To evaluate the nutritional status and functional gastrointestinal disorders (FGIDs) in children with drug-resistant epilepsy (DRE) and determine whether vagus nerve stimulation (VNS) influences gastrointestinal outcomes.
Methods
This cross-sectional study included 98 pediatric patients with DRE (30 with VNS and 68 without). Anthropometric status was assessed using LMS-derived Z-scores, and FGIDs were diagnosed according to the Rome IV criteria. Logistic regression and ROC analyses were used to investigate the relationship between antiseizure medication (ASM) burden and constipation.
Results
Each additional ASM increased the odds of constipation by 1.63 (95 % CI: 1.08–2.47; p = 0.021). A cutoff of ≥3 ASMs demonstrated a moderate predictive value for constipation (AUC 0.63). Earlier epilepsy onset was significantly associated with lower weight, height, and BMI Z-scores (all p < 0.05). Despite the higher ASM burden, children treated with VNS did not exhibit an increased frequency of gastrointestinal adverse effects.
Conclusion
ASM polytherapy is a measurable risk factor for constipation in pediatric DRE, and early epilepsy onset is associated with impaired growth. The absence of increased gastrointestinal symptoms among VNS recipients, despite a higher medication load, suggests a potential modulatory role of vagal neuromodulation. These findings highlight the need for routine nutritional surveillance and structured gastrointestinal assessments and support future longitudinal studies incorporating objective GI measures and biomarker-based evaluations.
{"title":"Nutritional status and functional gastrointestinal disorders in pediatric patients with drug-resistant epilepsy: Impact of vagus nerve stimulation","authors":"Ayse Akcay , Zeynep Ozturk , Alev Elci Karaduman , Esra Serdaroglu , Ebru Arhan , Ercan Demir , Tugba Hirfanoglu","doi":"10.1016/j.seizure.2025.12.005","DOIUrl":"10.1016/j.seizure.2025.12.005","url":null,"abstract":"<div><h3>Purpose</h3><div>To evaluate the nutritional status and functional gastrointestinal disorders (FGIDs) in children with drug-resistant epilepsy (DRE) and determine whether vagus nerve stimulation (VNS) influences gastrointestinal outcomes.</div></div><div><h3>Methods</h3><div>This cross-sectional study included 98 pediatric patients with DRE (30 with VNS and 68 without). Anthropometric status was assessed using LMS-derived Z-scores, and FGIDs were diagnosed according to the Rome IV criteria. Logistic regression and ROC analyses were used to investigate the relationship between antiseizure medication (ASM) burden and constipation.</div></div><div><h3>Results</h3><div>Each additional ASM increased the odds of constipation by 1.63 (95 % CI: 1.08–2.47; <em>p</em> = 0.021). A cutoff of ≥3 ASMs demonstrated a moderate predictive value for constipation (AUC 0.63). Earlier epilepsy onset was significantly associated with lower weight, height, and BMI Z-scores (all <em>p</em> < 0.05). Despite the higher ASM burden, children treated with VNS did not exhibit an increased frequency of gastrointestinal adverse effects.</div></div><div><h3>Conclusion</h3><div>ASM polytherapy is a measurable risk factor for constipation in pediatric DRE, and early epilepsy onset is associated with impaired growth. The absence of increased gastrointestinal symptoms among VNS recipients, despite a higher medication load, suggests a potential modulatory role of vagal neuromodulation. These findings highlight the need for routine nutritional surveillance and structured gastrointestinal assessments and support future longitudinal studies incorporating objective GI measures and biomarker-based evaluations.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"134 ","pages":"Pages 198-203"},"PeriodicalIF":2.8,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796921","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}
Pub Date : 2025-12-06DOI: 10.1016/j.seizure.2025.12.003
Xin Li , Jia-Jun Ma , Lin-Xue Meng , Zi-Yao Han , Qin-Lan Li , Xiao-Yue Yang , Ling-Ling Xie , Li Jiang
Background
Myocyte enhancer factor 2C (MEF2C) is among the important genes associated with neurodevelopmental disorders (NDDs). The phenotypic distinctions between MEF2C pathogenic variants and 5q14.3 microdeletions remain unclear.
Methods
We retrospectively collected the information of patients from our centre between May 2019 and October 2024 and identified them as having MEF2C mutations by whole-exome sequencing (WES). We searched the literature related to MEF2C mutations and 5q14.3 microdeletions and summarized the clinical features and genetic characteristics of the patients.
Results
Five patients with MEF2C mutations were identified from our hospital, and 34 articles were selected for analysis. Data from 62 MEF2C-associated copy number variations (CNVs) and 42 MEF2C mutations were analysed. We found that regression was more common in the mutation group (21.6 %, 8/37) than in the CNV group (2.0 %, 1/51; P = 0.008). Patients with mutations in MEF2C were more likely to present with a history of febrile seizures (45.2 % vs. 25.8 %, P = 0.040) and autistic traits (91.9 % vs. 74.5 %, P = 0.037). Myoclonic seizures (29.4 % vs. 70.6 %, P = 0.025), infantile epileptic spasm syndrome (3.3 % vs. 31.8 %, P = 0.018), refractory epilepsy (11.1 % vs. 47.8 %, P = 0.012), diffuse epileptiform discharges from electroencephalograms (15.0 % vs. 42.9 %, P = 0.2) and abnormal corpus callosum (23.1 % vs. 55.9, P = 0.06) may occur more often in the CNV group.
