Rumika Mascarenhas, Daria Merrikh, Maryam Khanbabaei, Navprabhjot Kaur, Navid Ghaderi, Tatiana Maroilley, Yiping Liu, Tyler Soule, Juan Pablo Appendino, Julia Jacobs, Samuel Wiebe, Walter Hader, Gerald Pfeffer, Maja Tarailo-Graovac, Karl Martin Klein
Objective: Somatic variants causing epilepsy are challenging to detect, as they are only present in a subset of brain cells (e.g., mosaic), resulting in low variant allele frequencies. Traditional methods relying on surgically resected brain tissue are limited to patients undergoing brain surgery. We developed an improved protocol to detect somatic variants using DNA from stereoelectroencephalographic (SEEG) depth electrodes, enabling access to a larger patient cohort and diverse brain regions. This protocol mitigates issues of contamination and low yields by purifying neuronal nuclei using fluorescence-activated nuclei sorting (FANS).
Methods: SEEG depth electrodes were collected upon extraction from 41 brain regions across 17 patients undergoing SEEG. Nuclei were isolated separately from depth electrodes in the affected brain regions (seizure onset zone) and the unaffected brain regions. Neuronal nuclei were isolated using FANS, and DNA was amplified using primary template amplification. Short tandem repeat (STR) analysis and postsequencing allelic imbalance assessment were used to evaluate sample integrity. High-quality amplified DNA samples from affected brain regions, patient-matched unaffected brain regions, and genomic DNA were subjected to whole exome sequencing (WES). A bioinformatic workflow was developed to reduce false positives and to accurately detect somatic variants in the affected brain region.
Results: Based on DNA yield and STR analysis, 14 SEEG-derived neuronal DNA samples (seven affected and seven unaffected) across seven patients underwent WES. From the variants prioritized using our bioinformatic workflow, we chose four candidate variants in MTOR, CSDE1, KLLN, and NLE1 across four patients based on pathogenicity scores and association with phenotype. All four variants were validated using digital droplet polymerase chain reaction.
Significance: Our approach enhances the reliability and applicability of SEEG-derived DNA for epilepsy, offering insights into its molecular basis, facilitating epileptogenic zone identification, and advancing precision medicine.
{"title":"Detecting somatic variants in purified brain DNA obtained from surgically implanted depth electrodes in epilepsy.","authors":"Rumika Mascarenhas, Daria Merrikh, Maryam Khanbabaei, Navprabhjot Kaur, Navid Ghaderi, Tatiana Maroilley, Yiping Liu, Tyler Soule, Juan Pablo Appendino, Julia Jacobs, Samuel Wiebe, Walter Hader, Gerald Pfeffer, Maja Tarailo-Graovac, Karl Martin Klein","doi":"10.1111/epi.18251","DOIUrl":"https://doi.org/10.1111/epi.18251","url":null,"abstract":"<p><strong>Objective: </strong>Somatic variants causing epilepsy are challenging to detect, as they are only present in a subset of brain cells (e.g., mosaic), resulting in low variant allele frequencies. Traditional methods relying on surgically resected brain tissue are limited to patients undergoing brain surgery. We developed an improved protocol to detect somatic variants using DNA from stereoelectroencephalographic (SEEG) depth electrodes, enabling access to a larger patient cohort and diverse brain regions. This protocol mitigates issues of contamination and low yields by purifying neuronal nuclei using fluorescence-activated nuclei sorting (FANS).</p><p><strong>Methods: </strong>SEEG depth electrodes were collected upon extraction from 41 brain regions across 17 patients undergoing SEEG. Nuclei were isolated separately from depth electrodes in the affected brain regions (seizure onset zone) and the unaffected brain regions. Neuronal nuclei were isolated using FANS, and DNA was amplified using primary template amplification. Short tandem repeat (STR) analysis and postsequencing allelic imbalance assessment were used to evaluate sample integrity. High-quality amplified DNA samples from affected brain regions, patient-matched unaffected brain regions, and genomic DNA were subjected to whole exome sequencing (WES). A bioinformatic workflow was developed to reduce false positives and to accurately detect somatic variants in the affected brain region.</p><p><strong>Results: </strong>Based on DNA yield and STR analysis, 14 SEEG-derived neuronal DNA samples (seven affected and seven unaffected) across seven patients underwent WES. From the variants prioritized using our bioinformatic workflow, we chose four candidate variants in MTOR, CSDE1, KLLN, and NLE1 across four patients based on pathogenicity scores and association with phenotype. All four variants were validated using digital droplet polymerase chain reaction.</p><p><strong>Significance: </strong>Our approach enhances the reliability and applicability of SEEG-derived DNA for epilepsy, offering insights into its molecular basis, facilitating epileptogenic zone identification, and advancing precision medicine.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921125","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}
Lennart N Kersting, Lennart Walger, Tobias Bauer, Vadym Gnatkovsky, Fabiane Schuch, Bastian David, Elisabeth Neuhaus, Fee Keil, Anna Tietze, Felix Rosenow, Angela M Kaindl, Elke Hattingen, Hans-Jürgen Huppertz, Alexander Radbruch, Rainer Surges, Theodor Rüber
Objective: Focal cortical dysplasia (FCD) is a common cause of drug-resistant focal epilepsy but can be challenging to detect visually on magnetic resonance imaging. Three artificial intelligence models for automated FCD detection are publicly available (MAP18, deepFCD, MELD) but have only been compared on single-center data. Our first objective is to compare them on independent multicenter test data. Additionally, we train and compare three new models and make them publicly available.
Methods: We retrospectively collected FCD cases from four epilepsy centers. We chose three novel models that take two-dimensional (2D) slices (2D-nnUNet), 2.5D slices (FastSurferCNN), and large 3D patches (3D-nnUNet) as inputs and trained them on a subset of Bonn data. As core evaluation metrics, we used voxel-level Dice similarity coefficient (DSC), cluster-level F1 score, subject-level detection rate, and specificity.
