achieving ≥75% reduction, and 18.2% achieving seizure freedom. Tonic seizures in dup15q and myoclonic seizures in AS showed the most notable reductions. EEG improvement was observed in 7/16 patients, with marked improvement observed in two dup15q patients. Clinical improvement on the Clinical Global Impression-Improvement scale was reported in 72.7%, alongside nonseizure benefits such as improved sleep, behavior, and attention in a subset of patients. CBD was well tolerated; no patient discontinued CBD due to side effects alone, and retention at last visit was 81.8%. These findings suggest that CBD may provide clinically meaningful benefit in patients with 15q-DDS, including seizure reduction and improvements in sleep, behavior, and attention in selected cases. PLAIN LANGUAGE SUMMARY: Epilepsy secondary to 15q11.2-q13.1 duplication or deletion syndromes (15q-DDS) is often severe, making daily life difficult for patients and their families. In this study, treatment with highly purified cannabidiol (CBD) reduced seizures in many patients with 15q-DDS. CBD was generally well tolerated, and caregivers also reported improvements in sleep, behavior, and attention in a number of cases. Overall, these findings suggest that CBD may be a helpful treatment option for people with 15q-DDS.</p>","PeriodicalId":12038,"journal":{"name":"Epilepsia Open","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}