Conclusion
Patients with CNVs presented a higher prevalence of refractory epilepsy and vascular malformations, whereas those with point mutations more frequently presented with developmental regression, febrile seizure history and autistic traits. These genotype–phenotype correlations could inform genetic testing strategies.
背景肌细胞增强因子2C （MEF2C）是与神经发育障碍（ndd）相关的重要基因之一。MEF2C致病变异和5q14.3微缺失之间的表型差异尚不清楚。方法回顾性收集2019年5月至2024年10月在本中心就诊的患者信息，通过全外显子组测序（WES）鉴定为MEF2C突变患者。我们检索了MEF2C突变和5q14.3微缺失的相关文献，总结了患者的临床特征和遗传特征。结果本院MEF2C突变患者5例，选取34篇文献进行分析。分析了62个MEF2C相关拷贝数变异（CNVs）和42个MEF2C突变的数据。我们发现突变组（21.6%,8/37）的回归比CNV组（2.0%,1/51;P = 0.008）更为常见。MEF2C基因突变的患者更有可能出现发热性惊厥史（45.2%对25.8%,P = 0.040）和自闭症特征（91.9%对74.5%,P = 0.037）。肌阵挛性发作（29.4% vs. 70.6%, P = 0.025）、婴儿癫痫痉挛综合征（3.3% vs. 31.8%, P = 0.018）、难固性癫痫（11.1% vs. 47.8%, P = 0.012）、脑电图弥漫性癫痫样放电（15.0% vs. 42.9%, P = 0.2）和胼胝体异常（23.1% vs. 55.9%, P = 0.06）在CNV组更常见。结论CNVs患者出现顽固性癫痫和血管畸形的比例较高，而点突变患者出现发育倒退、热性癫痫发作史和自闭症特征的比例较高。这些基因型-表型相关性可以为基因检测策略提供信息。
{"title":"Comparative analysis of clinical phenotypes and genetic characteristics in MEF2C-associated neurodevelopmental disorders","authors":"Xin Li , Jia-Jun Ma , Lin-Xue Meng , Zi-Yao Han , Qin-Lan Li , Xiao-Yue Yang , Ling-Ling Xie , Li Jiang","doi":"10.1016/j.seizure.2025.12.003","DOIUrl":"10.1016/j.seizure.2025.12.003","url":null,"abstract":"<div><h3>Background</h3><div>Myocyte enhancer factor 2C (<em>MEF2C</em>) is among the important genes associated with neurodevelopmental disorders (NDDs). The phenotypic distinctions between <em>MEF2C</em> pathogenic variants and 5q14.3 microdeletions remain unclear.</div></div><div><h3>Methods</h3><div>We retrospectively collected the information of patients from our centre between May 2019 and October 2024 and identified them as having <em>MEF2C</em> mutations by whole-exome sequencing (WES). We searched the literature related to <em>MEF2C</em> mutations and 5q14.3 microdeletions and summarized the clinical features and genetic characteristics of the patients.</div></div><div><h3>Results</h3><div>Five patients with <em>MEF2C</em> mutations were identified from our hospital, and 34 articles were selected for analysis. Data from 62 <em>MEF2C</em>-associated copy number variations (CNVs) and 42 <em>MEF2C</em> mutations were analysed. We found that regression was more common in the mutation group (21.6 %, 8/37) than in the CNV group (2.0 %, 1/51; <em>P</em> = 0.008). Patients with mutations in <em>MEF2C</em> were more likely to present with a history of febrile seizures (45.2 % vs. 25.8 %, <em>P</em> = 0.040) and autistic traits (91.9 % vs. 74.5 %, <em>P</em> = 0.037). Myoclonic seizures (29.4 % vs. 70.6 %, <em>P</em> = 0.025), infantile epileptic spasm syndrome (3.3 % vs. 31.8 %, <em>P</em> = 0.018), refractory epilepsy (11.1 % vs. 47.8 %, <em>P</em> = 0.012), diffuse epileptiform discharges from electroencephalograms (15.0 % vs. 42.9 %, <em>P</em> = 0.2) and abnormal corpus callosum (23.1 % vs. 55.9, <em>P</em> = 0.06) may occur more often in the CNV group.</div></div><div><h3>Conclusion</h3><div>Patients with CNVs presented a higher prevalence of refractory epilepsy and vascular malformations, whereas those with point mutations more frequently presented with developmental regression, febrile seizure history and autistic traits. These genotype–phenotype correlations could inform genetic testing strategies.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"134 ","pages":"Pages 152-164"},"PeriodicalIF":2.8,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748756","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}
Pub Date : 2025-12-06DOI: 10.1016/j.seizure.2025.12.004
Philippe Gélisse , Arielle Crespel , Pierre Genton , Charlotte Dravet
Lennox-Gastaut Syndrome (LGS) is a severe, lifelong form of epileptic encephalopathy that presents significant treatment challenges. The management of LGS remains primarily symptomatic. Historically, the effectiveness of traditional antiseizure medications (ASMs) has been limited, prompting practitioners to explore off-label treatments and anecdotal drugs, including medications not originally intended for epilepsy. Although some controlled clinical trials have been conducted, LGS management often remains empirical and largely dependent on clinical experience. Recent advances in ASMs and adjunctive therapies have enhanced patient outcomes, yet LGS remains one of the most treatment-resistant forms of epilepsy, with complete seizure control rarely being achieved. Beyond ASMs, interventions such as a ketogenic diet, vagus nerve stimulation, and callosotomy may be considered based on individual patient needs. Recent developments in deep brain stimulation have also presented promising new therapeutic options. This article aims to provide a comprehensive overview of both pharmacological and non-pharmacological treatment strategies for LGS, tracing progress from the syndrome's first description in 1966 to the current management approaches.