Results: We collected 329 subjects, 244 diagnosed with FCD (27.7 ± 14.4 years old, 54% male) and 85 healthy controls (7.1 ± 2.4 years old, 51% female). We used 118 subjects for model training and kept the remaining subjects as an independent test set. 3D-nnUNet achieved the highest F1 score of .58, the highest DSC of .36 (95% confidence interval [CI] = .30-.41), a detection rate of 55%, and a specificity of 86%. deepFCD showed the highest detection rate (82%) but had the lowest specificity (0%) and cluster-level precision (.03, 95% CI = .03-.04, F1 score = .07). MELD showed the least performance variation across centers, with detection rates between 46% and 54%.
Significance: This study shows the variance in performance for FCD detection models in a multicenter dataset. The two models with 3D input data showed the highest sensitivity. The 2D models performed worse than all other models, suggesting that FCD detection requires 3D data. The greatly improved precision of 3D-nnUNet may make it a sensible choice to aid FCD detection.
{"title":"Detection of focal cortical dysplasia: Development and multicentric evaluation of artificial intelligence models.","authors":"Lennart N Kersting, Lennart Walger, Tobias Bauer, Vadym Gnatkovsky, Fabiane Schuch, Bastian David, Elisabeth Neuhaus, Fee Keil, Anna Tietze, Felix Rosenow, Angela M Kaindl, Elke Hattingen, Hans-Jürgen Huppertz, Alexander Radbruch, Rainer Surges, Theodor Rüber","doi":"10.1111/epi.18240","DOIUrl":"https://doi.org/10.1111/epi.18240","url":null,"abstract":"<p><strong>Objective: </strong>Focal cortical dysplasia (FCD) is a common cause of drug-resistant focal epilepsy but can be challenging to detect visually on magnetic resonance imaging. Three artificial intelligence models for automated FCD detection are publicly available (MAP18, deepFCD, MELD) but have only been compared on single-center data. Our first objective is to compare them on independent multicenter test data. Additionally, we train and compare three new models and make them publicly available.</p><p><strong>Methods: </strong>We retrospectively collected FCD cases from four epilepsy centers. We chose three novel models that take two-dimensional (2D) slices (2D-nnUNet), 2.5D slices (FastSurferCNN), and large 3D patches (3D-nnUNet) as inputs and trained them on a subset of Bonn data. As core evaluation metrics, we used voxel-level Dice similarity coefficient (DSC), cluster-level F<sub>1</sub> score, subject-level detection rate, and specificity.</p><p><strong>Results: </strong>We collected 329 subjects, 244 diagnosed with FCD (27.7 ± 14.4 years old, 54% male) and 85 healthy controls (7.1 ± 2.4 years old, 51% female). We used 118 subjects for model training and kept the remaining subjects as an independent test set. 3D-nnUNet achieved the highest F<sub>1</sub> score of .58, the highest DSC of .36 (95% confidence interval [CI] = .30-.41), a detection rate of 55%, and a specificity of 86%. deepFCD showed the highest detection rate (82%) but had the lowest specificity (0%) and cluster-level precision (.03, 95% CI = .03-.04, F<sub>1</sub> score = .07). MELD showed the least performance variation across centers, with detection rates between 46% and 54%.</p><p><strong>Significance: </strong>This study shows the variance in performance for FCD detection models in a multicenter dataset. The two models with 3D input data showed the highest sensitivity. The 2D models performed worse than all other models, suggesting that FCD detection requires 3D data. The greatly improved precision of 3D-nnUNet may make it a sensible choice to aid FCD detection.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909346","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}
Jennifer Tinston, Matthew R Hudson, Anna Harutyunyan, Zhibin Chen, Nigel C Jones
Objective: The 5xFAD mouse model of Alzheimer disease (AD) recapitulates amyloid-beta (Aβ) deposition and pronounced seizure susceptibility observed in patients with AD. Forty-hertz audiovisual stimulation is a noninvasive technique that entrains gamma neural oscillations and can reduce Aβ pathology and modulate glial expression in AD models. We hypothesized that 40-Hz sensory stimulation would improve seizure susceptibility in 5xFAD mice and this would be associated with reduction of plaques and modulation of glial phenotypes.
Methods: 5xFAD mice and wild-type (WT) littermates received 1 h/day 40-Hz audiovisual stimulation or sham (n = 7-11/group), beginning 2 weeks before and continuing throughout amygdala kindling epileptogenesis. Postmortem analyses included Aβ pathology and morphology of astrocytes and microglia.
Results: 5xFAD mice exhibited enhanced susceptibility to seizures compared to WT, evidenced by fewer stimulations to reach kindling endpoint (incidence rate ratio [IRR] = 1.46, p < .0001) and a trend to higher seizure severity (odds ratio [OR] = .34, p = .059). Forty-hertz stimulation reduced the behavioral severity of the first seizure (OR = 4.04, p = .02) and delayed epileptogenesis, increasing the number of stimulations required to reach kindling endpoint (IRR = .82, p = .01) compared to sham, regardless of genotype. 5xFAD mice receiving sensory stimulation exhibited ~50% reduction in amyloid pathology compared to sham. Furthermore, markers of astrocytes and microglia were upregulated in both genotypes receiving 40-Hz stimulation.
Significance: Forty-hertz sensory entrainment slows epileptogenesis in the mouse amygdala kindling model. Although this intervention improves Aβ pathology in 5xFAD mice, the observed antiepileptogenic effect may also relate to effects on glia, because mice without Aβ plaques (i.e., WT) also experienced antiepileptogenic effects of the intervention.
