Epilepsia最新文献

{"title":"Blood neurofilament light chain as a biomarker for cognitive impairment in adults with epilepsy: Integrated evidence from clinical cohorts in Northeast China and European GWAS data.","authors":"Zhiqing Chen, Yujin Guo, Jingyi Yao, Jingqi Lin, Huaiyu Sun, Jiaai Li, Wuqiong Zhang, Shuai Hou, Hongmei Meng","doi":"10.1111/epi.18659","DOIUrl":"https://doi.org/10.1111/epi.18659","url":null,"abstract":"<p><strong>Objective: </strong>Epilepsy treatment aims not only to control seizures but also to enhance quality of life. However, reliable blood-based biomarkers for epilepsy-related cognitive impairment are lacking. This study investigated the association between plasma neurofilament light chain (NfL) levels and cognitive function in epilepsy by integrating evidence from observational and Mendelian randomization (MR) analyses across different populations.</p><p><strong>Methods: </strong>We conducted a cross-sectional observational study at the First Hospital of Jilin University, enrolling 152 adults with epilepsy. Demographic and clinical information was collected, and cognitive status and psychological status were assessed using the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Memory and Executive Screening (MES) scale, Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD). Plasma NfL levels were measured using enzyme-linked immunosorbent assay (ELISA). Statistical analyses included logistic regression, linear regression, and receiver-operating characteristic (ROC) curve analysis. In parallel, two-sample MR was performed using genome-wide association study (GWAS) summary statistics from European cohorts. Shared genetic variants between epilepsy and cognitive impairment were identified using multi-trait analysis of GWAS (MTAG) and cross-phenotype association (CPASSOC), and served as instrumental variables to estimate the causal effect on plasma NfL levels.</p><p><strong>Results: </strong>Plasma NfL levels were significantly higher in the cognitively impaired group. After adjusting for confounders, elevated NfL levels remained independently associated with increased risk of cognitive impairment and inversely correlated with cognitive scores. ROC curve analysis showed high diagnostic accuracy of plasma NfL. MR analysis confirmed a positive causal relationship between epilepsy-related cognitive impairment and plasma NfL levels.</p><p><strong>Significance: </strong>Plasma NfL is associated with cognitive impairment in epilepsy and may serve as an early blood-based biomarker for identifying cognitive dysfunction in this population.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delayed excitability recovery and downregulation of neurodevelopmental pathways contribute to phenotypic differences in KCNQ2-related disorders.","authors":"Yingying Wang, Min Liu, Ning Hua, Qing You, Shan Wang, Chudi Zhang, Jianhua Feng, Pingping Jiang, Wei Yang, Pu Miao","doi":"10.1111/epi.18653","DOIUrl":"https://doi.org/10.1111/epi.18653","url":null,"abstract":"<p><strong>Objective: </strong>Pathogenic variants in the KCNQ2 gene cause a spectrum of neonatal onset epilepsy, from self-limited familial neonatal epilepsy (SeLNE; mild end) to developmental and epileptic encephalopathy (DEE; severe end). The associations and differences in the molecular mechanisms between the developmental outcomes of different KCNQ2 variants (SeLNE vs. DEE) remain unclear.</p><p><strong>Methods: </strong>Using brain slice patch-clamp and single-nucleus RNA sequencing, we revealed developmental dysregulation in two different phenotypic Kcnq2 mice (DEE vs. SeLNE) during postnatal days 14-28 (P14-P28).</p><p><strong>Results: </strong>Compared to wild-type mice, both Kcnq2-SeLNE and Kcnq2-DEE mice exhibited neuronal hyperexcitability characterized by high-frequency firing of action potentials. Notably, whereas SeLNE mice showed timely recovery of excitability, DEE mice displayed delayed restoration of abnormal excitability in CA1 excitatory neurons. During P14-P28, particularly at P21, DEE mice demonstrated significant downregulation of synaptic plasticity- and cognitive development-related pathways in CA1 excitatory neuron subclusters (CA1.2/CA1.4 neurons). Conversely, SeLNE mice exhibited pronounced activation of neurodevelopmental signaling pathways. Transcriptomic analysis of differentially expressed genes between SeLNE and DEE mouse models revealed recurrent gene signatures, with persistent neuronal upregulation of Apoe in Kcnq2-DEE mice.