{"title":"History of lennox-gastaut syndrome: Sixty years of advancements in therapeutic practices","authors":"Philippe Gélisse , Arielle Crespel , Pierre Genton , Charlotte Dravet","doi":"10.1016/j.seizure.2025.12.004","DOIUrl":"10.1016/j.seizure.2025.12.004","url":null,"abstract":"<div><div>Lennox-Gastaut Syndrome (LGS) is a severe, lifelong form of epileptic encephalopathy that presents significant treatment challenges. The management of LGS remains primarily symptomatic. Historically, the effectiveness of traditional antiseizure medications (ASMs) has been limited, prompting practitioners to explore off-label treatments and anecdotal drugs, including medications not originally intended for epilepsy. Although some controlled clinical trials have been conducted, LGS management often remains empirical and largely dependent on clinical experience. Recent advances in ASMs and adjunctive therapies have enhanced patient outcomes, yet LGS remains one of the most treatment-resistant forms of epilepsy, with complete seizure control rarely being achieved. Beyond ASMs, interventions such as a ketogenic diet, vagus nerve stimulation, and callosotomy may be considered based on individual patient needs. Recent developments in deep brain stimulation have also presented promising new therapeutic options. This article aims to provide a comprehensive overview of both pharmacological and non-pharmacological treatment strategies for LGS, tracing progress from the syndrome's first description in 1966 to the current management approaches.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"134 ","pages":"Pages 165-172"},"PeriodicalIF":2.8,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748755","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}
Pub Date : 2025-12-04DOI: 10.1016/j.seizure.2025.12.001
Mohammad Shahbakhti , Anemoon T. Bosch , Xi Long , Johannes P. van Dijk , Roland D. Thijs
Objective:
The impact of seizures on the peripheral vascular system has not been well studied. Here, we used wearable photoplethysmography (PPG) to characterize peripheral vascular tone dynamics in children with refractory epilepsy.
Methods:
We used data from the PROMISE trial, which included children aged 4–16 years with nocturnal major motor seizures. We selected continuous 10-minute PPG segments, each spanning the seizure-free baseline, pre-ictal, ictal, and post-ictal phases. The amplitude modulation (AM) of the PPG signal, representing the slow variation in pulse amplitude and serving as a proxy for relative blood volume, was analyzed to characterize peripheral vascular tone. We applied a linear mixed-effects model to compare the AM across pre-ictal, ictal, and post-ictal phases relative to the baseline.
Results:
We studied 135 seizure events from 13 children (42% female; mean age: 9.7 3.6 years). Our analysis revealed a significant AM decrease during the pre-ictal phase (), with a more pronounced decrease during the ictal and post-ictal phases () relative to the baseline.
Significance:
Seizures impact peripheral vascular tone with signs of vasoconstriction that persists into the post-ictal phase.
{"title":"Characterizing vascular tone in nocturnal major motor seizures using wearable photoplethysmography","authors":"Mohammad Shahbakhti , Anemoon T. Bosch , Xi Long , Johannes P. van Dijk , Roland D. Thijs","doi":"10.1016/j.seizure.2025.12.001","DOIUrl":"10.1016/j.seizure.2025.12.001","url":null,"abstract":"<div><h3>Objective:</h3><div>The impact of seizures on the peripheral vascular system has not been well studied. Here, we used wearable photoplethysmography (PPG) to characterize peripheral vascular tone dynamics in children with refractory epilepsy.</div></div><div><h3>Methods:</h3><div>We used data from the PROMISE trial, which included children aged 4–16 years with nocturnal major motor seizures. We selected continuous 10-minute PPG segments, each spanning the seizure-free baseline, pre-ictal, ictal, and post-ictal phases. The amplitude modulation (AM) of the PPG signal, representing the slow variation in pulse amplitude and serving as a proxy for relative blood volume, was analyzed to characterize peripheral vascular tone. We applied a linear mixed-effects model to compare the AM across pre-ictal, ictal, and post-ictal phases relative to the baseline.</div></div><div><h3>Results:</h3><div>We studied 135 seizure events from 13 children (42% female; mean age: 9.7 <span><math><mo>±</mo></math></span> 3.6 years). Our analysis revealed a significant AM decrease during the pre-ictal phase (<span><math><mrow><mi>p</mi><mo><</mo><mn>0</mn><mo>.</mo><mn>05</mn></mrow></math></span>), with a more pronounced decrease during the ictal and post-ictal phases (<span><math><mrow><mi>p</mi><mo><</mo><mn>0</mn><mo>.</mo><mn>001</mn></mrow></math></span>) relative to the baseline.</div></div><div><h3>Significance:</h3><div>Seizures impact peripheral vascular tone with signs of vasoconstriction that persists into the post-ictal phase.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"134 ","pages":"Pages 186-189"},"PeriodicalIF":2.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796920","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}
Pub Date : 2025-12-02DOI: 10.1016/j.seizure.2025.12.002
Rui Li , Chu Wang , Runlu Geng , Xiaoqing Xu , Yichen Tao , Yuanyuan Dai
Objective
To analyse the clinical and genetic characteristics of children with epilepsy associated with SCN8A gene variants.