{"title":"Forty-hertz sensory entrainment impedes kindling epileptogenesis and reduces amyloid pathology in an Alzheimer disease mouse model.","authors":"Jennifer Tinston, Matthew R Hudson, Anna Harutyunyan, Zhibin Chen, Nigel C Jones","doi":"10.1111/epi.18222","DOIUrl":"https://doi.org/10.1111/epi.18222","url":null,"abstract":"<p><strong>Objective: </strong>The 5xFAD mouse model of Alzheimer disease (AD) recapitulates amyloid-beta (Aβ) deposition and pronounced seizure susceptibility observed in patients with AD. Forty-hertz audiovisual stimulation is a noninvasive technique that entrains gamma neural oscillations and can reduce Aβ pathology and modulate glial expression in AD models. We hypothesized that 40-Hz sensory stimulation would improve seizure susceptibility in 5xFAD mice and this would be associated with reduction of plaques and modulation of glial phenotypes.</p><p><strong>Methods: </strong>5xFAD mice and wild-type (WT) littermates received 1 h/day 40-Hz audiovisual stimulation or sham (n = 7-11/group), beginning 2 weeks before and continuing throughout amygdala kindling epileptogenesis. Postmortem analyses included Aβ pathology and morphology of astrocytes and microglia.</p><p><strong>Results: </strong>5xFAD mice exhibited enhanced susceptibility to seizures compared to WT, evidenced by fewer stimulations to reach kindling endpoint (incidence rate ratio [IRR] = 1.46, p < .0001) and a trend to higher seizure severity (odds ratio [OR] = .34, p = .059). Forty-hertz stimulation reduced the behavioral severity of the first seizure (OR = 4.04, p = .02) and delayed epileptogenesis, increasing the number of stimulations required to reach kindling endpoint (IRR = .82, p = .01) compared to sham, regardless of genotype. 5xFAD mice receiving sensory stimulation exhibited ~50% reduction in amyloid pathology compared to sham. Furthermore, markers of astrocytes and microglia were upregulated in both genotypes receiving 40-Hz stimulation.</p><p><strong>Significance: </strong>Forty-hertz sensory entrainment slows epileptogenesis in the mouse amygdala kindling model. Although this intervention improves Aβ pathology in 5xFAD mice, the observed antiepileptogenic effect may also relate to effects on glia, because mice without Aβ plaques (i.e., WT) also experienced antiepileptogenic effects of the intervention.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906496","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":"Thank you to our reviewers in 2024","authors":"Fernando Cendes","doi":"10.1111/epi.18233","DOIUrl":"10.1111/epi.18233","url":null,"abstract":"","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":"66 1","pages":"1-5"},"PeriodicalIF":6.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909363","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}
Jeffrey Tenney, Hisako Fujiwara, Jesse Skoch, Paul Horn, Seungrok Hong, Olivia Lee, Kelly Kremer, Ravindra Arya, Katherine Holland, Francesco Mangano, Hansel Greiner
Objective: The most common medically resistant epilepsy (MRE) involves the temporal lobe (TLE), and children designated as temporal plus epilepsy (TLE+) have a five-times increased risk of postoperative surgical failure. This retrospective, blinded, cross-sectional study aimed to correlate visual and computational analyses of magnetoencephalography (MEG) virtual sensor waveforms with surgical outcome and epilepsy classification (TLE and TLE+).
Methods: Patients with MRE who underwent MEG and iEEG monitoring and had at least 1 year of postsurgical follow-up were included in this retrospective analysis. User-defined virtual sensor (UDvs) beamforming was completed with virtual sensors placed manually and symmetrically in the bilateral amygdalohippocampi, inferior/middle/superior temporal gyri, insula, suprasylvian operculum, orbitofrontal cortex, and temporoparieto-occipital junction. Additionally, MEG effective connectivity was computed and quantified using eigenvector centrality (EC) to identify hub regions. More conventional MEG methods (equivalent current dipole [ECD], standardized low-resolution brain electromagnetic tomography, synthetic aperture magnetometry beamformer), UDvs beamformer, and EC hubs were compared to iEEG.
Results: Eighty patients (38 female, 42 male) with MRE (mean age = 11.3 ± 6.2 years, range = 1.0-31.5) were identified and included. Twenty-five patients (31.3%) were classified as TLE, whereas 55 (68.8%) were TLE+. When modeling the association between MEG method, iEEG, and postoperative surgical outcome (odds of a worse [International League Against Epilepsy (ILAE) class > 2] outcome), a significant result was seen only for UDvs beamformer (odds ratio [OR] = 1.22, 95% confidence interval [CI] = 1.01-1.48). Likewise, when the relationship between MEG method, iEEG, and classification (TLE and TLE+) was modeled, only UDvs beamformer had a significant association (OR = 1.47, 95% CI = 1.13-1.92). When modeling the association between EC hub location and resection/ablation to postoperative surgical outcome (odds of a good [ILAE 1-2] outcome), a significant association was seen (OR = 1.22, 95% CI = 1.05-1.43).
Significance: This study demonstrates a concordance between UDvs beamforming and iEEG that is related to both postsurgical seizure outcome and presurgical classification of epilepsy (TLE and TLE+). UDvs beamforming could be a complementary approach to the well-established ECD, improving invasive electrode and surgical resection planning for patients undergoing epilepsy surgery evaluations and treatments.
