Epilepsia最新文献

{"title":"Synaptic ultrastructural alterations in human focal cortical dysplasia: Insights from volume electron microscopy.","authors":"Gyu Hyun Kim, Na-Young Seo, Seung-Ki Kim, Jae-Kyung Won, Yang Hoon Huh, Ji Yeoun Lee, Kea Joo Lee","doi":"10.1111/epi.18626","DOIUrl":"https://doi.org/10.1111/epi.18626","url":null,"abstract":"<p><strong>Objective: </strong>Focal cortical dysplasia (FCD) is a developmental malformation of the cerebral cortex and a leading cause of drug-resistant epilepsy in children and young adults. Disruption of the excitation-inhibition (E-I) balance is a hallmark of neuronal hyperexcitability in FCD, yet the underlying synaptic ultrastructural changes remain poorly understood. This study aimed to investigate synaptic architecture and associated organelle alterations in epileptogenic cortex affected by FCD.</p><p><strong>Methods: </strong>Using volume electron microscopy, we performed a detailed morphological assessment of synaptic density, size, and organelle distribution within synapses in the temporal cortical layer III of a patient with FCD. Comparative analyses were conducted between dysplastic and nondysplastic cortical regions.</p><p><strong>Results: </strong>The dysplastic cortex exhibited a lower density of excitatory synapses but contained unusually large excitatory synapses with an increased number of synaptic vesicles. Inhibitory synapses were positioned farther from the nearest excitatory synapses along distal dendrites, potentially reducing the effectiveness of shunting inhibition in the dysplastic area. Presynaptic boutons in the dysplastic region showed increased mitochondrial density and abnormal mitochondrial morphology, whereas the proportion of postsynaptic protrusions containing a spine apparatus was reduced. These changes suggest potential deficits in intracellular calcium handling, metabolic homeostasis, and synaptic plasticity in the epileptogenic cortex. Additionally, maladaptive myelination was a prominent feature in the dysplastic region.</p><p><strong>Significance: </strong>This study identifies distinct synaptic and subcellular structural abnormalities in FCD that may contribute to E-I imbalance and neuronal hyperexcitability. These findings provide novel ultrastructural insights into the pathophysiology of FCD and may inform future therapeutic strategies targeting synaptic and metabolic dysfunction.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102803","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":"Effects of cell therapy on seizures in animal models of epilepsy: Systematic review and meta-analysis.","authors":"Afaf S Altalhi, Muhammad S Javaid, Nigel C Jones, Kim L Powell, Patrick Kwan, Terence J O'Brien, Ana Antonic-Baker","doi":"10.1111/epi.18633","DOIUrl":"https://doi.org/10.1111/epi.18633","url":null,"abstract":"<p><p>This study was undertaken to systematically evaluate the efficacy of cell therapy in reducing seizures in animal models of chronic epilepsy. Three databases, Ovid MEDLINE, Ovid Embase, and Web of Science, were searched using predetermined eligibility criteria. The relevant preclinical controlled studies were included for review and meta-analysis using a random-effects model to calculate summary estimates of the effect size (percentage reduction in seizures). The degree of heterogeneity among the included studies was assessed using the I² statistic. Subgroup meta-analysis and meta-regression were performed to further elucidate the sources of heterogeneity. Thirty published studies met the eligibility criteria, including a total of 1306 animals. The majority of studies used kainic acid and pilocarpine status epilepticus models of mesial temporal lobe epilepsy (MTLE). The random effects model revealed an overall reduction in seizure frequency of 54.8% (95% confidence interval = 48.0558-61.5455) compared to the control, and the heterogeneity was 87.1% among the included studies. The meta-regression revealed that seven study characteristics significantly accounted for the between-study heterogeneity. They can be grouped into three broad categories: epilepsy-specific, animal-specific, and cell transplantation-specific. The greatest seizure reduction was observed in the post-kainic acid status epilepticus model of chronic MTLE, when the cells were delivered intravenously and when the seizure reduction was measured as seizure frequency. Embryonic stem cell transplantation showed the greatest efficacy in reducing seizures. Cell transplantation shows favorable efficacy as a treatment that can reduce seizure recurrence in chronic animal models of epilepsy. High heterogeneity between studies reflects the diverse methodologies employed in preclinical research on cell therapy for epilepsy. Despite these encouraging findings, the high risk of publication bias and variability in study design emphasize the need for further robust preclinical studies to confirm these reported outcomes.