Epilepsy is a major public health challenge affecting individuals of all ages, especially in low- and middle-income countries (LMICs). Reliable prevalence projections are critical for healthcare planning and resource allocation. This study aimed to forecast the prevalence of epilepsy and its trends in LMICs by age, sex, year, and income level by 2050. Using data from the Global Burden of Disease Study (GBD) 2023, we projected the prevalence and number of idiopathic and secondary epilepsy cases in LMICs from 2024 to 2050. We developed a hybrid deep neural network (DNN)-Transformer framework that integrates Poisson regression and Autoregressive Integrated Moving Average (ARIMA) models for prevalence projection. Decomposition analysis was applied to quantify the contributions of population growth, aging, and prevalence change to the increase in epilepsy cases. Dementia-attributable epilepsy was independently projected to address secondary causes not included in GBD 2023. By 2050, the age-standardized prevalence rate (ASPR) of epilepsy in LMICs was projected to reach 907.22 per 100,000 [95% uncertainty interval (UI) 731.01-1083.56], a 33.32% increase from 2023, with cases rising to 72.04 million (95% UI 57.86-86.23), a 58.68% increase. The ASPRs of idiopathic and secondary epilepsy were estimated at 323.11 and 584.10 per 100,000 in 2050, respectively, with the increase in secondary epilepsy being more than 7-fold that of idiopathic epilepsy since 2023. The ASPR of secondary epilepsy due to neonatal disorders was projected to rise by 65.76%. Model validation demonstrated good predictive performance (root mean squared error <0.001). From 2023 to 2050, the increases in idiopathic and secondary epilepsy cases were forecast to be highest in low-income countries (LICs; 76.12% and 241.50%, respectively), with growth declining as income levels increased. Population growth (21.40%) primarily drove the increase in idiopathic epilepsy cases, whereas changes in prevalence (59.89%) predominantly drove the rise in secondary epilepsy cases. Dementia-attributable secondary epilepsy was projected to reach 3.40 million cases by 2050. We forecast a continuous increase in the prevalence and number of epilepsy cases in LMICs through 2050, with secondary epilepsy increasing more rapidly than idiopathic epilepsy. LICs may exhibit the greatest increases over the next three decades, necessitating targeted interventions and further investigation.
Electroconvulsive therapy (ECT) is widely used for severe psychiatric disorders, yet concerns remain regarding possible epileptogenic effects associated with prolonged or repeated exposure. We examined the association between cumulative ECT sessions and focal epilepsy in a nationwide Japanese cohort. We conducted a retrospective cohort study using a nationwide claims database including 3733 patients who received ECT between 2008 and 2025. For analyses of incident focal epilepsy, patients with a prior diagnosis of epilepsy before the first ECT session were excluded from the at-risk population. New-onset focal epilepsy was defined as a G40.2 diagnosis recorded after ECT initiation. Person-time accrued from the first ECT session to epilepsy diagnosis or last follow-up. Multivariable logistic regression assessed the association between cumulative ECT sessions and focal epilepsy, adjusting for age, sex, and psychiatric diagnoses. An exploratory time-varying Cox model evaluated cumulative exposure as a time-dependent variable. Among 3733 patients (mean age 56.9 years; 66.4% female), 96 (2.6%) developed focal epilepsy, corresponding to an incidence of 3748 per 100 000 person-years. A cumulative exposure pattern was observed, with diagnosis rates exceeding 5% among patients receiving ≥ 50 sessions and peaking at 9.1% in the 80-89 session group. Each additional ECT session was associated with higher odds of focal epilepsy (β = 0.0099, p = 0.004). Age, sex, and psychiatric diagnoses were not significant predictors. In exploratory time-varying analysis, reaching ≥ 50 sessions was associated with increased hazard, although event numbers were limited. Latency to diagnosis ranged from weeks to over 4000 days. Following epilepsy diagnosis, 70.8% discontinued ECT and 98.0% received antiseizure medication. In this nationwide cohort, greater cumulative ECT exposure was associated with focal epilepsy diagnosis. While causality cannot be established, these findings support consideration of careful neurological monitoring during prolonged ECT courses. Electroconvulsive therapy (ECT) is an effective treatment for severe mental illnesses. However, its long-term neurological effects are not fully understood. We analyzed nationwide data from 3733 patients in Japan who received ECT and examined whether repeated treatments were associated with new diagnoses of focal epilepsy. Ninety-six patients (2.6%) were diagnosed with focal epilepsy after starting ECT. The likelihood of diagnosis was higher among patients who received more ECT sessions, particularly those undergoing prolonged courses. Although this study cannot determine whether ECT directly causes epilepsy, our findings suggest that careful neurological monitoring may be considered during extended treatment.
