Epilepsia最新文献

{"title":"Developmental and cell type-specific contributions of thalamic serotonin 2A receptors to absence seizures.","authors":"Tatiana P Morais, Giulia Salamanca, Sandra H Vaz, Ana M Sebastião, Cristiano Bombardi, Vincenzo Crunelli, Giuseppe Di Giovanni","doi":"10.1002/epi.70272","DOIUrl":"https://doi.org/10.1002/epi.70272","url":null,"abstract":"<p><strong>Objective: </strong>Serotonin 2A receptors (5-HT_2ARs) play a complex role in focal and generalized seizures due to their diverse cellular and regional distribution. Although systemic activation of 5-HT_2ARs suppresses absence seizures (ASs) in Genetic Absence Epilepsy Rats From Strasbourg (GAERS) rats, the contribution of thalamic receptors and their cell-type specificity remains unclear. Here, we performed a developmental immunohistochemical analysis in the nucleus reticularis thalami (NRT) and the ventrobasal thalamic nucleus (VB) of GAERS rats to assess developmental alterations in 5-HT_2AR expression and used genetic manipulation to determine whether the antiabsence effect of systemic 5-HT_2AR activation depends on thalamocortical (TC) neurons or astrocytes.</p><p><strong>Methods: </strong>Double-immunofluorescence labeling of 5-HT_2ARs with either γ-aminobutyric acid (GABA) or glial fibrillary acidic protein in adult GAERS rats was used to investigate the neuronal and astrocytic distribution of these receptors in the NRT and VB. In addition, [³H]GABA uptake and its modulation by 5-HT_2AR activation were assessed in thalamic slices. Electroencephalographic and video recordings in freely moving GAERS were used to evaluate the effects of VB microinjection of TCB-2, a 5-HT_2AR agonist, on ASs. Finally, the cellular mechanisms underlying these effects were investigated using selective shRNA-mediated knockdown of 5-HT_2ARs in either TC neurons or astrocytes in the VB.</p><p><strong>Results: </strong>In the VB, at postnatal day (P) 25, 5-HT_2ARs were mainly expressed in TC neurons and in the majority of the few GABAergic interneurons, whereas by P90 they were exclusively localized to TC neurons. In the NRT, neuronal expression increased from ~60% to nearly 100% over development. Astrocytic 5-HT_2AR expression increased developmentally in the NRT but remained unchanged in the VB. GABA uptake was decreased in GAERS compared to Wistar rats and was not modified by 5-HT_2AR activation. In vivo, intra-VB injection of TCB-2 reduced ASs; this effect was abolished by shRNA knockdown of 5-HT_2ARs in TC neurons, but not in astrocytes.</p><p><strong>Significance: </strong>The developmental reorganization of thalamic 5-HT_2AR signaling coincides with the expression of ASs, suggesting a contributory role. Our findings indicate that neuronal, but not astrocytic, thalamic 5-HT_2ARs drive seizure modulation, identifying a potential therapeutic target.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835079","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":"Current management of low-grade, epilepsy-associated brain tumors in Europe.","authors":"Alexis Arzimanoglou, Sébile Tchaicha, Belén Trebino Harrington, Angelika Mühlebner, Imad Najm, Ingmar Blümcke","doi":"10.1002/epi.70277","DOIUrl":"https://doi.org/10.1002/epi.70277","url":null,"abstract":"<p><p>Low-grade epilepsy-associated brain tumors (LEATs) are a frequent cause of drug-resistant focal epilepsy in both children and adults. Epilepsy surgery is a well-recognized treatment option, with almost 80% of patients being seizure-free at 1 year, and 50% of children being seizure- and drug-free at 5 years. Despite these outcomes, standardized management guidelines remain lacking. The present study aimed to assess current practices in Europe. A comprehensive web-based survey was conducted by EpiCARE (European Reference Network for Rare and Complex Epilepsies). Responses were collected from 172 clinicians representing 75 institutions in 26 European region countries. The questionnaire addressed institutional protocols, individual practices, referral pathways, presurgical evaluation, histopathology, molecular diagnostics, and follow-up. Clinicians largely agreed that epileptic seizures are a major comorbidity in LEAT patients, and most reported that seizure frequency and duration influence their treatment approach. This reflects an understanding of LEATs not only as an oncological entity, but above all as an epileptogenic lesion with a strong impact on quality of life, systematically requiring a multidisciplinary approach. Significant inconsistencies were identified, particularly regarding referral pathways, presurgical assessment (66% referred systematically to an epilepsy team), and molecular diagnostics. Only 48% of respondents reported having institutional protocols in place. Although the majority supported early referral to an epilepsy surgery team after diagnosis (even in the absence of confirmed drug resistance), 13% still required failure of at least two antiseizure medications. Long-term postsurgical follow-up was recommended by 89% of clinicians beyond 1 year after surgery. Almost all clinicians acknowledged that histopathology influenced clinical decision-making for follow-up, and 87.2% were familiar with the World Health Organization 2021 central nervous system tumor classification and molecular diagnostics. This large European study shows growing alignment with international recommendations, but significant inconsistencies remain in clinical practice, particularly regarding referral pathways, presurgical assessment, and molecular diagnostics. These findings highlight the need for consensus-driven international guidelines for LEAT management.