{"title":"User-defined virtual sensors: A new solution to the problem of temporal plus epilepsy sources.","authors":"Jeffrey Tenney, Hisako Fujiwara, Jesse Skoch, Paul Horn, Seungrok Hong, Olivia Lee, Kelly Kremer, Ravindra Arya, Katherine Holland, Francesco Mangano, Hansel Greiner","doi":"10.1111/epi.18247","DOIUrl":"https://doi.org/10.1111/epi.18247","url":null,"abstract":"<p><strong>Objective: </strong>The most common medically resistant epilepsy (MRE) involves the temporal lobe (TLE), and children designated as temporal plus epilepsy (TLE+) have a five-times increased risk of postoperative surgical failure. This retrospective, blinded, cross-sectional study aimed to correlate visual and computational analyses of magnetoencephalography (MEG) virtual sensor waveforms with surgical outcome and epilepsy classification (TLE and TLE+).</p><p><strong>Methods: </strong>Patients with MRE who underwent MEG and iEEG monitoring and had at least 1 year of postsurgical follow-up were included in this retrospective analysis. User-defined virtual sensor (UDvs) beamforming was completed with virtual sensors placed manually and symmetrically in the bilateral amygdalohippocampi, inferior/middle/superior temporal gyri, insula, suprasylvian operculum, orbitofrontal cortex, and temporoparieto-occipital junction. Additionally, MEG effective connectivity was computed and quantified using eigenvector centrality (EC) to identify hub regions. More conventional MEG methods (equivalent current dipole [ECD], standardized low-resolution brain electromagnetic tomography, synthetic aperture magnetometry beamformer), UDvs beamformer, and EC hubs were compared to iEEG.</p><p><strong>Results: </strong>Eighty patients (38 female, 42 male) with MRE (mean age = 11.3 ± 6.2 years, range = 1.0-31.5) were identified and included. Twenty-five patients (31.3%) were classified as TLE, whereas 55 (68.8%) were TLE+. When modeling the association between MEG method, iEEG, and postoperative surgical outcome (odds of a worse [International League Against Epilepsy (ILAE) class > 2] outcome), a significant result was seen only for UDvs beamformer (odds ratio [OR] = 1.22, 95% confidence interval [CI] = 1.01-1.48). Likewise, when the relationship between MEG method, iEEG, and classification (TLE and TLE+) was modeled, only UDvs beamformer had a significant association (OR = 1.47, 95% CI = 1.13-1.92). When modeling the association between EC hub location and resection/ablation to postoperative surgical outcome (odds of a good [ILAE 1-2] outcome), a significant association was seen (OR = 1.22, 95% CI = 1.05-1.43).</p><p><strong>Significance: </strong>This study demonstrates a concordance between UDvs beamforming and iEEG that is related to both postsurgical seizure outcome and presurgical classification of epilepsy (TLE and TLE+). UDvs beamforming could be a complementary approach to the well-established ECD, improving invasive electrode and surgical resection planning for patients undergoing epilepsy surgery evaluations and treatments.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909366","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}
Objective: Fenfluramine (FFA), stiripentol (STP), and cannabidiol (CBD) are approved add-on therapies for seizures in Dravet syndrome (DS). We report on the long-term safety and health care resource utilization (HCRU) of patients with DS treated with FFA under an expanded access program (EAP).
Methods: A cohort of 124 patients received FFA for a median of 2.8 years (34.4 months). We compared data on safety and HCRU during FFA treatment with those from a same pre-treatment period. Echocardiography was conducted every 6 months. Information collected included gender, age, and auxological parameters (height, weight, and body mass index [BMI]) at the start (T0) and follow-up (T1); FFA treatment details (start, withdrawal, dosage); adverse events (AEs); and HCRU data including hospital admissions, status epilepticus (SE) episodes, and rescue medication use. We grouped patients by weight: ≤37.4 kg (n = 68, 54.8%) and ≥37.5 kg (n = 56; 45.1%), with FFA dosing adjusted accordingly. Statistical analyses included paired t test, Wilcoxon signed-rank test, Kaplan-Meier analysis, and Bonferroni correction to adjust for multiple testing.
Results: Mean age was 47 months at clinical diagnosis and 81 months at T0. The last follow-up average FFA dose was .5 mg/kg/day, with a median of .4 mg/kg/day. FFA led to a 9.5% reduction in prior treatment load. At last follow-up, 118 of 124 (91.5%) remained on FFA. Rescue medication use decreased significantly from 4.5 to 1, hospitalizations from 1 to 0, and SE episodes from 0-240 to 0-180 (p < .001 for all). Seizure freedom was achieved in 9 of 118 patients (7.6%). AEs occurred in 39 of 124 patients (31.5%), with no cardiac issues or deaths. There was an overall mean reduction in BMI, with no statistical significance, and never requiring FFA withdrawal.
Significance: FFA is well tolerated, without cardiac toxicity, and reduces treatment load and HCRU, suggesting improved patient management. BMI reduction in young children highlights the need for growth and nutritional monitoring.
