Neuroinflammation plays a key role in epileptogénesis, with interleukin 6 (IL-6) implicated in drug-resistant epilepsy (DRE). The objective was to compare serum IL-6 levels between patients with DRE and non-drug-resistant epilepsy (n-DRE) and to evaluate their relationship with the use of anti-seizure drugs (ASDs). Retrospective multicentre study (March 2019 to April 2022) in two hospitals in Buenos Aires. Patients >18 years of age with epilepsy, at least 2 years of follow-up and no seizures in the last 2 weeks were included. Serum IL-6 was measured by ELISA. Demographic, clinical and treatment data were collected. Comparisons were made using the t-test, Mann-Whitney test, chi-square test, or Fisher's exact test. 121 patients were included (43 with DRE and 78 with n-DRE). The median IL-6 levels did not differ significantly between the two groups. Focal epilepsy and focal seizures with altered consciousness were more frequent in patients with DRE (p = 0.039). In monotherapy, higher IL-6 levels were observed in patients receiving valproic acid (p = 0.027), especially in women (p < 0.05). In this cohort, IL-6 levels were not associated with drug resistance. However, IL-6 concentrations varied according to ASD and sex. Future studies are needed to clarify the role of cytokines in epileptogénesis and their possible value as prognostic biomarkers. Introducción: La neuroinflamación desempeña un papel clave en la epileptogénesis, estando la interleucina 6 (IL-6) implicada en la epilepsia farmacorresistente (EFR). El objetivo fue comparar los niveles séricos de IL-6 entre pacientes con EFR y epilepsia no resistente a los fármacos (n-EFR), y evaluar su relación con el uso de drogas anticrisis (DAC). Materiales y métodos: Estudio multicéntrico retrospectivo (marzo de 2019 a abril de 2022) en dos hospitales de Buenos Aires. Se incluyeron pacientes mayores de 18 años con epilepsia, al menos con 2 años de seguimiento y sin convulsiones en las últimas 2 semanas. La IL-6 sérica se midió mediante ELISA. Se recopilaron datos demográficos, clínicos y de tratamiento. Las comparaciones se realizaron mediante la prueba t, Mann-Whitney, chi-cuadrado o la prueba exacta de Fisher. Resultados: Se incluyeron 121 pacientes (43 con EFR y 78 con n-EFR). La mediana de los niveles de IL-6 no difirió significativamente entre ambos grupos. La epilepsia focal y las crisis focales con alteración del estado de conciencia fueron más frecuentes en los pacientes con EFR (p = 0.039). En monoterapia, se observaron niveles mayores de IL-6 en pacientes que recibían ácido valproico (p = 0.027), especialmente en mujeres (p < 0.05). Conclusión: En esta cohorte, los niveles de IL-6 no se asociaron con la resistencia a los fármacos. Sin embargo, las concentraciones de IL-6 variaron según las DAC y el sexo. Futuros estudios son necesarios para esclarecer el papel de las citocinas en la epileptogénesis y su posible valor como biomarcadores pronósticos.
In temporal lobe epilepsy (TLE), recurrent seizures can cause structural and functional disruptions within the temporal lobe and nearby language regions, resulting in neural reorganization. In this study, we leverage task-based functional magnetic resonance imaging (tb-fMRI) to understand how this language reorganization process varies based on the seizure location, the timing of seizure onset, and the chronicity of epileptic activity. 84 drug-resistant TLE patients who completed a tb-fMRI sentence completion task were included in this study. Analysis included group comparison of activation and comparison of the extent of reorganization in the whole brain and standard language regions of interest (ROI) level. We also measured the impact of the age of onset and the duration of epilepsy in the reorganization process. A significantly higher degree of language network reorganization is observed in left (L) TLE than in right (R) TLE at the whole brain level. At the regional level, a higher degree of reorganization is observed in temporal and frontal lobe ROIs in LTLE compared to RTLE, especially in the middle frontal gyrus and posterior temporal gyrus. The effects of age of onset and epilepsy duration were prominent in LTLE subjects at both the whole-brain and ROI levels. Patients with LTLE show greater changes in the middle frontal and posterior temporal regions, particularly in those with an earlier age of onset and longer disease duration. Identifying these patterns may assist in surgical planning and personalizing treatment to protect cognitive function.