The pathophysiology of epilepsy remains poorly understood. One of the less explored areas is the role of the lung-brain axis, a sophisticated and intricate bidirectional connection between these two vital organs. Inhaled air pollutants can disrupt lung microbiome homeostasis. This disruption, analogous to gut dysbiosis implicated in neurological conditions, may contribute to epilepsy pathogenesis. Here, we review the existing evidence and theoretical foundations supporting the hypothesis that dysbiosis within the lung microbiota may play a role in the pathophysiology of epilepsy. This includes the links between environmental factors (particularly air pollution) and epilepsy susceptibility; the associations between lung-intrinsic microbiota dysregulation and neurological dysfunction; and the underlying molecular, immunological, and neural mechanisms that enable the lung-brain axis to modulate epileptogenesis. Furthermore, we outline the possible potential pathogenic mechanisms of epilepsy from the perspective of the microbiota-lung-brain axis, offer fresh perspectives on the pathophysiology of epilepsy, and explore potential new research directions related to the lung-brain axis and epilepsy. We propose that a deeper understanding of the function of the lung-brain axis will provide new insights into the etiology, diagnosis, prognosis, and treatment of epilepsy.
To evaluate whether varying degrees of lymphocyte count decline in HIV-positive adults are associated with increased short-term incidence of epilepsy or convulsions. A retrospective cohort study was conducted using the TriNetX global research network. HIV-positive patients with a lymphocyte count ≥ 1.2 × 10³/µL were categorized based on subsequent decline within 3 months: mild (1.01-1.19), moderate (0.81-1.0), or significant (0.61-0.8). Risk analysis and Kaplan-Meier survival analysis were performed and patients with prior diagnosis of epilepsy (G40) or convulsions (R56.9) were excluded. The risk of developing epilepsy or convulsions increased with greater lymphocyte decline. Compared to patients with stable counts, the odds ratios were 1.073 for the mild group, 2.222 for the moderate group, and 3.189 for the significant drop group. Hazard ratios followed a similar trend, reaching 3.24 in the 0.61-0.8 group. Only the mild drop group did not show a statistically significant difference in risk or survival curves. Kaplan-Meier analysis at 1 year showed significant separation between survival curves for all groups except the mild group (p = 0.6973). Among HIV-positive adults, greater short-term lymphocyte count decline is associated with a higher short-term risk of epilepsy or convulsions. These findings suggest that lymphocyte trends may serve as an early signal for neurologic vulnerability. Further investigation is warranted to clarify the underlying mechanisms and clinical implications.
In Uganda, the quality of life (QoL) of patients with epilepsy (PWE) remains poor due to clinical, psychological, and social challenges. While several quantitative studies have documented correlates of poor QoL in Ugandan PWE, the specific mechanisms, contextual meanings, and patient-defined priorities through which epilepsy affects daily life remain poorly understood. This study aimed to explore the lived experiences that influence QoL among PWE at Mulago National Referral Hospital (MNRH) in Uganda. We conducted a qualitative study among 12 purposefully selected adult PWE at MNRH. We collected data using in-depth interview guides and analysed the data using inductive thematic analysis with ATLAS.ti software. We used purposive sampling guided by gender and duration of epilepsy care to ensure depth and breadth of perspectives. Data collection continued until thematic saturation was achieved. Three major themes captured the lived experiences that influence QoL. 1)Psychosocial experiences encompassed social support from friends and religious communities, family relationships that functioned as sources of both support and strain, stigma and discrimination, and psychological, cognitive, and coping processes. 2) Economic and daily living challenges encompassed financial barriers to treatment, employment disruption alongside economic adaptation, and seizure-related physical injury. 3) Healthcare and treatment experiences encompassed access to free antiepileptic drugs (AEDs) and diagnostic services, provider-led counselling and health education, and medication-related effects. Healthcare services should prioritise a shift to holistic, patient-centred care that integrates psychosocial well-being, economic circumstances, and lived treatment experiences into routine epilepsy management.