Methods
High-throughput whole-exome sequencing was performed on children suspected of having gene variant-related epilepsy. A total of 14 children with seizures caused by SCN8A gene variants were identified. A retrospective analysis was conducted to collect and summarise the medical records and genetic results of these children.
Results
Eleven cases were identified with de novo variants and three with inherited heterozygous variants. The earliest age of onset was 10 min after birth, and the maximum age of onset was 2 years. Three patients were treated with a single drug, four were treated with two anti-seizure medicines (ASMs), seven were treated with three or more ASMs and two were treated with a ketogenic diet, but the efficacy was not satisfactory. Eight patients responded to sodium channel blockers, with doses ranging from higher than the standard paediatric dosage. Except for one case with a normal electroencephalogram, all others showed abnormalities, mainly characterised by multifocal and widespread discharges.
Conclusion
Typically, SCN8A gene variants cause early-onset childhood epilepsy, often within the first year of life, even in the neonatal period, and most cases are caused by de novo variants. Sodium channel blockers show some efficacy, but often require higher doses, and single-drug therapy is usually insufficient. The clinical phenotype of de novo variants is severe, with frequent seizures. Most patients still experience seizures despite treatment with 3–4 drugs, and focal or focal secondary generalised seizures are common. Seizure types such as spasms and myoclonus are rare.
{"title":"Clinical and genetic analysis of epilepsy in children with SCN8A gene variants","authors":"Rui Li , Chu Wang , Runlu Geng , Xiaoqing Xu , Yichen Tao , Yuanyuan Dai","doi":"10.1016/j.seizure.2025.12.002","DOIUrl":"10.1016/j.seizure.2025.12.002","url":null,"abstract":"<div><h3>Objective</h3><div>To analyse the clinical and genetic characteristics of children with epilepsy associated with SCN8A gene variants.</div></div><div><h3>Methods</h3><div>High-throughput whole-exome sequencing was performed on children suspected of having gene variant-related epilepsy. A total of 14 children with seizures caused by SCN8A gene variants were identified. A retrospective analysis was conducted to collect and summarise the medical records and genetic results of these children.</div></div><div><h3>Results</h3><div>Eleven cases were identified with de novo variants and three with inherited heterozygous variants. The earliest age of onset was 10 min after birth, and the maximum age of onset was 2 years. Three patients were treated with a single drug, four were treated with two anti-seizure medicines (ASMs), seven were treated with three or more ASMs and two were treated with a ketogenic diet, but the efficacy was not satisfactory. Eight patients responded to sodium channel blockers, with doses ranging from higher than the standard paediatric dosage. Except for one case with a normal electroencephalogram, all others showed abnormalities, mainly characterised by multifocal and widespread discharges.</div></div><div><h3>Conclusion</h3><div>Typically, SCN8A gene variants cause early-onset childhood epilepsy, often within the first year of life, even in the neonatal period, and most cases are caused by de novo variants. Sodium channel blockers show some efficacy, but often require higher doses, and single-drug therapy is usually insufficient. The clinical phenotype of de novo variants is severe, with frequent seizures. Most patients still experience seizures despite treatment with 3–4 drugs, and focal or focal secondary generalised seizures are common. Seizure types such as spasms and myoclonus are rare.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"134 ","pages":"Pages 147-151"},"PeriodicalIF":2.8,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145745627","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}
Pub Date : 2025-11-30DOI: 10.1016/j.seizure.2025.11.021
Meizhuang Zhou , Yu Luo , Ruihan Yang , Liting Zhang , Weili Hao , Dezhi Cao , Zhigang Liu , Qing Zhou , Xiaorong Liu , Bingmei Li , Peng Zhou , Bin Li , Xingwang Song
Background
The PIGA gene plays a critical role in glycosylphosphatidylinositol (GPI) biosynthesis. PIGA variants have been linked to multiple congenital anomalies-hypotonia-seizures syndrome 2. While epilepsy is a common manifestation and patients usually show developmental delay, it is unclear whether PIGA variants are associated with pure epilepsy.
Method
Trio-based whole-exome sequencing was performed on individuals with focal epilepsy from the China Epilepsy Gene 1.0 project. The sub-molecular effect, damaging effect of the variants, and spatial-temporal expression of PIGA were analyzed to explore its role in epilepsy.
Results
Six PIGA variants were identified in seven unrelated cases with focal epilepsy. In one family, the variant co-segregated with two affected males. All the variants were inherited from the asymptomatic mothers, consistent with an X-linked recessive inheritance pattern. Five of the variants were absent in the general population and one variant had extremely low frequencies. These variants were predicted to be damaging by commonly used in silico tools. Four cases presented with developmental delay and three showed normal development. Further analysis revealed that variants associated with a severe phenotype were located within the GPI biosynthesis domain, whereas variants associated with focal epilepsy and a favorable outcome were outside functional domains, suggesting a sub-molecular effect. Patients with more severe phenotype also had variants with higher damaging scores, indicating a potential genotype-phenotype correlation. PIGA was highly expressed at the embryoid stage, decreased after birth, and then increased again during infancy and the juvenile stage, consistent with the onset age of the patients.