</p><p><strong>Significance: </strong>This study identifies that the age-related spontaneous remission of seizures is due to time-limited changes in neuronal excitability, and treatment interventions for KCNQ2-DEE patients need to consider critical developmental time windows. In the future, better therapeutic outcomes may be achieved through spatiotemporal transcriptional coordination with neurodevelopmental gene networks.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippocampal abnormality and response to vagus nerve stimulation in epilepsy.","authors":"Harry J Clifford, Sonja Fenske, Jonathan Horsley, Callum Simpson, Nathan Evans, Yujiang Wang, Tiago da Silva Costa, Rhys H Thomas, Sabahat Iqbal, Cameron A Elliott, John S Duncan, Peter N Taylor","doi":"10.1111/epi.18658","DOIUrl":"https://doi.org/10.1111/epi.18658","url":null,"abstract":"<p><p>Vagus nerve stimulation (VNS) reduces seizure frequency and severity in some, but not all, individuals with epilepsy. The hippocampus has been implicated in VNS response, but is yet to be studied structurally using T1-weighted (T1w) magnetic resonance imaging (MRI). In this study we hypothesized greater hippocampal abnormality in VNS non-responders. Using hippocampal morphometrics, we extracted the volumes of four hippocampal regions from T1w MRI across three groups; VNS responders ( <math> <semantics><mrow><mi>n</mi> <mo>=</mo> <mn>42</mn></mrow> <annotation>$$ n=42 $$</annotation></semantics> </math> ), non-responders ( <math> <semantics><mrow><mi>n</mi> <mo>=</mo> <mn>50</mn></mrow> <annotation>$$ n=50 $$</annotation></semantics> </math> ), and healthy controls ( <math> <semantics><mrow><mi>n</mi> <mo>=</mo> <mn>100</mn></mrow> <annotation>$$ n=100 $$</annotation></semantics> </math> ). We first calculated the multivariate Mahalanobis distance using z-scores from all four hippocampal regions to measure abnormality relative to controls. We then compared traditional univariate measures to the Mahalanobis distance. Response to VNS was defined as having a <math> <semantics><mrow><mo>≥</mo> <mn>50</mn> <mo>%</mo></mrow> <annotation>$$ ge 50% $$</annotation></semantics> </math> seizure reduction 2 years post-implantation. Hippocampal morphometrics were significantly more abnormal in non-responders than responders ( <math> <semantics><mrow><mi>p</mi> <mo>=</mo> <mn>.005</mn> <mo>,</mo> <mtext>biserial</mtext> <mspace></mspace> <mi>r</mi> <mo>=</mo> <mn>.32</mn></mrow> <annotation>$$ p=.005,mathrm{biserial} r=.32 $$</annotation></semantics> </math> ) using the multivariate Mahalanobis distance. Univariate approaches did not differ significantly between responders and non-responders ( <math> <semantics><mrow><mi>p</mi> <mo>></mo> <mn>.05</mn></mrow> <annotation>$$ p>.05 $$</annotation></semantics> </math> ). At the group level, non-responders to VNS had greater structural hippocampal abnormality when using the multivariate approach. Conversely, this effect was lost with the univariate analysis. This suggests that abnormality is likely present in different parts of the hippocampus in different individuals. Future studies should incorporate multivariate, and potentially multi-modal, information to better characterize the mechanisms of VNS response.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of epilepsy on people experiencing homelessness: A mixed-methods study.","authors":"Hannah Lucey, Ciara Anderson, Rian McDermott, Sinéad Forde, Jess Sears, Cara Synnott, Colin P Doherty, Elisabeth Doran, Clíona Ní Cheallaigh, Georgia Richard","doi":"10.1111/epi.18663","DOIUrl":"https://doi.org/10.1111/epi.18663","url":null,"abstract":"<p><strong>Objective: </strong>People experiencing homelessness (PEH) are more likely to be diagnosed with epilepsy and to experience seizure-related morbidity and mortality. However, despite the increased prevalence of this condition, there is limited research examining