目的:芬氟拉明(FFA)、斯蒂利戊醇(STP)和大麻二酚(CBD)被批准用于治疗Dravet综合征(DS)癫痫发作。我们报告了在扩大准入计划(EAP)下接受FFA治疗的DS患者的长期安全性和卫生保健资源利用(HCRU)。方法:124例患者接受FFA治疗,平均时间为2.8年(34.4个月)。我们比较了FFA治疗期间的安全性和HCRU数据与相同治疗前的数据。每6个月进行一次超声心动图检查。收集的信息包括开始(T0)和随访(T1)时的性别、年龄和生理参数(身高、体重和身体质量指数[BMI]);FFA治疗细节(开始、停药、剂量);不良事件(ae);HCRU数据包括住院、癫痫持续状态(SE)发作和抢救用药。我们将患者按体重分组:≤37.4 kg (n = 68, 54.8%)和≥37.5 kg (n = 56;45.1%),并相应调整FFA的剂量。统计分析包括配对t检验、Wilcoxon符号秩检验、Kaplan-Meier分析和Bonferroni校正以调整多重检验。结果:临床诊断时平均年龄47个月,T0时平均年龄81个月。最后一次随访的平均FFA剂量为0.5 mg/kg/天,中位数为0.4 mg/kg/天。FFA导致先前治疗负荷减少9.5%。最后随访时,124例患者中有118例(91.5%)仍在接受FFA治疗。急救用药从4.5次减少到1次,住院次数从1次减少到0次,SE发作从0-240次减少到0-180次(p显著性:FFA耐受性良好,无心脏毒性,降低治疗负荷和HCRU,表明患者管理得到改善。幼儿身体质量指数的降低凸显了对生长和营养监测的必要性。
{"title":"Fenfluramine treatment for Dravet syndrome: Long term real-world analysis demonstrates safety and reduced health care burden.","authors":"Alessandra Boncristiano, Simona Balestrini, Viola Doccini, Nicola Specchio, Nicola Pietrafusa, Marina Trivisano, Francesca Darra, Alberto Cossu, Domenica Battaglia, Michela Quintiliani, M Luigia Gambardella, Eliana Parente, Rita Monni, Sara Matricardi, Carla Marini, Francesca Ragona, Tiziana Granata, Pasquale Striano, Antonella Riva, Renzo Guerrini","doi":"10.1111/epi.18241","DOIUrl":"https://doi.org/10.1111/epi.18241","url":null,"abstract":"<p><strong>Objective: </strong>Fenfluramine (FFA), stiripentol (STP), and cannabidiol (CBD) are approved add-on therapies for seizures in Dravet syndrome (DS). We report on the long-term safety and health care resource utilization (HCRU) of patients with DS treated with FFA under an expanded access program (EAP).</p><p><strong>Methods: </strong>A cohort of 124 patients received FFA for a median of 2.8 years (34.4 months). We compared data on safety and HCRU during FFA treatment with those from a same pre-treatment period. Echocardiography was conducted every 6 months. Information collected included gender, age, and auxological parameters (height, weight, and body mass index [BMI]) at the start (T0) and follow-up (T1); FFA treatment details (start, withdrawal, dosage); adverse events (AEs); and HCRU data including hospital admissions, status epilepticus (SE) episodes, and rescue medication use. We grouped patients by weight: ≤37.4 kg (n = 68, 54.8%) and ≥37.5 kg (n = 56; 45.1%), with FFA dosing adjusted accordingly. Statistical analyses included paired t test, Wilcoxon signed-rank test, Kaplan-Meier analysis, and Bonferroni correction to adjust for multiple testing.</p><p><strong>Results: </strong>Mean age was 47 months at clinical diagnosis and 81 months at T0. The last follow-up average FFA dose was .5 mg/kg/day, with a median of .4 mg/kg/day. FFA led to a 9.5% reduction in prior treatment load. At last follow-up, 118 of 124 (91.5%) remained on FFA. Rescue medication use decreased significantly from 4.5 to 1, hospitalizations from 1 to 0, and SE episodes from 0-240 to 0-180 (p < .001 for all). Seizure freedom was achieved in 9 of 118 patients (7.6%). AEs occurred in 39 of 124 patients (31.5%), with no cardiac issues or deaths. There was an overall mean reduction in BMI, with no statistical significance, and never requiring FFA withdrawal.</p><p><strong>Significance: </strong>FFA is well tolerated, without cardiac toxicity, and reduces treatment load and HCRU, suggesting improved patient management. BMI reduction in young children highlights the need for growth and nutritional monitoring.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909351","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}
Panagiota Karatza, Dorottya Cserpan, Katharina Moser, Santo Pietro Lo Biundo, Johannes Sarnthein, Georgia Ramantani
Objective: This study aimed to investigate two key aspects of scalp high-frequency oscillations (HFOs) in pediatric focal lesional epilepsy: (1) the stability of scalp HFO spatial distribution across consecutive nights, and (2) the variation in scalp HFO rates in response to changes in antiseizure medication (ASM).
Methods: We analyzed 81 whole-night scalp electroencephalography (EEG) recordings from 20 children with focal lesional epilepsy. We used a previously validated automated HFO detector to assess scalp HFO rates (80-250 Hz) during non-rapid eye movement (NREM) sleep. The spatial distribution of HFO rates across consecutive nights was evaluated using Hamming similarity, and changes in ASM were classified as increased, decreased, or stable.
Results: For each patient, we analyzed 3 ± 1 whole-night scalp EEG recordings, with a mean duration of 650 ± 215 min per recording. The distribution of HFO remained stable across consecutive nights, with a Hamming similarity of 88% ± 6%. Four patients had at least one ASM dosage decrease, nine patients had both ASM dosage decreases and increases, two patients had only ASM dosage increases, and five patients had no changes in ASM during the study period. A decrease in ASM dosage was associated with increased HFO rates (from .16 ± .32 to .22 ± .36 HFO/min; p = .03), whereas an increase in ASM dosage led to decreased HFO rates (from .32 ± .54 HFO/min to .22 ± .38 HFO/min; p = .005) when comparing the last night to the first.
Significance: The spatial distribution of scalp HFOs remained consistent across multiple nights, whereas fluctuations in HFO rates correlated with changes in ASM dosage. These findings suggest that scalp HFOs may not only help identify epileptogenic brain tissue but also monitor treatment response.