Balancing seizure outcomes and cognitive deficits is always a challenge in both mesial and neocortical temporal lobe epilepsy cohorts. The present study evaluated the long-term seizure outcomes and perceived quality of life (QOL) in both of these groups, along with factors predictive of these outcomes. A retrospective analysis of patients undergoing temporal lobe epilepsy (TLE) surgery from 2015 to 2023, with at least 1 year of follow-up (N = 175), is presented. Patients were grouped as MTLE (mesial temporal sclerosis only) and NTLE (neocortical) based on neuroimaging. Surgical approaches included standard anterior temporal lobectomy with amygdalohippocampectomy (ATL + AH) and hippocampal-sparing resections. Seizure outcomes were classified using Engel's scale; QOL was assessed telephonically using a questionnaire adopted from QOLIE-10-P. Predictors for seizure freedom and perceived QOL outcomes were studied in both groups. At a mean follow-up of 55 months, 83.5% of patients achieved seizure freedom, MTLE (85%), and NTLE (81%) patients. Of the entire TLE cohort, 38% were free from drugs at the last follow-up. In MTLE, the presence of red flags significantly lowers the chances of complete seizure freedom (59% vs. 93%.) (OR 0.11, 95% CI 0.03-0.37; p < 0.001). Preserving the hippocampus in NTLE is associated with a lower the seizure freedom rate (68% vs. 86%) (OR 0.34, 95% CI 0.10-1.08). In NTLE, the odds of perceived memory decline were marginally higher in the standard ATL + AH group (OR 1.48, 95% CI 0.37-5.87) compared to hippocampus-preserving resection (p = 0.7). Approx. 75% patients reported improvement in all QOL parameters in the entire TLE cohort. No mortality or permanent neurological deficits recorded. TLE surgery provides robust seizure control and significant perceived QOL improvements for most patients in the long term. Hippocampal sparing surgery in NTLE did not seem to affect perceived memory difficulties but was more likely to be associated with suboptimal seizure outcomes.
Major depressive disorder (MDD) is the most common psychiatric comorbidity in epilepsy but is often undertreated due to concerns about antidepressant effects on seizure frequency. This study evaluated the efficacy of agomelatine versus escitalopram in people with epilepsy (PwE) and comorbid MDD, including effects on seizure frequency, sleep, cognition, and quality of life (QoL). In this double-blind, randomized, phase IV study across three centers, 64 PwE and comorbid MDD were screened, and 51 were randomized to agomelatine (25 mg) or escitalopram (10 mg). Outcome measures were Beck Depression Inventory-II (BDI-II), Hamilton Depression Rating Scale (HDRS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), QoL in Epilepsy Inventory-31, Mental Deterioration Battery, and seizure frequency. Depression scores did not differ between groups, although both groups improved over time. No significant between-group differences were found for QoL or cognitive performance. However, QoL improved significantly only in the escitalopram group. After correction for multiple comparisons, verbal memory improved significantly only in the agomelatine group, whereas the cognitive changes observed with escitalopram did not remain significant after correction. No significant differences in seizure frequency, PSQI, or ESS scores were observed in either group. Adverse events were mild to moderate (7.8%), and no serious adverse event occurred. In conclusion, agomelatine and escitalopram improved depressive symptoms in PwE, without worsening seizure frequency, sleep, or daytime alertness. Escitalopram showed a more consistent pattern of benefit on mood and QoL, whereas cognitive effects were limited after correction for multiple testing. Larger studies are needed to confirm these findings.
The cerebral operculum comprises the cortical folds of the frontal, central, parietal, and temporal lobes that overlie the insula. Although historically described as a simple anatomical "cover," the operculum is now recognized as a morphologically complex periSylvian region embedded within multiple cortico-cortical and cortico-subcortical networks. In this review, a comprehensive synthesis of opercular organization is provided, integrating topographic anatomy, structural connectivity, and vascular supply. The topographic anatomy of the operculum is described in relation to periSylvian sulcal landmarks that define four opercular subregions-the frontal, rolandic (i.e., central), parietal, and temporal opercula-and to the outer Sylvian membrane, which separates the superficial from the medial operculum. Structural connectivity involves well-defined major white matter tracts-including the superior longitudinal, arcuate, inferior fronto-occipital, uncinate, and middle longitudinal fasciculi-alongside operculum-specific associative connections, commissural pathways, and projection fibers. Within this structural framework, the operculum emerges as a critical hub in language, auditory, visual, and gustatory networks, supporting multimodal integration and higher-order processing. Cortical and white matter vascularization of the opercular region is dominated by centripetal branches arising from the M2 to M4 segments of the middle cerebral artery, which supply both superficial and deeper opercular layers. Collectively, the complex morphology, dense structural connectivity, and complex vascular organization of the operculum provide a structural basis for its functional importance and help explain the clinical heterogeneity of opercular epilepsy, including the challenges associated with its diagnosis and surgical management.