Conclusion
PIGA variants are potentially associated with focal epilepsy with favorable outcome. The sub-molecular effect helps explain phenotype variations.
{"title":"PIGA variants are associated with focal epilepsy with favorable outcome and the sub-molecular effect","authors":"Meizhuang Zhou , Yu Luo , Ruihan Yang , Liting Zhang , Weili Hao , Dezhi Cao , Zhigang Liu , Qing Zhou , Xiaorong Liu , Bingmei Li , Peng Zhou , Bin Li , Xingwang Song","doi":"10.1016/j.seizure.2025.11.021","DOIUrl":"10.1016/j.seizure.2025.11.021","url":null,"abstract":"<div><h3>Background</h3><div>The <em>PIGA</em> gene plays a critical role in glycosylphosphatidylinositol (GPI) biosynthesis. <em>PIGA</em> variants have been linked to multiple congenital anomalies-hypotonia-seizures syndrome 2. While epilepsy is a common manifestation and patients usually show developmental delay, it is unclear whether <em>PIGA</em> variants are associated with pure epilepsy.</div></div><div><h3>Method</h3><div>Trio-based whole-exome sequencing was performed on individuals with focal epilepsy from the China Epilepsy Gene 1.0 project. The sub-molecular effect, damaging effect of the variants, and spatial-temporal expression of <em>PIGA</em> were analyzed to explore its role in epilepsy.</div></div><div><h3>Results</h3><div>Six <em>PIGA</em> variants were identified in seven unrelated cases with focal epilepsy. In one family, the variant co-segregated with two affected males. All the variants were inherited from the asymptomatic mothers, consistent with an X-linked recessive inheritance pattern. Five of the variants were absent in the general population and one variant had extremely low frequencies. These variants were predicted to be damaging by commonly used <em>in silico</em> tools. Four cases presented with developmental delay and three showed normal development. Further analysis revealed that variants associated with a severe phenotype were located within the GPI biosynthesis domain, whereas variants associated with focal epilepsy and a favorable outcome were outside functional domains, suggesting a sub-molecular effect. Patients with more severe phenotype also had variants with higher damaging scores, indicating a potential genotype-phenotype correlation. <em>PIGA</em> was highly expressed at the embryoid stage, decreased after birth, and then increased again during infancy and the juvenile stage, consistent with the onset age of the patients.</div></div><div><h3>Conclusion</h3><div><em>PIGA</em> variants are potentially associated with focal epilepsy with favorable outcome. The sub-molecular effect helps explain phenotype variations.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"134 ","pages":"Pages 139-146"},"PeriodicalIF":2.8,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696408","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}
Pub Date : 2025-11-28DOI: 10.1016/j.seizure.2025.11.019
Sumitha Murugesu, Ahmad Rithauddin Mohamed, Husna Binti Musa, Jun Xiong Lee, Muhamad Azamin Anuar, Teik Beng Khoo
Purpose
Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic encephalopathy that can occur at any age, with limited treatment options. Conventional immunotherapies often show poor efficacy. We evaluated the effectiveness and safety of the interleukin-6 receptor blocker, tocilizumab, in children with FIRES.
Methods
We retrospectively reviewed medical records, electroencephalography, and neuroimaging of seven children with FIRES treated at our center between 2018 and 2022. Outcomes included cessation of super-refractory status epilepticus (SRSE), seizure burden, and functional outcome using the Pediatric Cerebral Performance Category (PCPC) scale.
Results
Seven previously healthy children (median age 9 years; range 2–13) developed SRSE following febrile illness. Extensive investigations, including cerebrospinal fluid studies, viral panels, and autoimmune testing were negative, consistent with cryptogenic FIRES. Initial MRI was normal in six children; one showed symmetrical T2/FLAIR hyperintensities involving deep grey matter structures. All patients received a multimodal therapeutic strategy including intravenous midazolam, high-dose phenobarbitone, ketogenic diet, therapeutic hypothermia, and/or immunotherapy—prior to tocilizumab. Intravenous tocilizumab was initiated at a median of 17 days from illness onset (range 6–46). SRSE resolved within a median of 5 days (range 2–12) after administration. At 6-month follow-up, six of seven patients developed chronic epilepsy, characterised by weekly to monthly seizures, while one remained seizure free. Functional recovery was noted in four patients, each achieving a Pediatric Cerebral Performance Category (PCPC) score of ≤2. Adverse events included grade 2 leukopenia or diarrhoea (n = 3) and grade 4 sepsis (n = 1); all resolved with treatment. No deaths occurred.
Conclusion
Tocilizumab was associated with rapid resolution of SRSE, seizure reduction, and functional recovery in children with FIRES, with manageable side effects. While causality cannot be confirmed given concurrent therapies and variable timing of administration, these findings support consideration of interleukin-6 blockade as a potential adjunctive treatment in FIRES.