Epilepsy is a common pediatric neurologic disorder, and its surgical management has increased over time. To characterize longitudinal changes in patient selection, surgical approach and outcomes, we report a 30-year retrospective review at a high-volume level 4 epilepsy center. Consecutive epilepsy surgeries from 1989 to 2018 were analyzed and grouped into early (1989-2003) and late (2004-2018) 15-year eras. Demographic, clinical, radiographic, surgical, and 2-year Engel outcome data were collected and analyzed. Multivariable logistic regression assessed independent associations between era, patient characteristics, imaging findings, surgical procedures, and seizure outcomes. Of 1241 surgical records, 1128 pediatric cases were included (415 early, 713 late; 55.50% male). Patients in the late era were older at surgery (10.27 vs. 8.53 years, p < .001), and repeat surgery was more common (p < .001). Focal (OR 1.72, p = .005) and cerebral insult related (OR 2.74, p < .001) MRI abnormalities were more frequently treated in the late era. Hemispherectomies, lobectomies and corpus callosotomies were performed less often (all p ≤ .001), while focal and multilobar resections remained stable (p > .05). Use of invasive monitoring and electrical stimulation mapping declined over time (p < .001). Seizure freedom rates were stable, however, ≥ 90% seizure reduction was more common in the late era (OR 1.60, p = .038). Over three decades, pediatric epilepsy surgical volume increased, surgery shifted towards older patients, with reduced extensive resection and reduced reliance on invasive monitoring. Despite these changes, seizure freedom rates remained stable, with improved near-complete seizure control in the later era.
Epilepsy is a common chronic neurological disorder characterized by recurrent, unprovoked seizures arising from abnormal neuronal hyperexcitability and hypersynchronous electrical activity within the brain. Despite advances in antiseizure medications, effective epilepsy management remains challenging because of pharmacoresistance, limited blood-brain barrier (BBB) permeability, inadequate intracerebral drug accumulation, and systemic toxicity. Moreover, currently available therapies primarily provide symptomatic seizure control without addressing the fundamental pathological processes involved in epileptogenesis, neuroinflammation, oxidative stress, and neuronal degeneration. Intranasal administration has emerged as an attractive non-invasive approach for direct brain targeting, enabling therapeutic agents to circumvent BBB-associated transport barriers and access the central nervous system through the olfactory and trigeminal neural pathways. In this context, biodegradable nanomedicine platforms have gained considerable attention due to their favorable biocompatibility, controlled drug release, enhanced mucosal permeation, and potential for targeted intracerebral delivery. This review provides a comprehensive and critical overview of recent advances in intranasal biodegradable nanomedicine for epilepsy, integrating current knowledge on disease pathophysiology, biological and pharmaceutical barriers, nose-to-brain transport mechanisms, biodegradable nanoparticle platforms, and emerging functionalization strategies. Importantly, the review critically evaluates the current evidence, distinguishing encouraging preclinical findings and discusses the major translational challenges that continue to hinder clinical implementation. Finally, future perspectives are highlighted to identify opportunities for developing safer, more effective, and clinically translatable therapies for epilepsy management.
A fundamental but unanswered question in neuropsychiatry is whether the psychiatric symptoms of epilepsy are caused by the same or a separate pathophysiology as seizures. To address this question, we investigated a monogenic form of epilepsy (pyridoxine-dependent epilepsy) caused by aldehyde dehydrogenase 7 family member A1 (ALDH7A1) mutations. ALDH7A1 global knockout mice exhibited both seizure-associated and maladaptive affective behavioral phenotypes. However, seizure phenotypes were caused by ALDH7A1 deletion in hepatocytes whereas maladaptive affective behaviors were caused by ALDH7A1 deletion in astrocytes. Deletion in astrocytes disrupted astrocyte redox homeostasis, impairing regulation of extracellular ion concentrations and reducing neuronal activity in the prelimbic cortex. Sulforaphane, which activates the NRF2 antioxidant pathway, restored prelimbic neuronal activity and rescued maladaptive affective behaviors in ALDH7A1 knockout mice but did not prevent seizures. These studies implicate astrocyte redox homeostasis and prelimbic hypoactivity in maladaptive affective behavioral phenotypes in a congenital form of epilepsy, which are mechanistically and therapeutically dissociable from seizure pathophysiology.