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085429","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":"Peri-ictal respiratory dysfunction: Expanding the association between mTOR pathway disorders and ictal central apnea.","authors":"Margherita Burani, Giada Giovannini, Niccolò Orlandi, Matteo Pugnaghi, Leonardo Affronte, Mara Malerba, Lisa Taruffi, Laura Madrassi, Simona Scolastico, Alice Ballerini, Anna Elisabetta Vaudano, Irene Florindo, Enrico Ambrosini, Elisa Micalizzi, Gian Marco Duma, Elisa Osanni, Alberto Danieli, Fabiana Mambretti, Paolo Bonanni, Stefano Meletti","doi":"10.1111/epi.18646","DOIUrl":"https://doi.org/10.1111/epi.18646","url":null,"abstract":"<p><p>Among the etiologies of focal epilepsy, mutations of the GATOR1 complex genes-comprising NPRL3, NPRL2, and DEPDC5-are known to result in overactivation of mTORC1. A recent study highlighted an association between ictal and postictal central apnea (ICA) and pathogenic variants of DEPDC5. Here, we analyzed data from 134 patients across two independent cohorts diagnosed with focal epilepsy who underwent video-electroencephalographic long-term monitoring (VLTM) with cardiorespiratory polygraphy. Genetic testing results done for clinical-diagnostic purposes were reviewed in patients with epilepsy of unknown etiology and patients with magnetic resonance imaging (MRI)-defined/suspected focal cortical dysplasia (FCD). In 46 patients, we recorded at least one seizure associated with ICA. Genetic testing was performed in 21 of 22 MRI-negative patients with ICA, revealing variants in mTOR pathway genes in 10 cases (48%), including DEPDC5 (n = 6), NPRL3 (n = 3), and MTOR (n = 1). Regarding MRI-positive patients with ICA (n = 24), an acquired lesional etiology was found in 11. Of 13 patients with MRI-defined FCD, genetic testing was carried out in seven, all of whom had negative results. Moreover, no pathogenic variants were detected in the 14-MRI negative patients without ICA. Our findings confirm that variants in mTOR pathway genes (not only in DEPDC5) are present in patients with ICA and underline the potential risk of sudden unexpected death in epilepsy. These results also highlight the importance of performing respiratory polygraphy during VLTM to document ictal apnea.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091310","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":"Extracellular vesicle microRNAs are biomarkers of focal epilepsy but not epilepsy-related respiratory dysfunction.","authors":"Sylvain Rheims, Hayet Kouchi, Florence Busato, Stanislas Lagarde, David Derbala, Sébastien Boulogne, Mathilde Leclercq, Jessica Chenais, Sandrine Bouvard, Fabrice Bartolomei, Laurent Bezin, Jorg Tost","doi":"10.1111/epi.18641","DOIUrl":"https://doi.org/10.1111/epi.18641","url":null,"abstract":"<p><strong>Objective: </strong>This study was undertaken to evaluate the diagnostic value of a set of preselected candidate microRNAs (miRNAs) extracted from plasma-based extracellular vesicles (EVs) to identify patients with seizure-related respiratory dysfunction.</p><p><strong>Methods: </strong>A two-step design was applied. Step 1 entailed selection of the relevant miRNAs based on the combination of a literature review and an exploratory study in epileptic rats with or without interictal respiratory dysfunction. Step 2 involved evaluation of the diagnostic value of this preselected panel of circulating exosomal miRNAs in a case-control study conducted in 25 healthy subjects and 50 patients with drug-resistant focal epilepsy undergoing video-electroencephalographic (EEG) monitoring. Based on video-EEG data, patients were separated into two groups: those with ictal/postictal hypoxemia (PIH; n = 24) and those without (noPIH; n = 26). Blood samples were collected in the interictal period (>24 h after the last seizure). Expression level of each miRNAs in EVs was compared (1) between all patients with epilepsy and controls and (2) between PIH and noPIH. Receiver operating characteristic (ROC) curves were generated, and the area under the curve (AUC) was calculated.