{"title":"Scalp high-frequency oscillation spatial distribution is consistent over consecutive nights, while rates vary with antiseizure medication changes.","authors":"Panagiota Karatza, Dorottya Cserpan, Katharina Moser, Santo Pietro Lo Biundo, Johannes Sarnthein, Georgia Ramantani","doi":"10.1111/epi.18250","DOIUrl":"https://doi.org/10.1111/epi.18250","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate two key aspects of scalp high-frequency oscillations (HFOs) in pediatric focal lesional epilepsy: (1) the stability of scalp HFO spatial distribution across consecutive nights, and (2) the variation in scalp HFO rates in response to changes in antiseizure medication (ASM).</p><p><strong>Methods: </strong>We analyzed 81 whole-night scalp electroencephalography (EEG) recordings from 20 children with focal lesional epilepsy. We used a previously validated automated HFO detector to assess scalp HFO rates (80-250 Hz) during non-rapid eye movement (NREM) sleep. The spatial distribution of HFO rates across consecutive nights was evaluated using Hamming similarity, and changes in ASM were classified as increased, decreased, or stable.</p><p><strong>Results: </strong>For each patient, we analyzed 3 ± 1 whole-night scalp EEG recordings, with a mean duration of 650 ± 215 min per recording. The distribution of HFO remained stable across consecutive nights, with a Hamming similarity of 88% ± 6%. Four patients had at least one ASM dosage decrease, nine patients had both ASM dosage decreases and increases, two patients had only ASM dosage increases, and five patients had no changes in ASM during the study period. A decrease in ASM dosage was associated with increased HFO rates (from .16 ± .32 to .22 ± .36 HFO/min; p = .03), whereas an increase in ASM dosage led to decreased HFO rates (from .32 ± .54 HFO/min to .22 ± .38 HFO/min; p = .005) when comparing the last night to the first.</p><p><strong>Significance: </strong>The spatial distribution of scalp HFOs remained consistent across multiple nights, whereas fluctuations in HFO rates correlated with changes in ASM dosage. These findings suggest that scalp HFOs may not only help identify epileptogenic brain tissue but also monitor treatment response.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909358","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}
Objective: At our institute, most pediatric patients undergo epilepsy surgery following a thorough presurgical evaluation without intracranial electroencephalography (EEG). We conducted an initial validation of our noninvasive presurgical strategy by assessing the seizure and developmental outcomes of 135 children.
Methods: All 135 pediatric patients were <15 years old, had undergone curative surgery, and were followed for at least 2 years postoperatively. Presurgical evaluations and postoperative seizure and developmental outcomes were investigated. Thorough noninvasive evaluation included 3-T magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) in all patients. Intracranial EEG was mainly indicated for patients whose MRIs were negative or subtle. We defined Engel class I as favorable and Engel classes II-IV as unfavorable seizure outcomes. Intelligence quotient (IQ) and developmental quotient (DQ) before and 2 years after surgery were used to assess developmental/neuropsychological outcomes.
Results: MRI was positive in 130 of 135 patients (96.3%), including 39 of 40 with focal cortical dysplasia (FCD) type II and 30 of 33 with FCD type I. FDG-PET revealed concordant localizing findings in 119 of 132 patients (90.2%). Ictal single photon emission computed tomography provided concordant localizing information in 85 of 91 patients (93.4%). Intracranial EEG was performed in only 10 of 135 patients (7.4%). Ninety-seven of 135 patients (71.9%) were seizure-free 2 years after surgery. The final seizure-free rate was 99 of 135 (73.3%). Temporal lobe surgery predicted a favorable seizure outcome by multivariate analysis, whereas FCD type I and preoperative IQ/DQ < 70 predicted an unfavorable outcome. The mean IQ change was +1.3 points, and the mean DQ change was +1.0 points. Mean DQ significantly improved following extratemporal surgery (multivariate regression, p < .05), and mean DQ significantly decreased in patients with epileptic spasms (multivariate regression, p < .01).
Significance: Thorough noninvasive presurgical evaluation enables detection of subtle MRI lesions and curative epilepsy surgery without intracranial EEG in most patients, including those with FCD type II and type I, and leads to favorable seizure and developmental/neuropsychological outcomes.
{"title":"Favorable seizure and developmental outcomes without preoperative intracranial electroencephalography in pediatric patients following epilepsy surgery: A single epilepsy center retrospective study.","authors":"Taro Okumura, Naotaka Usui, Akihiko Kondo, Hiroshi Ogawa, Mitsuru Hashiguchi, Yosuke Kuromi, Tokito Yamaguchi, Hideyuki Otani, Katsumi Imai, Tomotaka Ishizaki, Takafumi Tanei, Satoshi Maesawa, Ryuta Saito","doi":"10.1111/epi.18249","DOIUrl":"https://doi.org/10.1111/epi.18249","url":null,"abstract":"<p><strong>Objective: </strong>At our institute, most pediatric patients undergo epilepsy surgery following a thorough presurgical evaluation without intracranial electroencephalography (EEG). We conducted an initial validation of our noninvasive presurgical strategy by assessing the seizure and developmental outcomes of 135 children.</p><p><strong>Methods: </strong>All 135 pediatric patients were <15 years old, had undergone curative surgery, and were followed for at least 2 years postoperatively. Presurgical evaluations and postoperative seizure and developmental outcomes were investigated. Thorough noninvasive evaluation included 3-T magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) in all patients. Intracranial EEG was mainly indicated for patients whose MRIs were negative or subtle. We defined Engel class I as favorable and Engel classes II-IV as unfavorable seizure outcomes. Intelligence quotient (IQ) and developmental quotient (DQ) before and 2 years after surgery were used to assess developmental/neuropsychological outcomes.</p><p><strong>Results: </strong>MRI was positive in 130 of 135 patients (96.3%), including 39 of 40 with focal cortical dysplasia (FCD) type II and 30 of 33 with FCD type I. FDG-PET revealed concordant localizing findings in 119 of 132 patients (90.2%). Ictal single photon emission computed tomography provided concordant localizing information in 85 of 91 patients (93.4%). Intracranial EEG was performed in only 10 of 135 patients (7.4%). Ninety-seven of 135 patients (71.9%) were seizure-free 2 years after surgery. The final seizure-free rate was 99 of 135 (73.3%). Temporal lobe surgery predicted a favorable seizure outcome by multivariate analysis, whereas FCD type I and preoperative IQ/DQ < 70 predicted an unfavorable outcome. The mean IQ change was +1.3 points, and the mean DQ change was +1.0 points. Mean DQ significantly improved following extratemporal surgery (multivariate regression, p < .05), and mean DQ significantly decreased in patients with epileptic spasms (multivariate regression, p < .01).</p><p><strong>Significance: </strong>Thorough noninvasive presurgical evaluation enables detection of subtle MRI lesions and curative epilepsy surgery without intracranial EEG in most patients, including those with FCD type II and type I, and leads to favorable seizure and developmental/neuropsychological outcomes.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892976","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}
Shashank Vadlamani, Mustafa Ozmen, James J Gugger, Amanda Cheney, Megan Amuan, Ramon Diaz-Arrastia, Mary Jo Pugh, Eamonn Kennedy
Objective: Traumatic brain injury (TBI) is a significant risk factor for epilepsy, but little work has explored whether risk of epilepsy after TBI may operate through intermediary mechanisms. The objective of this study was to statistically screen for potentially mediating effects among 64 comorbidities for epilepsy risk following TBI among Post-9/11 U.S. veterans.