{"title":"Tocilizumab for super-refractory status epilepticus in children with FIRES: A case series","authors":"Sumitha Murugesu, Ahmad Rithauddin Mohamed, Husna Binti Musa, Jun Xiong Lee, Muhamad Azamin Anuar, Teik Beng Khoo","doi":"10.1016/j.seizure.2025.11.019","DOIUrl":"10.1016/j.seizure.2025.11.019","url":null,"abstract":"<div><h3>Purpose</h3><div>Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic encephalopathy that can occur at any age, with limited treatment options. Conventional immunotherapies often show poor efficacy. We evaluated the effectiveness and safety of the interleukin-6 receptor blocker, tocilizumab, in children with FIRES.</div></div><div><h3>Methods</h3><div>We retrospectively reviewed medical records, electroencephalography, and neuroimaging of seven children with FIRES treated at our center between 2018 and 2022. Outcomes included cessation of super-refractory status epilepticus (SRSE), seizure burden, and functional outcome using the Pediatric Cerebral Performance Category (PCPC) scale.</div></div><div><h3>Results</h3><div>Seven previously healthy children (median age 9 years; range 2–13) developed SRSE following febrile illness. Extensive investigations, including cerebrospinal fluid studies, viral panels, and autoimmune testing were negative, consistent with cryptogenic FIRES<strong>.</strong> Initial MRI was normal in six children; one showed symmetrical T2/FLAIR hyperintensities involving deep grey matter structures. All patients received a multimodal therapeutic strategy including intravenous midazolam, high-dose phenobarbitone, ketogenic diet, therapeutic hypothermia, and/or immunotherapy—prior to tocilizumab. Intravenous tocilizumab was initiated at a median of 17 days from illness onset (range 6–46). SRSE resolved within a median of 5 days (range 2–12) after administration. At 6-month follow-up, six of seven patients developed chronic epilepsy, characterised by weekly to monthly seizures, while one remained seizure free. Functional recovery was noted in four patients, each achieving a Pediatric Cerebral Performance Category (PCPC) score of ≤2. Adverse events included grade 2 leukopenia or diarrhoea (<em>n</em> = 3) and grade 4 sepsis (<em>n</em> = 1); all resolved with treatment. No deaths occurred.</div></div><div><h3>Conclusion</h3><div>Tocilizumab was associated with rapid resolution of SRSE, seizure reduction, and functional recovery in children with FIRES, with manageable side effects. While causality cannot be confirmed given concurrent therapies and variable timing of administration, these findings support consideration of interleukin-6 blockade as a potential adjunctive treatment in FIRES.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"134 ","pages":"Pages 180-185"},"PeriodicalIF":2.8,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769672","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}
Pub Date : 2025-11-28DOI: 10.1016/j.seizure.2025.11.020
Yingfan Wang , Minghao Li , Xu Huang , Peilin Jiang, Xinyi Zhou, Ke Hu, Xiaoshan Wang
Objectives
Childhood Absence Epilepsy (CAE) and Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTS) are common, clinically associated syndromes, yet their shared and distinct pathophysiological mechanisms remain unclear. This study aimed to systematically compare interictal resting-state neuromagnetic networks among drug-naive children with CAE, SeLECTS, and healthy controls (HC) to identify common and syndrome-specific neurophysiological signatures.
Methods
We recruited 51 drug-naive CAE patients, 50 SeLECTS patients, and 30 age- and sex-matched HC. We analyzed 30-second epochs of interictal epileptiform discharge (IED)-free resting-state magnetoencephalography (MEG) data. Source-level spectral power and functional connectivity (corrected amplitude envelope correlation, AEC-c) were computed across six frequency bands (delta to high-gamma). Group differences were assessed using Network-Based Statistics (NBS) and cluster-based permutation test.
Results
Both epilepsy groups, compared to HCs, exhibited a shared pattern of pathological brain 'slowing': significantly increased low-frequency (delta) power and decreased high-frequency (alpha, beta, gamma) power. At the network level, this was mirrored by alpha-band hyperconnectivity and gamma-band hypoconnectivity. Crucially, syndrome-specific patterns emerged. CAE was characterized by global network dysregulation, with widespread delta/theta hyperconnectivity and a profound reduction in parieto-occipital alpha power. In contrast, SeLECTS displayed features of focal origin with widespread impact, including extreme low-to-mid frequency (delta-to-alpha) hyperconnectivity across distinct subnetworks and a widespread decrease in high-frequency (beta to gamma) power, most prominent in the temporal lobes.
Significance
This study provides the first direct neuromagnetic comparison of drug-naive CAE and SeLECTS. While a shared signature of pathological brain slowing suggests a common substrate of network instability, their distinct patterns of network dysfunction—global dysregulation in CAE versus focal-origin hyperconnectivity and widespread high-frequency power collapse in SeLECTS—elucidate divergent pathophysiological mechanisms. These syndrome-specific neuromagnetic features hold potential as non-invasive biomarkers for differential diagnosis and therapeutic monitoring.