Brain inflammation is increasingly recognized as a critical contributor to seizure generation and neuronal hyperexcitability. Among proinflammatory mediators, interleukin-1β (IL-1β) has been implicated in epileptogenesis; however, its acute temporal dynamics during seizure initiation remain poorly characterized because of limitations in conventional sampling approaches. In this study, we investigated the minute-by-minute intracerebral dynamics of IL-1β in a rat model of acute epileptiform activity induced by 4-aminopyridine (4-AP) and compared it with that induced by a classical inflammatory stimulus, lipopolysaccharide (LPS). Adult male Wistar rats (10-12 weeks old) were implanted with a push-pull guide cannula in the right lateral ventricle and electrodes over the ipsilateral and contralateral cortices to enable simultaneous cerebrospinal fluid (CSF) sampling and electroencephalographic (EEG) recordings. IL-1β concentrations were quantified at one-minute resolution using a nanodot blot immunodetection method, while epileptiform activity was assessed through EEG amplitude analysis and discharge train identification. Intraventricular administration of 4-AP (75 mM) induced robust epileptiform activity accompanied by a rapid and transient surge in IL-1β levels, reaching a peak concentration of 199 ± 28 ng/mL within 14 min (p < 0.05 vs. NaCl) and closely coinciding with the onset of epileptiform discharges. In contrast, intraventricular administration of LPS (25 µg/µL) elicited a delayed and sustained increase in IL-1β which was statistically significant at 240 and 300 min post-administration and did not induce epileptiform activity during the evaluated period. Although cumulative IL-1β exposure was comparable between 4-AP and LPS groups, their temporal profiles were markedly distinct. These findings demonstrate that acute epileptiform activity is associated with a rapid release of IL-1β that temporally coincides with seizure-like events, supporting a role for early cytokine signaling in seizure initiation. Moreover, this study highlights the importance of minute-resolution approaches for identifying neuroinflammatory processes that are otherwise obscured by conventional sampling strategies.
Epilepsy is a devastating neurological disorder affecting about 1-2% of the global population and is characterized by recurrent, unprovoked seizures that can severely impair quality of life. Despite the availability of antiseizure medications, nearly one-third of individuals with epilepsy continue to experience drug-resistant seizures, underscoring the need for novel therapeutic strategies. Growing evidence supports neuroinflammation as a key driver of epileptogenesis following brain insults. At the biochemical level, this neuroinflammatory response is largely propagated through the classic arachidonic acid metabolic cascade. Within this pathway, lipoxygenase (LOX) enzymes play a pivotal role in mediating oxidative stress, lipid peroxidation, and pro-inflammatory signaling through the generation of bioactive lipid metabolites. Dysregulation of LOX activity contributes to epileptogenic processes, such as blood-brain barrier disruption, glial activation, cytokine release, immune-cell infiltration, neuronal hyperexcitability, and neuronal death. Emerging evidence indicates that LOX pathways, particularly those mediated by 5-LOX and 12/15-LOX, play a major role in the pathophysiology of epileptic seizures and may also contribute to neuropsychiatric comorbidities that substantially reduce quality of life. In this review, we discuss the therapeutic potential of targeting 5-LOX and 12/15-LOX for seizure disorders, integrating current preclinical evidence and mechanistic insights to advance the development of novel, safer, and more effective therapies for epilepsy and its associated neurological comorbidities. Together, these perspectives highlight promising avenues for future research and therapeutic innovation.