Methods: This longitudinal matched cohort study used an established algorithm to identify veterans in Department of Defense (DoD) and Veterans Health Administration (VHA) records with a history of the primary exposure, TBI, between 2003 and 2023, who were demographically matched 1:1 with veterans without history of TBI exposure from the same cohort. In the observation time window after index date, mediation models estimated the proportion eliminated of the total TBI-epilepsy relationship by other factors. Cox proportional hazard models were implemented for 64 comorbidities determined using International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) codes, each individually tested for the potential mediation of epilepsy onset after date of first TBI (index date), adjusting for demographic and military covariates. Age-stratified mediation analyses were conducted. Biologically plausible mechanisms were investigated.
Results: Among N = 292 200 veterans in the TBI and matched groups, 8458 (2.9%) had an epilepsy diagnosis that met study criteria between 2003 and 2023. The adjusted hazard ratio (HR, 95% CI) for epilepsy given TBI was 6.76 [6.33-7.21]. The median duration between TBI documentation and epilepsy diagnosis was 3.3 years. In the observation time after index date (median duration: 12.2 years), Cox proportional hazard models identified the primary meditators of epilepsy risk after TBI as post-concussive symptoms (10.3%), cognitive dysfunction (7.0%), suicidal ideation/attempt (5.1%), overdose and drug abuse (3.8%-4.8%), and stroke (3.8%).
Significance: This study identified neurological conditions and symptoms that may play an intermediary role in the TBI-epilepsy relationship. Specific changes in health status after TBI may present useful targets for future trials and experimental approaches of PTE prevention.
{"title":"Mediators of epilepsy risk after traumatic brain injury: A 20-year U.S. veteran cohort study.","authors":"Shashank Vadlamani, Mustafa Ozmen, James J Gugger, Amanda Cheney, Megan Amuan, Ramon Diaz-Arrastia, Mary Jo Pugh, Eamonn Kennedy","doi":"10.1111/epi.18248","DOIUrl":"https://doi.org/10.1111/epi.18248","url":null,"abstract":"<p><strong>Objective: </strong>Traumatic brain injury (TBI) is a significant risk factor for epilepsy, but little work has explored whether risk of epilepsy after TBI may operate through intermediary mechanisms. The objective of this study was to statistically screen for potentially mediating effects among 64 comorbidities for epilepsy risk following TBI among Post-9/11 U.S. veterans.</p><p><strong>Methods: </strong>This longitudinal matched cohort study used an established algorithm to identify veterans in Department of Defense (DoD) and Veterans Health Administration (VHA) records with a history of the primary exposure, TBI, between 2003 and 2023, who were demographically matched 1:1 with veterans without history of TBI exposure from the same cohort. In the observation time window after index date, mediation models estimated the proportion eliminated of the total TBI-epilepsy relationship by other factors. Cox proportional hazard models were implemented for 64 comorbidities determined using International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) codes, each individually tested for the potential mediation of epilepsy onset after date of first TBI (index date), adjusting for demographic and military covariates. Age-stratified mediation analyses were conducted. Biologically plausible mechanisms were investigated.</p><p><strong>Results: </strong>Among N = 292 200 veterans in the TBI and matched groups, 8458 (2.9%) had an epilepsy diagnosis that met study criteria between 2003 and 2023. The adjusted hazard ratio (HR, 95% CI) for epilepsy given TBI was 6.76 [6.33-7.21]. The median duration between TBI documentation and epilepsy diagnosis was 3.3 years. In the observation time after index date (median duration: 12.2 years), Cox proportional hazard models identified the primary meditators of epilepsy risk after TBI as post-concussive symptoms (10.3%), cognitive dysfunction (7.0%), suicidal ideation/attempt (5.1%), overdose and drug abuse (3.8%-4.8%), and stroke (3.8%).</p><p><strong>Significance: </strong>This study identified neurological conditions and symptoms that may play an intermediary role in the TBI-epilepsy relationship. Specific changes in health status after TBI may present useful targets for future trials and experimental approaches of PTE prevention.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892977","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}
Line Gavnholt, Joanna Gesche, Emanuele Cerulli Irelli, Thomas Krøigård, Sofie Bloch Mangaard, Carlo Di Bonaventura, Guido Rubboli, Richard Röttger, Christoph Patrick Beier
Objective: Idiopathic generalized epilepsy (IGE) in adults comprise juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic-clonic seizures alone (EGTCS), which are defined by their seizure types but also cover a broad endophenotype of symptoms. Controversy exists on whether adult IGE is a group of distinct diseases or a clinical spectrum of one disease. Here, we used a deeply phenotyped cohort to test the hypothesis that IGE comprises three distinct clinical entities.