</p><p><strong>Results: </strong>Following Step 1, the final set of miRNAs selected for evaluation in the case-control study included 24 miRNAs, with nine selected from published data in patients because of their potential regulatory role in the serotoninergic pathway, brain response to hypoxia, or epilepsy and 15 selected from the preclinical study in epileptic rats. Three miRNAs significantly differed between patients with epilepsy and controls (ROC curve AUC: hsa-miR-22-3p, .74 [95% confidence interval (CI) = .63-.85]; hsa-miR-106b-5p, .69 [95% CI = .57-.82]; and hsa-miR-26a-5p, .72 [95% CI = .58-.85]). Only a trend toward higher expression levels was observed for hsa-miR-140-3p in PIH compared to noPIH (+5%, p = .064).</p><p><strong>Significance: </strong>Whereas three miRNAs were robustly associated with epilepsy, none was significantly associated with seizure-related respiratory dysfunction. Additional studies are required, including analysis of the expression of plasmatic cell-free miRNAs, especially the miRNAs associated with interictal respiratory dysfunction in epileptic rats.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079886","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":"Decreased cholinergic neuronal firing in a mouse model of temporal lobe seizures with impaired consciousness.","authors":"Shixin Liu, Patrick Paszkowski, Jiayin Qu, Lim-Anna Sieu, Jiayang Liu, Marcus Valcarce-Aspegren, Waleed Khan, Sarah McGill, Dana Lee, Alvaro Duque, Hal Blumenfeld","doi":"10.1111/epi.18625","DOIUrl":"https://doi.org/10.1111/epi.18625","url":null,"abstract":"<p><strong>Objective: </strong>Impaired consciousness during seizures significantly impacts the quality of life for individuals with epilepsy, and recent research has introduced the network inhibition hypothesis, suggesting that impaired consciousness results from the active inhibition of subcortical arousal mechanisms. However, direct evidence in awake animals has been lacking. Our study aimed to address this gap by recording the activity of individual neurons in crucial brainstem and basal forebrain nuclei in a novel behaving mouse model.</p><p><strong>Methods: </strong>We conducted recordings in head-fixed mice running on a freely moving wheel with implanted electrodes in the orbitofrontal cortex and hippocampi. Focal limbic seizures were induced by applying current pulses, and simultaneously we obtained juxtacellular single unit activity recordings from arousal nuclei in the brainstem and basal forebrain. Double immunofluorescence was performed postrecording to confirm cell locations and cholinergic identities.</p><p><strong>Results: </strong>Our findings revealed that focal seizure activity suppressed behavior based on decreased running wheel speed, and the orbitofrontal cortex exhibited slow waves resembling encephalopathy or deep sleep. Single unit recordings showed diverse firing patterns during seizures, with some neurons reducing firing, others increasing, and some remaining relatively stable. Importantly, cholinergic neurons in the brainstem pedunculopontine and laterodorsal tegmental nuclei exhibited significant reductions in firing during focal limbic seizures.</p><p><strong>Significance: </strong>Our findings provide direct evidence that focal limbic seizures are associated with decreased cholinergic neuronal firing in brainstem arousal nuclei, linking subcortical suppression to cortical impairment. Further exploration of these pathways promises a deeper understanding of ictal unconsciousness and potential novel treatments for people with epilepsy.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074738","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":"Spectrum of epileptogenicity in different cortical tuber radiological subtypes: A stereoelectroencephalographic study.","authors":"Haixiang Wang, Aileen McGonigal, Bingqing Zhang, Qian Feng, Jie Shi, Jing He, Jianjun Bai, Jiuluan Lin, Siyu Wang, Xiaoyan Liu, Liping Zou, Wenjing Zhou","doi":"10.1111/epi.18639","DOIUrl":"https://doi.org/10.1111/epi.18639","url":null,"abstract":"<p><strong>Objective: </strong>Tuberous sclerosis complex (TSC) causes focal drug-resistant epilepsy. Prediction of which tubers are epileptogenic remains challenging. We used stereoelectroencephalography (SEEG) to investigate epileptogenic zone (EZ) organization in TSC-related epilepsy, focusing on epileptogenicity of different tuber radiological subtypes.