Older adults with epilepsy are at increased risk for Alzheimer's disease (AD), yet the mechanisms underlying this association remain poorly understood. We applied a validated AD neuroimaging signature to older adults with epilepsy to examine 1) whether older adults with epilepsy mirror AD-related changes, 2) associations with clinical, cognitive, and plasma biomarker outcomes, and 3) utility for identifying subgroups at heightened risk for cognitive decline. Our multicenter, prospectively enrolled cohort allowed for direct examination of differences in AD signatures between those with early-onset and late-onset unexplained epilepsy. Participants included 449 older adults: 87 with focal epilepsy from the multicenter Brain Aging and Cognition in Epilepsy (BrACE) cohort (age=66.10 [SD=6.86], including early-onset (<55 years at seizure onset) and late-onset (≥55 years at seizure onset) epilepsy); 362 from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU) healthy controls and individuals with mild cognitive impairment (MCI) or AD dementia. An AD signature was derived from regional cortical thickness and hippocampal volume weighted by their sensitivity to AD-related neurodegeneration in prior work. Associations between the AD signature, epilepsy characteristics, plasma biomarkers (β-amyloid 42/40, phosphorylated tau [pTau217, pTau181], neurofilament light chain [NfL]), and cognition were evaluated in BrACE. Participants with epilepsy demonstrated more AD-like signatures compared to ADNI CU controls (β= -0.43, p adj <0.001), reflecting reduced thickness/volume in AD-vulnerable regions. This effect was stronger among early-onset (β= -0.57) versus late-onset (β= -0.26) epilepsy. In BrACE, the AD signature correlated with NfL (β= -0.30, p adj =0.050), memory performance (β= 0.30, p adj =0.006), and predicted greater odds of cognitive impairment specifically among those with early-onset, but not late-onset, epilepsy (interaction p adj =0.043). Further, among those with early-onset epilepsy, the AD signature significantly improved identification of cognitive impairment over and beyond the effects of plasma AD biomarkers ( p =0.041). Findings were similar when examining the effects of epilepsy duration rather than epilepsy onset age. AD neuroimaging signatures may help identify clinically meaningful subgroups among older adults with epilepsy, particularly when integrated with AD biomarkers. Findings support a multimodal framework for assessing AD-related risk in epilepsy and highlight interactive effects of epilepsy chronicity and AD-related processes that can influence cognitive outcomes.
Objective To synthesize population-based studies of epilepsy prevalence published between 1980 and 2025, estimate pooled global prevalence, characterize regional differences, quantify temporal trends, and examine the influence of study characteristics and development indicators (Human Development Index [HDI] and Socio-demographic Index [SDI]). Methods We systematically searched PubMed, Embase, Web of Science, Scopus, and the Cochrane Library for observational studies published from January 1, 1980 to December 31, 2025. Random-effects meta-analysis was used to pool prevalence estimates. Pre-specified subgroup analyses were conducted by geographical region, survey period, study design, data source, sample size, and HDI/SDI strata. Methodological subgroup analyses and sensitivity analyses were further performed to assess the robustness of the pooled estimates. Temporal patterns were assessed using regression-based β trend analysis across study survey years and estimated annual percentage change (EAPC) derived from the Global Burden of Disease (GBD) database. Results We included 216 studies comprising 278,651,975 participants and 2,114,157 epilepsy cases. The pooled global prevalence was 7.57 per 1,000 population (95% confidence interval [CI], 6.78-8.45). Literature-based trend analysis suggested an increase in reported prevalence estimates from 1980 to 2025 (β = 0.206 per 1,000 population per year; P < 0.01). GBD-based analyses also showed an overall increase from 1990 to 2021 (EAPC = 0.102% per year), with significant increases during 1990-2009 but no significant change during 2010-2021. Prevalence differed significantly across geographical regions (P < 0.001), highest in Africa (10.67 per 1,000) and lowest in Asia (5.20 per 1,000). Prevalence was higher in low-HDI settings than in very high-HDI settings, but meta-regression did not support significant linear associations between prevalence and HDI or SDI (both P > 0.05). No significant sex difference was observed (P = 0.76). Sensitivity analyses supported the robustness of the main pooled estimate, and methodological subgroup analyses showed no major variation across prevalence definitions, case ascertainment methods, or diagnostic confirmation approaches. Conclusions Epilepsy prevalence remains high worldwide, with an overall increase in reported prevalence over the past four decades but a slower recent rise. Marked geographical disparities were observed, with higher reported prevalence in low-resource settings. Strengthening standardized epidemiological surveillance and improving access to diagnosis and treatment remain priorities, particularly in resource-limited regions.