The aging Danish population is associated with increasing morbidity and healthcare utilization. This study examines age-related differences in resource utilization and diagnostic outcomes between older (65-95 years) and younger adults (18-64 years) evaluated for suspected epilepsy, including clinical management, diagnostic yield, and final diagnoses. This single-center retrospective cohort study used electronic health record registry data from adults referred for epilepsy evaluation at Aalborg University Hospital between April 1, 2022, and January 8, 2024, with 1-year follow-up. Patients were stratified into different age groups and the relative risk (RR) of receiving an epilepsy diagnosis was modeled using a modified Poisson regression method, with age as the primary predictor. The diagnostic yield of magnetic resonance/computed tomography (MR/CT) and the sensitivity and specificity of electroencephalography (EEG) were compared using the chi-square test and Fisher's exact test. Of 530 patients evaluated, 30% received an epilepsy diagnosis and 17% were diagnosed with a first unprovoked seizure. International Classification of Diseases, 10th Revision (ICD-10) codes varied with age, and the RR for epilepsy was significantly higher in older adults 65-95 years of age compared with both adults 18-64 years of age and those 40-64 years of age. This association remained unchanged after adjustment for sex. Furthermore, 97.7% underwent neuroimaging, and 92.6% underwent an EEG. The diagnostic yield of EEG and neuroimaging (magnetic resonance imaging [MRI] and CT) did not differ significantly between the two age groups. Older adults referred for epilepsy evaluation were more likely to receive an epilepsy diagnosis. More than half of patients initially thought to have epilepsy, or a first unprovoked seizure, were ultimately assigned a diagnosis other than epilepsy after comprehensive clinical assessment. These findings underscore the importance of careful, age-sensitive diagnostic evaluation, and highlight the need for further research to elucidate age-related diagnostic patterns and refine inclusion criteria and workup strategies in first-seizure clinics.
Every revision of the seizure classification-most recently the 2025 International League Against Epilepsy (ILAE) update-refines terminology, yet it is worth asking whether patients are treated better because their seizures were renamed. The focal versus generalized dichotomy has organized epilepsy classification since the 1960 s and is grounded in a pharmacologic rationale, but head-to-head data from the SANAD trials show that efficacy differences between individual antiseizure medications frequently equal or exceed differences across the focal/generalized boundary. Meanwhile, the distinction that is genuinely transformative-whether an epilepsy is surgically remediable-produces seizure-freedom differences of an entirely different order of magnitude, and yet epilepsy surgery remains among the most underutilized evidence-based treatments in medicine. We argue that classification should elevate therapeutic trajectory over electroclinical phenomenology, and we propose an Interventional Axis built around three pathways: focal resection, neuromodulation, and palliative surgery, operating in parallel with pharmacotherapy rather than after its serial failure. Refining terminology improves communication, but the ultimate metric of a classification is outcome, not taxonomic elegance.
Diagnostic MRI evaluation of temporal lobe epilepsy (TLE) depends on the subjective visual interpretation of MRI images. These interpretations could be enhanced by quantitative artificial intelligence (AI) support tools. Humans often make sequential and conditional decisions during their radiological interpretations, such as whether an abnormality is present and, if present, characterizing the abnormality. It is not known whether it is superior to train AI to treat every decision separately in a similar step-wise manner or to train a model holistically on all decisions simultaneously. Here, we analysed three large epilepsy MRI datasets [n = 3676, 2320 people with epilepsy and 1356 healthy controls (HC)] to perform two tasks: (i) establish the presence of a TLE pattern on MRI and (ii) determine TLE pattern lateralization. We compared Step-wise models that independently classify TLE versus HC and lateralize patients as left TLE (L-TLE) or right TLE (R-TLE), against a simultaneous model trained to distinguish all three classes in a single step. To do this, 3D volumetric T1-weighted images were input into an EfficientNetV2 model multiple times to ensure reproducibility of results. Class prediction, model classification confidence and saliency maps were output for interpretability. Step-wise models outperformed the Simultaneous model on both tasks (both Ps < 0.001), with an average ∼2.8% accuracy increase for discriminating HC from TLE and an average 12.7% accuracy increase for distinguishing L-TLE from R-TLE. For both the Step-wise and Simultaneous models, important features discriminating TLE from HC included the known TLE limbic pattern involving the hippocampus, parahippocampal cortical regions, cingulate cortex and lateral temporal regions. However, there was less concordance between the Step-wise and Simultaneous models for the L-TLE versus R-TLE task (all Fisher's Zs > 10.5, Ps < 0.001); the Step-wise model focused less on subcortical regions such as the thalamus and hippocampus and focused more on distributed cortical pathology. Across the two Step-wise models, 95.1% of TLE patients had accurate classifications in either HC versus TLE and/or L-TLE versus R-TLE tasks. These results included 69.6% of patients being both correctly labelled as TLE and lateralized, 13.9% being correctly labelled TLE but lateralized incorrectly and 11.6% being lateralized correctly but not detected as TLE. These findings provide evidence that diagnostic tasks with simpler, Step-wise AI models may enhance diagnostic performance and interpretability in clinical workflows. Future AI clinical support tools can leverage this step-wise approach in the early identification of TLE-related structural patterns, supporting timely diagnosis and treatment decisions.