Methods: Patients (>18 years old) with IGE were recruited between 2016 and 2020 at Odense University Hospital and the Danish Epilepsy Center. Complete data were available for basic demographics, imaging, social status, and treatment response. Subjects were offered neuropsychological screening (including symptoms of psychiatric disease). Electroencephalograms (EEGs) were reanalyzed, and missing data were imputed. After selecting the features and normalizing the data, the dataset and an identical randomized dataset were subjected to k-means cluster analysis.
Results: The dataset comprised 502 patients and 22 distinct nonoverlapping clinical features. Elbow and gap analyses revealed an optimal number of clusters of 1; the features with the highest eigenvalues were age at diagnosis and self-reported executive dysfunction. Applying k-means clustering yielded three low-quality clusters as assessed by silhouette score (mean = .400 ± .01). The corresponding mean silhouette score for the randomized control dataset was .390 (±.002). Age at diagnosis was associated with the epileptic discharges on EEG and treatment response. Self-reported executive dysfunction showed associations with psychiatric symptoms and impulsivity. JME, JAE, and EGTCS were loosely associated with the clusters (k = .088, p = .002) but showed a specific distribution within a matrix defined by age at diagnosis and self-reported executive dysfunction.
Significance: IGE in adults is best described as a continuum of symptoms, where age at diagnosis and executive dysfunction are two main factors explaining most of its clinical variability. The seizure-defined syndromes cover different patient groups within the clinical spectrum.
目的:成人特发性全身性癫痫(IGE)包括青少年肌阵挛性癫痫(JME)、青少年失智性癫痫(JAE)和癫痫伴全身性强直-阵挛性发作(EGTCS),它们由发作类型定义,但也涵盖了广泛的症状内表型。成人IGE是一组不同的疾病还是一种疾病的临床谱存在争议。在这里,我们使用了一个深度表型队列来验证IGE包含三个不同临床实体的假设。方法:2016年至2020年在欧登塞大学医院和丹麦癫痫中心招募IGE患者(bb0 - 18岁)。基本人口统计学、影像学、社会地位和治疗反应的完整数据。受试者接受神经心理学筛查(包括精神疾病症状)。重新分析脑电图(eeg),并输入缺失数据。选择特征并对数据进行归一化后,对数据集和一个相同的随机数据集进行k-means聚类分析。结果:数据集包括502例患者和22个不同的不重叠的临床特征。肘部和间隙分析显示最佳簇数为1;特征值最高的特征是诊断时的年龄和自我报告的执行功能障碍。应用k-means聚类得到3个低质量聚类,按轮廓评分评估(平均值= 0.400±0.01)。随机对照数据集相应的平均轮廓评分为0.390(±0.002)。诊断时的年龄与脑电图上的癫痫放电和治疗反应有关。自我报告的执行功能障碍与精神症状和冲动有关。JME、JAE和EGTCS与聚类呈松散相关(k =。088, p = .002),但在由诊断年龄和自我报告的执行功能障碍定义的矩阵中显示出特定的分布。意义:成人的IGE最好被描述为症状的连续体,其中诊断时的年龄和执行功能障碍是解释其大多数临床变异性的两个主要因素。癫痫发作定义的综合征涵盖临床范围内的不同患者群体。
{"title":"Unsupervised clustering of a deeply phenotyped cohort of adults with idiopathic generalized epilepsy.","authors":"Line Gavnholt, Joanna Gesche, Emanuele Cerulli Irelli, Thomas Krøigård, Sofie Bloch Mangaard, Carlo Di Bonaventura, Guido Rubboli, Richard Röttger, Christoph Patrick Beier","doi":"10.1111/epi.18225","DOIUrl":"https://doi.org/10.1111/epi.18225","url":null,"abstract":"<p><strong>Objective: </strong>Idiopathic generalized epilepsy (IGE) in adults comprise juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic-clonic seizures alone (EGTCS), which are defined by their seizure types but also cover a broad endophenotype of symptoms. Controversy exists on whether adult IGE is a group of distinct diseases or a clinical spectrum of one disease. Here, we used a deeply phenotyped cohort to test the hypothesis that IGE comprises three distinct clinical entities.</p><p><strong>Methods: </strong>Patients (>18 years old) with IGE were recruited between 2016 and 2020 at Odense University Hospital and the Danish Epilepsy Center. Complete data were available for basic demographics, imaging, social status, and treatment response. Subjects were offered neuropsychological screening (including symptoms of psychiatric disease). Electroencephalograms (EEGs) were reanalyzed, and missing data were imputed. After selecting the features and normalizing the data, the dataset and an identical randomized dataset were subjected to k-means cluster analysis.</p><p><strong>Results: </strong>The dataset comprised 502 patients and 22 distinct nonoverlapping clinical features. Elbow and gap analyses revealed an optimal number of clusters of 1; the features with the highest eigenvalues were age at diagnosis and self-reported executive dysfunction. Applying k-means clustering yielded three low-quality clusters as assessed by silhouette score (mean = .400 ± .01). The corresponding mean silhouette score for the randomized control dataset was .390 (±.002). Age at diagnosis was associated with the epileptic discharges on EEG and treatment response. Self-reported executive dysfunction showed associations with psychiatric symptoms and impulsivity. JME, JAE, and EGTCS were loosely associated with the clusters (k = .088, p = .002) but showed a specific distribution within a matrix defined by age at diagnosis and self-reported executive dysfunction.</p><p><strong>Significance: </strong>IGE in adults is best described as a continuum of symptoms, where age at diagnosis and executive dysfunction are two main factors explaining most of its clinical variability. The seizure-defined syndromes cover different patient groups within the clinical spectrum.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892978","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}