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812556","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":"Unique deficits in place coding across subfields of the hippocampus in a mouse model of temporal lobe epilepsy.","authors":"Brittney L Boublil, Margaret M Donahue, Cathy B Dang, Gergely Tarcsay, Laura A Ewell","doi":"10.1002/epi.70276","DOIUrl":"10.1002/epi.70276","url":null,"abstract":"<p><strong>Objective: </strong>Memory problems are comorbid with temporal lobe epilepsy (TLE). Animal models of TLE reveal impairments in spatial firing fields of hippocampal place cells, providing a potential neural substrate for memory problems. Each subfield of the hippocampus carries out unique aspects of spatial memory, yet little is known about how individual subfields are perturbed. Here, we investigated the spatial coding properties of the three major subfields of the hippocampus.</p><p><strong>Methods: </strong>Single unit recordings were made from CA1, CA3, and the dentate gyrus (DG) of mice (n = 10, 6 male [M]/4 female [F]) induced with epilepsy using the suprahippocampal kainate model and in control mice injected with saline (n = 6, 3 M/3F). Place cell activity was measured while mice foraged in highly familiar environments to assess basic place cell properties and in novel environments to assess remapping.</p><p><strong>Results: </strong>A lower percentage of cells were classified as place cells in CA1 of epileptic mice, whereas percentages were similar in CA3 and DG compared to control. Place fields of CA1 were less coherent, place fields of CA3 were less stable, and place fields in DG had smaller differences between in-field and out-of-field firing. All regions constructed new distinct maps within the first session of exposure to a novel environment; however, new maps in CA3 trended toward instability.</p><p><strong>Significance: </strong>These results point to specific deficits within subfields of the hippocampus, which may indicate that there are different cellular and network mechanisms at play. Such heterogeneity would be predicted to contribute differently to memory deficits.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812528","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":"Integrating benefit and harm in epilepsy treatment: Illustrating the usefulness of the likelihood of being helped versus harmed.","authors":"Francesco Brigo","doi":"10.1002/epi.70269","DOIUrl":"https://doi.org/10.1002/epi.70269","url":null,"abstract":"<p><p>Balancing the potential benefits and harms of antiseizure medications (ASMs) remains a central challenge in epilepsy care. Although randomized trials routinely report efficacy and adverse-event outcomes, these are typically presented separately, limiting their usefulness for shared decision-making. The Likelihood of Being Helped versus Harmed (LHH)-the ratio of the number needed to harm (NNH) to the number needed to treat (NNT)-offers a simple, intuitive way to integrate these dimensions into a single measure. Using data from a previously published comparative analysis, this brief report illustrates how the LHH can summarize the relative probability of achieving a clinical benefit vs experiencing a treatment-related harm. As an example, an ASM with an LHH of 1.9 would be interpreted as being almost twice as likely to produce a ≥50% seizure reduction as to lead to discontinuation due to adverse effects, whereas an LHH below 1 would indicate that harm is more likely than benefit. These examples demonstrate how the LHH can support clearer communication of benefit-harm trade-offs and complement emerging tools for individualized seizure-risk prediction.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765804","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 fenfluramine and sigma-1-dependent pharmacological and genetic modulation in a mouse kindling model.","authors":"Eva-Lotta von Rüden, Verena Buchecker, Amelie Wagner, Victoria M Stocker, Liga Zvejniece, Heidrun Potschka","doi":"10.1002/epi.70270","DOIUrl":"https://doi.org/10.1002/epi.70270","url":null,"abstract":"<p><strong>Objective: </strong>Sigma-1 is a chaperone protein that serves as a key homeostatic regulator, implicated in neuronal excitability and seizure control. Positive allosteric modulators offer a use-dependent means to enhance Sigma-1 activity, potentially with favorable tolerability compared to direct agonists. This study examined the role of sigma-1 in ictogenesis, seizure spread, and termination, and evaluated whether sigma-1 targeting could modify progression in the amygdala kindling model.