</p><p><strong>Methods: </strong>We retrospectively studied consecutive patients with TSC-related epilepsy explored by SEEG. Presence of \"focal EZ\" (comprising \"focal tuber,\" \"tuber-plus,\" and \"focal nontuber\") or \"diffuse EZ\" was determined. In focal EZ involving tubers, interictal and ictal epileptogenic biomarkers were compared to the radiological appearance of tubers. In addition to four previously described tuber subtypes, we propose a novel subtype: type E (focal cortical depression, hypointense base on T2/fluid-attenuated inversion recovery).</p><p><strong>Results: </strong>Among 63 patients, 55 (87.3%) patients exhibited focal EZ, including focal tuber (n = 32, 50.8%), tuber-plus (n = 11, 17.5%), and focal nontuber (n = 12, 19.0%, of which 7/12 involved focal cortical dysplasia [FCD]). In the 43 of 63 (68.3%) patients with focal EZ involving at least one tuber, epileptogenicity of 265 explored tubers was analyzed with regard to radiological subtypes. Tuber subtypes A and B were most prevalent (186/265, 70.2%) but among the least epileptogenic on SEEG. The highest ictal epileptogenicity was in subtypes D (77.8%) and E (77.5%) compared to type A/B/C (Fisher exact test; all p < .05). Type D/E tubers exhibited higher interictal biomarkers than type A/B/ C (linear mixed model; p < .05). In patients with focal EZ, following surgical intervention, 36 of 55 (65.5%) achieved Engel class I outcomes, with a higher odds ratio of Engel I in the combined group of focal tuber/focal nontuber compared to tuber-plus EZ (p < .05).</p><p><strong>Significance: </strong>Most TSC-related epilepsy represents focal EZ related to tubers, but focal extratuber EZ can also occur (FCD or hippocampus). Radiologically, calcified tubers (type D) and tubers with focal cortical depression and central hypointensity (type E) exhibit the highest epileptogenicity, similar to FCD type II.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069356","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":"Clinical features and prognosis of first-ever acute symptomatic seizures due to acute systemic causes.","authors":"Nicholas Lawn, William Wallefeld, Judy Lee, John Dunne","doi":"10.1111/epi.18554","DOIUrl":"https://doi.org/10.1111/epi.18554","url":null,"abstract":"<p><strong>Objective: </strong>This study was undertaken to assess the clinical features and prognosis in patients with a first-ever acute symptomatic seizure due to an acute systemic cause (ASAS).</p><p><strong>Methods: </strong>Patients with a first-ever ASAS were prospectively identified and compared to age- and sex-matched controls, and to patients with first-ever unprovoked seizure without obvious cause. Referrals were predominantly from local emergency departments. Patients underwent clinical assessment, routine electroencephalography (EEG), and neuroimaging. The primary outcome was the occurrence of a second seizure.</p><p><strong>Results: </strong>Three hundred and ninety-three patients with ASAS were identified between 2000 and 2015. The commonest etiology was a prescribed drug (36%), with the remainder related to illicit drug use (23%), alcohol (17%), drug withdrawal (9.5%), metabolic derangement (9.5%), and drug overdose (5%). EEG showed epileptiform abnormalities in 10% of patients, and neuroimaging identified a nonacute epileptogenic lesion in 6%. The 2-year cumulative probability of any seizure recurrence was 28.7% (95% confidence interval [CI] = 24.1-33.2), for ASAS recurrence 19.4% (95% CI = 15.3-23.5), and for an unprovoked seizure 11.2% (95% CI = 8.0-14.4), compared to 47.6% (95% CI = 44.2-50.9) recurrence after first unprovoked seizure without obvious cause. Etiology was not predictive of recurrence, other than an increase in the likelihood of an acute symptomatic recurrence for alcohol withdrawal seizures. Independent risk factors for unprovoked seizure recurrence were epileptogenic lesion on imaging, with a hazard ratio (HR) of 3.8 (95% CI = 1.7-8.7), and epileptiform abnormality on EEG (HR = 2.2, 95% CI = 1.0-5.1), but when present the 2-year cumulative probability of an unprovoked recurrence was only 23.9%. Furthermore, patients without these risk factors still had a 2-year likelihood of a subsequent unprovoked seizure of 8.0% (95% CI = 4.7-11.4), compared to 0.1% for any seizure in controls.</p><p><strong>Significance: </strong>The risk of an unprovoked seizure following ASAS was far higher than expected if simply attributable to a reversible acute symptomatic cause, and this has practical relevance when counseling patients.