Intraparenchymal schwannomas are a rare subtype of central nervous system tumor, with descriptions of this pathology within the neurosurgical literature exclusively consisting of case reports and small case series. The present study details an illustrative case of a young patient with this rare tumor type who was recently treated at our institution via craniotomy for resection of her intracranial neoplasm. We then conducted a systematic review of the published patient data on supratentorial intraparenchymal schwannomas, including a meta-analysis aimed at quantifying postoperative seizure-freedom rates in this patient population. The present study included both a surgical case report in addition to a PRISMA-compliant systematic review that involved individual-patient data (IPD) meta-analysis. The systematic review searched PubMed, the Cochrane Library, and Scopus, with 63 articles meeting inclusion criteria. The IPD meta-analysis utilized the nonparametric Kaplan-Meier estimator and a parametric Bayesian Weibull accelerated-failure-time (AFT) model to estimate seizure-freedom time after surgery. Our case report detailed a right frontal craniotomy for tumor resection in a 23-year old female. Gross total resection was achieved and postoperative pathology was ultimately consistent with WHO grade I schwannoma, with the neoplastic tissue staining positive for S-100 and SOX-10, in addition to being negative for OLIG-2 and positive for GFAP. Molecular profiling also detected a CHD7-VGLL3 fusion. Among the 63 articles identified via our systematic review, a total of 82 patients with supratentorial, intraparenchymal schwannomas were identified. Using the parametric AFT model, median seizure-free survival time was calculated as 133.43 months (95% CrI = 65.89-296.29 months; 90% CrI = 72.40-260.25 months; 50% CrI = 103.15-175.89 months), while the probability of remaining seizure-free 12, 36, and 60 months after surgery being 95.28% (95% CrI = 88.52-99.15%), 85.00% (95% CrI = 70.95-95.32%), and 74.75% (95% CrI = 54.05-90.44%), respectively. The observed postoperative seizure-freedom rate of 83.8% was statistically significantly greater than the 70% lower-bound benchmark established for low-grade epilepsy-associated neuroepithelial tumors (p = 0.044). The present study provides quantitative seizure-freedom estimates for patients undergoing surgical resection of epileptogenic intraparenchymal schwannoma, a rare disease entity with fewer than 100 reported cases in the neurosurgical literature. Given the inherent constraints of quantifying treatment outcomes of a rare disease, the ability to obtain such estimates underscores the utility of Bayesian methods for statistical inference under data-limited conditions. Our meta-analysis suggests that most patients can expect at least multiple years of seizure-freedom postoperatively following resection of an epileptogenic intraparenchymal schwannoma.
To investigate the clinical, imaging, pathological, and molecular characteristics of polymorphous low-grade neuroepithelial tumor of the young (PLNTY) and provide references for clinical diagnosis and treatment. We retrospectively analyzed the clinical data of one pathologically confirmed PLNTY patient, including medical history, clinical symptoms, imaging findings, pathological morphological features, immunohistochemical results and molecular testing data, and reviewed relevant literature. A 30-year-old male patient presented with a 6-year history of drug-resistant epilepsy as the primary manifestation, which progressed from focal facial myoclonus to mixed seizure phenotypes. Cranial magnetic resonance imaging (MRI) demonstrated an ovoid area of abnormal signal intensity in the left temporal pole, exhibiting isointensity on T1-weighted imaging (T1WI), hypointensity on T2-weighted imaging (T2WI) and fluid-attenuated inversion recovery (FLAIR) sequences, and no enhancement following contrast administration; the initial radiological impression was a suspected cavernous hemangioma. Twenty-four-hour video electroencephalography (vEEG) identified abnormal epileptiform discharges originating from the left anterior temporal lobe. Subsequent to left temporal lobe lesionectomy, pathological examination confirmed the diagnosis of polymorphous low-grade neuroepithelial tumor of the young (PLNTY), CNS WHO Grade 1. Microscopically, the lesion was characterized by thin-walled vascular clusters, focal vascular wall hyalinization, calcification, and adjacent reactive glial proliferation. Immunohistochemical (IHC) staining revealed diffuse CD34 positivity, glial fibrillary acidic protein (GFAP) (+), oligodendrocyte transcription factor 2 (Olig-2) (+), and a Ki-67 proliferation index of 1%, indicating low proliferative activity. Molecular testing confirmed BRAF mutation positivity, weak immunoreactivity for BRAF V600E (detected via VE1 antibody), and absence of malignant-associated mutations. Postoperatively, the patient achieved complete seizure control and remained seizure-free with uneventful recovery at the latest follow-up. PLNTY is typically characterized by long-standing drug-resistant epilepsy and has a predilection for the temporal lobe, with potential atypical imaging manifestations (e.g., hypointensity on T2WI as observed in this case). Definitive diagnosis requires the integration of pathological morphology, immunohistochemistry, and molecular testing. PLNTY harboring the BRAF V600E mutation exhibits indolent biological behavior; gross total resection serves as the core therapeutic modality, conferring a favorable prognosis. Molecular subtyping can guide individualized follow-up strategies, and clinicians should be vigilant against misdiagnosis of cases with atypical imaging features.