Childhood absence epilepsy (CAE) is a common genetic epilepsy with a frequently complex polygenic etiology, for which a genetically tractable animal model is lacking. Current anti-seizure medications fail to address the significant neurocognitive and social comorbidities of CAE, highlighting a critical unmet need for comprehensive therapies and a better understanding of the underlying mechanisms. To address this, we developed a digenic mouse model (Cacng2stargazer/+;Cacna1a+/-, hereafter DiGstg+Ca1A) that mimics human polygenicity. The double mutant mice exhibit both absence seizures and altered social novelty preference. We found that ethosuximide, a first-line anti-CAE medication targeting thalamic low-threshold T-type calcium currents, suppressed seizures in DiGstg+Ca1A mice but failed to rescue their social deficit. Similarly, deletion of Cacna1g, which encodes the T-type Ca2+ channel CaV3.1, prevented seizure generation but did not ameliorate the social deficit. These findings reveal a dissociation between the T-type current that mediates seizures and the mechanism underlying the social deficits. We further demonstrate that in Cacng2stargazer/+ mice, selective deletion of one copy of Cacna1a in stargazin-enriched parvalbumin (PV) interneurons induced absence seizures and impaired social behavior. Remarkably, chemogenetic activation of cortical and thalamic PV interneurons using DREADDs not only suppressed seizures but also rescued the impaired social behavior. Together, our results suggest that selective modulation of PV interneuron activity in polygenic absence epilepsy could serve as a promising therapeutic strategy to address both absence seizures, and the often treatment-resistant neurocognitive comorbidities observed in CAE.
Temporal lobe epilepsy (TLE), frequently associated with mesial temporal sclerosis (MTS), is the most common form of focal epilepsy in adults and is often accompanied by depressive symptoms that impair quality of life. While anterior hippocampectomy is an established surgical approach for drug-resistant TLE, its postoperative psychiatric and psychosocial impact remains insufficiently studied, particularly in non-Western populations. This study assessed changes in depressive symptoms and quality of life following anterior hippocampectomy in a Middle Eastern cohort. Depression was assessed preoperatively and at 1- and 3-month follow-up using the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Beck Depression Inventory (BDI). Quality of life was measured using the World Health Organization Quality-of-Life (WHOQOL) scale. Forty patients were included, of whom 18/40 (45.0%) screened positive for depression at baseline. BDI scores decreased significantly over time (p = 0.011) and WHOQOL scores improved significantly across follow-up (p = 0.016). PNDDI-E scores showed a non-significant reduction over time (p = 0.055). 9/18 (50.0%) of patients who screened positive for depression preoperatively converted to screen-negative status at 3 months, while 4/22 (18.2%) of preoperatively screen-negative patients developed new screen-positive status. Improvements in BDI and WHOQOL scores were not significantly influenced by age, sex, education, or surgical laterality. Anterior hippocampectomy in patients with drug-resistant TLE was associated with significant early improvements in BDI-II and WHOQOL scores. These findings should be regarded as preliminary given the small sample size, short follow-up, and absence of postoperative seizure outcome data. Given that a subset of patients may develop new or worsened depressive symptoms postoperatively, routine psychiatric screening and postoperative psychological support remain essential.
Pathogenic variants in AUTS2 are associated with neurodevelopmental disorders, commonly characterized by intellectual disability and autism spectrum disorder. Epilepsy in AUTS2-related syndromes has been reported only in a limited number of patients, usually with scant information on the electroclinical features and longitudinal outcome. We report a proband with AUTS2-related syndrome and performed a narrative literature review. The electroclinical features of our case fall within the spectrum of a developmental/epileptic encephalopathy with spike-wave activation in sleep. This case highlights the importance of a detailed electroclinical characterization of epilepsy in AUTS2-related syndrome and underscores the need for systematic EEG and cognitive monitoring to improve clinical management.
Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a recently defined malformation of cortical development that is an important cause of childhood-onset drug-resistant epilepsy. Clinically, the epilepsies associated with MOGHE are heterogeneous, with infantile epileptic spasms syndrome (IESS) being the most common manifestation. Histopathologically, MOGHE demonstrates subtle cortical dyslamination, heterotopic neurons in the white matter, hypomyelination, and a distinctive increase in the density and clustering of oligodendroglial cells, features that distinguish it from other malformations of cortical development such as focal cortical dysplasia (FCD). Recent genetic analyses of epileptogenic tissue resected from individuals with MOGHE have identified somatic mosaic loss-of-function variants in SLC35A2. This gene encodes the Golgi transmembrane UDP-galactose transporter, suggesting disrupted N-glycosylation as a distinct pathogenic mechanism underlying epilepsy in this disorder. In this review, we present the current clinical, histopathological, and molecular understanding of MOGHE, with a particular focus on recent insights gained from experimental rodent and human cellular models of SLC35A2 deficiency. We contextualise these findings against established models of mTORopathies including FCD type 2, placing MOGHE within the broader malformation of cortical development spectrum. Synthesising this evidence, we observe that neuronal activity in models of both MOGHE and mTORopathies such as FCD type 2 converge on reduced action potential firing, despite their distinct genetic aetiologies. Finally, we discuss how these findings inform our understanding of epileptogenesis, especially the emergence of infantile epileptic spasms, and the development of future precision therapeutic strategies across malformations of cortical development.
When confronted with negative events, regulating emotions is essential for self-management and mental health. Temporal lobe epilepsy (TLE) patients, particularly right TLE (rTLE) patients, show altered responses towards emotional stimuli. However, neural correlates of emotion regulation and its interplay with stimulus-based emotion processing have not been studied in TLE so far. Therefore, we compared functional MRI activity during up- and downregulation of emotions towards negative scenes among 21 left TLE and 18 rTLE patients, 18 frontal lobe epilepsy (FLE) patients and 17 healthy controls. To assess stimulus-based processing, participants were asked to permit their feelings towards negative or neutral pictures. Voxel-based analyses were complemented by network-based analyses, as epilepsy is a network disorder. During stimulus-based emotion processing, rTLE patients displayed less activation compared to all other groups. Regions of reduced activity were mostly part of the frontoparietal control network and the default mode network (both P FDR < 0.05) and included the frontal pole, the superior frontal gyrus, parietal regions and the cerebellum (all P FWE < 0.05). Activation patterns during emotion regulation were highly similar between controls and left TLE and rTLE patients. Direct group comparisons revealed that during upregulation of emotions, controls and left TLE patients displayed higher activity than FLE patients in areas of the left default mode network (all P FWE < 0.05). Our results dovetail with previous findings of diminished activity towards aversive stimuli in rTLE and show that in the same patients, neural underpinnings of emotion regulation are intact. In contrast, FLE patients displayed the opposite pattern with a largely intact response to aversive stimuli but disrupted neural underpinnings of emotion regulation, pointing to a double dissociation between rTLE and FLE.
Temporal lobe epilepsy (TLE), particularly mesial temporal lobe epilepsy (MTLE), often presents with visual working memory (VWM) impairments, with potential heterogeneity between hippocampal sclerosis (HS) and MRI-negative subtypes. However, task-related electrophysiological (EEG) evidence regarding brain network alterations during VWM processing in MTLE remains limited. This study aims to identify shared brain network alterations and their behavioral correlates in patients with MTLE and to further characterize subtype-specific differences between HS-MTLE and MRI negative-MTLE. We recruited 60 right-handed participants, including 30 patients with MTLE (12 HS-MTLE, 18 MRI negative-MTLE) and 30 healthy controls (HCs). All participants completed the Chinese version of the Wechsler Memory Scale-Revised (WMS-RC) and performed a VWM task during simultaneous EEG recording. Graph theory analysis was used to assess the in-degree and out-degree of directed functional networks in the theta and gamma frequency bands; the results were correlated with clinical and cognitive behavioral indicators. Behaviorally, patients with MTLE showed significant VWM impairments compared with HCs, with no significant difference between HS and MRI-negative subtypes. Common network alterations in patients with MTLE included decreased theta-band connectivity from occipital to temporal regions, with this theta-band connectivity significantly associated with slower task responses and reduced accuracy. In subgroup analysis, the HS-MTLE group showed reduced theta outflow and abnormally enhanced gamma activity in posterior occipital regions. Conversely, the MRI negative-MTLE group showed more widespread increases in gamma-band in-degree and out-degree across anterior regions, including prefrontal, frontocentral, and temporal areas. Patients with MTLE share a common alteration in occipital-to-temporal information transfer during VWM. Exploratory analyses suggest distinct network alterations between HS-MTLE and MRI negative-MTLE, presenting with abnormalities in posterior and anterior networks, respectively. These hypothesis-generating findings provide electrophysiological evidence to support precise subtyping of MTLE and targeted cognitive intervention development.