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063744","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":"Quality of life over time after new onset refractory status epilepticus.","authors":"Matthew D Gruen, Margaret T Gopaul, Anthony D Jimenez, Ayush Batra, Leah J Blank, Charlotte Damien, Gregory S Day, Krista Eschbach, Elizabeth E Gerard, Teneille E Gofton, Stephen T Hantus, Nathalie Jette, Amy Jongeling, Peter Kang, Karnig Kazazian, Marissa Kellogg, Minjee Kim, Bahar Madani, Mikaela Morales, Vineet Punia, Claude Steriade, Aaron Struck, Olga Taraschenko, Nathan Torcida, Mark S Wainwright, Ji Yeoun Yoo, Nicolas Gaspard, Nora Wong, Lawrence J Hirsch, Aurélie Hanin","doi":"10.1111/epi.18635","DOIUrl":"https://doi.org/10.1111/epi.18635","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to better characterize the long-term neurological quality of life (QOL) outcomes (using the Neuro-QOL scale) in survivors of new onset refractory status epilepticus (NORSE), including its subtype febrile infection-related epilepsy syndrome (FIRES), and provide guidance for psychological and social support strategies.</p><p><strong>Methods: </strong>Utilizing data from a multicenter prospective study of NORSE/FIRES led by Yale University, we enrolled patients who completed the validated, patient-reported Neuro-QOL scale at least once at 3-6 months (n = 37), 12 months (n = 29), 24 months (n = 23), or ≥36 months (n = 9) following discharge. The Neuro-QOL scale assesses physical, mental, and social health in patients with neurological disorders. QOL impairment (QOL-I) scores were calculated, with higher scores indicating greater impairment. T-scores enabled comparisons with reference populations.</p><p><strong>Results: </strong>In adults, median QOL-I improved from 44.1% at 3-6 months to 37.6% at 36+ months. Paired analysis showed significant improvement in QOL-I between 3-6 and 24 months (p = .016), with specific improvements in communication, satisfaction with social roles, fatigue, and mobility. Greater improvement was also observed for participation in social roles (5.5-point T-score gain) compared to the reference population, suggesting meaningful change. A gradual improvement in overall QOL-I scores was also observed in pediatric participants, despite a modest sample size (n = 5 with data at 3-6 and 12 months). Measures of fatigue and anxiety persisted in adults, and cognitive difficulties persisted in both adults and children. In adults, longer status epilepticus duration and intensive care unit stay were associated with poorer QOL. Additionally, a higher number of antiseizure medications was associated with more depression, cognitive impairments, and perceived stigma.</p><p><strong>Significance: </strong>These findings highlight the potential for recovery following an acute episode of NORSE, although many patients continue to face challenges requiring ongoing support, and the clinical meaning of the reported QOL improvement remains unclear. Furthermore, the findings underscore the importance of strategic multidisciplinary support systems in the years following discharge.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051376","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":"Potassium-chloride cotransporter 2 activity dampens induced ictal-like activity in neocortical slices containing the seizure propagation zone of temporal lobe epilepsy patients.","authors":"Alice Falck, Janna Lehnhoff, Mahraz Behbood, Egor Byvaltcev, Annette Aigner, Helena Radbruch, Pawel Fidzinski, Jan-Hendrik Schleimer, Gabriel M S Janach, Noah Döhne, Julia Onken, Thilo Kalbhenn, Thomas Sauvigny, Rudolf A Deisz, Susanne Schreiber, Martin Holtkamp, Ulf Strauss","doi":"10.1111/epi.18630","DOIUrl":"https://doi.org/10.1111/epi.18630","url":null,"abstract":"<p><strong>Objective: </strong>The K⁺/Cl^- cotransporter (KCC2), which acts as the main Cl^- extruder in the adult brain, coregulates the driving force and therewith indirectly the amount and polarity of γ-aminobutyric acidergic (GABAergic) currents. Whether the net effect of active KCC2 is inhibitory via such Cl^- extrusion or excitatory due to the concomitant increase of K⁺ in the extracellular space is context-dependent and difficult to predict. Consecutively, in rodent models, antiseizure- as well as seizure-facilitating effects of KCC2 block have been reported. Here, we attempted to gain more insight into KCC2's role in the seizure propagation zone in human temporal neocortex.