Hemispherotomy is a surgical intervention for severe drug-resistant epilepsy that fully disconnects the lesional brain hemisphere from the rest of the nervous system. This creates a rare opportunity to explore whether consciousness can be sustained without external input. The default-mode network, linked to introspective mental activity, is considered a necessary, though not sufficient, condition for consciousness. In this prospective case-control study, resting-state functional MRI data from 26 individuals post-hemispherotomy and 24 healthy controls were analysed. Default-mode network activity was assessed using seed-to-voxel correlations based on the peak activity in the precuneus of controls, delineated by group independent component analysis. In connected hemispheres, typical default-mode network patterns were preserved and did not differ significantly from controls. Isolated hemispheres also showed preserved positive default-mode network connectivity, though negative connectivity was significantly reduced compared to controls. In two patients with both pre- and post-surgical scans, the individual default-mode network remained detectable but was divided between the isolated and connected hemispheres. These findings suggest that default-mode network activity persists in isolated hemispheres, meeting a necessary condition for consciousness. However, the presence of default-mode network activity alone does not confirm conscious awareness, encouraging further investigation into the neural correlates of consciousness in isolated hemispheres.
Epilepsy is characterized by widespread structural brain alterations extending beyond the epileptic zone, involving both cortical and subcortical regions. Importantly, the clinical manifestation of epilepsy, including seizure types, psychiatric comorbidities, and treatment responses, has been shown to differ between sexes. However, sex differences in structural alterations in epilepsy have been seldomly reported in neuroimaging studies, partly due to limited sample sizes and single-center designs. Here, we systematically investigated sex differences in common epilepsies and their related clinical variables using structural neuroimaging biomarkers in an international multi-center cohort of 1,253 epilepsy patients and 1,077 healthy controls. We studied cortical thickness and subcortical volume in two types of epilepsy: temporal lobe epilepsy (TLE) and genetic generalized epilepsy (GGE). Both male and female patients with TLE showed widespread cortical and subcortical thinning compared with controls. In GGE, when compared separately to controls, male patients showed only subtle structural alterations, whereas female patients exhibited more widespread structural alterations. Sex-stratified analyses revealed some variation in the extent and distribution of cortical thickness and subcortical volume alterations between male and female patients in both epilepsy cohorts. Yet, we did not find significant sex-by-diagnosis interaction effects in TLE and GGE. Similarly, no significant interaction effects were observed between sex and age of onset or disease duration in either patient group. Overall, although we observed some differences in regional cortical thickness and subcortical volume between male and female patients with epilepsy, we did not find significant sex-by-diagnosis interactions. Our findings indicate that sex differences in behavioral and clinical outcomes of epilepsy may involve biological or functional processes that require further investigation.