Febrile infection-related epilepsy syndrome (FIRES) is a rare, severe epileptic encephalopathy characterized by refractory status epilepticus, primarily affecting previously healthy children aged 3-15 years. The pathogenesis remains unknown, and outcomes are predominantly poor. This study investigates the acute phase treatment of FIRES, focusing on antiseizure medications (ASMs) and deep sedation with therapeutic coma (TC) for the treatment of status epilepticus, to examine associations with long-term functional outcome. We retrospectively analyzed data from 93 children in a multicenter registry-based cohort from our FIRES registry, assessing acute phase ASMs and duration of TC. Neurological outcomes were assessed using the modified Rankin Scale (mRS), with correlation analyses, multivariate logistic regression, and Cox proportional hazard analyses to explore associations between treatment intensity, functional outcomes, and survival. Higher ASMs count was associated with worse outcome, with each additional medication for seizure control corresponding to 52% increased odds of mRS ≥4 (adjusted odds ratio 1.52, 95% confidence interval 1.17-2.10, P < 0.001). Longer duration of TC correlated with a more ASMs and higher mRS scores, indicating inferior outcome. In our analysis, increased acute treatment intensity and longer durations of TC were associated with worse functional outcomes. These observational associations are likely confounded by underlying disease severity. In the absence of proven causal therapies, the data might be compatible with spontaneous reduction of seizure activity over time in some patients and highlight the need for further research on pathogenesis and pathogenesis-targeted therapies for FIRES.
Epilepsy is a prevalent neurological disease, with one-third of individuals becoming nonresponsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we identify activation of cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN) signaling, in human DRE brain tissue. Microglia from individuals with DRE exhibit a robust type I IFN signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we similarly detect activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS attenuates seizure phenotypes, reduces glial inflammatory signatures and normalizes neuronal transcriptomic changes in mice with Dravet syndrome. Together, these findings identify cGAS-mediated neuroimmune signaling as a contributor to seizure pathology in Dravet syndrome and highlight this pathway as a potential therapeutic target.
SCN2A pathogenic mutations, such as the recurrent heterozygous Nav1.2-L1342P, are monogenic causes of epilepsy. In this human-induced pluripotent stem cell-derived model system, we aim to investigate the molecular and cellular mechanisms underlying SCN2A-L1342P-associated pathology. Using a human male induced pluripotent stem cell (iPSC) reference line (KOLF) carrying the Nav1.2-L1342P mutation, we generated three-dimensional (3D) cortical organoids for functional studies. Patch-clamp, multi-electrode array (MEA) recordings, immunocytochemistry, and RNA sequencing were used to characterize the disease phenotypes. Nav1.2-L1342P organoid neurons displayed increased intrinsic excitability and amplified excitatory post-synaptic currents, which are consistent with an increase in excitatory synapse formation revealed by SYN1/PSD95 immunostaining. Moreover, elevated network firing activity, as demonstrated by MEA, indicates a pronounced network hyperexcitability. Transcriptomic profiling of organoids carrying the Nav1.2-L1342P mutation further revealed significant alterations in synaptic, glutamatergic, developmental, and senescence/apoptotic pathways. Our findings demonstrate that the Nav1.2-L1342P mutation drives a multifaceted disease phenotype, including network hyperexcitability and disruption of pathways related to neuronal and synaptic functions. These results advance our understanding of SCN2A-related developmental and epileptic encephalopathy (DEE), laying a foundation for personalized interventions.