</p><p><strong>Methods: </strong>We induced network activity in postoperative acute neocortical brain slices from humans with temporal lobe epilepsy under low Mg²⁺ conditions, with and without elevated K⁺, and recorded it using microelectrode arrays. We analyzed ictal-like events and interictal-like discharges with a developed source-separating approach. Finally, we complemented these network-related studies by patch-clamp recordings of individual pyramidal neurons under regular ionic conditions to assess the inherent functionality of KCC2 and alternative transmembrane Cl^- routes.</p><p><strong>Results: </strong>Modulation of KCC2 activity altered the induced network activity; KCC2 block reversibly led to substantially increased activity, preferentially in and propagating through supragranular layers. Correspondingly, enhancing KCC2 activity reduced network activity there. Almost all individual supragranular pyramidal neurons tested had functional KCC2, that is, certain Cl^- extrusion capacity that was limited when loaded with higher Cl^- and presented variable predominantly positive values of GABA_A receptor driving force. In addition, we found tonic inhibition that increases after prolonged KCC2 block and may either contribute to Cl^- load or support Cl^- extrusion in supragranular pyramidal neurons, depending on their intracellular Cl^- concentration.</p><p><strong>Significance: </strong>Our data show that KCC2 mitigates ictal-like activity in the seizure propagation zone of human neocortex, thereby further promoting KCC2 as a therapeutic target.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033115","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":"Development and characterization of an autoresuscitation test for preclinical SUDEP models.","authors":"Shruthi H Iyer, Jillian E Hinman, Samantha B Draves, Stephanie A Matthews, Kristina A Simeone, Timothy A Simeone","doi":"10.1111/epi.18623","DOIUrl":"https://doi.org/10.1111/epi.18623","url":null,"abstract":"<p><p>The rate of sudden unexpected death in epilepsy (SUDEP) is ~1 per 1000 patients each year. Terminal events reportedly involve repeated and prolonged apnea, suggesting a failure to autoresuscitate. To better understand the mechanisms and identify novel therapeutics, standardized tests to screen for autoresuscitation efficacy are needed in preclinical SUDEP. To investigate the efficacy of the autoresuscitation response and potential contribution to SUDEP susceptibility, we adapted an anoxia-induced autoresuscitation test. The test was optimized to allow for survival of most wild-type (WT) mice, whereas autoresuscitation failure occurred for most Kcna1^-/- mice, a preclinical model of SUDEP. Using whole-body plethysmography, we assessed ventilatory parameters, gasp-apnea dynamics, and survival in WT, Kcna1^-/-, and Kcna1^+/- mice. A proof-of-concept pharmacological rescue was performed using a dual orexin receptor antagonist (DORA). WT mice exhibited robust autoresuscitation (80% survival), whereas only 20% of high-risk Kcna1^-/- mice survived the anoxic challenge, indicating a 4-fold increase in risk for autoresuscitation failure. Kcna1^-/- mice had disordered ventilatory responses, characterized by increased minute ventilation, tidal volume, and expiratory flow during anoxia. Kcna1^-/- mice initiated gasping earlier with reduced gasp number, lower gasp frequency, and longer post-gasp apnea durations. In-depth analyses revealed three phases of gasping. Phase III recovery gasping was significantly impaired in Kcna1^-/- mice, and they were unable to transition to eupnea. In contrast, low-risk Kcna1^-/- mice and Kcna1^+/-mice showed intermediate to normal autoresuscitation, respectively. DORA pretreatment improved survival to 80%, restored ventilatory patterns, and normalized gasp-apnea metrics to WT levels. This modified autoresuscitation test provides a reproducible and sensitive approach to probe respiratory vulnerability in preclinical SUDEP models. Our findings identify augmented ventilatory chemosensitivity and impaired autoresuscitation as critical pathophysiological features of SUDEP in Kcna1^-/- mice and support the utility of this test platform for preclinical therapeutic screening and mechanistic discovery.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023062","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}