the granular impact of epilepsy on PEH's daily lives and a dearth of research considering the perspectives of PEH themselves. This mixed-methods study aims to address these oversights by comparing the impact of epilepsy on homeless and housed people with epilepsy (PWE). As \"impact\" can be variously defined and understood, several validated questionnaires measuring psychiatric symptomatology, perceived stigma, epilepsy knowledge, and epilepsy-related quality of life (QoL), respectively, were used as proxies. PEH were also asked open-ended questions about their epilepsy-related experiences, to gather in-depth insights into the ways that epilepsy had shaped their lives.</p><p><strong>Methods: </strong>This was a mixed-methods study using a study-specific set of questionnaires including the following: sociodemographic information; measures of psychiatric symptomatology, epilepsy-related knowledge, QoL, and stigma; and open-ended questions on the impact of epilepsy on QoL.</p><p><strong>Results: </strong>PEH and housed PWE were recruited when attending an inner-city Dublin hospital. Data from 62 participants were included, 13 PEH and 49 housed participants. The results demonstrated that PEH had a higher burden of psychiatric symptomatology than housed PWE, including higher anxiety (p = .001) and depression (p < .001) scores. Once this was adjusted for, there was no difference in QoL between the two groups. PEH also reported significantly more epilepsy-related stigma relative to housed PWE (total revised Epilepsy Stigma Scale mean = 5.7 ± 3.0 vs. 1.6 ± 2.5, p < .001). PEH emphasized the emotional and affective burden that epilepsy presented in their lives.</p><p><strong>Significance: </strong>This research emphasizes the need for clinicians to remain cognizant of the social context in which chronic disease emerges and the importance of targeted, holistic, and multidisciplinary models of care to improve QoL and alleviate stigma for PEH experiencing epilepsy.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time to genetic testing in Dravet syndrome: Trends, barriers, and opportunities for improvement.","authors":"Ross A Carson, John E Maldonado Pacheco, Christina Briscoe Abath, Christelle Moufawad El Achkar","doi":"10.1111/epi.18666","DOIUrl":"https://doi.org/10.1111/epi.18666","url":null,"abstract":"<p><strong>Objective: </strong>Genetic testing can be necessary in the early diagnosis or confirmation of Dravet syndrome (DS). Despite major advances in availability of genetic testing, several barriers to timely testing persist. These include clinician recognition of the disease in its early stages and health disparities. Early diagnosis of DS has a growing list of management implications, including antiseizure medication selection, appropriate counseling regarding prognosis, access to resources, and clinical trial access.</p><p><strong>Methods: </strong>To understand the barriers to early genetic testing in DS, we performed a retrospective chart review of patients with DS due to SCN1A variants and analyzed factors hypothesized to affect time to testing. Factors including the initial clinical presentation and health disparities were correlated with length of time to testing from the first documented seizure.</p><p><strong>Results: </strong>Factors significantly correlated with time to testing included absence of early status epilepticus and the need for an English-language interpreter. Interestingly, neither race/ethnicity nor a composite social deprivation index were significantly correlated with delays in genetic testing in our population.</p><p><strong>Significance: </strong>We identified significant factors associated with delay to genetic testing in DS. Purposefully addressing these factors through education and resources will likely be important for continued improvement in early and equitable diagnosis for patients with DS.