</p><p><strong>Methods: </strong>Using the mouse amygdala kindling paradigm, we assessed the effects of subchronic administration of the sigma-1 positive allosteric modulator E1R and of the antiseizure medication fenfluramine on seizure thresholds, severity, duration, and progression of kindling. Tolerability, behavioral outcomes, and potential disease-modifying effects were evaluated. Additional experiments investigated the influence of sigma-1 antagonism (NE-100) and genetic sigma-1 deficiency on E1R efficacy and seizure development.</p><p><strong>Results: </strong>E1R delayed kindling acquisition, increased seizure thresholds in both naïve and kindled animals, and reduced seizure duration without evidence of tolerance or significant adverse effects. Subchronic E1R exposure slowed or prevented progression to generalized seizures, although effects did not persist after drug withdrawal. Sigma-1 deficiency prolonged seizure duration, supporting a role in the termination of endogenous seizures. High-dose NE-100 partially antagonized E1R effects, whereas genetic deficiency did not, possibly due to compensatory mechanisms. Fenfluramine did not affect kindling progression in this model.</p><p><strong>Significance: </strong>Positive allosteric modulation of sigma-1 attenuates ictogenesis and seizure severity and appears to contribute to endogenous seizure-termination mechanisms. Although E1R influences seizure generation in response to repeated stimulation, it does not produce sustained disease-modifying effects after discontinuation. These findings support a functional role of sigma-1 positive allosteric modulators as promising candidates for seizure management in the model used. The absence of persistent effects after withdrawal argues against disease modification under the current conditions and warrants further investigation in chronic epilepsy models evaluating long-term therapeutic, disease-modifying, or preventive potential.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766155","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":"Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep: Pathophysiological insights and treatment options.","authors":"Nicola Specchio, Stéphane Auvin, Andreas Brunklaus, Valentina De Giorgis, Valentina Di Micco, Elena Gardella, Floor E Jansen, Rima Nabbout, Chiara Pepi, Guido Rubboli, Marina Trivisano, Paolo Curatolo","doi":"10.1002/epi.70271","DOIUrl":"https://doi.org/10.1002/epi.70271","url":null,"abstract":"<p><p>Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (D/EE-SWAS) represents a rare but severe group of childhood onset epilepsies characterized by sleep-potentiated epileptiform activity, seizures, and developmental stagnation or regression affecting cognition, language, and behavior. Once considered a self-limited electroencephalographic (EEG) phenomenon, D/EE-SWAS is now recognized as a disorder of brain network dysfunction in which persistent epileptiform discharges during non-rapid eye movement sleep disrupt synaptic plasticity, sleep-dependent memory consolidation, and neurodevelopmental trajectories. This review synthesizes recent advances in clinical phenotyping, genetics, neurophysiology, and therapeutics. Etiologically, D/EE-SWAS is highly heterogeneous, with pathogenic variants identified in nearly half of affected individuals, including copy number variants and single-gene disorders involving ion channels, synaptic proteins, and transcriptional regulators. GRIN2A is the most frequently implicated gene, although marked intrafamilial and interfamilial variability underscores the role of modifying genetic and network-level factors. Structural lesions-particularly those affecting thalamocortical circuits-represent another major disease substrate and are critical for treatment stratification. At the mechanistic level, abnormal thalamocortical oscillations, impaired sleep architecture, and disruption of slow-wave and spindle activity provide a pathophysiological framework linking EEG abnormalities to cognitive and behavioral deterioration. Neuroimaging and EEG-functional magnetic resonance imaging studies support a model of widespread network inhibition and disconnection extending beyond the primary epileptogenic zone. Therapeutically, corticosteroids currently represent the most effective first-line treatment, demonstrating superior cognitive outcomes compared with benzodiazepines, although relapse after tapering is common, and optimal dosing strategies remain undefined. Precision medicine approaches, including N-methyl-D-aspartate receptor-targeted therapies for GRIN variants and channel-specific treatments such as primidone for TRPM3 gain of function, offer promising avenues toward disease modification. Epilepsy surgery should be considered early in children with unilateral structural etiologies, where it can provide substantial neurodevelopmental benefit. Future priorities include standardized outcome measures, integration of sleep-based biomarkers, refinement of steroid protocols, and international collaborative trials to improve long-term neurodevelopmental outcomes in this vulnerable population.