Drug-resistant epilepsy (DRE) affects approximately one-third of individuals with epilepsy. Although surgery offers the best chance of durable seizure freedom in appropriately selected patients, postoperative outcomes remain difficult to predict. Artificial intelligence (AI) has been proposed to improve individualized presurgical prediction, but its diagnostic performance has not been quantitatively synthesized. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of AI models for predicting 12-month seizure freedom after surgery in patients with focal DRE. PubMed, Embase, Scopus, Web of Science, and IEEE Xplore were searched from January 2015 to October 2025, and studies reporting threshold-dependent metrics enabling reconstruction of 2 × 2 contingency tables were included. Ten retrospective studies comprising 721 evaluable patients were analyzed. Mean prevalence of seizure freedom was 60.5%. Pooled sensitivity was 0.85 (95% CI, 0.80-0.89), whereas specificity was 0.39 (95% CI, 0.24-0.58). The area under the hierarchical summary receiver operating characteristic curve was 0.82, and the pooled diagnostic odds ratio was 3.66 (95% CI, 1.45-9.20). Between-study heterogeneity was low for sensitivity (τ² = 0.06) and substantial for specificity (τ² = 1.11), with a strong negative correlation between sensitivity and false-positive rate (ρ ≈ -1.00). Externally validated models showed lower sensitivity than internally validated models (0.79 vs 0.87). Overall, AI-based models showed moderate discriminatory performance, with greater ability to identify patients likely to achieve seizure freedom than to exclude those at risk of persistent seizures. These findings support their use as adjunctive tools within presurgical evaluation rather than as stand-alone determinants of surgical candidacy.
Deep learning is advancing EEG processing for automated epileptic seizure detection and onset zone localization, yet its performance relies heavily on high-quality annotated training data. However, scalp EEG is susceptible to high noise levels, which in turn leads to imprecise annotations of the seizure timing and characteristics. This "label noise" presents a significant challenge in model training and generalization. In this paper, we introduce Bayesian UncertaiNty-aware Deep Learning (BUNDL), a novel algorithm that informs a deep learning model of label ambiguities, thereby enhancing the robustness of seizure detection systems. By integrating domain knowledge into an underlying Bayesian framework, we derive a novel KL-divergence-based loss function that capitalizes on uncertainty to better learn seizure characteristics from scalp EEG. Thus, BUNDL offers a straightforward and model-agnostic method for training deep neural networks with noisy training labels that does not add any parameters to existing architectures. Additionally, we explore the impact of improved detection system on the task of automated onset zone localization. We validate BUNDL using a comprehensive simulated EEG dataset and two publicly available datasets collected by Temple University Hospital (TUH) and Boston Children's Hospital (CHB-MIT). Results show that BUNDL consistently identifies noisy labels and improves the robustness of three base models under various label noise conditions. We also conduct ablation experiments on uncertainty quantification, evaluate cross-site generalizability to Siena EEG dataset, and quantify computational cost of all methods. Furthermore, we demonstrate that BUNDL improves seizure onset zone localization accuracy. Ultimately, BUNDL presents as a reliable method that can be seamlessly integrated with existing deep models used in clinical practice, enabling the training of trustworthy models for epilepsy evaluation.
Pathogenic variants in SLC6A1, which encodes the γ-aminobutyric acid (GABA) transporter GAT-1, cause developmental and epileptic encephalopathies (DEEs) through reduced GABA uptake, impaired transporter trafficking, and functional haploinsufficiency. 4-Phenylbutyrate (PBA) is a clinically available small molecule with chemical-chaperone and histone-deacetylase-inhibitor activities that can rescue misfolded GABAergic proteins, but variant-level rescue data are needed to guide precision treatment. We report a newly identified de novo SLC6A1 missense variant, p.Ala305Val (A305V), in a patient with myoclonic-atonic epilepsy and a developmental and epileptic encephalopathy phenotype. A305V was compared with the residue-matched comparator p.Ala305Thr (A305T). Variant effects were evaluated by (i) protein-structure prediction across nine stability-prediction algorithms using the cryo-EM-derived human GAT-1 template (PDB 7Y7W); (ii) 3H-GABA uptake assays in HEK293T cells and in human iPSC-derived astrocytes and cortical neurons; (iii) live-cell confocal microscopy of ER colocalization; (iv) pharmacologic rescue with PBA, TUDCA and salubrinal (v) and GAT-1 cDNA gene-augmentation, alone and in combination with PBA. AI-based stability predictors uniformly indicated destabilization