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Digital Response Test in Epilepsy assesses interictal epileptiform discharge effects in real time.","authors":"Andreas von Allmen, Diyuan Lu, Caroline Jagella, Yasmina Abukhadra, Rune Markhus, Jochen Triesch, Margaret Gopaul, Lawrence J Hirsch, Felix Rosenow, Hal Blumenfeld, Heinz Krestel","doi":"10.1111/epi.18629","DOIUrl":"https://doi.org/10.1111/epi.18629","url":null,"abstract":"<p><strong>Objective: </strong>Interictal epileptiform discharges (IEDs) in people with epilepsy (PWE) can impair cognitive functions and increase reaction time (RT) and the likelihood of missed reactions. These effects are not routinely assessed, because reliable methods for detecting IEDs of variable appearance in real time and suitable tests to measure IED effects do not yet exist. The objective was to assess different IED effects using new artificial intelligence and medical electronics.</p><p><strong>Methods: </strong>The Digital Response Test in Epilepsy (DigRTEpi) consisted of a laptop and electronic circuits in a closed loop. Our model with Markov Transition Fields and a deep neural network (ResNet34) visualized the electroencephalogram (EEG) and classified the resulting images. IED detection triggered stimuli in a driving game or in a new cognitive assessment, the interictal Automated Responsiveness Test (iART). DigRTEpi was validated in a prospective case series with 20 people with focal and generalized epilepsies. During offline analysis, sensitivity, specificity, false-positive IED detection rate, latency of EEG classification, IED-induced RT prolongation, virtual crashes, and impaired responses to neuropsychological tasks were determined.</p><p><strong>Results: </strong>The model detected IEDs with 84% sensitivity and 96% specificity in our training dataset. In the prospective study with 20 PWE, median sensitivity was 90% (95% confidence interval [CI] = .81-.95), and false-positive IED detection rate was 2.8 (95% CI 2.1-5.9). The ongoing EEG was classified window-by-window in a median 98.7 ms (95% CI = 98.0-99.4). Median RT prolongation and crash probability due to IEDs were 43.8 ms (95% CI = 20.3-64.7) and .9% (95% CI = 0-6.0) per person, respectively. Two patients (10%) had delays of >100 ms, found to be clinically relevant in our prior publication. IEDs caused four patients (20%) each to respond incorrectly or miss answers to neuropsychological tasks. The median false-positive IED detection rates were 2.8/min (95% CI = 2.1-5.9; driving game) and 2.1/min (95% CI = 1.5-3.2; iART).</p><p><strong>Significance: </strong>By effectively detecting IEDs of variable morphology in real time, DigRTEpi assessed the severity of IED-associated transitory impairment of virtual driving and cognition to improve personalized care.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term memory trajectories in seizure-free patients following epilepsy surgery for hippocampal sclerosis.","authors":"William Alves Martins, Roberta Gomes, Eduardo Leal-Conceição, Wyllians Vendramini Borelli, Rafael Paglioli, Thomas More Frigeri, Mirna Portuguez, Eliseu Paglioli, Andre Palmini","doi":"10.1111/epi.18648","DOIUrl":"https://doi.org/10.1111/epi.18648","url":null,"abstract":"<p><strong>Objective: </strong>This study was undertaken to study long-term memory trajectories over the years in patients with temporal lobe epilepsy and unilateral hippocampal sclerosis (TLE/HS) seizure-free since surgery.</p><p><strong>Methods: </strong>This cross-sectional study included patients with TLE/HS from a single-center epilepsy surgery program who had been seizure-free for at least 10 years following anterior temporal lobectomy (ATL) or selective amygdalohippocampectomy (SAH). Memory performance was evaluated preoperatively (T1), 1-4 years postoperatively (T2), and 10-15 years after surgery (T3). Logistic regression evaluated variables correlated with memory function at each point in time. A reliable change index was performed to identify changes in individual measures.