{"title":"Shared and divergent neuromagnetic network signatures in childhood absence epilepsy and self-limited epilepsy with centrotemporal spikes","authors":"Yingfan Wang , Minghao Li , Xu Huang , Peilin Jiang, Xinyi Zhou, Ke Hu, Xiaoshan Wang","doi":"10.1016/j.seizure.2025.11.020","DOIUrl":"10.1016/j.seizure.2025.11.020","url":null,"abstract":"<div><h3>Objectives</h3><div>Childhood Absence Epilepsy (CAE) and Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTS) are common, clinically associated syndromes, yet their shared and distinct pathophysiological mechanisms remain unclear. This study aimed to systematically compare interictal resting-state neuromagnetic networks among drug-naive children with CAE, SeLECTS, and healthy controls (HC) to identify common and syndrome-specific neurophysiological signatures.</div></div><div><h3>Methods</h3><div>We recruited 51 drug-naive CAE patients, 50 SeLECTS patients, and 30 age- and sex-matched HC. We analyzed 30-second epochs of interictal epileptiform discharge (IED)-free resting-state magnetoencephalography (MEG) data. Source-level spectral power and functional connectivity (corrected amplitude envelope correlation, AEC-c) were computed across six frequency bands (delta to high-gamma). Group differences were assessed using Network-Based Statistics (NBS) and cluster-based permutation test.</div></div><div><h3>Results</h3><div>Both epilepsy groups, compared to HCs, exhibited a shared pattern of pathological brain 'slowing': significantly increased low-frequency (delta) power and decreased high-frequency (alpha, beta, gamma) power. At the network level, this was mirrored by alpha-band hyperconnectivity and gamma-band hypoconnectivity. Crucially, syndrome-specific patterns emerged. CAE was characterized by global network dysregulation, with widespread delta/theta hyperconnectivity and a profound reduction in parieto-occipital alpha power. In contrast, SeLECTS displayed features of focal origin with widespread impact, including extreme low-to-mid frequency (delta-to-alpha) hyperconnectivity across distinct subnetworks and a widespread decrease in high-frequency (beta to gamma) power, most prominent in the temporal lobes.</div></div><div><h3>Significance</h3><div>This study provides the first direct neuromagnetic comparison of drug-naive CAE and SeLECTS. While a shared signature of pathological brain slowing suggests a common substrate of network instability, their distinct patterns of network dysfunction—global dysregulation in CAE versus focal-origin hyperconnectivity and widespread high-frequency power collapse in SeLECTS—elucidate divergent pathophysiological mechanisms. These syndrome-specific neuromagnetic features hold potential as non-invasive biomarkers for differential diagnosis and therapeutic monitoring.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"134 ","pages":"Pages 106-116"},"PeriodicalIF":2.8,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145693651","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}
Pub Date : 2025-11-24DOI: 10.1016/j.seizure.2025.11.018
Shahla Melikova , Aytan Mammadbayli
Objective
To prospectively investigate seizure control during pregnancy in women with focal epilepsies, to assess the impact of specific forms of focal epilepsy (FE) on delivery and neonatal outcomes, and to compare these outcomes with those in pregnancies of women without epilepsy.
Methods
Seventy-nine women with FE, recruited from a large cohort of pregnant women, were prospectively evaluated for over a ten-year period. Seizure, obstetric, and neonatal outcomes were analyzed across the different forms of FE.
Results
Seizures occurred in 77.2 % of women with FE, with higher incidence in frontal lobe epilepsy (FLE) (88.2 %) and temporal lobe epilepsy (TLE) (84.1 %) compared with other focal epilepsies (OFEs) (50.0 %) (p = 0.02 and p = 0.0078, respectively). Women with FLE experienced higher rates of seizure worsening and lower odds of remaining seizure-free during pregnancy compared with those with temporal lobe epilepsy TLE and OFEs. Non-adherence to antiseizure medications was significantly associated with increased seizure frequency (p < 0.0001). WWE had higher rates of cesarean section, preterm birth, and premature rupture of membranes compared with women without epilepsy. Neonates of WWE had higher rates of five-minute Apgar scores ≤7 and perinatal hypoxia (pH), with pH significantly associated with any in utero seizure exposure (OR 9.33; p = 0.04), independent of seizure form. Offspring of women with FLE had the highest prevalence of low Apgar scores compared with TLE and OFEs.
Conclusion
Seizure occurrence during pregnancy, rather than the specific form of FE alone, can be considered the primary factor contributing to adverse maternal and neonatal outcomes. These findings emphasize the importance of continuous seizure management, ASM adherence, and individualized perinatal care in WWE.
{"title":"Seizure control, delivery, and neonatal outcomes in pregnant women with focal epilepsies: a prospective cohort study","authors":"Shahla Melikova , Aytan Mammadbayli","doi":"10.1016/j.seizure.2025.11.018","DOIUrl":"10.1016/j.seizure.2025.11.018","url":null,"abstract":"<div><h3>Objective</h3><div>To prospectively investigate seizure control during pregnancy in women with focal epilepsies, to assess the impact of specific forms of focal epilepsy (FE) on delivery and neonatal outcomes, and to compare these outcomes with those in pregnancies of women without epilepsy.</div></div><div><h3>Methods</h3><div>Seventy-nine women with FE, recruited from a large cohort of pregnant women, were prospectively evaluated for over a ten-year period. Seizure, obstetric, and neonatal outcomes were analyzed across the different forms of FE.</div></div><div><h3>Results</h3><div>Seizures occurred in 77.2 % of women with FE, with higher incidence in frontal lobe epilepsy (FLE) (88.2 %) and temporal lobe epilepsy (TLE) (84.1 %) compared with other focal epilepsies (OFEs) (50.0 %) (<em>p</em> = 0.02 and <em>p</em> = 0.0078, respectively). Women with FLE experienced higher rates of seizure worsening and lower odds of remaining seizure-free during pregnancy compared with those with temporal lobe epilepsy TLE and OFEs. Non-adherence to antiseizure medications was significantly associated with increased seizure frequency (<em>p</em> < 0.0001). WWE had higher rates of cesarean section, preterm birth, and premature rupture of membranes compared with women without epilepsy. Neonates of WWE had higher rates of five-minute Apgar scores ≤7 and perinatal hypoxia (pH), with pH significantly associated with any in utero seizure exposure (OR 9.33; <em>p</em> = 0.04), independent of seizure form. Offspring of women with FLE had the highest prevalence of low Apgar scores compared with TLE and OFEs.</div></div><div><h3>Conclusion</h3><div>Seizure occurrence during pregnancy, rather than the specific form of FE alone, can be considered the primary factor contributing to adverse maternal and neonatal outcomes. These findings emphasize the importance of continuous seizure management, ASM adherence, and individualized perinatal care in WWE.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"134 ","pages":"Pages 117-125"},"PeriodicalIF":2.8,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145693581","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}
Pub Date : 2025-11-23DOI: 10.1016/j.seizure.2025.11.016
Debopam Samanta , Sunil Naik
Objective
To evaluate the efficacy and safety of cenobamate in developmental and epileptic encephalopathies (DEE) through systematic review and meta-analysis.