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766192","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":"Epilepsy in emerging adulthood: Clinical, psychosocial, and surgical challenges.","authors":"Graham A McLeod, Colin B Josephson, Samuel Wiebe","doi":"10.1002/epi.70221","DOIUrl":"https://doi.org/10.1002/epi.70221","url":null,"abstract":"<p><strong>Objective: </strong>Emerging adulthood (EAs; ages 19-29 years) is a unique developmental stage marked by major psychological, social, and occupational transitions. We sought to characterize the clinical, psychosocial, and surgical features of epilepsy in emerging adulthood, considering both current age and age at epilepsy onset.</p><p><strong>Methods: </strong>We conducted cross-sectional analyses in two cohorts, an adult epilepsy registry in Calgary, Canada (single tertiary center; first visits 2007-2024), and a multi-center epilepsy surgery satisfaction cohort recruited from three Canadian centers and Gothenburg, Sweden. Age categories were <19, 19-29, and >29 years. Outcomes included seizure freedom, anti-seizure medications, substance use, patient-reported outcomes measures, and surgical characteristics (procedure type, wait times, seizure and psychosocial outcomes, and satisfaction).</p><p><strong>Results: </strong>Of 7439 registry patients, 1724 (23%) were EAs and 1252 had EA-onset epilepsy. Compared with other ages, EAs had lower 1-year seizure freedom and higher depression, anxiety, disability, and substance use (all p's < .001). EA-onset epilepsy showed similar psychosocial burden, especially for anxiety and substance use. In 240 epilepsy surgery patients (69 EAs), EAs were less likely to undergo selective amygdalohippocampectomy (odds ratio [OR] .17, 95% confidence interval [CI] .03-.94) and had higher rates of permanent complications (OR 6.01, 95% CI 1.45-24.94). EA also spent a greater proportion of life waiting for epilepsy surgery and reported lower post-operative psychosocial satisfaction despite a seizure-freedom rate similar to that for other ages.</p><p><strong>Significance: </strong>Epilepsy during emerging adulthood is associated with elevated psychosocial morbidity and less seizure freedom, whereas EAs undergoing epilepsy surgery have a distinct case profile with comparable seizure freedom, more complications, and lower post-operative psychosocial satisfaction. These findings highlight the distinctive impact of epilepsy during this developmental stage and underscore the need for targeted transitional care, mental-health support, and timely surgical evaluation. Longitudinal studies are warranted to elucidate causal mechanisms and inform targeted interventions.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766251","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":"Insights from multimodal simultaneous SEEG-EEG and SEEG-MEG recordings: A case of combined generalized and focal epilepsy.","authors":"Thandar Aung, Katsiah Cadet, Lazarus Mayoglou, Umit Aydin, Ajay Niranjan, Anto I Bagić","doi":"10.1002/epi.70249","DOIUrl":"https://doi.org/10.1002/epi.70249","url":null,"abstract":"<p><p>Despite formal recognition of \"combined generalized and focal epilepsy\" in the 2017 International League Against Epilepsy classification, its implications for therapeutic decision-making remain ambiguous. We report a case demonstrating how focal cortical pathology can interact with distributed epileptic networks using multimodal electrophysiology. A patient with long-standing presumed generalized epilepsy and a left frontal malformation of cortical development (MCD) underwent multimodal evaluation with simultaneous scalp electroencephalography-stereoelectroencephalography (SEEG; left frontal lesion-targeted implantation with a right frontal sentinel electrode) and simultaneous SEEG-magnetoencephalography (MEG). Simultaneous scalp EEG and SEEG demonstrated generalized spike-wave (GSW) discharges with bilateral frontal and thalamic involvement, without focal interictal epileptiform activity at the lesion site. Direct cortical stimulation of SEEG contacts adjacent to the MCD reproduced habitual seizures, producing localized afterdischarges followed by widespread thalamocortical engagement and delayed focal cortical evolution. Simultaneous SEEG-MEG recordings of GSWs revealed early posterior hemispheric involvement with subsequent frontal recruitment, supporting a distributed network mechanism. Left frontal MCD resection was associated with elimination of convulsive seizures, with persistent thalamic spike-wave activity recorded by a responsive neurostimulator that remained inactive for stimulation. Together, these findings demonstrate the limitations of fixed dichotomous focal-generalized distinctions and highlight the value of network-based approaches to epilepsy classification and surgical treatment.