of GAT-1(A305V) and GAT-1(A305T). A305V reduced 3 H-GABA uptake across HEK293T, astrocyte, and neurons. The mutant transporter accumulated within the endoplasmic reticulum (ER), with ER colocalization rising from approximately 30% in wildtype to ∼80% in A305V; PBA reduced ER retention to approximately ∼40% and restored total GAT-1 fluorescence toward wildtype levels. Pharmacochaperones (PBA, TUDCA) restored GABA uptake for the mutant transporters. Wildtype GAT-1 gene augmentation improved mutant GAT-1 uptake and combined PBA-plus-augmentation produced rescue greater than either intervention alone in the available dose-response ranges. SLC6A1 A305V is a trafficking-impaired, loss-of-function GAT-1 variant whose dysfunction is tractable to two convergent therapeutic axes: pharmacologic correction of folding and trafficking, and augmentation of functional transporter dose. These findings support a two-pronged precision-medicine framework for SLC6A1-related DEEs in which PBA increased the transporter function augmented by increased gene therapy. This work links the patient-derived SLC6A1 A305V variant to a defined molecular mechanism-GAT-1 destabilization, ER retention, and reduced GABA uptake-and demonstrates that the deficit is reversible by two independent interventions that converge at the same downstream endpoint of functional surface transporter. Because PBA is already clinically deployable and GAT-1 cDNA augmentation models a future viral or non-viral gene therapy, the combined-rescue logic provides a falsifiable path for precision medicine in SLC6A1-related DEEs: chemical chaperoning corrects the folding bottleneck while transporter augmentation increases the pool available for rescue.
Sudden unexpected death in epilepsy (SUDEP) and long QT syndrome (LQTS) are severe disorders causing sudden death in the neurological and cardiovascular systems, respectively, and have traditionally been viewed as distinct clinical entities. However, their overlapping clinical phenotypes and partially shared genetic backgrounds suggest that, in a subset of patients, overlapping molecular mechanisms may contribute to neurocardiac vulnerability. This review systematically elucidates and bridges the potential mechanistic intersections between these two conditions at the level of ion channel dysfunction. It focuses on key shared ion channel genes, such as KCNQ1, KCNH2, and SCN5A, and analyzes how their variants may simultaneously induce neuronal hyperexcitability and cardiomyocyte repolarization abnormalities, thereby suggesting a potential risk-modifying framework of "cardio-cerebral ion channelopathies" in specific clinical scenarios. Additionally, this article discusses the significant implications of this shared mechanism for clinical practice, particularly in evaluating the cardiac safety of anti-seizure medications (ASMs), integrating genetic risk stratification, and developing future therapeutic strategies. By synthesizing and integrating existing evidence, this review aims to provide a broader pathophysiological perspective on the intrinsic links between SUDEP and LQTS, offering novel insights for interdisciplinary precision medicine.
Limited health literacy among individuals with epilepsy is associated with poor health outcomes, highlighting the importance of accessible, evidence-based self-care resources. Mobile health applications represent a promising avenue for supporting epilepsy self-management; however, the quality and reliability of app content may significantly affect patient trust, clinical interactions, and health outcomes. Therefore, this study aims to evaluate the quality of available Persian-language epilepsy-related mobile applications. Persian-language apps related to epilepsy and seizures were systematically identified from Google Play, Café Bazaar, and IranApps using relevant keywords. After excluding non-Persian and duplicate apps, the eligible applications were independently evaluated using the user version of the Mobile Application Rating Scale (uMARS) and DISCERN tools. Of 659 identified applications, 78 were epilepsy-related; following exclusions, 11 apps met the inclusion criteria for full evaluation. The mean overall uMARS score was 2.8 ± 0.5 out of 5, with six of the 11 apps (54%) scoring above 3. The section-specific mean scores were as follows: engagement, 2.2 ± 0.5; functionality, 4.0 ± 0.4; esthetics, 3.3 ± 0.9; and information, 2.3 ± 0.4, out of 5. DISCERN total scores ranged from 26 to 40 out of 80 (mean 34.5 ± 4.2), and the mean reliability score was 18.2 ± 3.9. The results showed that Persian-language epilepsy-related apps demonstrated high functionality but limited support for behavior change, engagement, and esthetics. Information quality was generally poor, and none of the evaluated apps were free of charge. These findings highlight the urgent need for developing high-quality, evidence-based epilepsy apps that support comprehensive self-care and behavioral change strategies for Persian-speaking users.
暂无摘要（点击查看详情）
暂无摘要（点击查看详情）