Methods
We systematically searched electronic databases for studies reporting cenobamate outcomes in DEE. Primary outcome was the proportion of patients achieving ≥50 % seizure reduction. Secondary outcomes included seizure freedom, treatment retention, and treatment-emergent adverse events (TEAEs). Study quality was assessed using the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool. Generalized linear mixed-model (GLMM) meta-analyses with logit transformation were performed. Between-study heterogeneity was assessed using I² statistics. Leave-one-out sensitivity analysis identified influential studies. Meta-regression explored associations between study characteristics and outcomes. Evidence quality was evaluated using GRADE criteria.
Results
Fourteen studies involving 368 DEE patients were included; individual studies reported mean ages ranging from 8.7 to 42 years and follow-up durations of 3 to 24 months. Patients had extensive treatment histories (8–15 prior antiseizure medications). The pooled ≥50 % responder rate was 56.8 % (95 % CI: 41.9–70.6 %; I² = 74.9 %). Sensitivity analysis excluding four influential studies produced a similar estimate (63.4 %, 95 % CI: 46.5–77.6 %) with no heterogeneity. Seizure freedom was achieved in 10.3 % (95 % CI: 6.6–15.7 %; I² = 21.3 %). Treatment retention was high at 88.6 % (95 % CI: 66.9–96.7 %), though longitudinal data showed decline over time. TEAEs occurred in 60.3 % (95 % CI: 53.5–66.7 %), most often somnolence, dizziness, and ataxia, typically manageable with dose adjustments. No cases of DRESS were reported. Meta-regression found no significant association between age, follow-up duration, or prior/current antiseizure medication burden and treatment response.
Significance
Cenobamate demonstrates promising efficacy in highly refractory DEEs, with over half of patients achieving ≥50 % seizure reduction and ∼10 % attaining seizure freedom despite extensive prior treatment failures. The high retention rate and manageable safety profile support its use as a valuable therapeutic option in this difficult-to-treat population.
{"title":"Efficacy and safety of cenobamate in developmental and epileptic encephalopathies: A systematic review and meta-analysis","authors":"Debopam Samanta , Sunil Naik","doi":"10.1016/j.seizure.2025.11.016","DOIUrl":"10.1016/j.seizure.2025.11.016","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the efficacy and safety of cenobamate in developmental and epileptic encephalopathies (DEE) through systematic review and meta-analysis.</div></div><div><h3>Methods</h3><div>We systematically searched electronic databases for studies reporting cenobamate outcomes in DEE. Primary outcome was the proportion of patients achieving ≥50 % seizure reduction. Secondary outcomes included seizure freedom, treatment retention, and treatment-emergent adverse events (TEAEs). Study quality was assessed using the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool. Generalized linear mixed-model (GLMM) meta-analyses with logit transformation were performed. Between-study heterogeneity was assessed using I² statistics. Leave-one-out sensitivity analysis identified influential studies. Meta-regression explored associations between study characteristics and outcomes. Evidence quality was evaluated using GRADE criteria.</div></div><div><h3>Results</h3><div>Fourteen studies involving 368 DEE patients were included; individual studies reported mean ages ranging from 8.7 to 42 years and follow-up durations of 3 to 24 months. Patients had extensive treatment histories (8–15 prior antiseizure medications). The pooled ≥50 % responder rate was 56.8 % (95 % CI: 41.9–70.6 %; I² = 74.9 %). Sensitivity analysis excluding four influential studies produced a similar estimate (63.4 %, 95 % CI: 46.5–77.6 %) with no heterogeneity. Seizure freedom was achieved in 10.3 % (95 % CI: 6.6–15.7 %; I² = 21.3 %). Treatment retention was high at 88.6 % (95 % CI: 66.9–96.7 %), though longitudinal data showed decline over time. TEAEs occurred in 60.3 % (95 % CI: 53.5–66.7 %), most often somnolence, dizziness, and ataxia, typically manageable with dose adjustments. No cases of DRESS were reported. Meta-regression found no significant association between age, follow-up duration, or prior/current antiseizure medication burden and treatment response.</div></div><div><h3>Significance</h3><div>Cenobamate demonstrates promising efficacy in highly refractory DEEs, with over half of patients achieving ≥50 % seizure reduction and ∼10 % attaining seizure freedom despite extensive prior treatment failures. The high retention rate and manageable safety profile support its use as a valuable therapeutic option in this difficult-to-treat population.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"134 ","pages":"Pages 86-96"},"PeriodicalIF":2.8,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145624253","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}
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