</p><p><strong>Results: </strong>A total of 54 patients were included, of whom 36 (66%) were male and 52 (96%) right-handed. Patients with left HS and normal preoperative Rey Auditory Verbal Learning Test or Wechsler Memory Scale-Revised (WMS-R) logical memory showed worsening at T2 (13% × 52%, p = .029; 0 × 31%, p < .015, respectively) and T3 (27% × 63%, p = .045; 22% × 81%, p < .001, respectively). Visual reproduction (WMS-R) following nondominant surgery also deteriorated at T3 for patients who improved or sustained normal performance between T1 and T2 (33% × 50%, p = .64). The predictive factors for memory decline included normal preoperative memory function (odds ratio [OR] = 15, 95% confidence interval [CI] = 4.03-55.9, p < .001 for logical memory; OR = 1.5, 95% CI = 1.12-2.01, p = .007 for visual reproduction), younger age (OR = 1.2, 95% CI = 1.12-1.28, p < .001), dominant-side surgery (OR = 3.66, 95% CI = 1.49-8.95, p < .01), and lower education level (OR = 8.74, 95% CI 1.77-43.2, p = .008). The SAH technique was associated with better long-term verbal learning outcomes compared to ATL (OR = 3.02, 95% CI = 1.17-7.81, p = .02).</p><p><strong>Significance: </strong>Memory preservation or improvement in the first few postoperative years is usually not sustained in the long term, suggesting that disease progression surpasses plasticity over the years.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motives and predictors of modified Atkins diet discontinuation as treatment of adults with drug-resistant epilepsy.","authors":"Raquel Samões, Ana Cavalheiro, Maria Manuel Tavares, Catarina Teixeira, Bárbara Leal, João Chaves, Sara Cavaco","doi":"10.1111/epi.18657","DOIUrl":"https://doi.org/10.1111/epi.18657","url":null,"abstract":"<p><strong>Objective: </strong>This study was undertaken to explore the motives and predictors of modified Atkins diet (MAD) discontinuation as a treatment of adults with drug-resistant epilepsy (DRE).</p><p><strong>Methods: </strong>A single-center observational longitudinal study was made of a cohort of patients treated with MAD during the first 6 years at a multidisciplinary outpatient clinic dedicated to adult patients. Time to MAD discontinuation analyses were used to explore sociodemographic, clinical, and biochemical predictors of MAD persistence.</p><p><strong>Results: </strong>Eighty patients initiated MAD (54% females, median age = 29 years, median epilepsy duration = 21 years, median baseline seizure frequency = 30/month, median antiseizure medications = 4, 68% focal epilepsy, 64% structural etiology, and 26% genetic cause). The patients used the diet for a median time of 122 days. Fifteen percent of patients were very early dropouts (before 30 days), 20% were early dropouts (30-89 days), and 17.5% were late dropouts (>365 days). The motives for dropout (n = 64) were noncompliance (34.4%), inefficacy (23.4%), side effects (23.4%), and diet tiredness (18.8%). Female sex (adjusted hazard ratio [HR] = 1.75, p = .042), focal seizures with preserved consciousness (adjusted HR = 2.69, p = .017), higher glycemic level at baseline (adjusted HR = 1.03, p = .044), and lower level of serum total proteins at baseline (adjusted HR = .55, p = .052) were associated with shorter persistence on MAD. The HR for discontinuation was also higher for patients without daily seizures (HR = 1.72, p = .038). Among patients with at least 3 months in MAD (n = 51), reduced clinical response at month 3 was associated with earlier discontinuation of MAD, as measured by lower percent seizure reduction (HR = .98, p = .004) and <50% seizure reduction (HR = 2.44, p = .027).</p><p><strong>Significance: </strong>The dropout rate of MAD in adults with DRE is high even at dedicated centers. Females, patients with less severe epilepsies, and patients previously on carbohydrate-based diets may be more prone to earlier dropouts. These patients require closer monitoring in specialized ketogenic diet clinics to prevent MAD discontinuation before the minimum period necessary to evaluate response.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Haploinsufficiency of brain-specific kinase BRSK1 causes epilepsy and neurodevelopmental disorders.","authors":"Qi Zhang, Hiroshi Yamanaka, Ping Li, Yingfeng Li, Tian Luo, Miao Xia, Ting Liu, Xueyan Liu, Qing Lu, Bin Yang, Fan He, Kaixian Du, Yousheng Shu, Bo Peng, Yong-Hui Jiang, Yi Wang","doi":"10.1111/epi.18621","DOIUrl":"https://doi.org/10.1111/epi.18621","url":null,"abstract":"<p><strong>Objective: </strong>The BRSK1 gene encodes brain-specific serine/threonine kinase 1 (also known as SAD-B kinase), which is almost exclusively expressed in the brain and plays critical roles in neuronal polarization, neurotransmitter release, mitochondrial dynamics, and neuronal maturation. This study aimed to investigate the pathogenicity of BRSK1 variants in epilepsy and neurodevelopmental disorders.