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766246","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":"Compound heterozygous SLC12A5 variants expand the molecular and functional spectrum of KCC2-developmental and epileptic encephalopathy.","authors":"Mira Hamze, Robyn Whitney, Dorothée Ville, Nathalie Villeneuve, Anna-Maria Hartmann, Lisa Becker, Jens Hausmann, Jinwei Zhang, Cathy Brier, Lucie I Pisella, Perrine Friedel, Audrey Labalme, Eudeline Alix, Nicolas Chatron, Damien Sanlaville, Sylvie Gory-Fauré, Eric Denarier, Christophe Porcher, Gaetan Lesca, Igor Medina","doi":"10.1002/epi.70258","DOIUrl":"https://doi.org/10.1002/epi.70258","url":null,"abstract":"<p><strong>Objective: </strong>This study was undertaken to characterize the functional impact of novel SLC12A5 variants in two unrelated patients with early onset developmental and epileptic encephalopathy (DEE) and to investigate the mechanisms underlying KCC2 dysfunction.</p><p><strong>Methods: </strong>Clinical, genetic, and functional analyses were performed in two patients (Cases A and B) with DEE. SLC12A5 encodes two KCC2 splice isoforms (KCC2a and KCC2b). Functional effects of the identified variants on KCC2b ion transport, phosphorylation, mRNA processing, and KCC2-dependent synaptogenesis were assessed using in vitro assays in heterologous expression systems and primary neurons, supported by in silico structural modeling.</p><p><strong>Results: </strong>Both patients developed severe neonatal onset DEE characterized by developmental delay, axial hypotonia, extrapyramidal features, and bilateral migratory seizures within 24 h of birth. Both cases resulted in early mortality (Case A at 9 years; Case B at 6 months). Sequencing revealed distinct biallelic compound heterozygous SLC12A5 variants in both individuals, each inherited from one unaffected parent. Functional analyses demonstrated that in Case A, one variant markedly reduced KCC2-mediated ion transport, whereas the second variant preserved transport activity but exhibited an altered phosphorylation profile at Ser940, located on the intracellular C-terminal region. This variant also disrupted wild-type (WT) KCC2-dependent excitatory synapse formation in immature rat hippocampal neurons. In Case B, one variant disrupted normal mRNA transcript processing consistent with loss of expression, and the second variant exhibited reduced ion transport activity.</p><p><strong>Significance: </strong>These data demonstrate that SLC12A5-related DEE can result from combined impairment of KCC2-dependent chloride homeostasis and disruption of chloride-independent KCC2 functions critical for early neuronal development. This work expands the mutational and mechanistic spectrum of SLC12A5-DEE and highlights the importance of KCC2 regulatory roles in early brain development, providing new knowledge and tools for basic research and potential avenues for targeted precision therapies.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766182","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":"Plasma neurofilament light chain: A novel biomarker of neuroaxonal injury associated with depressive symptoms in epilepsy.","authors":"Zhiqing Chen, Huaiyu Sun, Jiaai Li, Jingqi Lin, Jingyi Yao, Wuqiong Zhang, Shuai Hou, Hongmei Meng","doi":"10.1002/epi.70260","DOIUrl":"https://doi.org/10.1002/epi.70260","url":null,"abstract":"<p><strong>Objective: </strong>Depression is the most common psychiatric comorbidity in patients with epilepsy (PWE) but remains frequently underdiagnosed. Identifying objective biomarkers may improve early detection and intervention. Neurofilament light chain (NfL), a marker of neuroaxonal injury, has been linked to both epilepsy-related neuronal damage and depression, yet its role in comorbidity is unclear.</p><p><strong>Methods: </strong>We conducted a cross-sectional study including 152 adult PWE recruited from a large tertiary hospital in Northeast China. Depressive symptoms were assessed using the Hamilton Depression Scale (HAMD), and plasma NfL concentrations were measured by enzyme-linked immunosorbent assay. Binary logistic regression models were applied to examine the association between plasma NfL and depressive symptoms, and linear regression models with HAMD scores as a continuous outcome were performed as sensitivity analyses. Both approaches were conducted with adjustment for potential confounders. Receiver operating characteristic (ROC) analysis was conducted to evaluate the discriminative performance of plasma NfL, and k-fold cross-validation (k = 5) was performed to assess the robustness of the ROC analysis.</p><p><strong>Results: </strong>Of the 152 participants, 61 (40.1%) had depressive symptoms. Higher plasma NfL levels were independently associated with both increased odds of depressive symptoms and higher HAMD scores. ROC analysis demonstrated good discriminative accuracy (area under the curve [AUC] = .838), with an optimal cutoff value of 44.85 pg/mL yielding a sensitivity of .82 and a specificity of .74. The mean AUC obtained from k-fold cross-validation was .842, which was consistent with the overall ROC result.</p><p><strong>Significance: </strong>These findings suggest that plasma NfL may serve as a candidate biomarker for identifying comorbid depression in epilepsy and provide new insight into shared neurobiological mechanisms.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765929","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}