</p><p><strong>Methods: </strong>Trio-based exome sequencing was performed in 394 probands with epilepsy. Expression analyses and functional validation were conducted using a newly generated Brsk1 exon 4-7 knockout mouse line (Brsk1^Δ4-7), with subsequent behavioral, electrophysiological, proteomic, and phosphoproteomic assessments.</p><p><strong>Results: </strong>Six novel BRSK1 variants were identified in seven probands, including four single nucleotide variants (SNVs) and two indels; five were de novo, one inherited, and one recurrent. Frameshift or nonsense variants led to complete loss of detectable BRSK1 protein, whereas one missense variant reduced protein levels. Both heterozygous and homozygous Brsk1^Δ4-7 mice exhibit increased seizure susceptibility, neuronal hyperexcitability, and neurobehavioral impairments-recapitulating key clinical features associated with BRSK1 haploinsufficiency in humans. Proteomic and phosphoproteomic analyses revealed dysregulation of pathways critical for axonal development and synaptic function.</p><p><strong>Significance: </strong>Our genomic and functional studies strongly support BRSK1 haploinsufficiency as a pathogenic mechanism in a human epilepsy syndrome. To our knowledge, this is the first study to implicate the brain-specific serine/threonine kinase BRSK1 in epilepsy and neurodevelopmental disorders.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selecting effective antiseizure medications for early treatment of SCN8A-related epilepsy using a machine learning approach incorporating clinician and caregiver assessments.","authors":"Joshua B Hack, Michael F Hammer","doi":"10.1111/epi.18632","DOIUrl":"https://doi.org/10.1111/epi.18632","url":null,"abstract":"<p><strong>Objective: </strong>Despite rapid advances in understanding the disease spectrum and its progression, little is known about which antiseizure medications (ASMs) are likely to be beneficial or detrimental as first-line therapies for patients with SCN8A-related epilepsy (SCN8A-RE). This is a critical issue given low rates of seizure freedom and treatment resistance rates that exceed 75%. In this study, we test the hypothesis that machine learning (ML) algorithms can improve selection of ASMs that are likely to benefit patients with SCN8A-RE.</p><p><strong>Methods: </strong>We leverage comprehensive medical data in the International SCN8A Patient Registry to construct a neural network that recommends ASMs based on a caregiver-centered composite measure incorporating improvements in seizure control, alertness, and side effects. We directly compare the recommendations of the algorithm to preferences of clinician experts through a follow-up survey and evaluate how ASM selection is influenced when informed by the ML algorithm.</p><p><strong>Results: </strong>Despite challenges resulting from the prevalent use of polypharmacy and frequent suboptimal treatment responses, the algorithm identified ASMs likely to be beneficial in 76% ± 3% of cases while never recommending a detrimental ASM in 1100 trials. Clinician experts independently recommended beneficial ASMs in 22% (16/72) of cases, a rate that increased to 46% (11/24) when choices were given based on algorithm recommendations.</p><p><strong>Significance: </strong>The results indicate that ML algorithms can improve selection of ASMs that are likely to be beneficial in the early treatment of SCN8A-RE patients, with little risk of recommending ASMs with detrimental effects-a particular hazard for patient populations requiring long-term maintenance on polypharmacy. The results also expand the number of recommended ASMs from two sodium channel blockers (SCBs) identified in a recent consensus process to five SCBs and a γ-aminobutyric acidergic drug. The algorithm lays the groundwork for incorporating composite measures that include both seizure control and quality of life metrics.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}